Methods for the prophylaxis and treatment of stroke related disorders

Abstract

The present invention recognizes that there is a need for the prophylaxis or treatment of Stroke Related Disorders, which includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases, or combinations thereof, or combinations thereof. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of Stroke Related Disorders using various pharmaceutical compositions. A second aspect of the present invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of Stroke Related Disorders.

Description

[0001] Title METHODS FOR THE PROPHYLAXIS AND TREATMENT OF STROKE RELATED DISORDERS Cross Reference to Related Applications The present application: claims benefit of priority to United States Provisional Application Serial No.63 / 566,392, filed March 18, 2024; each of which is incorporated by reference herein in its entirety. Technical Field The present invention relates generally to the fields of treatment and prophylaxis of Stroke Related Disorders, which includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), related cardiovascular diseases, or combinations thereof. Background In 2023, 15 million people worldwide had a stroke. In 2021, stroke was the third biggest cause of death, responsible for approximately 10% of total deaths. ("Stroke, cerebrovascular accident". https: / / www.emro.who.int / health-topics / stroke-cerebrovascular-accident / index.html - World Health Organization.2024.). In 2015, stroke was the second most frequent cause of death after coronary artery disease, accounting for 6.3 million deaths (11% of the total). About 3.0 million deaths resulted from ischemic stroke while 3.3 million deaths resulted from hemorrhagic stroke. About half of people who have had a stroke live less than one year. ("The top 10 causes of death". https: / / www.who.int / news-room / fact-sheets / detail / the-top-10-causes-of-death - World Health Organization.2024). Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioning properly. Signs and symptoms of stroke may include an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, or loss of vision to one side. Signs and symptoms often appear soon after the stroke has occurred. If symptoms last less than 24 hours, the stroke is a transient ischemic attack (TIA), also called a mini-stroke. Hemorrhagic stroke may also be associated with a severe headache. The symptoms of stroke can be permanent. Long-term complications may include pneumonia and loss of bladder control. (Donnan GA, Fisher M, Macleod M, Davis SM (May 2008). "Stroke". Lancet.371 (9624): 1612–23. doi:10.1016 / S0140-6736(08)60694-7). Ischemic stroke is typically caused by blockage of a blood vessel, though there are also less common causes. Hemorrhagic stroke is caused by either bleeding directly into the brain or into the space between the brain's membranes. Bleeding may occur due to a ruptured brain aneurysm. (Types of Strokes- https: / / www.nhlbi.nih.gov / health / stroke - March 26, 2014). Ischemic strokes, if detected within three to four-and-a-half hours, may be treatable with medication that can break down the clot while hemorrhagic strokes sometimes benefit from surgery. Treatment for an ischemic stroke or transient ischemic attack (TIA) may include medicines and medical procedures. The main treatment for an ischemic stroke is a medicine called tissue plasminogen activator (tPA) which breaks up the blood clots that block blood flow to the brain. The main limitations of tPA for treating stroke include the risk of intracranial hemorrhage. While tPA is effective in dissolving blood clots that cause strokes, it also carries a risk of causing bleeding in the brain (ICH). The effectiveness of tPA is highly time-dependent, with the greatest benefit seen when administered within the first 3 hours of stroke onset. The longer the delay in treatment, the less likely tPA is to be effective, and the greater the risk of complications. This narrow time window requires rapid diagnosis and treatment, which can be challenging in some cases. There are several contraindications to tPA use, including a history of bleeding problems, recent surgery or trauma, uncontrolled high blood pressure, or a recent head injury. Patients who have received heparin within 48 hours and have an elevated aPTT (greater than upper limit of normal for laboratory) are also contraindicated for tPA. Current use of oral anticoagulants (ex: warfarin) and INR >1.7, or current use of direct thrombin inhibitors or direct factor Xa inhibitors are also contraindications. A platelet count <100,000 is also a contraindication. Emerging data suggests that tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. tPA may not penetrate deeply into the clot, leading to surface erosion with little penetration into the clot. While tPA remains a cornerstone of ischemic stroke treatment, its limitations necessitate alternative therapies. Ongoing research aims to develop new neuroprotective strategies to enhance stroke treatment and expand therapeutic options for patients worldwide. US Patent 11,090,303 (“Tran ‘303) relates to cyclic Prolyl Glycine (“cyclic PG " or " cPG ”) and analogues and mimetics thereof. Summary The present invention recognizes that there is a need for the prophylaxis or treatment of Stroke Related Disorders, which includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), related cardiovascular diseases. The development of neuroprotective drugs like cPG analogues represents a promising frontier in stroke treatment. By targeting both neurogenesis and neuroprotection, future therapies may help prevent long-term neurological decline and reduce the risk of developing neurodegenerative diseases., or combinations thereof. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases using various pharmaceutical compositions. A second aspect of the present invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases. Brief Description of the Figures FIG.1 generally depicts the effect of delayed administration of CPG or vehicle treatment on area of infarct (in mm2) following an Et-1 MCAO model. Five hours post Et-1 injection, CPG- treated (3 mg / kg / h) (▪, n=15) or vehicle-treated (succinate buffer) (□, n=14) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M. and significance was defined at p<0.05. FIG.2 generally depicts the effect of delayed administration of cGMeP or vehicle treatment on area of infarct (in mm2) following an Et-1 MCAO model. Five hours post Et-1 injection, cGMeP- treated (0.3 mg / kg / h) (▪, n=14) or vehicle-treated (succinate buffer) (□, n=13) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M. and significance was defined at p<0.05. FIG.3 generally depicts the effect of delayed administration of CPG or vehicle treatment on GFAP staining (as a percentage) following an Et-1 MCAO model. Five hours post Et-1 injection, CPG-treated (3 mg / kg / h) (▪, n=10) or vehicle-treated (succinate buffer) (□, n=10) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M. and significance was defined at p<0.01. FIG.4 generally depicts the effect of delayed administration of CPG or vehicle treatment on GFAP staining (as a percentage) following an Et-1 MCAO model. Five hours post Et-1 injection, CPG-treated (0.3 mg / kg / h) (▪, n=10) or vehicle-treated (succinate buffer) (□, n=10) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M. FIG.5 generally depicts the effect of delayed administration of CPG or vehicle treatment on microglial activation (cell count) following an Et-1 MCAO model. Five hours post Et-1 injection, CPG-treated (3 mg / kg / h) (▪, n=10) or vehicle-treated (succinate buffer) (□, n=10) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M. and significance was defined at p<0.01. FIG.6 generally depicts the effect of delayed administration of CPG or vehicle treatment on microglial activation (cell count) following an Et-1 MCAO model. Five hours post Et-1 injection, CPG-treated (0.3 mg / kg / h) (▪, n=10) or vehicle-treated (succinate buffer) (□, n=10) animals were continuously infused i.v. via the jugular vein at 0.5 ml / h for four hours. Data are presented as mean±S.E.M and significance was defined at p<0.01 FIG.7A and FIG.7B generally depicts the effect of CPG administered i.v. (0, 0.3, 3 mg / kg / h) on foot-faults (FIG.7A) and neurological disability score (FIG.7B), tested either 24 h or 72 h following penetrating ballistic brain injury (PBBI). FIG.8 generally depicts the effect of CPG administered i.v. (0, 0.3, 3 mg / kg / h) on total injury volume to the brain assessed post-mortem following PBBI insult. FIG.9A and FIG.9B generally depicts the efficacy of CPG administered for 12 hours post- trauma on beam-walking performance (FIG.9A) and neurological disability score (FIG.9B). Detailed Description of the Invention Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, chemistry, microbiology, molecular biology, cell science and cell culture described below are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the plural of that term is contemplated; and where a term is provided in the plural, the singular of that term is contemplated. The nomenclature used herein and the laboratory procedures described below are those well-known and commonly employed in the art. As employed throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: “Directly” refers to direct causation of a process that does not require intermediate steps. “Indirectly” refers to indirect causation that requires intermediate steps. “About” refers to plus or minus 10% of the indicated value. Stroke is a medical emergency that occurs when blood flow to the brain is interrupted, which can be caused by, for example, a blockage (ischemic stroke) or a ruptured blood vessel (hemorrhagic stroke). Rapid intervention is critical to minimize brain damage and improve patient outcomes. Stroke includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, related cardiovascular disease, transient ischemic attack (TIA), or combinations thereof. Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. Introduction The present invention recognizes that there is a need for the prophylaxis or treatment of stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases or combinations thereof. As a non-limiting introduction to the breath of the present invention, the present invention includes several general and useful aspects, including: 1) methods of prophylaxis or treatment of stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases using various pharmaceutical compositions. 