CN110799522B - Peptides for treating, ameliorating or preventing cerebral hemorrhage and uses thereof - Google Patents
Peptides for treating, ameliorating or preventing cerebral hemorrhage and uses thereof Download PDFInfo
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- CN110799522B CN110799522B CN201780092737.2A CN201780092737A CN110799522B CN 110799522 B CN110799522 B CN 110799522B CN 201780092737 A CN201780092737 A CN 201780092737A CN 110799522 B CN110799522 B CN 110799522B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present application provides a pharmaceutical composition for the treatment of cerebral hemorrhage, comprising a peptide comprising amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, or a pharmaceutically acceptable salt of said peptide. The application also provides medical application of the pharmaceutical composition.
Description
Technical Field
The present application relates generally to the field of medicine. In particular, the application provides peptides and uses thereof for treating, ameliorating or preventing cerebral hemorrhage.
Background
Cerebral hemorrhage generally refers to hemorrhage caused by rupture of blood vessels in the brain parenchyma. The non-traumatic cerebral hemorrhage accounts for 20% -30% of the total cerebral apoplexy, and the death rate in the acute phase is 30% -40%.
Studies have reported that activated thrombin receptor PAR1 induces Src activation after cerebral hemorrhage, which mediates Src kinase, enhances Src-PSD95-GluN2A signaling pathway, up-regulates GluN2A phosphorylation, and further regulates NMDA receptor activity. And it has been reported that PAR1 and Src-PSD95-GluN2A1 signal pathways are involved in apoptosis of neuronal cells in ICH.
The Src family is a class of non-receptor tyrosine kinases. Src is not only a cytoplasmic effector enzyme of the G-protein coupled receptor PAR1, but also a functional enzyme that regulates ion channels NMDAR, which may be an important bridge linking the G-protein coupled receptor (PAR 1) and NMDAR. The N-methyl-D-aspartate receptor (NMDAR) is a ligand-gated ion channel receptor, consisting of two subunits, gluN1 and GluN 2. NMDA receptors are key molecules in many pathological processes of brain injury or in neurological diseases.
After neuronal excitatory glutamate damage, postsynaptic compact Proteins (PSD), receptor proteins, cytoskeletal proteins, and various signaling molecules (including protein kinases, phosphatases) may bind directly or indirectly to NMDA receptors to form complexes, the process being reversible. PSD95 includes three N-terminal PDZ domains (PDZ 1, PDZ2, PDZ 3), one SH3 domain and one C-terminal GK domain. PSD95 can bind to NMDA receptor subunits GluN2 (GluN 2A and GluN 2B) via the PDZ2 domain, and its PDZ3 domain binds to the SH2 domain of Src PTK. The Src PTK and GluN2A subunit of the NMDA receptor form an SRC-PSD95-GluN2A signaling complex with PSD. This signal complex is stable, resulting in full Src contact with GluN2A and promoting GluN2A tyrosine phosphorylation. Activated NMDA receptors accelerate calcium ion flow, thereby exacerbating neuronal damage. This conclusion demonstrates that PAR contributes to the formation of Src-PSD95-GluN2A signaling complex and therefore thrombin-PAR-SRC-PSD 95-GluN2A is an important molecule in ICH model that causes neuronal apoptosis. These results indicate that blocking Src-PSD95-GluN2A complex formation, or finding a safe and effective molecule that inhibits PSD95-GluN2A interactions, can be developed as a drug for the treatment of cerebral hemorrhage.
In view of the high clinical incidence of cerebral hemorrhage and the possible serious impact on body health, the development of effective treatment protocols is of great importance.
Summary of The Invention
In a first aspect, the application provides a pharmaceutical composition for use in the treatment of cerebral hemorrhage, the pharmaceutical composition comprising a peptide comprising amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, or a pharmaceutically acceptable salt thereof.
In some embodiments, the peptide is a chimeric peptide comprising amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof and an internalization peptide that facilitates uptake of the chimeric peptide by a cell.
In some embodiments, the internalization peptide comprises the amino acid sequence YGRKRRQRRRR (SEQ ID NO: 2).
In some embodiments, the chimeric peptide comprises amino acid sequence YGRKKRRQRRRYEKLLDTEI (SEQ ID NO: 3).
In some embodiments, the functional variant is a variant produced by one or more conservative substitutions of the LDTEI portion of SEQ ID NO. 1.
In some embodiments, the conservative substitution is selected from the group consisting of a substitution between D and E, a substitution between L, V and I, and a substitution between T and S.
In some embodiments, the functional variant is a variant produced after substitution of the LDTEI moiety in SEQ ID NO. 1 with any of the following sequences: LDTEL, LDTEV, LDTDI, LDTDL, LDTDV, LDSEI, LDSEL, LDSEV, LDSDI, LDSDL, LDSDV, LETEI, LETEL, LETEV, LETDI, LETDL, LETDV, VDTEI, VDTEL, VDTEV, VDTDI, VDTDL, VDTDV, IDTEI, IDTEL, IDTEV, IDTDI, IDTDL, IDTDV, IETEI, IETEL, IETEV, IETDI, IETDL, IETDV.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetate, acetate, hydrochloride, and phosphate.
In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and/or excipient.
In some embodiments, the pharmaceutical composition is a pre-lyophilized formulation, preferably comprising histidine and trehalose.
In some embodiments, the pharmaceutical composition is a lyophilized formulation, preferably prepared by lyophilizing the pre-lyophilized formulation described above.
In some embodiments, the pharmaceutical composition is a reconstituted formulation, preferably prepared by combining the lyophilized formulation described above with an aqueous solution.
In a second aspect, the present application provides a method of treating, ameliorating or preventing cerebral hemorrhage in a subject, the method comprising administering to a subject in need thereof the pharmaceutical composition of the first aspect.
In a third aspect, the application provides the use of a peptide comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, amelioration or prevention of cerebral hemorrhage in a subject.
