EP1068239A2 - Peptides antioxydants - Google Patents

Peptides antioxydants

Info

Publication number
EP1068239A2
EP1068239A2 EP99914142A EP99914142A EP1068239A2 EP 1068239 A2 EP1068239 A2 EP 1068239A2 EP 99914142 A EP99914142 A EP 99914142A EP 99914142 A EP99914142 A EP 99914142A EP 1068239 A2 EP1068239 A2 EP 1068239A2
Authority
EP
European Patent Office
Prior art keywords
leu
gln
glu
lys
val
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99914142A
Other languages
German (de)
English (en)
Inventor
David Y. Hui
Patrick Tso
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Cincinnati
Original Assignee
University of Cincinnati
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Cincinnati filed Critical University of Cincinnati
Publication of EP1068239A2 publication Critical patent/EP1068239A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to a method for treating diseases associated with lipid oxidation. Specifically, the present invention is a new method for treating atherosclerosis and other oxidative disorders.
  • CHD corthelial heart disease
  • the atherosclerosis is a process of degeneration of the arterial wall and represents the main cause of many vascular pathologies like ischaemic cardiopathies (angina pectoris and myocardial infarction) and cerebral thrombosis, main causes of death in the industrial countries.
  • the atherosclerosis is a process with composite etiology that involves in varied measure different factors and cell types.
  • Ross R. in New Engl. J. Med., 314, 488-495, (1986) assumes that the endothelial damages, caused by exposure to many risk factors, represent the main event in the genesis of the atheroma and in Amer. J. Pathol., 143, 987- 1001, (1993 ) finds out an important cause of the induction of such endothelial damage and of the progress and complication of the atheromatous plaque in the high serum rates of lipids and cholesterol that characterize the hyperlipidaemias and that often aggravate the diabetic pathologies.
  • LDL low density lipoproteins
  • the endogenous antioxidizers challenge the chain of propagation by means of an effective scavenging of the peroxylic radicals and the concentration of hydroperoxides increases only when the endogenous antioxidizers are depleted (latency period).
  • MDA malondialdehyde
  • 4-hydroxynonenal cause important changes in the primary structure of the main LDL apoprotein, the B-100 apolipoprotein (apo B-100).
  • Such modification by helping the LDL absorption by the macrophages, causes the intracellular accumulation of esters of the cholesterol and the formation of foam cells with subsequent development of the atherosclerotic plaque, as reported by Vanderyse L., et al. in Atherosclerosis, 97, 187-199, (1992).
  • the compounds object of the present invention are endowed with antioxidant and hypoUpidaemic properties, in particular they show the capability to prevent and/or to delay the oxidative modification of the LDL, i.e. they compete with the chain of propagation of the lipidic peroxidation through an effective scavenging of the peroxylic radicals.
  • LDL low density lipoproteins
  • pharmacological composition will comprise an apolipoprotein (apo) A-IV compound, derivative or fragment thereof with a pharmaceutically acceptable carrier, fillers or excipients.
  • the administering step may comprise administering a pharmacological composition comprising an apolipoprotein (apo) A-IV compound, derivative or fragment thereof along with pharmaceutically acceptable carrier, fillers or excipients.
  • the method may be by oral administration of an apolipoprotein (apo) A-IV compound, derivative or fragment thereof or a pharmaceutically acceptable salt or derivative thereof into said mammal.
  • apo apolipoprotein
  • the administering step comprises parenteral administration of the an apolipoprotein (apo) A-IV compound, derivative or fragment thereof or a pharmaceutically acceptable salt or derivative thereof into said mammal.
  • This administration may be by transdermai administration, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, intrathecal injection, intraventricular and intracerebroventricular injection and infusion techniques.
  • the methods also comprise administering an apolipoprotein (apo) A-IV compound, derivative or fragment thereof or a pharmaceutically acceptable salt or derivative thereof along with a solvent or carrier.
  • apolipoprotein (apo) A-IV compound, derivative or fragment thereof or a pharmaceutically acceptable salt or derivative thereof along with a solvent or carrier.
  • the UpophiUc solvent or carrier may be an organic solvent, phosphatidyl choline and cholesterol. Accordingly, an object of the present invention is to provide treating a mammal having a condition associated with Upid oxidation.
  • a number of novel Upid oxidation suppressant peptides derived from apolipoprotein A-IV, have been made. These peptides possess lipid oxidation inhibiting properties which when administered oraUy or intravenously, can be used to decrease atherosclerosis. Since the peptides comprise specific portions of the native apo A-IV protein, there should be no immunogenicity problems associated with their administration to humans.
  • the peptides of the present invention correspond to specific areas of the apoUpoprotein A-IV molecule and comprise at least a six amino acid sequence derived from the amino terminal portion of the mature apoUpoprotein A-IV. Larger peptides of 15 and 90 amino acids, each containing within its sequence the aforementioned repeat sequence are also contemplated by the present invention.
