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The invention relates to compounds including a peptide therapeutic bound to a peptide vector and uses thereof. Peptides, such as peptide hormones, have found a variety of therapeutic uses. One of the challenges in treatment of patients using peptides is to ensure delivery of peptides to the desired tissue. In particular, delivery to brain tissues is often reduced or prevented by the blood-brain barrier BBB.
In the development of a new therapy for brain pathologies, the blood-brain barrier BBB is considered a major obstacle for the potential use of drugs for treating disorders of the central nervous system CNS.
This may explain the lack of therapeutic options available for major neurological diseases. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the BBB and the blood-cerebrospinal fluid barrier BCSFB. The BBB is considered to be the major route for the uptake of serum ligands since its surface area is approximately fold greater than that of BCSFB. The brain endothelium, which constitutes the BBB, represents the major obstacle for the use of potential drugs against many disorders of the CNS.
As a general rule, only small lipophilic molecules may pass across the BBB, i. Many drugs that have a larger size or higher hydrophobicity show high efficacy in CNS targets but are not efficacious in animals as these drugs cannot effectively cross the BBB.
Thus, peptide and protein therapeutics are generally excluded from transport from blood to brain, owing to the negligible permeability of the brain capillary endothelial wall to these drugs. Brain capillary endothelial cells BCECs are closely sealed by tight junctions, possess few fenestrae and few endocytic vesicles vitaprost vs prostatilen compared to capillaries of other organs.
BCECs are surrounded by extracellular matrix, astrocytes, pericytes, and microglial cells. The close association of endothelial cells with the astrocyte foot processes and the vitaprost vs prostatilen membrane of capillaries are important for the development and maintenance of the BBB properties vitaprost vs prostatilen permit tight control of blood-brain exchange.
Thus, there exists a need for improved delivery of peptide therapeutics to tissues, including tissues protected by the BBB. We have developed compounds that include a a peptide such as a peptide therapeutic e.
These compounds are useful in treating any disorder where increased transport of the peptide therapeutic across the BBB or into particular cell types is desired.
In one particular example, the compound includes a GLP-1 agonist as a peptide therapeutic, which may be used to treat metabolic disorders such as diabetes and obesity. The peptide vector is capable of transporting the peptide therapeutic either across the blood-brain barrier BBB or into a particular cell type e.
Surprisingly, we have shown that lower doses of exemplary peptide therapeutics, exendin-4 analogs, when conjugated to a peptide vectors as described herein, are effective in treating glycemia. The compound may also exhibit increased stability, improved pharmacokinetics, or reduced degradation in vivo, as compared to the unconjugated peptide therapeutic.
The compound may be substantially pure. The compound may be formulated with a pharmaceutically acceptable carrier e. In another aspect, the invention features methods of making the compound A-X-B. In one embodiment, the method includes conjugating the peptide vector A to a linker Xand conjugating the peptide vector-linker A-X to a peptide therapeutic Bthereby forming the compound A-X-B.
In another embodiment, the method includes conjugating the peptide vector A to a peptide therapeutic Bwhere either A or B optionally include a linker Xto form the compound A-X-B. In another aspect, the invention features a nucleic acid vitaprost vs prostatilen that encodes the compound A-X-B, where the compound is a polypeptide.
The nucleic acid molecule may be operably linked to a promoter and may be part of a nucleic acid vector. The vector may be in a cell, such as a prokaryotic cell e. In another aspect, the invention features methods of making a compound of the formula A-X-B, where A-X-B is a polypeptide.
In one embodiment, the method includes expressing a nucleic vitaprost vs prostatilen vector of the previous vitaprost vs prostatilen in vitaprost vs prostatilen cell to produce the polypeptide; and purifying the polypeptide.
In another aspect, the invention features a method of treating e. The method includes administering a compound of the first aspect in an amount sufficient to treat the disorder e. In certain embodiments, the metabolic disorder is diabetes e.
In another aspect, the invention features a method of reducing food intake by, or reducing body weight of, a subject. The method includes administering a compound of the first aspect of the invention e. The subject may be overweight, obese, or bulimic. The method includes administering a compound of the first aspect of the invention vitaprost vs prostatilen a subject in an amount sufficient to treat or prevent the disorder.
The invention also features a method of vitaprost vs prostatilen neurogenesis in a subject. The method includes administering a compound of the first aspect to a subject. The subject may desire, or may be in need of neurogenesis. In certain embodiments, the vitaprost vs prostatilen may be vitaprost vs prostatilen from a disease or disorder of the central nervous system such as Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS, stroke, ADD, and neuropsychiatric syndromes.
In other vitaprost vs prostatilen, the increase in neurogenesis can improve learning or enhance neuroprotection. The method includes vitaprost vs prostatilen to a subject a compound of the first aspect e.
The amount sufficient may reduce a side effect e. The subject may be a mammal such as a human. In any of the above aspects, the peptide vector may be a polypeptide substantially vitaprost vs prostatilen to any of the sequences set Table 1, or a fragment thereof.
The peptide vector or conjugate may be efficiently transported into a particular cell type e. In another embodiment, the peptide vector or conjugate is able to enter a particular cell type e. The peptide vector may be of any length, for example, at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 25, 35, 50, 75, or amino acids, or any range between these numbers. In certain embodiments, the peptide vector is 10 to 50 amino acids in length.
The polypeptide may be produced by recombinant genetic technology or chemical synthesis. Polypeptides Nos. In any of the above aspects, the peptide vector may include an amino acid sequence having the formula:.