In some embodiments, the functional variant is a variant produced by one or more conservative substitutions of the LDTEI portion of SEQ ID NO. 1.
In some embodiments, the conservative substitution is selected from the group consisting of a substitution between D and E, a substitution between L, V and I, and a substitution between T and S.
In some embodiments, the functional variant is a variant produced after substitution of the LDTEI moiety in SEQ ID NO. 1 with any of the following sequences: LDTEL, LDTEV, LDTDI, LDTDL, LDTDV, LDSEI, LDSEL, LDSEV, LDSDI, LDSDL, LDSDV, LETEI, LETEL, LETEV, LETDI, LETDL, LETDV, VDTEI, VDTEL, VDTEV, VDTDI, VDTDL, VDTDV, IDTEI, IDTEL, IDTEV, IDTDI, IDTDL, IDTDV, IETEI, IETEL, IETEV, IETDI, IETDL, IETDV.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of trifluoroacetate, acetate, hydrochloride, and phosphate.
In some embodiments of any of the above aspects, the cerebral hemorrhage is selected from the group consisting of traumatic cerebral hemorrhage and non-traumatic cerebral hemorrhage.
In some embodiments of any of the above aspects, the cerebral hemorrhage is selected from the group consisting of basal brain section hemorrhage, shell cerebral hemorrhage, thalamus hemorrhage, caudate nucleus hemorrhage, ventricular hemorrhage, cerebral leaflet hemorrhage, cerebral hemorrhage, cerebellar hemorrhage, brain stem hemorrhage, and subarachnoid hemorrhage.
In some embodiments of any of the above aspects, cerebral hemorrhage is caused by any one or a combination of the following factors: microaneurysms or microaneurysms, cerebral arteriovenous malformations, amyloid cerebrovascular disease, cystic hemangiomas, intracranial venous thrombosis, epidural fistulas, specific arteritis, fungal arteritis, aerosol diseases, arterial anatomical variations, carotid arteriovenous fistulas, hypertension, migraine, anticoagulation, antiplatelet or thrombolytic therapy, haemophilus infection, leukemia, thrombopenia, intracranial tumors, alcohol, amphetamines, cocaine, sympathomimetics.
Brief description of the drawings
FIG. 1 shows that the Pull-Down experiment detects the interaction of P5 with PDZ1/2 domain. M represents a protein molecular weight marker; lane 1 is His+PDZ1/2+P5; lane 2 is P5 alone; lane 3 is his+p5; lane 4 is His+PDZ1/2. The elution band shown in lane 1 contains both P5 and PDZ1/2, confirming that P5 is able to bind the PDZ1/2 domain.
Figure 2 shows the scores of the individual groups of rat balance tests.
Fig. 3 shows the scores of the Berderson test for each group of rats.
Fig. 4 shows a brain hematoma volume comparison for each group of rats.
Fig. 5 shows the results of hematoxylin-eosin staining of brain tissue sections of rats of each group, wherein a. Normal group; B. a sham surgery group; C. a model group; na-1 dosing group; gm treated group; F. p5 administration group (5 mg/kg) 1 hour after autologous blood injection; G. p5 administration group (20 mg/kg) 1 hour after autologous blood injection; H. p5 administration group (10 mg/kg) 1 hour after autologous blood injection; I. p5 administration group (10 mg/kg) 2 hours after autologous blood injection; J. p5 administration group (10 mg/kg) 3 hours after autologous blood injection.
FIG. 6 shows a graph of immunohistochemical analysis of brain tissue sections of rats in each group, wherein the antigen used in the immunohistochemical analysis is Bax-2, wherein A. The normal group; B. a sham surgery group; C. a model group; na-1 dosing group; gm treated group; F. p5 administration group (5 mg/kg) 1 hour after autologous blood injection; G. p5 administration group (20 mg/kg) 1 hour after autologous blood injection; H. p5 administration group (10 mg/kg) 1 hour after autologous blood injection; I. p5 administration group (10 mg/kg) 2 hours after autologous blood injection; J. p5 administration group (10 mg/kg) 3 hours after autologous blood injection.
FIG. 7 shows a graph of immunohistochemical analysis of brain tissue sections of rats in each group, wherein antigen used in the immunohistochemical analysis is Caspase-3, wherein A. Normal group; B. a sham surgery group; C. a model group; na-1 dosing group; gm treated group; F. p5 administration group (5 mg/kg) 1 hour after autologous blood injection; G. p5 administration group (20 mg/kg) 1 hour after autologous blood injection; H. p5 administration group (10 mg/kg) 1 hour after autologous blood injection; I. p5 administration group (10 mg/kg) 2 hours after autologous blood injection; J. p5 administration group (10 mg/kg) 3 hours after autologous blood injection.
FIG. 8 is a graph showing the levels of CK in serum of each group of rats.
Detailed Description
The inventors of the present application have conducted intensive studies on peptides that reduce the damaging effects of neurological disorders mediated at least in part by NMDAR excitotoxicity. Without wishing to be bound by any theory, it is believed that such peptides act at least in part by inhibiting the interaction between NMDAR and postsynaptic density 95 protein (PSD-95) (i.e., a PSD-95 inhibitor). Based on the above, the inventor of the application carries out deep thinking on a plurality of targets for treating cerebral hemorrhage, designs and screens polypeptide neuron protective agents through in-vitro and in-vitro pharmacological and pharmacodynamic experiments, and screens to obtain peptides with ideal properties.
Definition of the definition
Unless otherwise indicated, terms used in the present application have meanings commonly understood by those skilled in the art.
The single-letter or three-letter abbreviations used for amino acids in the present application follow international convention.
The term "PDZ domain" refers to a modular protein domain of about 90 amino acids characterized by significant (e.g., at least 60%) sequence identity to brain synaptotagmin PSD-95, drosophila (Drosophila) spacer connexin ics-Large (DLG) and epithelial tight junction protein Z01 (Z01). PDZ domains are also known as dis-Large homology repeats ("DHRs") and GLGF repeats. The PDZ domain generally shows retention of the core consensus sequence (Doyle, d.a.,1996,Cell 85:1067-76). Exemplary PDZ domain-containing proteins and PDZ domain sequences are disclosed in U.S. application No. 10/714,537.