  • homologues the conesponding peptides derived from other known apo A-IV proteins and having the same or substantially the same Upid oxidation inhibition properties.
  • analogs substitutions in the amino acid sequences of the peptides, providing the Upid oxidation inhibition properties are retained. Analogs may also encompass additional amino acids, added to the N- and/or C-terminal portion of the peptide.
  • analogs of the peptides of the invention may contain cysteine or another amino acid, at the amino or carboxyl end of the peptide by which the peptide may be covalently attached to a carrier protein, e.g., albumin, for in vivo administration.
  • carrier molecules include polyethylene glycol (PEG) which functions to avoid proteolytic cleavage and clearing of peptides from the blood.
  • PEG polyethylene glycol
  • the peptides of the present invention may be linked to an additional sequence of amino acids by either or both the N-terminus and the C-terminus, wherein the additional sequences are from 1 to about 45 amino acids in length.
  • additional amino acid sequences, or linker sequences can be conveniently affixed to a detectable label or solid 5 matrix, or carrier. Labels, solid matrices and carriers that can be used with peptides of the present invention are described below. Typical amino acid residues used for linking are tyrosine, cysteine, lysine, glutamic acid and aspartic acid, or the like.
  • the Upid oxidation inhibiting peptides of the present invention substantiaUy correspond to the foUowing amino acid sequences: 0 (A) MFLKAWLTV
  • the one-letter symbols used to represent the amino acid residues in the peptides of the present invention are those symbols commonly used in the art.
  • substantially conesponding is meant an amino acid sequence having a homology to any of the Usted sequences of about 70% .
  • the present invention also provides compositions for Upid oxidation inhibition in animals, including man.
  • the compositions have as their active ingredients, at least one of the above peptides according to the present invention, admixed with a physiologically acceptable carrier.
  • pharmaceutically acceptable refers to a molecular entity or composition that does not produce an aUergic or similar unwanted reaction when administered to animals or humans.
  • compositions may be formulated in any suitable carrier for oral Uquid formulation such as suspensions, elixirs and solutions.
  • suitable carrier for oral Uquid formulation such as suspensions, elixirs and solutions.
  • Compositions for Uquid oral dosage include any of the usual pharmaceutical media such as, for example, water, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
  • carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used.
  • carriers such as liposomes, microemulsions and self emulsifiable glasses may be used.
  • compositions of the present invention may also be formulated for intravenous administration.
  • the peptides are admixed with sterile water and saUne or other pharmaceuticaUy acceptable carrier.
  • the peptides of the present invention may be altered with modifying structures such as PEG to prevent both proteolysis of the peptides and reduce the clearing of peptides from the blood.
  • Other objects, features and advantages of the present invention wiU become apparent from the foUowing detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of Ulustration only, since various changes and modifications within the scope of the invention wiU become apparent to those skiUed in the art from this detailed description.
  • Fig. 1 Inhibition effect of different doses of apoA-IV on copper mediated oxidation of fasting lymph and LDL.
  • Fasting intestinal lymph or LDL were oxidized in the absence or presence of apoA-IV at the concentration indicated.
  • Fasting lymph was
  • Fig. 2 Kinetics of LDL oxidation in the presence or absence of apoUpoproteins.
  • LDL 50 ⁇ g/ml
  • CuSO 4 10 ⁇ M
  • conjugated dienes Conjugated diene formation in LDL was determined in the absence of apoUpoproteins ( ⁇ ), or in the presence of 2.5 ⁇ g/ml of apoA-IV (O), 5 ⁇ g/ml of apoA-IV
  • Fig. 3 Inhibitory effect of apoA-TV during the propagation phase of LDL oxidation.
  • LDL oxidation monitored by the conjugated diene assay, was allowed to proceed to the propagation phase of oxidation.
  • ApoA-IV was added to the oxidation reaction during the propagation phase, and conjugated dienes were continuously measured in samples containing only LDL (D), LDL plus tris-saline (X ), LDL plus 5 ⁇ g/ml apoA-
  • inset shows the change in slope before and after the addition of apoA-IV.
  • the present invention provides for a number of lipid oxidation inhibiting peptides of approximately 5-90 amino acids in length, which substantially co ⁇ espond in sequence to amino acid sequence found in specific portions of apolipoprotein A-IV ("apo A-IV")- Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or plaque.
  • apo A-IV apolipoprotein A-IV
  • Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or plaque.
  • the identification of those patients who are in need of treatment for atherosclerosis is weU within the abiUty and knowledge of one of ordinary skttl in the art.
  • individuals who are either suffering from cUnicaUy significant atherosclerosis or who are at risk of developing clinically significant atherosclerosis are patients in need of treatment for atherosclerosis.
  • a cUnician ofordinary skiU in the art can readily determine, by the use of clinical tests, physical examination
  • An effective anti-atherosclerotic amount is an amount which is effective in inhibiting the development or growth of atherosclerosis in a patient in need thereof.