2) pharmaceutical compositions used for the prophylaxis or treatment of stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), and related cardiovascular diseases. These aspects of the invention, as well as others described herein, can be achieved by using the methods, articles of manufacture and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the invention. I. METHODS OF TREATMENT OF AT LEAST ONE STROKE RELATED DISORDERS A first aspect of the present invention includes a method of prophylaxis or treatment of at least one Stroke Related Disorder, including: (a) providing a subject in need of the prophylaxis or treatment of at least one Stroke Related Disorder; (b) providing at least one pharmaceutical composition including: 1) at least one cPG compound, optionally in combination with one or more of the following components; (i) at least one IGF-1 compound; (ii) at least one Des-(1-3) IGF-1 compound; (iii) at least one glycine-proline-glutamate compound; or combinations thereof; wherein the components are administered together or separately; further wherein the components are provided together or separately; (c) administering a pharmaceutically effective amount of the said at least one pharmaceutical composition to the subject; wherein the subject is provided prophylaxis or treatment of the at least one Stroke Related Disorder. A. COMPONENTS An aspect of the present invention includes wherein the components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof. Another aspect of the present invention includes wherein the components, individually or combinations thereof, are provided as or in a pharmaceutically acceptable salt. A further aspect of the present invention includes wherein the components are administered separately. An additional aspect of the present invention includes wherein the components are administered together. B. PROPHYLAXIS / TREATMENT OF AT LEAST ONE STROKE RELATED DISORDER An aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Stroke Related Disorder includes comprises stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA), related cardiovascular disease , or combinations thereof. Another aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Stroke Related Disorder includes addressing an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, loss of vision to one side, headache, severe headache , or combinations thereof. C. cPG COMPOUND A further aspect of the present invention includes wherein the at least one cPG compound includes at least one of Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl), or combinations thereof. An additional aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Prolyl Glycine. An aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. A further aspect of the present invention includes the Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. An additional aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered about once a day, about twice a day, or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered orally, intravenously, intranasally, or combinations thereof. A further aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Glycyl-2-Allyl Proline. An additional aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg. An aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. A further aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered about once a day, twice a day, once a week, twice a week, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered orally, intravenously, intranasally, or combinations thereof. Another aspect of the present invention includes wherein the at least one cPG compound includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl). A further aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. An additional aspect of the present invention includes wherein the Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. An aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl-L- prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, about twice a day, or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intranasally, or combinations thereof. D. IGF-1 COMPOUND An aspect of the present invention includes wherein the at least one IGF-1 compound includes at least one of: a) at lest one IGF-1; b) at least one IGF-2; c) at least one IGF receptor (IGF- 1R); d) at least one IGF binding proteins (IGFBP); e) or combinations thereof. Another aspect of the present invention includes wherein the at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, once a week, twice a week, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. An aspect of the present invention includes wherein the at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, once a week, twice a week, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week or combinations thereof. An additional aspect of the present invention includes wherein the at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, once a week, twice a week, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a day, twice a day, once a week, twice a week or combinations thereof. A further aspect of the present invention includes wherein the at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, once a week, twice a week, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. E. DES (1-3)-IGF-1 COMPOUND Another aspect of the present invention includes wherein the at least one des-(1-3)-IGF-1 compound includes at least one of: a) Des-(1-3)IGF-1 which is truncated for the N-terminal tripeptide; b) R3IGF-1 that is substituted by arginine for glutamic acid at position 3; c) LONGTMR3IGF-1 whose N-terminus is prolonged by additional 13 residues compared with R3IGF-1; d) or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition including at least one Des-(1-3) IGF-1 compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously, intravenously, or combinations thereof; c) is administered about once a day, twice daily, once a week, twice a week, or combinations thereof; d) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; e) or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. F. GLYCINE-PROLINE-GLUTAMATE COMPOUND Another aspect of the present invention includes wherein the at least one glycine-proline- glutamate compound comprises at least one of: a) D-GPE – a modified version using D-amino acids to enhance stability against enzymatic degradation; b) Cyclo-GPE – a cyclic form that has increased resistance to metabolic breakdown; c) GPE-amide – an amidated form that has improved membrane permeability; d) N-methyl-GPE – a derivative where the N-terminal amino group is methylated for enhanced pharmacokinetic properties; e) PEGylated GPE – GPE conjugated with polyethylene glycol (PEG) to increase half-life in circulation; f) or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously, intravenously, or combinations thereof; c) is administered about once a day, or twice a day, once a week, twice a week, or combinations thereof; d) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; e) or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is administered once a day, twice a day, once a week, twice a week or combinations thereof. G. GLYCYL-PROLYL-GLUTAMIC ACID (GPG) COMPOUND) Another aspect of the present invention includes wherein the at least one Glycyl-prolyl- glutamic acid (GPE). Glycyl-prolyl-glutamic acid (GPE) is a tripeptide that has been studied for its neuroprotective and neurotrophic properties. Chemical structure of Glycyl-prolyl-glutamic acid. Several analogues and derivatives of GPE have been investigated to improve its stability, bioavailability, and efficacy. Some notable GPE analogues include: 1. D-GPE – A modified version using D-amino acids to enhance stability against enzymatic degradation. 2. Cyclo-GPE – A cyclic form that has increased resistance to metabolic breakdown. 3. GPE-amide – An amidated form that may improve membrane permeability. 4. N-methyl-GPE – A derivative where the N-terminal amino group is methylated for enhanced pharmacokinetic properties. 5. PEGylated GPE – GPE conjugated with polyethylene glycol (PEG) to increase half- life in circulation. 6. Gly-Pro-Glu analogues with different terminal modifications – Variants with different functional groups added to improve activity or receptor affinity A further aspect of the present invention includes wherein the at least one pharmaceutical composition including at least one GPE compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously; c) is administered about twice / day; d) is administered for about six months; e) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; f) or combinations thereof. H. OUTCOMES Another aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Stroke Related Disorder results in global improvement in symptoms of Stroke Related Disorder, including but not limited to an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, loss of vision to one side, headache, severe headache, or combinations thereof. However, Stroke treatment outcomes vary, with some individuals recovering almost completely, while others experience long-term or lifelong disabilities, and some may require long-term care. Early and effective treatment, including rehabilitation, is important for improving outcomes and minimizing long-term impairments. A further aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Stroke Related Disorder is prophylaxis. An additional aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Stroke Related Disorder is treatment. I. SUBJECT An aspect of the present invention includes wherein the subject is a human. J. ADMINSTERED TOGETHER OR SEPARATELY Another aspect of the present invention includes wherein the components are administered together in a single or multiple doses. A further aspect of the present invention includes wherein the components are administered separately in a single or multiple doses. K. PROVIDED TOGETHER OR SEPARATELY An additional aspect of the present invention includes wherein the components are provided together in a single or multiple containers. An aspect of the present invention includes wherein the components are provided separately in a single or multiple containers. L. GENERAL AND PREFERRED ASPECTS OF THE PRESENT INVENTION Another aspect of the present invention includes wherein the at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. A further aspect of the present invention includes wherein the at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof. An additional aspect of the present invention includes wherein the at least one cPG compound is provided in a regime of between once per hour to about once per three months. II. PHARMACEUTICAL COMPOSITIONS A second aspect of the present invention includes a pharmaceutical composition for the prophylaxis or treatment of at least one Stroke Related Disorder, including at least one of: a) at least one cPG compound, optionally in combination with; b) at least one IGF-1 compound; c) at least one IGF-2 compound; d) at least one Des (1-3) IGF-1 compound; e) at least one glycine-proline- glutamate compound; f) combinations thereof; wherein the components are provided together or