The term "specific binding" refers to the binding between two molecules (e.g., a ligand and a receptor) characterized by the ability of one molecule (ligand) to bind to another specific molecule (receptor), i.e., the ability to exhibit preferential binding of one molecule to another in a heterogeneous mixture of molecules, even in the presence of many other different molecules. Specific binding of the ligand to the receptor is also demonstrated as follows: in the presence of excess unlabeled ligand, the binding of the detectably labeled ligand to the receptor is reduced (i.e., a binding competition experiment).
Statistically significant means that the p-value is <0.05, preferably p <0.01, most preferably <0.001.
The term "functional variant" refers to a variant that has the same or similar biological function and properties as the parent. As a non-limiting example, a "functional variant" may be obtained by making one or more conservative substitutions in the parent.
The term "lyophilization" relates to a process by which the material to be dried is frozen and then biochemically freed from ice or frozen solvent under vacuum.
In this specification and claims, the words "comprise", "comprising" and "includes" mean "including but not limited to", and are not intended to exclude other moieties, additives, components or steps.
In a first aspect, the application provides a pharmaceutical composition for use in the treatment of cerebral hemorrhage, the pharmaceutical composition comprising a peptide comprising amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, or a pharmaceutically acceptable salt thereof.
There are studies showing that the occurrence of cerebral hemorrhage is associated with various factors. For non-traumatic cerebral hemorrhage, which is mainly associated with lesions of cerebral blood vessels, may cause hypertension, hyperlipidemia, diabetes, vascular aging, smoking, amyloid cerebrovascular disease, cerebral vascular malformation, tumor stroke, leukemia, etc.
The present application demonstrates (e.g., see examples below) by direct cerebral hemorrhage models that the peptides of the present application have effective therapeutic and palliative effects on cerebral hemorrhage and its complications (e.g., behavioral changes or formation of cerebral hematomas).
In some embodiments, the cerebral hemorrhage may be traumatic cerebral hemorrhage or non-traumatic cerebral hemorrhage.
In some embodiments, the cerebral hemorrhage may be basal brain region hemorrhage, shell cerebral hemorrhage, thalamus hemorrhage, caudate nucleus hemorrhage, ventricular hemorrhage, brain lobe hemorrhage, cerebral hemorrhage, cerebellar hemorrhage, brainstem hemorrhage, subarachnoid hemorrhage, or multiple site hemorrhage above.
In some embodiments, cerebral hemorrhage may be cerebral hemorrhage caused by an arteriole or microangioma, cerebral arteriovenous malformation, amyloid cerebrovascular disease, cystic hemangioma, intracranial venous thrombosis, epidural fistula, specific and fungal arteritis, smog disease, arterial anatomical variation, jugular arteriovenous fistula.
In some embodiments, the cerebral hemorrhage may be cerebral hemorrhage caused by migraine.
In some embodiments, cerebral hemorrhage may be cerebral hemorrhage caused by anticoagulation, antiplatelet or thrombolytic therapy, haemophilus infection, leukemia, thrombopenia, and the like.
In some embodiments, the cerebral hemorrhage may be cerebral hemorrhage caused by an intracranial tumor.
In some embodiments, the cerebral hemorrhage may be cerebral hemorrhage caused by alcohol, amphetamine, cocaine, sympathomimetics, and the like.
In some embodiments, the cerebral hemorrhage may be hypertensive cerebral hemorrhage.
In some embodiments, the peptide is a chimeric peptide comprising amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof and an internalization peptide that facilitates uptake of the chimeric peptide by a cell.
"internalization peptides", which may also be referred to as transmembrane peptides, are widely used in the field of protein pharmaceuticals to facilitate uptake and absorption of an active peptide bound thereto by a cell. It will be appreciated by those skilled in the art that the purpose of the chimeric of an active peptide and an internalization peptide is primarily to better target the active peptide to the site of action, and thus, internalization peptides suitable for use in the present application are not limited to a particular species, as long as the purpose of membrane penetration, internalization is achieved. It will also be appreciated by those skilled in the art that internalization peptides that are specifically adapted to neuronal cells are preferred, as the target of action of the active peptide is primarily located within the neuronal cell. In some embodiments, the internalization peptide may be a Tat peptide. In some embodiments, the amino acid sequence of the Tat peptide is YGRKRRQRRRR (SEQ ID NO: 2). In some embodiments, the chimeric peptide comprises amino acid sequence YGRKKRRQRRRYEKLLDTEI (SEQ ID NO: 3).
It will be appreciated that the internalization peptide may be linked to the active peptide by an amide linkage as a fusion peptide, but may also be joined by other suitable means, such as chemical bonding. Coupling of the two components may be achieved by a coupling agent or a conjugation agent. A large number of such agents are commercially available and can be found in S.S. Wong, chemistry of Protein Conjugation and Cross-Linking, CRC Press (1991). Some examples of crosslinking agents include J-succinimide-3- (2-pyridyldithio) propionate (SPOP) or N, N' - (1, 3-phenylene) bismaleimide; n, N' -ethylene-bis- (iodoacetamide) or other such agents having a 6 to 11 carbon methylene bridge (other sulfhydryl groups are relatively specific); and 1, 5-difluoro-2, 4-dinitrobenzene (which forms an irreversible linkage with amino and tyrosine groups). Other crosslinking agents include P, P '-difluoro-m, m' -dinitrodiphenyl sulfone (which forms irreversible crosslinks with amino groups and phenolic groups); dimethyl diethylamine-substituted hexanoate (which is specific for amino groups); phenol-1, 4-disulfonyl chloride (which reacts predominantly with amino groups); 1, 6-hexamethylene diisocyanate or diisothiocyanate, or phenylazo-p-diisocyanate (which reacts predominantly with amino groups); glutaraldehyde (which reacts with several different side chains) and diazobenzidine (which reacts mainly with tyrosine and histidine).