  • successful treatment of a patient for atherosclerosis is understood to include effectively slowing, interrupting, arresting, or stopping atherosclerotic lesion or plaque development or growth and does not necessarily indicate a total eUrnination of atherosclerosis. It is further understood and appreciated by those of ordinary skiU in the art that successful treatment for atherosclerosis can include prophylaxis in preventing atherosclerotic lesion or plaque formation.
  • Peroxidation of LDL lipid such as the unsaturated fatty acid portions of LDL cholesteryl esters and phosphoUpids, is known to faciUtate the deposition of cholesterol in macrophages which subsequently are deposited in the vessel waU and are transformed into foam ceUs.
  • the identification of those patients who are in need of inhibition of peroxidation of LDL lipid is well within the ability and knowledge of one of ordinary skill in the art. For example, those individuals who are in need of treatment for atherosclerosis as defined hereinabove, are also patients who are in need of inhibition of peroxidation of LDL lipid.
  • An effective antioxidant amount is an amount which is effective in inhibiting the peroxidation of LDL lipid in a patient's blood.
  • the term "patient” refers to a warm-blooded animal or mammal which is in need of treatment for a chronic heart disease, atherosclerosis, hypercholesterolemia or which is in need of inhibiting oxidation.
  • a “therapeuticaUy effective amount” is an amount which is effective, upon single or multiple dose administration to the patient, in providing reUef of symptoms associated with atherosclerotic diseases.
  • ReUef of symptoms refers to decrease in severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the disease. ReUef of symptoms is also intended to include prophylaxis.
  • peptide refers to a linear series of less than about 100 amino acid residues connected to one another by peptide bonds between the alpha-amino and carboxy groups of adjacent amino acid residues.
  • synthetic peptide is intended to refer to a chemicaUy derived chain of amino acid residues linked together by peptide bonds and which is free of naturaUy occurring proteins and fragments thereof. AdditionaUy, analogs, homologues, fragments, chemical derivatives and pharmaceuticaUy acceptable salts of the novel peptides provided herein are included within the scope of the term "peptide”.
  • peptide analog is meant a peptide which differs in amino acid sequence from the native peptide only by conservative amino acid substitutions, for example, substitution of Leu for Val, or Arg for Lys, etc., or by one or more non-conservative amino acid substitutions, deletions, or insertions located at positions which do not destroy the biological activity of the peptide (in this case, the ability of the peptide to target vascular lesions).
  • a peptide analog, as used herein, may also include, as part or aU of its sequence, one or more amino acid analogues, molecules which mimic the structure of amino acids, and/or natural amino acids found in molecules other than peptide or peptide analogues.
  • homologues is meant the corresponding peptides derived from other known apo A-IV proteins having the same or substantiaUy the same appetite suppressant and feeding inhibition properties.
  • an analog is meant substitutions or alterations in the amino acid sequences of the peptides of the invention, which substitutions or alterations do not aboUsh the appetite suppressant or feeding inhibition properties of the peptides.
  • an analog might comprise a peptide having a substantiaUy identical amino acid sequence to a peptide provided herein as SEQ ID NO: 1-13 and in which one or more amino acid residues have been conservatively substituted with chemicaUy similar amino acids. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine, leucine or methionine for another.
  • the present invention contemplates the substitution of one polar (hydrophiUc) residue such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another or the substitution of one acidic residue such as aspartic acid or glutamic acid for another is also contemplated.
  • analogs of the subject peptides may contain an N- or C-te ⁇ ninal cysteine, by which, if desired, the peptide may be covalently attached to a carrier protein, e.g., albumin. Such attachment, it is beUeved, wiU minimize clearing of the peptide from the blood and also prevent proteolysis of the peptides.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of synthetic organic chemistry, protein chemistry, molecular biology, microbiology, and recombinant DNA technology, which are weU within the skiU of the art. Such techniques are explained fully in the Uterature.
  • the peptide or peptide analog is water soluble; or is soluble in a physiological fluid, preferably, one which is at physiological pH, for example, blood plasma.
  • the peptide has a molecular conformation analogous to the molecular conformation (size, shape, charge) of a surface region of the apoUpoprotein A-IV (apo A-IV) moiety.