separately; further wherein the pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of Stroke Related Disorder is so prevented from or treated for the at least one Stroke Related Disorder. Any of the components disclosed and described herein can be used as components in this aspect of the present invention, including but not limited to the cPG compounds, the additional compounds such as but not limited to IGF-1 compounds, Des-(1-3) IGF-1 compounds, GPG compounds, or combinations thereof. III. DETAILED DESCRIPTION OF CERTAIN ASPECTS AND EMBODIMENTS OF THE PRESENT INVENTION The present invention is directed in part towards compounds that are effective in preventing and treating Stroke Related Disorders, which includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, related cardiovascular disease, transient ischemic attack (TIA), or combinations thereof. Stroke is a serious and life-threatening medical condition that occurs when blood supply to the brain is interrupted, leading to brain cell death. As one of the leading causes of disability and mortality worldwide, stroke can have devastating consequences on individuals and their families. There are three main types of stroke: ischemic stroke, hemorrhagic stroke, and transient ischemic attack (TIA), also known as a “mini-stroke.” Stroke is closely linked to cardiovascular diseases, as both share common risk factors such as hypertension, diabetes, and high cholesterol. Understanding the causes, symptoms, and treatments of stroke is crucial for effective prevention and management. Ischemic Stroke Ischemic stroke accounts for approximately 87% of all stroke cases and occurs when a blood clot blocks or narrows an artery supplying blood to the brain. This blockage is often caused by atherosclerosis, a condition where fatty deposits accumulate in blood vessels, leading to the formation of plaques that can rupture and cause clot formation. Early treatment is critical for minimizing brain damage. The primary treatment for ischemic stroke is thrombolytic therapy using tissue plasminogen activator (tPA), a drug that dissolves blood clots if administered within 4.5 hours of symptom onset. For patients who are not eligible for tPA, mechanical thrombectomy is an alternative procedure where a catheter is inserted into the blood vessel to remove the clot directly. Hemorrhagic Stroke Hemorrhagic stroke accounts for about 13% of stroke cases and occurs when a blood vessel in the brain bursts, leading to bleeding in or around the brain. Treatment for hemorrhagic stroke focuses on controlling bleeding and reducing intracranial pressure. Common approaches include: • Surgical intervention to remove a hematoma or repair a ruptured aneurysm • Medications to lower blood pressure and prevent further bleeding • Endovascular procedures, such as coiling or clipping aneurysms to stop bleeding Recovery often involves intensive rehabilitation, as hemorrhagic strokes can cause significant brain damage and disability. Transient Ischemic Attack (TIA) A transient ischemic attack (TIA), often called a “mini-stroke,” occurs when there is a temporary blockage of blood flow to the brain. Unlike a full ischemic stroke, a TIA does not cause permanent brain damage because the blockage resolves on its own within minutes to hours. However, a TIA is a warning sign of an impending stroke, and individuals who experience a TIA are at higher risk of a major stroke in the future. Since TIA symptoms resolve quickly, they are often overlooked. However, a thorough medical evaluation, including MRI, CT scans, and carotid ultrasound, is necessary to determine the cause and prevent a future stroke. Since a TIA is a warning sign of stroke, treatment focuses on reducing stroke risk through lifestyle modifications and medications, such as: • Antiplatelet drugs (aspirin, clopidogrel) • Blood pressure control • Cholesterol-lowering drugs (statins) • Surgical intervention, such as carotid endarterectomy, to remove blockages in the carotid arteries Stroke and Related Cardiovascular Disease Stroke and cardiovascular disease share common risk factors and often occur together. Conditions such as atrial fibrillation, coronary artery disease (CAD), and heart failure increase the risk of stroke by causing blood clots that can travel to the brain. Treatment of Clinical Stroke Related Disorders With cPG Stroke occurs when the blood supply to the brain is disrupted, causing neuronal damage and brain cell death. In recent years, research has increasingly focused on neuroprotection—strategies aimed at preserving and restoring brain function following a stroke. Stroke is also closely linked to neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, as they share common pathological mechanisms, including oxidative stress, inflammation, and excitotoxicity. Understanding the relationship between stroke, neuroprotection, and neurodegeneration is essential for developing novel treatments to improve brain recovery and long-term outcomes. Stroke causes a rapid loss of brain function due to ischemia (blockage of blood flow) or hemorrhage (bleeding in the brain). The brain is highly dependent on oxygen and glucose, and when blood flow is interrupted, neurons begin to die within minutes. This process, known as ischemic cascade, involves: • Excitotoxicity: Excessive release of glutamate leads to overactivation of NMDA receptors, resulting in calcium overload and neuronal damage. • Oxidative stress: Reduced blood flow increases the production of reactive oxygen species (ROS), damaging brain cells. • Neuroinflammation: Activated microglia and astrocytes release inflammatory cytokines, exacerbating brain injury. • Apoptosis: Programmed cell death pathways are triggered, leading to widespread neuronal loss. These damaging effects contribute to the neurological deficits seen in stroke patients, including cognitive impairment, motor dysfunction, and speech difficulties. Neuroprotection refers to strategies that prevent neuronal death and promote brain recovery after stroke. Various therapeutic approaches are under investigation, including pharmacological treatments, stem cell therapy, and lifestyle modifications. Stroke and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease share several pathological features. Stroke increases the risk of developing dementia and accelerates cognitive decline in neurodegenerative conditions. Cyclic Prolyl Glycine (cPG) is a small molecule drug, which is a metabolite of analog of the terminal tripeptide of IGF-1, IGF1(1-3). As an IGF-1 mimetic analog, cPG exerts trophic and neuroprotective effects in various animal models. (Lloyd Tran-US Patent 7,232,798 US and 11,090,303). Cyclic Prolyl Glycine (cPG analogues) has shown promise in promoting neurogenesis (the growth of new neurons) and protecting brain cells from ischemic damage. By targeting key pathways involved in neuroprotection, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), may help restore brain function after stroke. The development of neuroprotective drugs like cPG analogues represents a promising frontier in stroke treatment. By targeting both neurogenesis and neuroprotection, future therapies may help prevent long-term neurological decline and reduce the risk of developing neurodegenerative diseases. In the present invention, methods of using cPG as a viable effective at treating Stroke Related Disorders, which includes but is not limited to stroke, ischemic stroke, hemorrhagic stroke, related cardiovascular disease, transient ischemic attack (TIA), or combinations thereof resulting from neuronal damage as described above. In one aspect of the present invention an "effective amount" or “pharmaceutically effective amount” refers to an amount sufficient to cure, alleviate, or partially arrest the clinical manifestations of a given disease or state and its complications. An amount adequate to accomplish this is defined as "effective amount" or “pharmaceutically effective amount.” Effective amounts or pharmaceutically effective amounts for each purpose will depend on the severity of the disease or injury. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. A. cPG COMPOUNDS The present invention relates to a composition comprising of cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound or at least one cPG Compound, for the treatment and prevention of Stroke Related Disorders. The present invention relates to a composition comprising a metabolite of IGF-1, known a cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound, for the treatment and prevention of Stroke Related Disorders. Cyclic Glycine-Proline (cGP) regulates the homeostasis of insulin-like growth factor (IGF)-1 function and cGP / IGF-1 ratio determines IGF-1 bioactivity in vitro and in vivo. Cyclic Prolyl Glycine (“cyclic PG” or “cPG”) has the following structure: Prolyl Glycine The present invention includes novel diketopiperazines that are structurally related to cPG. One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below. cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline referred herein as “cGAL”. Where R can be an Alkyl” which refers to a saturated branched, straight chain or cyclic hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert- butyl, cyclopropylmethyl, hexyl and the like. Where R can be an Ally, which refer to a group is a substituent with the structural formula H2C=CH−CH2R, where R is the rest of the molecule. With R is a methyl, an aspect of the present invention that includes Cyclic Glycyl-2-Alkyl Proline is (8aS)-Methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, which is referred to as Cyclic Glycyl-2- Methyl-Proline or cyclicGMeP or cGMeP. Structure 3: Cyclic G-2MeP (which is available for purchase from polypeptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA)). In general, c(PG)3 and cGAL can be prepared by methods such as are already well-known to persons of ordinary skill in the art of peptide and modified peptide synthesis. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993. Synthesis of the diketopiperazine compounds of this invention may be by solution-phase synthesis as discussed in the Examples or via the solid-phase synthesis method exemplified by Merrifield et al.1963 J. Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention. In the present application, notably but not limited to this section where compound names and structures and abbreviations are provided, the various compounds can all be used in all aspects of the present invention included herein. For example, should cPG be indicted in the specification, then all other compounds of this section (and the application as a whole) that are cPG compounds and related derivatives such as but not limited to cGAL are included in that and other descriptions, notably but not limited to methods of treatment of a variety of conditions described herein.