In addition, the peptides described above can optionally be derivatized (e.g., acetylated, phosphorylated, and/or glycosylated) to facilitate affinity with the inhibitor, facilitate the ability of the inhibitor to be transported across a cell membrane, or facilitate stability.
The active peptides of the application and fusion peptides fused to internalization peptides can be synthesized by solid phase synthesis or recombinant methods. The peptidomimetics can be synthesized using a variety of protocols and methods described in the scientific and patent literature, such as Organic Syntheses Collective Volumes, gilman et al (ed.) John Wiley & Sons, inc., NY, al-Obeidi (1998) mol. Biotechnol.9:205-223; hruby (1997) Curr.Opin. Chem. Biol.1:114-119; ostergaard (1997) mol. Differences.3:17-27; ostresh (1996) Methods enzymes 267:220-234.
In some embodiments, the functional variant is a variant produced by one or more conservative substitutions of the LDTEI portion of SEQ ID NO. 1.
According to prior studies, some active peptides that inhibit the interaction between NMDAR and PSD-95 are based on NMDAR structures. For example, NMDAR2B has GenBank ID4099612, which is FNGSSNGHVYEKLSSLESDV at the C-terminal 20 amino acids, and contains the PL motif ESDV. Some of the active peptides already exist that select for a partial amino acid sequence at the C-terminus of NMDAR2B, resulting in competitive inhibition of PSD-95 with NMDAR 2B. There are studies that suggest that ESDV or LESDV segments in the above peptides play an important role in inhibiting the interaction between NMDAR and PSD-95 protein. Without being bound by any theory, the inventors of the present application surprisingly found that in the active peptide YEKLLDTEI (SEQ ID NO: 1) disclosed herein, which does not contain SS two residues after KL relative to the C-terminal amino acid composition of NMDAR2B described above, while increasing the YEKL amino acid sequence in the N-terminal direction relative to the PL motif, the present application demonstrates that such changes can enhance the interaction of the active peptide with the PDZ1/2 domain. Meanwhile, LDTEI at the C-terminal end of the yeKL motif can be changed, and the activity of the active peptide is not expected to be influenced or possibly increased. Thus, in some embodiments, the functional variants provided herein are variants of the LDTEI portion of SEQ ID NO. 1 resulting from one or more conservative substitutions.
In some embodiments, the conservative substitution is selected from the group consisting of a substitution between D and E, a substitution between L, V and I, and a substitution between T and S.
In more specific embodiments, the functional variant is a variant produced by substitution of the LDTEI moiety in SEQ ID NO. 1 with any of the following sequences: LDTEL, LDTEV, LDTDI, LDTDL, LDTDV, LDSEI, LDSEL, LDSEV, LDSDI, LDSDL, LDSDV, LETEI, LETEL, LETEV, LETDI, LETDL, LETDV, VDTEI, VDTEL, VDTEV, VDTDI, VDTDL, VDTDV, IDTEI, IDTEL, IDTEV, IDTDI, IDTDL, IDTDV, IETEI, IETEL, IETEV, IETDI, IETDL, IETDV.
In some embodiments, the functional variants disclosed herein further include amino acid sequences having at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or even higher identity to the above-mentioned peptides. It is known in the art that "identity" between two proteins is determined by aligning the amino acid sequence of one protein with the sequence of a second protein whose conservative amino acid substitution is made. The degree of identity between the two proteins is determined using computer algorithms and methods well known to those skilled in the art. Identity between two amino acid sequences is preferably determined by using the BLASTP algorithm.
In some embodiments, the functional variants disclosed herein include substitutions, deletions, additions and/or insertions of amino acid residues having 1, 2, 3, 4,5 or more positions compared to the peptides mentioned above, differing from the specific peptides disclosed above.
As noted above, functional variants may differ from the specific peptides disclosed above by one or more substitutions, deletions, additions and/or insertions. These variants may be naturally occurring or synthetically produced, e.g., by modification of one or more of the above-described peptide sequences disclosed herein and assessing their biological activity as described herein using any of a variety of techniques well known in the art.
Pharmaceutically acceptable salts are salts that substantially retain the biological activity of the free base and are prepared by reaction with mineral acids. Drug salts tend to be more soluble in water and other protic solvents than the corresponding free base form.
In some embodiments, the pharmaceutically acceptable salt may be in any suitable pharmaceutically acceptable salt form. In some embodiments, the pharmaceutically acceptable salt is trifluoroacetate salt. In some embodiments, the pharmaceutically acceptable salt is acetate. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt is a phosphate salt.
In some embodiments, the pharmaceutical compositions disclosed herein may be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active peptide or chimeric peptide into preparations which can be used pharmaceutically. Proper formulation depends on the route of administration selected.
In some embodiments, administration may be parenteral, intravenous, oral, subcutaneous, intraarterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Intravenous administration is preferred.
In some embodiments, the pharmaceutical composition for parenteral administration is preferably sterile and substantially isotonic. For injection, the active peptide or chimeric peptide or pharmaceutically acceptable salt thereof may be formulated into an aqueous solution, preferably into a physiologically compatible buffer such as Hank's solution, ringer's solution, or physiological saline or acetate buffer (to alleviate discomfort at the injection site). The solution may contain a formulation such as a suspending, stabilizing and/or dispersing agent.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. The route of administration may be used to deliver the compound to the nasal cavity or for sublingual administration.
In some embodiments, for oral administration, the active peptide or chimeric peptide or pharmaceutically acceptable salt thereof may be formulated with a pharmaceutically acceptable carrier as a tablet, pill, lozenge, capsule, liquid, gel, syrup, slurry, suspension, or the like, for oral ingestion by a patient being treated. For oral solid formulations such as powders, capsules and tablets, suitable excipients include fillers such as sugars, e.g., lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or povidone (PVP); granulating agents and binders. If desired, disintegrating agents can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. The solid dosage forms may be sugar coated or enteric coated if desired using standard techniques. For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycerol, oils, alcohols. In addition, flavoring agents, preservatives, coloring agents, and the like may be added.