  • prefened peptide or peptide analogues include: Met-Phe-I ⁇ u-Lys-Ala-V -Val-Leu-Thr-Val-Ala-Leu-Val-Ala-Ile-Thr-Gly-Thr-Gln- Ala-Glu-Val-Thr-Ser-Asp-Gln-Val-Ala-Asn-Val (SEQ LD NO:l); Met-Trp-Asp-Tyr-Phe-Thr-Gln-Leu-Ser-Asn-Asn-Ala-Lys-Glu-Ala-Val-Glu-Gln-Leu- Gm-Lys-Thr-Asp-V -Thr-Gln-Gln-Leu-Asn-Thr-Leu-Phe-Gln-Asp-Lys-Leu-Gly-Asn-Ile- Asn-Thr-Tyr-Ala-Asp-Asp-
  • Met-Glu-Gly-Leu-Ala-Phe-Gln SEQ ID NO:9; Met-Lys-Lys-Asn-Ala-Glu-Glu-Leu-His-Thr-Lys-Val-Ser-Thr-Asn-Ile-Asp-Gln-Leu- Gln-Lys-Asn-Leu-Ala-Pro-Leu-Val-Glu-Asp-Val-Gln-Ser-Lys-Leu-Lys-Gly-Asn-Thr-
  • Val-Phe-Arg-Arg-Ala-Val-Glu-Pro-Leu-Gly-Asp-Lys-Phe-Asn SEQ ID NO: 10
  • the peptide or peptide analog has an
  • peptide analogues include:
  • H2N-Met- Ala-Leu- Val-Gln-Gln-CONH2 (SEQ ID NO: 11); CH3CONH-Met- Ala-Leu- Val-Gln-Gln-CONH2 (SEQ ED NO: 11);
  • derived from having an amino acid sequence identical or substantiaUy identical to the sequence of, as used herein, a vascular-associated protein.
  • substantiallyUy identical to is meant having an amino acid sequence which differs only by conservative amino acid substitutions or by non-conservative amino acid substitutions, deletions, or insertions located at positions which do not destroy the biological activity of the peptide.
  • peptide analogues having different amino acid sequences, provided that the local charge distribution (and overall net charge) and secondary structure, and hence the biological activity is maintained.
  • Such peptide analogues wiU generaUy differ from the native protein sequences by conservative amino acid substitutions (e.g., substitution of Leu for VaL or Arg for Lys, etc.) weU known to those skilled in the art of biochemistry.
  • the peptides, once designed, can be synthesized by any of a number of estabUshed procedures, including, e.g., the expression of a recombinant DNA encoding that peptide in an appropriate host ceU.
  • these peptides can be produced by the estabUshed procedure of soUd phase peptide synthesis. Briefly, this procedure entails the sequential assembly of the appropriate amino acids into a peptide of a desired sequence whUe the end of the growing peptide is linked to an insoluble support. UsuaUy, the carboxyl terminus of the peptide is linked to a polymer from which it can be Uberated upon treatment with a cleavage reagent. The peptides so synthesized are then labeUed with a reagent which enables the monitoring of the peptide after its administration to a patient.
  • substantially corresponds means a peptide amino acid sequence having approximately 70% homology in amino acid sequence to an apolipoprotein A-IV peptide.
  • chemical derivative is meant to include any peptide derived from a peptide of the present invention and in which one or more amino acids have been chemicaUy derivatized by reaction of one or more functional side groups of the amino acid residues present in the peptide.
  • a “chemical derivative” as used herein is a peptide which is derived from the peptides identified herein by one or more chemical steps.
  • Examples of derivatized molecules include molecules where free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, thiourethane-type derivatives, trifluroroacetyl groups, chioroacetyl groups or formyl groups.
  • Free carboxyl groups may be derivatized to form salts, methyl and ethyl esters or other types of esters or hydrazides.
  • Free hydroxyl groups may be derivatized to form 0-acyl or 0-alkyl derivatives.
  • the imidazole nitrogen of histidine may be derivatized to form N-im-benzyUiistidine.
  • chemical derivatives are those peptides which contain one or more naturaUy occurring amino acid derivatives of the twenty standard amino acids. For example, 4- hydroxyproline may be substituted for proline; 5-hydroxylysine may be substituted for lysine; 3-methylhistidine may be substituted for histidine; homoserine may be substituted for serine; and oir ⁇ thine may be substituted for lysine.
  • fragment refers to any subject peptide having an amino acid sequence shorter than that of any peptide depicted in SEQ ID NO: 1-13 and which a fragment retains the appetite suppressant or feeding inhibition properties as the subject peptides.
  • the peptides of the present invention, homologues and analogs thereof may be synthesized by a number of known techniques. For example, the peptides may be prepared using the soUd-phase synthetic technique or other peptide synthesis techniques weU known to those skiUed in the art.
  • the peptides of the present invention might also be prepared by chemical or enzymatic cleavage from larger portions of the apolipoprotein A-IV molecule or from the entire apo A-IV molecule.
  • the peptides of the present invention may also be prepared by recombinant DNA techniques. For most of the amino acids used to build proteins, more than one coding nucleotide triplet (codon) can code for a particular amino acid residue. This property of the genetic code is known as redundancy. Therefore, a number of different nucleotide sequences may code for a particular subject eating suppressant peptide.
  • the present invention also contemplates a deoxyribonucleic acid (DNA) molecule or segment that defines a gene coding for, i.e., capable of expressing, a subject polypeptide or a subject chimeric polypeptide from which a polypeptide of the present invention may be enzymaticaUy or chemicaUy cleaved.