[0002] re for cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) The chemical synthesis of cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) was carried out as published in Israel Journal of Chemistry, Vol.12, Nos.1-2, 1974, pp.15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout. Synthesis of Cyclic (glycyl-L -prolyl-glycyl-L -prolyl-glycyl-L -prolyl) A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethyl-formamide (DMF) (20 ml, dried over sodium sulfate) was added dropwise with stirring over 6 hours to 500 ml of reagent-grade pyridine, at room temperature. The bright yellow mixture was constantly stirred over 48 hours at room temperature. Solvents were removed by rotary-evaporator-high vacuum pump system at 45°. The residue was washed with 20 ml of acetone which dissolved the p-nitrophenol and pyridine hydrochloride, but left the peptidic fraction insoluble. The insoluble materials and acetone were transferred to a flask and allow acetone to evaporate at 45°. The material was then dissolved in a minimum of DMF. The white microcrystalline precipitate was shown to be Cyc / o(glycyl-L -prolyl- glycyl-L -prolyl-glycyl-L -prolyl) (155 mg, with 28% yield), formed complexed with DMF. Crystallization from methanol-ether of 100 mg of this material gave crystalline cyclo(Pro-Gly)3(55 mg) free of DMF. Chemical analysis: Calculated for C2IH30N606H20 : C, 52.49; H, 6.71; N, 17.49. Elemental analysis found C, 52.60; H, 6.81; N, 17.38. In still other aspects, present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues with structural formulas given above to treat a disease, disorder, or condition, including but not limited to Stroke Related Disorders and its related conditions. Pharmaceutical Compositions and Administration In general, compounds of this invention can be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination with at least one other compound of this invention and / or at least one other conventional therapeutic agent for the disease being treated. A therapeutically effective amount may vary widely depending on the disease or injury, the severity of the disease, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. As anti-apoptotic, anti-necrotic, anti- neurodegenerative, therapeutically effective amounts of compounds of this invention can range from about 0.001 milligrams per kilogram (mg / kg) to about 100 (mg / kg) mass of the animal, for example, about 0.1 to about 10 mg / kg, with lower doses such as about 0.001 to about 0.1 mg / Kg, e.g. about 0.01 mg / Kg, being appropriate for administration through the cerebrospinal fluid, such as by intracerebroventricular administration, and higher doses such as about 1 to about 100 mg / Kg, e.g. about 10 mg / Kg, being appropriate for administration by methods such as oral, systemic (e.g. transdermal), or parenteral (e.g. intravenous) administration. A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease or injury. In general, compounds of this invention can be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection), by administration to the CNS (e.g. by intraspinal or intercisternal injection); by implantation, and by infusion through such devices as osmotic pumps, transdermal patches, and the like. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulation, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable or physiological acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, may be found in such standard references as Gennaro A R: Remington: The Science and Practice of Pharmacy, 20thed., Lippincott, Williams & Wilkins, 2000. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, glycols, and the like, with isotonic solutions being preferred for intravenous, intraspinal, and intracisternal administration and vehicles such as artificial cerebrospinal fluid being also especially suitable for administration of the compound to the CNS. The above text is expressly incorporated herein fully by reference. Compounds of this invention can be administered after or before onset of a condition that is likely to result in neurodegeneration or a symptom thereof. For example, it is known that hypoxia / ischemia can occur during coronary artery bypass graft (CABG) surgery. Thus, a patient can be pre-treated with a compound of this invention before being placed on an extracorporeal oxygenation system. In some embodiments, it can be desirable to administer a compound of this invention beginning about 4 hours before surgery or before an event that is likely to lead to traumatic or other neurological injury. In other embodiments, it can be desirable to infuse a compound of this invention during the surgery or during a surgical procedure to repair a neurological injury. Compounds of this invention can also be used in emergency situations, for example in a patient that has just experienced a stroke, hypoxic event, traumatic brain injury or other acute insult. In such situations, a compound of this invention can be administered immediately after a diagnosis of neural injury is made. In some situations, kits containing compound of this invention can be prepared in advance of use in the field. A kit can contain a vial containing a compound of the invention in a pharmaceutically acceptable formulation (e.g., for injection), along with a syringe or other delivery device, and instructions for use. In situations in which a seizure is diagnosed, a compound of this invention can be administered along with an anticonvulsant. Many anticonvulsants are known in the art and need not be described in detail herein. Additionally, “secondary” neurological injuries can occur after a primary insult such as a traumatic injury, stroke or surgical procedure. For example, after a stroke, penetrating brain injury or a CABG procedure, inflammation of neural tissue can lead to neurodegeneration. Secondary injuries can be reflected by increased activation of inflammatory cells (e.g., astrocytes and / or microglia), and actions of inflammatory mediators can cause neurological damage. Thus, in some embodiments, it can be desirable to administer a compound of this invention for periods beginning before the insult, to up to about 100 hours after the insult. In other embodiments, it can be desirable to administer a compound of this invention beginning before the insult, during the insult and after the insult, either continuously, as an infusion, or in discrete doses separated by a desired time interval. Desirably, if possible, when administered as an anti-apoptotic agent, an anti-necrotic agent, or an anti-neurodegenerative agent, compounds of this invention can be administered orally. The amount of a compound of this invention in the composition can vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art. In general, the final composition can comprise from about 0.0001 percent by weight (% w) to about 10% w of the compound of this invention, preferably about 0.001% w to about 1% w, with the remainder being an excipient or excipients. A composition may optionally contain, in addition to a compound of this invention, at least one agent selected from, for example, growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone binding protein, IGF-binding proteins (especially IGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, the hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3 and FHF-4, karatinocyte growth factor 2, glial- activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor, activity-dependant neurotrophic factor, cytokine leukaemia inhibiting factor, oncostatin M, interleukin), α-, β-, γ-, or consensus interferon, and TNF-α. Other forms of neuroprotective therapeutic agents include, for example, clomethiazole; kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, andrenocorticotropin-(4- 9) analogue [ORG 2766] and dizolcipine (MK-801), selegiline; glutamate antagonists such as, NPS1506, GV1505260, MK-801, GV150526; AMPA antagonists such as 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline (NBQX), LY303070 and LY300164; anti-inflammatory agents directed against the addressin MAdCAM-1 and / or its integrin α4 receptors (α4β1 and α4β7), such as anti-MAdCAM-1mAb MECA-367 (ATCC accession no. HB-9478). Most of these agents, especially the peptides such as the growth factors, etc. are not orally active, and will require administration by injection or infusion. Preparation of Compositions Starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to the person of ordinary skill in the art following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols.1-17, John Wiley and Sons, New York, N.Y., 1991. In most instances, amino acids and their esters or amides, and protected amino acids, are widely commercially available; and the preparation of modified amino acids and their amides or esters are extensively described in the chemical and biochemical literature and thus well-known to persons of ordinary skill in the art. Starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data. Compounds of this invention may be prepared by the methods described below and as given in the Examples. B. IGF-1 COMOUNDS IGF-1 is a protein that in humans is encoded by the IGF1 gene. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 daltons. C71H119N17O19S IGF-1 is produced primarily by the liver. Production is stimulated by growth hormone (GH). Most of IGF-1 is bound to one of 6 binding proteins (IGF-BP). IGFBP-1 is regulated by insulin. IGF-1 is produced throughout life; the highest rates of IGF-1 production occur during the pubertal growth spurt. IGF-1 is a hormone that is structurally very similar to insulin and mediates the effects of growth hormone (GH) thus affecting metabolism, regeneration, and overall development. The GH- IGF-1 signaling pathway is crucial in the process of vascular remodeling and angiogenesis, i.e., the process of building new blood vessels and thus, helps in maintaining blood circulation in the body. In the brain, IGF-1 is abundant in various cells and regions and research over the years, suggest an imperative role of IGF-1 activity in neurodevelopment making it critical in learning and memory. A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure in children with severe IGF-1 deficiency. Cyclic glycine-proline (cGP) is a metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes it a more favorable candidate for manipulating the binding-release process between IGF-1 and its binding protein, thereby normalizing IGF-1 function. As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types, and causing significant metabolic effects One important metabolic effect of IGF-1 is signaling cells that sufficient nutrients are available for them to undergo hypertrophy and cell division. Its effects also include inhibiting cell apoptosis and increasing the production of cellular proteins. IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types. IGF- 1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types. The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin. (Suwa