In addition to the previously described formulations, the pharmaceutical compositions may also be formulated as a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the pharmaceutical composition may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
Alternatively, other drug delivery systems may be used. Liposomes and emulsions can be used to deliver chimeric peptides. Certain organic solvents such as dimethyl sulfoxide may also be used. In addition, sustained release systems (e.g., semipermeable matrices of solid polymers containing the therapeutic agent) can be used to deliver the pharmaceutical composition.
Depending on its chemical nature, sustained release capsules can release peptides for several weeks up to over 100 days. Other strategies for protein stabilization may be used depending on the chemical nature and biological stability of the therapeutic agent.
The compounds of the present application or pharmaceutically acceptable salts thereof may be prepared in the form of lyophilized formulations. In some embodiments, the application provides lyophilized formulations. The freeze-dried preparation is prepared from a pre-freeze-dried preparation by freeze-drying and at least comprises an active ingredient, a buffer solution, a filling agent and water, wherein the active ingredient is the compound or pharmaceutically acceptable salt thereof. In some embodiments, the preferred buffer is histidine. Other buffers are selected from succinate, citrate, gluconate, acetate, phosphate, tris, and the like. Bulking agents provide structure to the lyophilized compounds. In some embodiments, the bulking agent is selected from mannitol, trehalose, dextran-40, glycine, lactose, sorbitol, sucrose, and the like, with trehalose being preferred. In some embodiments, the lyophilized formulation of the present application comprises a compound as described above or a pharmaceutically acceptable salt thereof, and histidine and trehalose.
The lyophilized formulation may be reconstituted by rehydrating the lyophilized formulation with a solution to a solution of particles that are invisible to the naked eye. In some embodiments, the present application provides reconstituted formulations prepared by combining a lyophilized formulation with an aqueous solution. In some embodiments, the aqueous solution is water for injection. In some embodiments, the aqueous solution is a physiological saline solution.
The pharmaceutical compositions provided herein are used in an amount effective to achieve the intended purpose (e.g., to reduce or alleviate cerebral hemorrhage). A therapeutically effective amount means: an amount of the pharmaceutical composition sufficient to significantly reduce the damage caused by cerebral hemorrhage in a patient (or animal model population) treated with the pharmaceutical composition disclosed herein relative to cerebral hemorrhage in a control population of patients (or animal models) not treated with the pharmaceutical composition disclosed herein. An amount is also considered therapeutically effective if the individual treated patient achieves a better output than the average output (as measured by cerebral hematoma volume or disability index) in a comparable patient control population not treated by the methods disclosed herein. An amount is also considered to be a therapeutically effective amount if the individual treated patient shows 2 or less disabilities on the Rankin scale and 75 or more on the Barthel scale. Dosages are also considered therapeutically effective if the treated patient population shows a significantly improved (i.e., less disabled) score distribution on the disability scale compared to a comparable untreated population, see les et al, N Engl J Med 2006;354:588-600. A therapeutically effective regimen represents a combination of a therapeutically effective dose and the frequency of administration required to achieve the intended purpose described above. Often a single application is sufficient.
In some embodiments, preferred dosage ranges for the pharmaceutical compositions provided herein include administration of 0.001 to 20 μmol per kg of patient body weight, optionally 0.03 to 3 μmol per kg of patient body weight, including any value therebetween or ranges between any two values. In some methods, 0.1 to 20. Mu. Mol of the pharmaceutical composition of the application is administered per kg of patient body weight over 6 hours. In some methods, 0.1 to 10. Mu. Mol of the pharmaceutical composition of the application is administered per kg of patient body weight within 6 hours, more preferably about 0.3. Mu. Mol of the pharmaceutical composition of the application is administered per kg of patient body weight within 6 hours. In other cases, the dosage range is 0.005 to 0.5. Mu. Mol of the pharmaceutical composition of the application per kg of patient body weight. The different surface areas can be compensated by dividing by 6.2: mass ratio, whereas the dose per kg body weight was converted from rat to human. Suitable dosages of the pharmaceutical composition of the application for use in humans may be in grams of 0.01 to 100mg/kg of patient body weight, or more preferably 0.01 to 30mg/kg of patient body weight or 0.01 to 10mg/kg of patient body weight, or 0.01 to 1mg/kg of patient body weight, including any value therebetween or a range between any two values.
In some embodiments, the amount of the pharmaceutical composition administered depends on the subject being treated, the weight of the subject, the severity of the affliction, the mode of administration, and the regulation of the prescribing physician. The treatment may be repeated when symptoms are detectable or even undetectable. The treatment may be provided alone or in combination with other drugs.
In some embodiments, a therapeutically effective dose of the pharmaceutical compositions disclosed herein is capable of providing therapeutic benefit without causing significant toxicity. Toxicity of chimeric peptides can be determined in cell culture or experimental animals by standard pharmaceutical procedures, for example by determining LD50 (the dose lethal to 50% of the population) or LD100 (the dose lethal to 100% of the population). The dose ratio of toxic effects to therapeutic effects is the therapeutic index. Pharmaceutical compositions exhibiting a high therapeutic index are preferred (see e.g. Fingl et al 1975,In:The Pharmacological Basis of Therapeutics chapter 1, page 1).
In a second aspect, the present application provides a method of treating, ameliorating or preventing cerebral hemorrhage in a subject, the method comprising administering to the subject a pharmaceutical composition according to the first aspect.
In a third aspect, the application provides the use of a peptide comprising the amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, amelioration or prevention of cerebral hemorrhage in a subject.
"individuals" as used herein include birds, reptiles and mammals. In some embodiments, the animals are mammals, including primates and non-primates, e.g., humans, chimpanzees, cattle, horses, pigs, sheep, goats, dogs, cats, and rodents such as rats and mice.