  • DNA deoxyribonucleic acid
  • DNA molecules that encode the subject peptides can be synthesized by chemical techniques, for example, the phosphotriester method of Matteuccie et al, Chem. Soc. 103:3185 (1981). Using a chemical DNA synthesis technique, desired modifications in the peptide sequence can be made by making substitutions for bases which code for the native amino acid sequence. Ribonucleic acid equivalents of the above described DNA molecules may also be used.
  • a nucleic acid molecule comprising a vector capable of repUcation and expression of a DNA molecule defining coding sequence for a subject polypeptide or subject chimeric polypeptide is also contemplated.
  • the peptides of the present invention are preferably chemically synthesized by the Merrifield soUd phase technique.
  • the method comprises the sequential addition of one or more amino acid residues to a growing peptide chain.
  • a suitable, selectively removable protecting group is protected by a suitable, selectively removable protecting group.
  • a different, selectively removable protecting group is utilized for amino acids containing a reactive side group such as lysine.
  • Any peptide of the present invention may be used in the form of a pharmaceutically acceptable salt.
  • suitable acids which are capable of forming salts with the peptides of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, phosphoric acid and the like; and organic acids such as formic acid, acetic acid, propionic acid, glycoUc acid, lactic acid, pyruvic acid, oxaUc acid, malonic acid, succinic acid, maleic acid, fumaric acid, anthraniUc acid, cinnamic acid, naphthalene sulfonic acid, sulfaniUc acid or the like.
  • Suitable bases capable of forming salts with the subject peptides include inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide and the like; and organic bases such as mono-, di-and tri-alkyl amines (e.g., triethyl amine, dusopropyl amine, methyl amine, dimethyl amine and the like) and optionaUy substituted ethanolamines (e.g. ethanolamine, diethanolamine and the like).
  • inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide and the like
  • organic bases such as mono-, di-and tri-alkyl amines (e.g., triethyl amine, dusopropyl amine, methyl amine, dimethyl amine and the like) and optionaUy substituted ethanolamines (e.g. ethanolamine, diethanolamine and the like).
  • the peptides of the present invention were synthesized using an automatic soUd phase peptide synthesizer (MiUigen 9050).
  • the synthesis was started by packing a column with a mixture of polystyrene resin (that has attached to it the C terminus amino acid of the target peptide) and glass beads (150-220 micron diameter).
  • the amino acid bound to the resin was protected prior to packing the column and the process of peptide synthesis started by first washing the column with a 20% v/v solution of piperidine / N,N-dimethyl formamide (DMF) in order to deprotect the C teirninus residue.
  • DMF piperidine / N,N-dimethyl formamide
  • an FMOC protected L-amino acid in the form of a pentafluorophenyl ester
  • HOBT/DMF hydroxybenzotriazole
  • the solution of amino acid/DMF was passed over the column for an extended period of 45-90 minutes. If residue attachment proved difficult due to stearic reasons, the coupling time was extended by a manual modification of the instrument's buUt in chemical protocols.
  • the protocol for synthesis basicaUy consisted of a number of cycles, each one performing the following operations: deprotection of previous residue with piperidine, washing of the column with DMF, and attachment of the next residue.
  • the effective antioxidant amount or dose of an apoUpoprotein (apo) A-IV compound, derivative or fragment thereof a number of factors are considered by the attending diagnostician, including, but not limited to: the species of the mammal; its size, age, and general health; the response of the individual patient; the particular compound administered; the mode of administration; the bioavaUabiUty characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a therapeuticaUy effective amount wiU generaUy vary from about 1 miUigram per kUogram of body weight per day (mg/kg/day) to about 5 grams per kilogram of body weight per day (gm/kg/day).
  • a daily dose of from about 1 mg/kg to about 500 mg/kg is preferred.
  • an apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment and mixtures thereof can be administered in any form or mode which makes the compound bioavaUable in effective amounts, including oral and parenteral routes.
  • the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectaUy, and the like.
  • Oral administration is generally preferred.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the relevant circumstances.
  • An apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment and mixtures thereof can be administered in the form of pharmaceutical compositions or medicaments which are made by combining an apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment and mixtures thereof with pharmaceuticaUy acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice.
  • the pharmaceutical compositions or medicaments are prepared in a manner weU known in the pharmaceutical art.
  • the carrier or excipient may be a soUd, semi-soUd, or Uquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are weU known in the art.
  • the pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like.
  • compositions may be administered oraUy, for example, with an inert dUuent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • an apoUpoprotein (apo) A-IV compound, derivative or fragment thereof may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the Uke.
  • These preparations should contain at least 4% of an apolipoprotein (apo) A-IV compound, derivative or fragment thereof the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the active ingredient present in compositions is such that a unit dosage form suitable for administration will be obtained.