In some embodiments, at least one e. In some embodiments, the polypeptide has one or more additional cysteine residues at the N-terminal of the polypeptide, the C-terminal of the polypeptide, or both.
In any of the above aspects, vitaprost vs prostatilen peptide therapeutic may vitaprost vs prostatilen selected from the group consisting of antimicrobial or antibiotic peptides, gastrointestinal peptides, pancreatic peptides, peptide hormones, hypothalamic hormones, pituitary hormones, and neuropeptides.
The gastrointestinal or pancreatic peptide may be a cholecystokinin, gastrin, glucagon, epidermal growth factor, vasoactive intestinal peptide VIPinsulin, or a GLP-1 agonist. The hypothalamic or pituitary hormone vitaprost vs prostatilen be a pituitary hormone-releasing hormone e. The neuropeptide may be any of angiotensin, bombesin, bradykinin, calcitonin, a cholecystokinin, delta sleep inducing peptide, galanin, vitaprost vs prostatilen inhibitory polypeptide, gastrin, neuropeptide Y, neurotensin, an opioid peptide e.
Other peptide hormones include adiponectins, adrenomedullins, ghrelin, gonadotropins, inhibins, natriuretic peptides, parathyroid hormone PTH and parathyroid hormone related peptide PTHrPpeptide YY, vitaprost vs prostatilen, and relaxins. In other embodiments, the peptide therapeutic is a distintegrin.
Other peptide therapeutics include disintegrins, endothelins, and secretory protein inhibitor proteins. The peptide therapeutic may an vitaprost vs prostatilen or fragment of any of these peptides e. In certain embodiments, the analog or fragment has the same biological activity as the parent peptide. In any of the above aspects, the peptide therapeutic may be a GLP-1 agonist.
In particular embodiments, the GLP-1 agonist is an exendin-4 analog selected from the group consisting of [Lys 39 ]exendin-4 and [Cys 32 ]exendin In particular embodiments, the peptide conjugated to the vector is selected from the group consisting of leptin, monomethyl auristatin E MMAEdiphtheria toxin, botunilum toxin, tetanus toxin, pertussis toxin, staphylococcus enterotoxins, toxin shock syndrome toxin TSST-1, adenylate cyclase toxin, shiga toxin, cholera enterotoxin, endostatin, catechins, vitaprost vs prostatilen IP, inhibitors of matrix metalloproteinase MMPIsanastellin, vironectin, antithrombin, herceptin, avastin, panitumumab, a vitaprost vs prostatilen fluorescent protein, a His tag protein, galactosidase, luciferase, peroxidase and phosphatase.
In certain embodiments of any of the above aspects, the peptide vector or peptide therapeutic is modified e. The peptide may be amidated, acetylated, or both. Such modifications may be at the amino or carboxy terminus of the polypeptide. The polypeptide may also include peptidomimetics e. The polypeptide vitaprost vs prostatilen be in a multimeric form, for example, dimeric form e.
In certain embodiments, the peptide vector or peptide therapeutic has an amino acid sequence described herein with at least one amino acid substitution e.
The polypeptide may contain, for example, 1 to 12, 1 to 10, 1 to 5, or 1 to 3 amino acid substitutions, for example, 1 to 10 e. The amino acid substitution s may be conservative or non-conservative. For example, the peptide vector may have an vitaprost vs prostatilen at one, two, or three of the positions corresponding to positions 1, 10, and 15 of the amino acid sequence of any of SEQ ID NO:1, Angiopep-1, Angiopep-2, Angiopep-3, Angiopep-4a, Angiopep-4b, Angiopep-5, Angiopep-6, and Angiopep In certain embodiments, the GLP-1 agonist may have a cysteine or lysine substitution or addition at any position e.
In any of the above aspects, the linker X may be any linker known in the art or described herein. In particular embodiments, the linker is a covalent bond e. In certain embodiments, the linker has the formula:.
The vector may be attached to covalently or not or conjugated to peptide therapeutic and thereby may be able to transport the peptide therapeutic into a particular cell type or across the BBB.
In certain embodiments, the vector may bind to receptors present on cancer cells or brain endothelial cells and thereby be transported into the cancer cell or across vitaprost vs prostatilen BBB by transcytosis. The vector may be a molecule for which high levels of transendothelial transport may be obtained, without affecting the cell or BBB integrity.
The vector may be a polypeptide or a peptidomimetic and may be naturally occurring or produced by chemical synthesis or recombinant genetic technology. Agonists can include peptides or small molecule compounds e.
Assays for determining whether a particular compound is a GLP-1 agonist are known in the art and described herein. In one example, a subject who is being treated for a metabolic disorder vitaprost vs prostatilen one who a medical practitioner has diagnosed as having such a condition.
Diagnosis may be performed by any suitable means, such as those described herein. A subject in whom the development of diabetes or obesity is being treated prophylactically may or may not have received such a diagnosis. One in the art will understand that subject of the invention may have been subjected to standard tests or may have been identified, without examination, as one vitaprost vs prostatilen high risk due to the presence of one or more risk factors, such as family history, obesity, particular ethnicity e.
An adult who is more than pounds overweight, is considered to be morbidly obese. Such disorders include those resulting from an alteration in glucose homeostasis resulting, for example, in hyperglycemia. Metabolic disorders include obesity and diabetes e. Desirably, glucose levels are reduced to normoglycemic levels, i. Such reduction in glucose levels may be obtained by increasing any one of the biological activities associated with the clearance of glucose from the blood e.
For example, the equivalent dosage of 1. Such activities are described in detail in International Application Vitaprost vs prostatilen No.