It should be understood that the foregoing detailed description is only for the purpose of making apparent to those skilled in the art the contents of the application, and is not intended to be limiting in any way. Various modifications and changes to the described embodiments will occur to those skilled in the art.
Examples
The following examples are provided merely to illustrate some embodiments of the present application and are not intended to be limiting in any way.
Example 1: screening of active peptide molecules
According to the reported results, the Tat transmembrane peptide YGRKRRQRRRR (SEQ ID NO: 2) was selected and linked to a different number of amino acids to form a peptide pool. The chimeric peptide molecules in the peptide library interact with PDZ1/2 structural domains expressed and purified in vitro respectively, and the polypeptides are primarily screened according to the strength of interaction force.
The immobilized molecules (ligands) are PDZ1/2 proteins, molecular weight: about 20kD, concentration: 2mg/ml; mobile phase molecules (analytes): polypeptide to be screened, molecular weight: about 2kD, concentration: 10mg/ml. CM5 chips were immobilized using a Biacore 3000 instrument. The running buffer was PBS +0.005% tween 20. Immobilization was performed using an amino coupling method. The concentration of ligand was 10. Mu.g/ml. The fixation buffer was 10mM sodium acetate, pH 4.0. Fixed amount: 1400RU, fixed to flow cell 2. The flow rate used was 10. Mu.l/ml and the ligand was injected for 1 min. Regeneration was performed at a flow rate of 30. Mu.l/min using 10mM Gly at pH2.0+2.5 as regeneration solution. The sample injection time was 30s.
Kinetic analysis was performed using the following conditions: control channel: flow cell 1; the electrophoresis buffer solution is PBS; using Kinetic Analysis Wizard mode, concentration gradients of 6.25n, 12.5n, 25n, 50n, 100n, 200n, 400nM; sampling time is 1 minute; the dissociation time is 2min; the flow rate was 30. Mu.l/min.
Data were fitted using fitting software BIAevaluation 4.1 software. Fitting model 1:1 binding model. The dissociation constant KD is inversely proportional to the force.
Through screening, a chimeric peptide with strong interaction ability with PDZ1/2 structural domain is obtained, which is named as P5 and has the following sequence:
P5:YGRKKRRQRRRYEKLLDTEI(SEQ ID NO:3)
for direct comparison with the analogous chimeric peptide in the reported study, a control chimeric peptide NA-1 was introduced, with the following sequence:
NA-1:YGRKKRRQRRRKLSSIESDV(SEQ ID NO:4)
in addition, by comparing the structural differences between P5 and NA-1, a chimeric peptide YE-NA-1 was additionally introduced in which two residues of YE were added to the N-terminus of the active peptide of the chimeric peptide NA-1, and the sequence was as follows:
YE-NA-1:YGRKKRRQRRRYEKLSSIESDV(SEQ ID NO:5)
chimeric peptides NA-1, YE-NA-1 and P5 were simultaneously tested for interaction with the PDZ1/2 domain as described above, and the results are shown in Table 1 below:
TABLE 1 detection of interaction force of three chimeric peptides with PDZ1/2 Domain
Chimeric peptides | NA-1 | YE-NA-1 | P5 |
KD(M) | 7.53E-08 | 5.44E-08 | 2.99E-08 |
As shown in Table 1, chimeric peptides YE-NA-1 and P5 interact more strongly with the PDZ1/2 domain and the P5 has better performance properties than the control chimeric peptide NA-1. Thus, according to the inventors' hypothesis, the additional two amino acid residues YE at the N-terminus of the active peptide have some enhancement of the interaction of the polypeptide with the PDZ1/2 domain. Furthermore, P5 reduces the two less hydrophobic serine (SS) s relative to the carboxy-terminus of YE-NA-1, which, according to the inventors' hypothesis, may therefore further increase the interaction of the polypeptide with the PDZ1/2 domain.
Chimeric peptide P5 was further tested in the following experiments, and NA-1 and YE-NA-1 were used as controls in some of the experiments.
Example 2: P.mu.ll-Down experiments to detect P5 interaction with PDZ1/2 Domain
To demonstrate that P5 can interact with the PDZ1/2 domain, a Pμ ll-Down experiment was performed.
The column was equilibrated with 100. Mu.l His beads and 1ml MCAC-0 buffer for 5min. Shaking at 4 ℃. The mixture was centrifuged at 5000g for 1 min at 4℃and the supernatant was discarded. To the mixture was added 1mg of PDZ1/2 protein and the mixture was made up to 1ml with buffer. The mixture was spin-bonded for 1 hour at 4 ℃. The mixture was centrifuged at 5000g for 1 min at 4℃and the supernatant was discarded. Wash 3 times with 1ml of MCAC-0 buffer for 5 minutes each (shake wash at 4 ℃). To the mixture was added 1mg of P5 protein and the mixture was made up to 1ml with buffer. The mixture was spin-bonded for 2 hours at 4 ℃. The mixture was centrifuged at 5000g for 1 min at 4℃and the supernatant was discarded. Washing was performed 3 times with 1ml of lysate for 5 minutes each (shaking washing at 4 ℃). After washing 20. Mu.l of MCAC-300 was added. Centrifuging, and taking eluent for SDS-PAGE detection. The experimental results are shown in fig. 1.
As demonstrated in fig. 1, both the P5 and PDZ1/2 domains are contained in the elution band of chimeric peptide P5, thereby confirming that chimeric peptide P5 is able to bind PDZ1/2 domains.
EXAMPLE 3 therapeutic Effect of P5 Polypeptides on rat cerebral hemorrhage model
Experimental animals and materials:
animals: adult SD rats, SPF grade, weighing 400+ -30 g were used.
Instruments and medicines: the P5 polypeptide and NA-1 polypeptide are synthesized by Kirschner; gangliosides (GM) were purchased from kululu pharmaceutical limited, national drug standard H20046213, brain locator, paraffin microtome, turbo dental drill, dental cement, supplied by beijing zhongdi-wound science and technology development limited liability company.