  • the tablets, piUs, capsules, troches and the Uke may also contain one or more-of the foUowing adjuvants: binders, such as microcrystaUine ceUulose, gum tragacanth or gelatin; excipients, such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the Uke; lubricants, such as magnesium stearate or Sterotex; gUdants, such as coUoidal siUcon dioxide; and sweetening agents, such as sucrose or saccharin may be added or flavoring agents, such as peppermint, methyl saUcylate or orange flavoring.
  • binders such as microcrystaUine ceUulose, gum tragacanth or gelatin
  • excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the Uke
  • lubricants such as magnesium stearate or Sterot
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a Uquid carrier such as polyethylene glycol or a fatty oU.
  • a Uquid carrier such as polyethylene glycol or a fatty oU.
  • Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or piUs may be coated with sugar, sheUac, or other enteric coating agents.
  • a syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceuticaUy pure and non-toxic in the amounts used.
  • an apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment or mixtures thereof may be incorporated into a solution or suspension.
  • These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof.
  • the amount of the active ingredient present in such compositions is such that a suitable dosage will be obtained.
  • the peptide compositions When administered intravenously, the peptide compositions may be combined with other ingredients, such as carriers and/or adjuvants.
  • the peptide can also be covalently attached to a protein carrier, such as albumin, so as to minimize clearing of the peptides.
  • a protein carrier such as albumin
  • the peptide compositions of the invention may also be impregnated into transdermai patches or contained in subcutaneousi inserts, preferably in a Uquid or semi-Uquid form A which patch or insert time releases therapeuticaUy effective amounts of one or more of the subject peptides.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In aU cases the ultimate solution form must be sterile and fluid.
  • Typical carriers include a solvent or dispersion medium containing, for example, water buffered aqueous solutions (i.e., biocompatible buffers), ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oUs.
  • Sterilization can be accompUshed by any art-recognized technique, including but not limited to, filtration or addition of antibacterial or antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid or thimerosal. Further, isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
  • Production of sterile injectable solutions containing the subject peptides is accomplished by incorporating these compounds in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by sterilization, preferably filter sterilization. To obtain a sterile powder, the above solutions are vacuum- dried or freeze-dried as necessary.
  • the solutions or suspensions may also include one or more of the foUowing adjuvants depending on the solubiUty and other properties of an apoUpoprotein (apo) A- r compound, derivative or fragment thereof: sterile dUuents such as water for injection, saline solution, fixed oUs, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose.
  • sterile dUuents such as water for injection, saline solution, fixed oUs, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl para
  • parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • the pharmacological composition wiU preferably comprise an apoUpoprotein (apo) A-IV or derivative or fragment thereof along with a pharmaceuticaUy acceptable carrier, fiUers or excipients.
  • the administering step may comprise administering a pharmacological composition comprising an apoUpoprotein (apo) A-IV compound, derivative or fragment thereof along with pharmaceuticaUy acceptable carrier, fillers or excipients.
  • the methods may be by oral aciministration of the antioxidant composition or a pharmaceutically acceptable salt or derivative thereof into said mammal.
  • the methods according to the present invention preferable allows the administration of the antioxidant molecule is administered in a unitary dose of from about 1 to about 1000 mg.
  • a unitary dose is generally administered from about 1 to about 3 time a day.
  • the administering step may comprise parenteral administration of the antioxidant compound or a pharmaceutically acceptable salt or derivative thereof into said mammal.
  • This administration may be by transdermai administration, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, intrathecal injection, intracerebroventricular injection and infusion techniques.
  • the method of also comprises adininistering antioxidant compound or a pharmaceuticaUy acceptable salt or derivative thereof along with a UpophiUc compound, such as a UpophiUc solvent or carrier.
  • the UpophiUc solvent or carrier may be an organic solvent, phosphatidyl choline and cholesterol.
  • compositions of the present invention can be formulated for the oral, subUngual, subcutaneous, intravenous, transdermic or rectal administrations in dosage units and in admixture with pharmaceutical excipients or vehicles.
  • Convenient dosage forms include, among those for oral administration, tablets, powders, granulates, and, among those for parenteral administration, solutions especiaUy for transdermai administration, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, intrathecal injection and infusion techniques.
  • the dosage can vary widely as a function of the age, weight and state of health of the patient, the nature and the severity of the aUment, as well as of the administration route. These doses can naturally be adjusted for each patient according to the results observed and the blood analyses previously carried out.
  • Food Preservative can naturally be adjusted for each patient according to the results observed and the blood analyses previously carried out.
  • the apolipoprotein A-IV compounds of the present invention may be made into edible nonionic lipid-soluble additives which are effective antioxidants in food products such as fats, oil, foods, and ingredients of foods without imparting undesirable flavors, aromas, and precipitates.
  • Oxidation of fats, vegetable oils, carotenoids and their biologically active derivatives, Vitamin A, and of essential oUs and other flavorings results in degradation of their quaUty, and is deleterious to foodstuffs containing the oxidized products.
  • the art shows many methods of inhibiting Upid oxidation by adding fat-soluble antioxidants to the substrate.