S, Katsumata N, Maesaka H, Tokuhiro E, Yokoya S (December 1988). "Serum insulin-like growth factor I (somatomedin-C) level in normal subjects from infancy to adulthood, pituitary dwarfs and normal variant short children". Endocrinologia Japonica.35 (6): 857– 864. doi:10.1507 / endocrj1954.35.857. ) (Keating GM (2008). "Mecasermin". BioDrugs.22 (3): 177–188. doi:10.2165 / 00063030- 200822030-00004. PMID 18481900) IGF-1 is part of the insulin-like growth factor (IGF) system. This system consists of three ligands (insulin, IGF-1 and IGF-2), two tyrosine kinase receptors (insulin receptor and IGF-1R receptor) and six ligand binding proteins (IGFBP 1–6). Together they play an essential role in proliferation, survival, regulation of cell growth and affect almost every organ system in the body. (García-Mato Á, Cervantes B, Murillo-Cuesta S, Rodríguez-de la Rosa L, Varela-Nieto I. "Insulin- like Growth Factor 1 Signaling in Mammalian Hearing". Genes.12 (10): 1553. doi:10.3390 / genes12101553. PMC 8535591. PMID 34680948.) Similarly to IGF-1, IGF-2 is mainly produced in the liver and after it is released into circulation, it stimulates growth and cell proliferation. IGF-2 is thought to be a fetal growth factor, as it is essential for a normal embryonic development and is highly expressed in embryonic and neonatal tissues The IGF-1 family includes but is not limited to: • IGF-1, • IGF-2 • IGF receptors (IGF-1R) and • IGF binding proteins (IGFBP). The therapeutic applications of IGF-1 are limited due to its poor central uptake and potential side-effects. IGF-1 that is not bound to its binding protein bares a very short half-life and is cleaved by enzymes to form the tripeptide glycine-proline-glutamate (GPE). However, the enzymatic instability of GPE, with a plasma half-life of less than 4 minutes, is further cleaved to produce the final product, cyclic-Glycine-Proline (cGP) IGF1 (Mecasermin-Increlex∗) was administered subcutaneously twice / day for six months. The caretakers were trained to perform the injections at home. For the first and the last weeks the drug dosage was 0.05 mg / Kg; during the remaining periods the dosage was 0.1mg / Kg. The dosage is the same used in the IGF1- deficiency treatment. The maintaining dosage is the one approved for treating IGF deficiencies in children. C. DES(1-3)IGF-1 COMPOUNDS des(1-3)IGF-1 is a naturally occurring, endogenous protein, as well as drug, and truncated analogue of insulin-like growth factor 1 (IGF-1). des(1-3)IGF-1 lacks the first three amino acids at the N-terminus of IGF-1 (for a total of 67 amino acids, relative to the 70 of IGF-1). As a result of this difference, it has considerably reduced binding to the insulin-like growth factor-binding proteins (IGFBPs) and enhanced potency (about 10-fold in vivo) relative to IGF-1. Des( l-3)IGF-I is a 67 amino acid protein that is identical to human IGF-I but with the tripeptide Gly-Pro-Glu omitted from the N-terminal (see Fig.1). The molecule is maintained in relatively tight conformation by three di-sulphide bridges, Cys6-Cys48, Cys18-Cys61and Cys47-Cys52, the amino acid numbers being those in full length IGF-I. Primary structures of (a) human IGF-1 (MW 7648.7); (b) des(1-3)IGF-1 (MW 7365.5), which is truncated for the N-terminal tripeptide; (c) R3IGF-1 (MW 7675.8), that is substituted by arginine for glutamic acid at position 3; and (d) LONGTMR3IGF-1 (MW 9111.6), whose N- terminus is prolonged by additional 13 residues compared with R3IGF-1. Removal of the three amino-terminal amino acids of insulin-like growth factor-I (IGF-1) produces des(l-3)IGF-1, a growth factor that is more potent in several cell culture assays than the full-length peptide. This increased potency is most likely a consequence of the relatively poor association of des(l-3)IGF-I with IGF-binding proteins secreted by the cultured cells. See, for example, Ballard, F. J., Francis, G. L., Ross, M., Bagley, C. J., May, B. & Wallace, J.C. (1987). Natural and synthetic forms of insulin-like growth factor-1 (IGF-1) and the potent derivative, des- tripeptide IGF-1: Biological activities and receptor binding. Biochemical and Biophysical Research Communications 149, 398-404. D. PHARMACEUTICAL DOSAGES - VARIOUS EMBODIMENTS An administered dose may contain from 0.5mg to 1.5 mg / kg or between 30 mg to 150 mg for a typical adult of 70 kg weight, or between 60 mg to 150 mg for obese person normally weighing 80 -120 kg An administered dose may range from 0.5 mg to 1.5 mg / kg, which corresponds to 30 mg to 90 mg for a typical 70 kg adult, or 60 mg to 180 mg for an obese individual weighing between 80 kg and 120 kg. Pharmaceutical compositions comprising a pharmaceutically acceptable salt, amide, or ester thereof, and a pharmaceutically acceptable excipient may be prepared as is known in the art. A composition may be administered in several dosage forms, for example as a solution; a suspension; emulsion; a microemulsion; multiple emulsions; a foam; a salve; a paste; a plaster; an ointment; a tablet; a coated tablet; a chewing gum; a rinse; a capsule such as hard or soft gelatin capsules; a suppositories; a rectal capsule; drops; a gel; a spray; a powder; an aerosol; an inhalant; eye drops; an ophthalmic ointment; an ophthalmic rinse; a vaginal pessary; a vaginal ring; a vaginal ointment; an injection solution; an in situ transforming solution such as in situ gelling, setting, precipitating, and in situ crystallization; an infusion solution; or as an implant. A composition may further be compounded in a drug carrier or drug delivery system, e.g. in order to improve stability, bioavailability, and / or solubility. In a particular embodiment a composition may be attached to such system through covalent, hydrophobic, and / or electrostatic interactions. The purpose of such compounding may be, e.g., to decrease adverse effects, achieve chronotherapy, and / or increase patient compliance. A composition may also be used in the formulation of controlled, sustained, protracting, retarded, and / or controlled release drug delivery systems. The composition may be administered by parenteral administration. Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe, or by means of an infusion pump. Pharmaceutical compositions are well known in the medical arts and can include formulations in solid form such as a tablet to be administered orally. Formulations of the present invention can also include liquid, gel, semisolid, colloidal, vapor and gas phase formulations capable of oral, nasal, bronchial, intestinal, or colonic (anal and perianal) delivery. In one embodiment, the compositions of the present invention are administered mucosally (for example, to the mucosa of the subject). By mucosa is meant anybody mucosa including oral, nasal, bronchial, esophageal, intestinal, and anal or perianal. It will be recognized to the skilled clinician, choice of a carrier, including a physiologically acceptable compound, depends, for example, on the manner in which the peptide or encoding polynucleotide is to be administered, as well as on the route of administration of the composition and its dose. Where the composition is administered under immunizing conditions, for example, as a vaccine, it generally is administered intramuscularly, intradermally, or subcutaneously, but also can be administered parenterally such as intravenously, and can be administered by injection, intubation, or other such method known in the art. Where the desired modulation of the immune system is tolerization, the composition preferably is administered orally, or can be administered as above. The term "therapeutically effective amount" or "effective amount" means the amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Thus, the total amount of a composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, and can be followed up with one or more booster doses over a period of time. The amount of the composition to stimulate an immune response in a subject depends on various factors including the age and general health of the subject, as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled clinician will know to adjust the particular dosage as necessary. The total amount of a compound or composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol, in which multiple doses are administered over a prolonged period of time. One skilled in the art would know that the amount of the compositions of the present invention to treat SARS in a subject depends on many factors including the age and general health of the subject as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose as necessary. In general, the formulation of the pharmaceutical composition and the routes and frequency of administration are determined, initially, using Phase I and Phase II clinical trials. All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the present invention. More specifically, the described embodiments are to be considered in all respects only as illustrative and not restrictive. All similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit and scope of the present invention as defined by the appended claims. Alternatively, or additionally, additional antiviral agent may optionally be unsuitable for the frequency of administration of the composition, for example, wherein the composition is formulated for administration once per day, and the additional antiviral agent is more suitable for administration once per week (for example., a PEGylated interferon-alpha). The composition may be, for example, in the form of a liquid, a semi-solid (for example, gel), or solid. In some embodiments of the present invention, the composition is in a solid form. Examples of solid forms for a composition include, without limitation, a tablet, a capsule (for example, comprising an encapsulated solid), a caplet, a powder, microspheroids, and granules. The composition is preferably formulated in accordance with the intended frequency of administration of the composition. This, in turn, will depend on the properties of the active agents. As discussed herein, artemether and atazanavir may be administered, for example, once per day, but also at other frequencies (for example, twice or thrice a day). It is to be appreciated that an active agent can be made more suitable for less frequent administration (for example, once per day, as is particularly convenient, instead of twice or more per day) by formulating a composition appropriately, for example, by formulating the composition for slow release of the active agents therein. Slow release preparations typically include slow release biodegradable carriers. Slow release biodegradable carriers are well known in the art. These are materials that may form particles that may capture therein an active compound(s) and slowly degrade / dissolve under a suitable environment (for example, aqueous, acidic, basic, etc.) and thereby degrade / dissolve in body fluids and release