Establishing a cerebral hemorrhage model:
the cerebral hemorrhage model adopted in the experiment is based on brain infusion of autologous blood, and the specific steps are as follows.
The scalp wound at the top of the rat cranium is cut for 5-10 mm, the periosteum of the cranium is gently cut, the center of the circle falls at the position of 2mm behind the right 3mm of the anterior cranium, and the diameter is about 1 mm. The center of the circle was perforated, a 10. Mu.l syringe was advanced 6mm and 1. Mu.l of 0.6CDU collagenase IV was injected within 5 minutes, and the needle was slowly withdrawn 15 minutes apart. The whole process was about 3 minutes.
The tail of the rat is soaked in warm water at 50 ℃, and after the blood vessel of the tail of the rat is full and the tail tip is broken by about 5mm, the tail is gently rubbed, more than 120 mu l of blood is extruded, and 110 mu l of blood is collected by a 100 mu l syringe. The collagenase was then injected at the same site, 6mm into the needle, and 110 μl of the tail tip was injected within 12 minutes to originate from the whole blood. After 20 minutes of coagulation, the cranial hole was closed by uniform needle withdrawal within 3 minutes. The total injection time of collagenase and autologous blood is about 35-40 minutes, and the subsequent administration time is counted from the time when the total injection of autologous blood is completed.
Experimental grouping:
the experiments were divided into a normal control group, a sham operation group (1. Mu.l of physiological saline was injected instead of collagenase and autologous blood was not injected), a model group (untreated group, labeled ICH group in the drawing), a positive drug treatment group, a P5 polypeptide administration group, and a NA-1 administration group. The P5 polypeptide administration group includes the following subgroups: three doses of P5 administration groups of 20mg/kg, 10mg/kg and 5mg/kg were injected into the tail vein 1 hour after the total injection of autologous blood; the group to which P5 was administered at a dose of 10mg/kg was administered 2 hours and 3 hours after the total injection of autologous blood. The positive drug treatment group was a treatment group in which 0.4ml/kg GM (ganglioside) was intramuscular injected 1 hour after all autologous blood injection. The NA-1 administration group was a group administered by tail vein injection of 10mg/kg NA-1 hour after all autologous blood injection. Each group of 6-8 rats.
1. Behavioral observations
The behavior of each model was evaluated 24 hours after the model was built (time 0 point when all autologous blood was injected).
Balance beam scoring method: balance beam length 80cm, width 2.5cm, distance from ground 10cm, and grading 6 grades. 0 point: jumping on balance beam, and walking without falling; 1, the method comprises the following steps: jumping on balance beam, wherein the falling probability is less than 50%;2, the method comprises the following steps: jumping on balance beam, wherein the falling probability is more than 50%;3, the method comprises the following steps: jumping on balance beams, and the affected side cannot help to move; 4, the following steps: cannot walk, but can sit on the chair; 5, the method comprises the following steps: falls down from the balance beam.
The results of the behavioral observations of the balance beam test are shown in fig. 2. The results showed that there were significant statistical differences for GM treated groups, 1 hour-5 mg/kg P5 dosed groups, 1 hour-10 mg/kg P5 dosed groups, 1 hour-20 mg/kg P5 dosed groups, and 2 hours-10 mg/kg P5 dosed groups relative to the model groups; there were statistically significant differences between the P5-10mg/kg dosing groups 1 hour after all autologous blood injections relative to the model group.
Berderson scoring: the tail is slightly grabbed, the tail is lifted to be 10cm higher than the table top, and the front claw is straightened. 0 point: no nerve function damage; 1, the method comprises the following steps: the diseased contralateral wrist joint and elbow joint are flexed, and the shoulder is adducted and flexed; 2, the method comprises the following steps: the physical sign + paralysis side pushing group force is reduced; 3, the method comprises the following steps: during the activity, the rear-end collision is caused by looping.
The results of the behavioral assessment using the Berderson score are shown in figure 3. The results showed statistically significant differences between the 1 hour-10 mg/kg P5 dosing group and the model group.
2. Determination of cerebral hematoma volume
Immediately after the behavioral evaluation, the rat was sacrificed at the break. Brain tissue was taken, frozen and sectioned into sections of 2mm thickness. The middle 6 pieces were taken and the total volume was calculated again by calculating the area of each piece using software ImageJ. For brain slices with similar bleeding areas on the front and back sides, the volume of hematoma is recorded by multiplying the back area by the thickness of 2 mm; for brain slices with larger difference in blood areas of the front and back sides, the larger blood area multiplied by 1mm was recorded as hematoma volume. Finally, the volumes of the hematomas of the brain slices are accumulated to obtain the total volume.
The measurement results of the cerebral hematoma volume are shown in FIG. 4. The results showed significant statistical differences (P < 0.01) between the 1 hour-5 mg/kg P5 dosing group, 1 hour-10 mg/kg P5 dosing group, 1 hour-20 mg/kg P5 dosing group versus the model group; there was a statistical difference (P < 0.05) between the 2 hr-10 mg/kg P5 dosing group relative to the model group.
3. Pathological morphology observation of brain tissue
The brain is extracted by formaldehyde perfusion, and the brain tissue is dehydrated, transparent, waxed, embedded and sliced by conventional gradient. The brain tissue sections were subsequently stained with hematoxylin-eosin and observed under a light microscope.
The results of the observation of the brain histopathological morphology are shown in FIG. 5. In addition, immunohistochemical studies were performed on the resulting brain histopathological sections. The immunohistochemical antigens were selected for Bax-2 (FIG. 6) and Caspase-3 (FIG. 7), respectively.