  • the art does not show the stabiUzation of fats, oUs, fatty foods and ingredients of foods employing apoUpoprotein A-IV and active deriviatives and fragments in a form effective for such purpose.
  • a method of preventing oxidation in a Upid-containing food comprising incorporating in the food an oxidation-inhibiting amount of an apoUpoprotein A-IV compound, derivative, analog, homolog, fragment and mixtures thereof to protect the food from oxidation.
  • the apoUpoprotein A-IV molecule is a peptide sequence from about 5 to about 90 amino acids in length.
  • the food composition may further comprise carriers, fUlers, and excipients.
  • the apoUpoprotein A-IV compound makes up about 0.01% to about 10% of the final weight of the food product. More preferably, the apoUpoprotein A-IV compound makes up from about 0.02% to about 5% of the final weight of the food product.
  • a fat, oil, fatty food or food ingredient substrate stabilized against oxidation with such composition such a stabilized substrate wherein the substrate includes a carotenoid
  • a method of stabilizing a fat, oU, food, or food ingredient substrate which includes the step of introducing into the substrate such a composition as set forth in the foregoing, and such a method wherein the substrate includes a carotenoid.
  • compositions of the present invention may also be used as a method of preventing oxidation in Upid-containing pharmaceuticals.
  • This embodiment involves incorporating in the pharmaceutical an oxidation-inhibiting amount of an apoUpoprotein A-IV, derivative, analog, homolog, fragment or mixture thereof.
  • GeneraUy the apoUpoprotein A-IV molecule is a peptide sequence from about 5 to about 90 amino acids in length.
  • the composition may further include carriers, fillers, and excipients.
  • the apoUpoprotein A-IV compound makes up about 0.01% to about 25% of the final weight of the pharmaceutical product. More preferably, the apoUpoprotein A-IV compound makes up from about 0.05% to about 10% of the final weight of the pharmaceutical product.
  • the present invention provides methods of preventing oxidation in a Upid-containing cosmetic or dermatological composition by incorporating, in a suitable vehicle containing cosmetic or dermatological composition, an oxidation- inhibiting amount of an apolipoprotein A-IV compound, derivative, analog, homolog, fragment or mixtures thereof.
  • the apoUpoprotein A-IV molecule is a peptide sequence from about 5 to about 90 amino acids in length.
  • the composition may further comprise carriers, fillers, and excipients.
  • the apolipoprotein A-IV compound is present at a concentration between about 0.005% and about 25% by weight with respect to the total weight of the composition. More preferably, the apoUpoprotein A-IV compound is present at a concentration between about 0.05% and about 10% by weight with respect to the total weight of the composition.
  • the present invention relates to a new antioxidant system based on an apoUpoprotein A-IV compound, derivative, analog, homolog, fragment or mixtures thereof for use as an antioxidant system in compositions based on an oleaginous material containing such a system and, principaUy, cosmetic compositions.
  • This embodiment generaUy provides for a cosmetic or dermatological composition containing, in a suitable vehicle, an oxidation-inhibiting amount of an apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment or mixtures thereof.
  • GeneraUy the apoUpoprotein (apo) A-IV molecule is a peptide sequence from about 5 to about 90 amino acids in length.
  • the cosmetic or dermatological composition may be in the form of a suspension or dispersion in a solvent or a fatty substance, or in the form of an emulsion, or in the form of an ointment, a gel, a solid stick or an aerosol foam.
  • the cosmetic or dermatological composition may additionally contain one or more cosmetic adjuvants such as lower alcohols, polyols, esters of, fatty acids, oils, and waxes, solvents, sUicones, thickeners, emollients, UV-A, UV-B and broad band sunscreens, antifoam agents, hydrating agents, perfumes, stabilizers, surfactants, fillers, sequestrants, anionic, cationic, nonionic and amphoteric polymers and mixtures thereof, propellents, alkalifying and acidifying agents, dyes and metal oxide pigments.
  • the apolipoprotein A-IV compound is present at a concentration between about 0.001% and about 25% by weight with respect to the total weight of the composition.
  • the apoUpoprotein A-IV compound is present at a concentration between about 0.005% and about 15% by weight with respect to the total weight of the composition.
  • the present invention relates to an antioxidant cosmetic system based on apoUpoprotein A-IV or at least one of its deriviatives or fragments thereof which contains either at least one basic agent or includes at least one tocopherol or a derivative.
  • the antioxidant system contains from 0.5 to 20 weight percent of a tocopherol or derivative thereof, 0.5 to 50 weight percent of a basic agent and 0.5 to 90 weight percent of apoUpoprotein A-IV and deriviatives and fragments thereof. This antioxidant system is employed in cosmetic or pharmaceutical compositions.
  • the present invention thus relates to a new antioxidant system based on at least one basic agent characterized by the fact that the system also includes at least one tocopherol or a tocopherol derivative and apolipoprotein A-IV compound, derivative, analog, homolog, fragment or mixtures thereof.