the active compound(s) therein. The particles are preferably nanoparticles (for example, in the nanometer range, for example, in the range of about 1 to about 500 nm in diameter, preferably about 50 to about 200 nm in diameter, most preferably about 100 nm in diameter). Oral slow-release forms are often designed to maintain therapeutic drug concentrations for greater than 12 hours. The absorption rate can be controlled by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins. Thus, for example, a slow-release formulation in tablet form, can be based on the use of a hydrophilic polymer which swells in contact with gastrointestinal fluids, to form a gel, which creates a barrier that enrobes the tablet. The barrier limits physical exchanges between the inside of the tablet and the surrounding medium. As a consequence, intrusion of water towards the tablet matrix and diffusion of drug are slowed down, allowing a controlled slow release of the drug. Various types of polymers may be used as a matrix for the slow-release of drugs, such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, and polyvinylacetate-polyvinyl chloride copolymers. In some embodiments of the present invention, the composition is a unit dosage form (for example, a unit dosage form formulated for oral administration). Pharmaceutical compositions can be administered by an appropriate route of administration at an appropriate dose and an appropriate regime. Pharmaceutical compositions for use in accordance with embodiments of the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients (artemether and antiviral agents described herein) into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the active ingredient(s) of embodiments of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol. For oral administration, the active ingredients can be formulated readily by combining the active ingredients described herein with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active ingredient(s) to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Pharmaceutical compositions, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients described herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. The active ingredients described herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multidose containers with optionally, an added preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection suspensions and emulsions (for example, water-in-oil, oil-in-water or water-in-oil in oil emulsions). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use. The active ingredients of embodiments of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository. For administration by inhalation, the active ingredient(s) for use according to embodiments of the present invention are conveniently delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and / or gaseous carriers) from a pressurized pack or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active ingredient(s) and a suitable powder base such as, but not limited to, lactose or starch. The choice of drug delivery methods requires understanding of tissue distribution, metabolism and cellular effects as well as an understanding of the interaction of the drug with the specific underlying pathological processes of the disease under treatment, for which general and specific teaching are available in the art. Because the route of drug administration determines bioavailability and tissue levels and distribution, change in delivery may modify fundamentally the location, nature, extent and duration of disease condition, as well as alter dosing requirements and toxicities. However, it was observed that when artemether is administered locally via nasal delivery system in vivo, the drug was adsorbed quickly with more bioavailability and short duration of action in treating the fever very quickly than when administered systemically. For pulmonary delivery, a therapeutic composition of the invention can be formulated and administered to the patient in solid or liquid particulate form by direct administration for example, inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. In general, particles ranging from about 1 to about 10 microns in size are within the general respirable range. The therapeutic composition containing the anti-malarial and antiviral compounds are preferably administered by direct inhalation into the respiratory system for delivery as a mist or other aerosol or dry powder. The dosage of active compound via this route may vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of anti-malarial and antiviral compound on the airway surfaces of the subject. Depending upon the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations. The daily dose administered via direct inhalation is normally much less than oral dose. For example, a daily dose of artemether administered via direct inhalation ranges from 20 to 40 mg per day and Atazanavir from about 25 mg to about 100 mg per day. The doses of the active compounds can be provided as one or several prepackaged units. Aerosols of liquid particles can be produced by any suitable means, such as inhalatory delivery systems. One is a traditional nebulizer which works in a mechanism similar to the familiar perfume atomizer. The airborne particles are generated by a jet of air from either a compressor or compressed gas cylinder-passing through the device (pressure driven aerosol nebulizer) (U.S. Pat. No.4,501,729- “Aerosolized amiloride treatment of retained pulmonary secretions”). All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified. EXAMPLES The following examples are intended to illustrate embodiments of this invention and are not intended to limit the scope to these specific examples. Example 1: Effects of Cyclo Prolyl Glycine on Animals With Stroke Animal studies were conducted using the well-recognized model of stroke, known as middle coronary artery occlusion (MCAO). This method is designed to mimic neurological and behavioral signs and symptoms of stroke in humans. The infarct size, and the appearance of GFAP-positive astrocytes and microglial cell activation are recognized as being indicators of brain damage. The GFAP and microglial cell activation results are indicative of stroke in humans. The reductions in GFAP staining and microglial cell activation are predictive of therapeutic effects in humans suffering from stroke. Materials and Methods Endothelin-1 Induced Middle Cerebral Artery Occlusion Adult male Sprague-Dawley rats (280-350 g) were used. All efforts were made to minimize any animal suffering and the number of animals used. The rats were anaesthetized by the administration of halothane and oxygen, with 5% halothane / oxygen was initially applied to anaesthetize the animal, and then 2.5% halothane was used to maintain the anesthesia. The anaesthetized rats had a guiding cannula implanted on the skull which was fixed into position with dental cement. Following this implantation, the jugular vein of the animal was also cannulated. Three days post cannula implantation and cannulation, the rats were anaesthetized again as above and subjected to MCA occlusion according to the method of Sharkey and co-workers (Sharkey et al., 1993). This involved placing the head of each rat on a stereotaxic frame and locking it into position. The animals were also placed on a heating pad, which is designed to maintain body temperature within the physiological range for the duration of the surgical procedure. The hair over the scalp was clipped short with a pair of scissors, sponged and wiped dry with a solution of Betadine® (iodine). Following this, a midline skin incision was made through the scalp to expose the coronal suture line (bregma) of the skull prior to a small opening being drilled through the cranial bone using the following co-ordinates 0.2 mm anterior to and 5.2 mm lateral to bregma. Through the guide cannula, a 28-gauge infusion needle that was connected to a 10 μl syringe containing 100 ρmol of porcine endothelin-1 (Et-1; Sigma-Aldrich Inc., Saint Louis, Mo., USA) in 3 μl of saline was vertically inserted to a depth of 8.7 mm below the surface of the skull. At a delivery rate of 1 μl per minute, a total volume of 3 μl of solution was manually infused over the period of three minutes. With the completion of the infusion, the needle was left in place for five more minutes before being withdrawn from the brain whilst the skin incision was sutured and the animals moved to a warmed incubator (37° C.) in order to recover from the surgery. Once awake, the animals were then transferred to their cages where they had full access to both food and water. CPG and CGMeP Treatment At five hours post Et-1 (100 ρmol) injection, CPG (3 mg / kg / h) (Bachem AG, Basal, Switzerland) or succinate buffer (vehicle treated group) in the first study and CPG (0.3 mg / kg / h) (NeuroActiva, Inc.) or succinate buffer (vehicle treated group) in the second study was continuously infused intravenously into the animal via the jugular vein cannula at a delivery rate of 0.5 ml / h for four hours. Histological Procedures Five days following the drug treatment, the animals were sacrificed using an overdose of sodium pentobarbital and the brains collected for histological evaluation of neuronal survival. The rats were perfused transcardially with 0.9% normal saline followed by 10% formalin. The brain was removed from the skull and stored in the same fixative solution for at least 24 hours. Three 2 mm coronal sections using a rodent brain matrix (RBM-3000C / RBM-4000C, ASI Instruments, USA) were cut. Section A: directly in front of the optical chiasma, section B: directly following section A posterior to the optical chiasma and section C directly following section B. The slices were held in 10% formalin for at least 24 hours, processed in increasing percentage of alcohol and in chloroform and embedded in paraffin for further cutting. At a thickness of 8 μm, coronal sections were cut on a Leica® microtome (Leica Biosystems, Dear Park , Illinois, USA), mounted onto Polysine™ microscope coated slides (Fisher Scientific, San Francisco, California USA) and stained with thionin-acid fuchsin prior to microscopic evaluation. Immunohistochemistry Eight-micron thickness paraffin-embedded sections were mounted to microscope slides, dewaxed in xylene and brought up to water through the standard graded ethanol procedure. These slides were then washed three times for five minutes (3×5 min) in 0.1 M phosphate buffered saline (PBS), before being transferred to a solution of 1% H2O2in absolute methanol for 30 minutes at room temperature in order to block for endogenous peroxidases. Following another conventional wash, non-specific protein binding was blocked with 2% normal horse serum (NHS) (Vector Laboratories Inc., Burlingame, California., USA) in 0.1M PBS at room temperature for an hour. After this time period, the NHS was drained away carefully and the respective primary