The result shows that the nuclei of the nerve cells of the normal brain tissue are clear and circular, and the nuclear membrane is complete; whereas the brain tissue of the rat in the cerebral hemorrhage model group has serious nerve cell necrosis, cell swelling, cell nucleus concentration, loose and pale dyeing of cytoplasm and cavitation; microscopic images of the 1-10 mg/kg P5 administration group, the 1-20 mg/kg P5 administration group and the 2-10 mg/kg P5 administration group showed better results than the GM treatment group and the NA-1 administration group, and the 1-5 mg/kg P5 administration group showed better results than the model group. These results fully demonstrate that P5 peptide administration is effective in treating or ameliorating cerebral hemorrhage symptoms.
4. Determination of serum biochemical detection index
Creatine Kinase (CK) is present in mitochondria of brain cells, and it is rarely entered into blood under normal conditions. When brain cells are damaged, the disintegrated brain cells release CK into the blood. The severity of damage to brain tissue can thus be assessed by measuring CK content in serum.
The measurement results of the CK levels in the serum of each group are shown in fig. 8. The results showed that serum CK levels were reduced in the 1-20 mg/kg P5-dosed group relative to the model group.
The above results show that the P5 peptide disclosed by the application can remarkably treat cerebral hemorrhage, and in the evaluation of certain indexes, the treatment effect is superior to that of the ganglioside which is a positive medicament for treating cerebral hemorrhage and is sold on the market.
All publications and patent documents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Various changes may be made to the embodiments of the present disclosure and equivalents may be substituted without departing from the spirit and scope of the disclosure. Any feature, step, or embodiment of the disclosure may be used in combination with any other feature, step, or embodiment unless the context indicates otherwise.
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Claims (14)
1. Use of a peptide consisting of amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof, wherein the functional variant is a variant produced by substitution of the ldei moiety in SEQ ID NO:1 with any one of the following sequences, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, ameliorating or preventing cerebral hemorrhage in a subject: LDTDI, LDSEI or LDSDI.
2. Use of a peptide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, ameliorating or preventing cerebral hemorrhage in a subject, wherein the peptide is a chimeric peptide consisting of amino acid sequence YEKLLDTEI (SEQ ID NO: 1) or a functional variant thereof and an internalizing peptide that facilitates uptake of the chimeric peptide by a cell, wherein the functional variant is a variant resulting from replacement of the LDTEI moiety in SEQ ID NO:1 with any one of: LDTDI, LDSEI or LDSDI.
3. The use according to claim 2, wherein the internalization peptide consists of the amino acid sequence YGRKKRRRRRRR (SEQ ID NO: 2).
4. The use according to claim 2, wherein the chimeric peptide consists of the amino acid sequence YGRKKRRQRRRYEKLLDTEI (SEQ ID NO: 3).
5. The use according to claim 1 or 2, wherein the cerebral hemorrhage is selected from traumatic cerebral hemorrhage and non-traumatic cerebral hemorrhage.
6. The use of claim 1 or 2, wherein the cerebral hemorrhage is selected from the group consisting of basal brain section hemorrhage, shell cerebral hemorrhage, thalamus hemorrhage, caudate nucleus hemorrhage, ventricular hemorrhage, brain lobe hemorrhage, cerebral hemorrhage, cerebellar hemorrhage, brain stem hemorrhage, and subarachnoid hemorrhage.
7. The use of claim 1 or 2, wherein the cerebral hemorrhage is caused by any one or a combination of the following factors: microaneurysms or microaneurysms, cerebral arteriovenous malformations, amyloid cerebrovascular disease, cystic hemangiomas, intracranial venous thrombosis, epidural fistulas, specific arteritis, fungal arteritis, aerosol diseases, arterial anatomical variations, carotid arteriovenous fistulas, hypertension, migraine, anticoagulation, antiplatelet or thrombolytic therapy, haemophilus infection, leukemia, thrombopenia, intracranial tumors, alcohol, amphetamines, cocaine, sympathomimetics.
8. The use of claim 1 or 2, wherein the medicament comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
9. The use of claim 1 or 2, wherein the medicament is a pre-lyophilized formulation.
10. The use of claim 9, wherein the medicament comprises histidine and trehalose.
11. The use of claim 1 or 2, wherein the medicament is a lyophilized formulation.
12. The use according to claim 11, wherein the medicament is prepared by lyophilizing the pre-lyophilized formulation of claim 9 or 10.
13. The use of claim 1 or 2, wherein the medicament is a reconstituted formulation.
14. The use according to claim 13, wherein the medicament is prepared by combining the lyophilized formulation of claim 11 or 12 with an aqueous solution.
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US11541098B2 (en) | 2017-09-30 | 2023-01-03 | Biocells (Beijing) Biotech Co., Ltd. | Peptide composition for treating excitatory neurotoxicity related injuries |
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WO2012176172A2 (en) * | 2011-06-24 | 2012-12-27 | Nono, Inc. | Combination therapy for ischemia |
CN107312069A (en) * | 2016-04-27 | 2017-11-03 | 拜西欧斯(北京)生物技术有限公司 | The treatment peptide of excititoxic associated injury |
CN107913395A (en) * | 2016-10-10 | 2018-04-17 | 拜西欧斯(北京)生物技术有限公司 | Nerve excitability damages purposes of the related polypeptide in prevention, alleviation or treatment pain |
CN110049994A (en) * | 2016-12-08 | 2019-07-23 | 拜西欧斯(北京)生物技术有限公司 | A kind of conjugate and its application |
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US20050059597A1 (en) * | 1999-06-02 | 2005-03-17 | Michael Tymianski | Method of reducing injury to mammalian cells |
WO2012176172A2 (en) * | 2011-06-24 | 2012-12-27 | Nono, Inc. | Combination therapy for ischemia |
CN107312069A (en) * | 2016-04-27 | 2017-11-03 | 拜西欧斯(北京)生物技术有限公司 | The treatment peptide of excititoxic associated injury |
CN107913395A (en) * | 2016-10-10 | 2018-04-17 | 拜西欧斯(北京)生物技术有限公司 | Nerve excitability damages purposes of the related polypeptide in prevention, alleviation or treatment pain |
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