antibodies were loaded onto the sections. For astrocytic immunostaining, glial fibrillary acidic protein (GFAP) was used as a marker. These sections were incubated with a primary monoclonal anti-GFAP (Sigma-Aldrich Inc., Saint Louis, Mo., USA) antibody from mouse at a dilution of 1:1000 in 0.1M PBS containing 2% NHS overnight at 4° C. in a humidified chamber. The primary antibody was washed off the next day with 0.1M PBS (3×5 min) and the section was incubated with horse-anti-mouse biotinylated secondary antibody (1:200, Vector Laboratories Inc., Burlingame, California., USA) in 0.1M PBS plus 2% NHS overnight at 4° C. in a humidified chamber. The antibody was washed off the following day and the section incubated with ExtrAvidin peroxidase conjugate (1:500, Sigma) in 0.1M PBS plus 2% NHS at room temperature. After three hours, the slides were washed and developed with DAB for the required time until a brown reaction product was observed. For microglial immunostaining, isolectin B4peroxidase labelled from Bandeiraea simplicifolia (Sigma-Aldrich Inc., Saint Louis, Mo., USA) was used as a marker. With the only exception of using 0.1M Tris-buffered saline (TBS) plus 0.2% triton as opposed to 0.1M PBS, these sections went through the exact similar protocol to that required for immunolabelling of GFAP. However, in this assay, there was no blocking for non-specific protein binding. Therefore, following the blocking for endogenous peroxidases step, a standard wash (3×5 min) in TBS plus 0.2% triton was carried out prior to the sections being loaded with reconstituted isolectin B4(10 μg / ml). The slides were incubated overnight at 4° C. in a humidified chamber. After 24 hours, the isolectin B4was washed off and sections developed with DAB for the required time until a brown reaction product was noticeable. The time required for DAB color development was controlled to be equal for all sections within both studies. Following DAB color development, the stained sections were dehydrated through the standard increasing ethanol gradient and xylene procedure. Finally the slides were quickly allowed to air dry, mounted using DPX mounting medium and cover slipped. Image Analysis Slides were visualized under bright-field illumination and the extent of neuronal damage, as well as the astrocytic and microglial responses were analysed on a Carl Zeiss Axioskope™ microscope using AxioVision™ software (AxioVision 3.0, Carl Zeiss Software, Hallbergmoos, Germany). For analysis of GFAP immunohistochemistry, the area of total GFAP immunostaining in the peri-infarct zone was calculated in mm2and converted into a percentage against the total area (in mm2) of the ipsilateral (injured) hemisphere, whilst for isolectin B4, the microglial immunopositive cells were counted in three screen fields (×10 magnification) and then averaged. Also, in every experiment, a control section with no primary antibody was used as a negative control. Furthermore, the histology and immunohistochemistry was analysed by an individual blinded to the treatment groups. Statistical Analysis Student t-test was used for comparing the treatment effects of CPG and its vehicle groups, respectively. All statistical calculations were carried out using GraphPad Prism™ software (Version 9.51, GraphPad Software Inc., La Jolla, California, USA). Data are presented as mean±S.E.M. and significance was defined at p<0.05. Results Effect of CPG on Infarct Size In the CPG study, the area of infarct in animals treated with vehicle was 43.4±7.4 mm2(n=13, FIG.1). Treatment with CPG (3 mg / kg / h) significantly reduced the area of the infarct to 17.3 ±5.4 mm2when compared to its vehicle treated group (n=15, * P<0.05). By contrast, in the cGMeP study, animals treated with vehicle had an area of infarct of 43.2±6.0 mm2(n=12, FIG.2). Treatment with cGMeP (0.3 mg / kg / h) significantly reduced the area of the infarct to 21.6 ±5.0 mm2as opposed to its vehicle treated group (n=14, *P<0.05). GFAP Immunostaining The astrocytic (GFAP positive cells) response following Et-1 induced MCA occlusion was determined in both studies. There was a significant reduction in the area of GFAP immunostaining after CPG treatment (11.5 ±1.8%, n=11, ** P<0.01) when compared with to its vehicle treated group (25.4 ±2.8%, n=11, FIG.3). However, treatment with CGMeP revealed only a strong inhibitory trend in GFAP immunostaining as opposed to its vehicle treated group (13.5±2.4% vs.23.8 ±2.3% for the control group, n=1, FIG.4). Microglia Immunostaining The response of microglia (isolectin B4 positive cells) was investigated. The number of microglial immuno-positive cells showed a significant (**P<0.01) decrease (278 ±65 vs.1352±187 for the vehicle treated group) after CPG treatment (n=10, FIG.5). CGMeP treated animals (n=10, FIG.6) also showed a reduction in the number of microglial immuno-positive cells as opposed to the vehicle treated group (516 ±165 vs.1473 ±387 for the vehicle group) although this difference did not reach statistical significance. Conclusions CPG and cGMeP showed strong neuroprotective actions following continuous i.v. infusion in adult male rats subsequent to an Et-1 induced MCA occlusion in a model of cerebral ischemia. It is noted that the neuroprotective effects of both these compounds were evident when administered at a time point of 6-9 h after focal cerebral ischemia demonstrating a wide window of therapeutic opportunity. These neuroprotective effects may be related to an inhibition of both astrocytic and microglial activation following cerebral ischemia. We conclude from these studies that CPG and cGMeP can be effective therapeutic agents useful in treating animals with middle cerebral artery occlusion. We further conclude that because the effects were observed in an animal system in vivo, in an art-recognized animal system that is predictive of effects in humans with stroke, that CPG and CGMeP can be effective in treating humans with stroke or other hypoxic or ischemic injury of the brain. Example 2: Neuroprotective Effects CPG in a Penetrating Ballistic Brain Injury To determine whether CPG might be a useful therapeutic agent in treating brain injury, we carried out a series of studies in rats that had received penetrating ballistic brain injury (PBBI) that mimics the types of injuries experienced by humans. In particular, behavioral tests of rats subjected to PBBI are useful in determining neurological deficits that commonly occur with such injuries. Introduction The rat penetrating ballistic brain injury (PBBI) paradigm models head injury caused by a high-energy bullet wound. It is a severe model of traumatic brain injury and has been characterized by using neurological, physiological and histopathological outcomes (Williams et al. Journal of Neurotrauma.2005: 22(2); pp.314-332.)), herein expressly incorporated fully by reference. CPG was evaluated in the PBBI model to investigate its effect on post-injury locomotor skills, defined by the competence of post-injury rats to traverse an elevated walking beam. PBBI Method Experiment 1: Sprague-Dawley rats were anaesthetized (induced with 5% isoflurane, maintained with 2% isoflurane) for surgery and placed in a stereotaxic device to enable an accurate and reproducible injury. A small burr hole was drilled in the skull to expose the right frontal pole (+4.5 mm AP, +2 mm medial; relative to Bregma) and additional bone was removed 1 mm anterior to the burr hole to enable insertion of the PBBI probe. The probe was mounted to the arm of the stereotaxic frame, at 50° from vertical and 25° counter-clockwise from the midline. The PBBI insult in this paradigm is designed to model the immediate tract caused by a 7.62 mm high velocity round, as well as the cavity that forms in the tract by energy dissipation from the missile. To achieve this, the probe was lowered to 12 mm depth from dura and the balloon that covers the probe expanded with a sudden inflation of air to create the cavity injury. The inflation / deflation lasts no more than 10-20 ms. After induction of the injury the probe was removed and the skull resealed with bone wax, and the scalp wound sutured. Thirty minutes following injury, rats were given either saline control or CPG (0.3 and 3.0 mg / kg / h) delivered by intravenous infusion for 4 or 12 hours. Rats were allowed a recovery period of either 24 hours or 72 hours post surgery prior to behavioral testing. For behavioral testing rats were placed on an elevated walking beam, and their capacity to traverse the beam was assessed. Automatic tracking of foot-faults occurring when the rats walked along the beam were recorded. In addition, rats were scored for severity of clinical signs (neurobehavioral dysfunction) and post-mortem for injury size following the PBBI (H&E staining) and activated microglia cell counts (OX-18 staining) Results The effects of CPG administered i.v. for 4 h (0, 0.3, 3 mg / kg / h) on foot-faults and neurological disability score were tested either 24 h or 72 h following PBBI. Foot-fault count was 54% lower and neurological disability score was 69% lower, in rats administered 3 mg / kg / h CPG when tested 72 h post-injury (FIGS.7A and FIG.7B respectively). No significant effect of CPG administered i.v. (0, 0.3, 3 mg / kg / h) on total injury volume to the brain assessed post-mortem following PBBI insult was observed (FIG.8). Experiment 2 In experiment 2 Rats were given either saline control or CPG for 12 hours at either 1.0 or 3.0 mg / kg / h, with infusion initiated 30 min post-PBBI insult. Results At a dose of 3 mg / kg / h CPG significantly reduced foot-fault count measured at 72 h post surgery (* p<0.01, ANOVA with Bonferroni post-hoc test) (FIG.9A). No statistically significant effects on neurological score (FIG.9B) or injury size (data not shown) were observed. Conclusion The studies show that CPG and cGMeP are effective in protecting the brain from neural injury caused by the interruption of blood supply to the brain. Because the studies were in vivo studies in an art-recognized animal system for study of brain injury, these results are predictive of effects observed in humans with similar types of injuries. Therefore, we conclude that CPG and cGMeP can be an effective therapeutic agent in treating people with strokes. While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of examples only, and not limitation. It will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents. The present invention is described with reference to specific embodiments thereof. Other features and embodiments of the present invention can be produced by those of skill in the art without undue experimentation and a reasonably likelihood of success. All of those and other embodiments are considered to be part of the present invention. All publication, including patent documents and scientific articles, referred to in this application, including any bibliography, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference.

Claims

Claims What is claimed is:

1. A method of prophylaxis or treatment of at least one Stroke Related Disorder, comprising: a. providing a subject in need of said prophylaxis or treatment of at least one Stroke Related Disorder; b. providing at least one pharmaceutical composition comprising: 1) at least one cPG compound, optionally in combination with one or more of the following components; a. at least one IGF-1 compound; b. at least one Des-(1-3) IGF-1 compound; c. at least one glycine-proline-glutamate compound; or combinations thereof; wherein said components are administered together or separately; further wherein said components are provided together or separately; c. administering a pharmaceutically effective amount of said at least one pharmaceutical composition to said subject; wherein said subject is provided prophylaxis or treatment of said at least one Stroke Related Disorder.

2. The method of claim 1, wherein said components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof.

3. The method of claim 1, wherein said components, individually or combinations thereof, are provided as or in a pharmaceutically acceptable salt.

4. The method of claim 1, wherein said components are administered separately.

5. The method of claim 1, wherein said components are administered together.

6. The method of claim 1, wherein said prophylaxis or treatment of said at least one Stroke Related Disorder comprises stroke, ischemic stroke, hemorrhagic stroke, transient ischemic attack (TIA) and related cardiovascular disease, or combinations thereof.

7. The method of claim 1, wherein said prophylaxis or treatment of said at least one Stroke Related Disorder addresses an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, loss of vision to one side, headache, severe headache, or combinations thereof.

8. The method of claim 1, wherein said at least one cPG compound comprises at least one of Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl), or combinations thereof.

9. The method of claim 8, wherein said at least one cPG compound comprises Cyclic Prolyl Glycine.

10. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

11. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

12. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

13. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

14. The method of claim 9, wherein said at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered about once a day, twice a day, once a week, twice a week, or combinations thereof.

15. The method of claim 9, wherein said at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered orally, intravenously, intranasally, or combinations thereof.

16. The method of claim 8, wherein said at least one cPG compound comprises Cyclic Glycyl-2-Allyl Proline.

17. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg.

18. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

19. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

20. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

21. The method of claim 16, wherein said at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered about once a day, twice a day, once a week, twice a week, or combinations thereof.

22. The method of claim 16, wherein said at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered orally, intravenously, intranasally, or combinations thereof.

23. The method of claim 8, wherein said at least one cPG compound comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl).

24. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

25. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

26. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

27. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

28. The method of claim 23, wherein said at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, twice a day, once a week, twice a week, or combinations thereof.

29. The method of claim 23, wherein said at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intranasally, intravenously, or combinations thereof.

30. The method of claim 1, wherein said at least one IGF-1 compound comprises at least one of: a) at lest one IGF-1; b) at least one IGF-2; c) at least one IGF receptor (IGF-1R); d) at least one IGF binding proteins (IGFBP); e) or combinations thereof.

31. The method of claim 30, wherein said at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, or intravenously, or combinations thereof; c) administered about once a day, twice daily, or a combination thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

32. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

33. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered once a day, twice a day, once a week, twice a week, or combinations thereof.

34. The method of claim 30, wherein said at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

35. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

36. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered once a day, twice a day, once a week, twice a week, or combinations thereof.

37. The method of claim 30, wherein said at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

38. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

39. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a day, twice a day, once a week, twice a week, or combinations thereof.

40. The method of claim 30, wherein said at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously, intravenously, or combinations thereof; c) administered about once a day, twice daily, or combinations thereof; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

41. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

42. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a day, twice a day, once a week, twice a week, or combinations thereof.

43. The method of claim 1, wherein said at least one des-(1-3)-IGF-1 compound comprises at least one of: a) Des-(1-3)IGF-1 which is truncated for the N-terminal tripeptide; b) b) R3IGF-1 that is substituted by arginine for glutamic acid at position 3; c) c) LONGTMR3IGF-1 whose N-terminus is prolonged by additional 13 residues compared with R3IGF-1; d) or combinations thereof.

44. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-(1-3) IGF-1 compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously, intravenously, or combinations thereof; c) is administered about once a day, twice daily, or combinations thereof; d) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; e) or combinations thereof.

45. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

46. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered once a day, twice a day, once a week, twice a week or combinations thereof.

47. The method of claim 1, wherein said at least one glycine-proline-glutamate compound comprises at least one of: a) D-GPE – A modified version using D-amino acids to enhance stability against enzymatic degradation. b) Cyclo-GPE – A cyclic form that may have increased resistance to metabolic breakdown. c) GPE-amide – An amidated form that may improve membrane permeability. d) N-methyl-GPE – A derivative where the N-terminal amino group is methylated for enhanced pharmacokinetic properties. e) PEGylated GPE – GPE conjugated with polyethylene glycol (PEG) to increase half-life in circulation f) or combinations thereof.

48. The method of claim 47, wherein said at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously, intravenously, or combinations thereof; c) is administered about once a day, twice a day, or combinations thereof; d) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; e) or combinations thereof.

49. The method of claim 47, wherein said at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

50. The method of claim 47, wherein said at least one pharmaceutical composition comprising at least one glycine-proline-glutamate compound is administered once a day, twice a day, once a week, twice a week or combinations thereof.

51. The method of claim 1, wherein said prophylaxis or treatment of said at least one Stroke Related Disorder results in prevention or improvement of the symptoms of Stroke Related Disorder, including but not limited to an inability to move or feel on one side of the body, problems understanding or speaking, dizziness, loss of vision to one side, headache, severe headache, or combinations thereof.

52. The method of claim 1, wherein said prophylaxis or treatment of said at least one Stroke Related Disorder is prophylaxis.

53. The method of claim 1, wherein said prophylaxis or treatment of said at least one Stroke Related Disorder is treatment.

54. The method of claim 1, wherein said subject is a human.

55. The method of claim 1, wherein said components are administered together in a single or multiple doses.

56. The method of claim 1, wherein said components are administered separately in a single or multiple doses.

57. The method of claim 1, wherein said components are provided together in a single or multiple containers.

58. The method of claim 1, wherein said components are provided separately in a single or multiple containers.

59. The method of claim 1, wherein said at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

60. The method of claim 1, wherein said at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenously, subcutaneously, or combinations thereof.

61. The method of claim 1, wherein said at least one cPG compound is provided in a regime of between once per hour to about once per three months.

2. A pharmaceutical composition for the prophylaxis or treatment of at least one Stroke Related Disorder, comprising at least one of: a) at least one cPG compound, optionally in combination with; b) at least one IGF-1 compound; c) at least one IGF-2 compound; d) at least one Des (1-3) IGF-1 compound; e) at least one glycine-proline-glutamate compound; f) combinations thereof; wherein said components are provided together or separately; further wherein said pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of obesity is so prevented from or treated for said at least one Stroke Related Disorder.

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