  • basic amino acid may, for example, be used as the basic agent.
  • basic amino acid is meant a natural basic amino acid such as, for example, lysine, arginine and histidine, their isomeric or racemic forms, as well as synthetic basic amino acids and derivatives of natural amino acids.
  • lysine or arginine is employed.
  • tocopherol there is meant not only alpha-tocopherol but also beta , gamma or delta tocopherol as well as their mixtures.
  • tocopherol derivatives mention can be made of the esters of tocopherol such as tocopherol acetate and tocopherol nicotinate.
  • the antioxidant system is preferably consisting of: 0.5 to 40 percent of a tocopherol or a tocopherol derivative, 0.5 to 50 percent of a basic amino acid and 0.5 to 90 percent of apoUpoprotein A-IV and deriviatives and fragments thereof.
  • the prefened ratio between the concentration of the basic amino acid and the concentration of the tocopherol ranges from 1 to 20.
  • compositions according to the invention are provided in the form of oUy solutions, water-in-oU or oU-in-water emulsions, optionaUy anhydrous products, lotions or even microdispersions or ionic or nonionic Upid vesicles. They constitute principaUy milks for the care of the skin, creams (face creams, hand creams, body creams, sunscreen creams, make-up remover creams, foundation creams), foundation fluids, make-up remover milks, sunscreen ⁇ dlks, bath oils, Upsticks, eyelid make-up, deodorant sticks, etc.
  • the pharmaceutical compositions according to the invention comprise vehicles and ingredients necessary to provide, for example, the composition in the form of ointments, creams, milks, pomades and oily solutions.
  • the cosmetic or dermopharrnaceutical compositions are provided in a form intended to be topically appUed and, in particular, creams intended for the protection of the lipids of the skin against oxidation.
  • the anti-oxidant system such as defined above, is generally present such that the following proportions, with respect to the total weight of the composition, are estabUshed:
  • compositions of the invention can also contain active compounds or ingredients conventionaUy employed in compositions mentioned above, such as surface active agents, dyes, perfumes, astringent products, ultraviolet absorbing products, organic solvents, water, etc. These compositions are prepared in accordance with conventional methods.
  • the compositions of the invention may also contain, in the aqueous phase, various complementary additives such as preserving agents, sequestering agents, gelling agents and the Uke.
  • the compositions of the invention may also contain, in the Upid phase, various complementary additives such as oUs, waxes or gums having, for example, emoUient or lubricating properties.
  • the compositions are most often provided in milk, cream or gel form, other modes of presentation not being excluded.
  • the present invention provides a process for the preparation of the compositions described above, comprising: (i) mixing (a) a fatty phase, comprising the UpophiUc surfactant, the hydrophiUc surfactant, and the fatty acid and (b) an aqueous phase comprising the basic agent and the cosmetically or dermatologically active apolipoprotein A-IV compound by stirring to obtain a mixture; and (ii) homogenizing the mixture by subjecting the mixture to cavitation.
  • compositions of the invention may, moreover, be advantageously used in combination with other compounds displaying retinoid-type activity, with the D vitamins or derivatives thereof, with corticosteroids, with anti-free radical agents, with alpha -hydroxy or alpha-keto acids or derivatives thereof, or alternatively with ion channel blockers, aU of these different active agents.
  • the present invention therefore also features cosmetic compositions comprising a carrier which is cosmeticaUy acceptable and suitable for a topical appUcation and apoUpoprotein A-IV.
  • a carrier which is cosmeticaUy acceptable and suitable for a topical appUcation and apoUpoprotein A-IV.
  • Such cosmetic compositions are advantageously presented in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or Upid or polymeric vesicles, a soap or a shampoo.
  • the concentration of the apoUpoprotein (apo) A-IV compound, derivative, analog, homolog, fragment or mixtures thereof in the cosmetic compositions according to the invention advantageously ranges from 0.001% to 30% by weight relative to the total composition.
  • the medicinal and cosmetic compositions according to the invention may, in addition, contain inert or even pharmacodynamicaUy or cosmetically active additives or combinations of these additives, and, especiaUy: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emolUents; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; antisebonhoeic or antiacne agents such as S-carboxymethylcysteine, S-benzylcysteamine, salts or derivatives thereof, benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin
  • compositions according to the invention may also contain taste- or flavor- enhancing agents, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV- A and UV-B screening agents, antioxidants such as alpha - tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
  • preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV- A and UV-B screening agents, antioxidants such as alpha - tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
  • apoUpoprotein (apo) A-IV in transgenic mice confers significant protection against atherosclerosis, despite a more severe atherogenic Upid profile (Duverger, N., Tremp, G., CaiUaud, J. M., etal. Protection against atherogenesis in mice mediated by human apolipoprotein ATV. Science 273, 966-968 (1996); Cohen, R. D., CasteUani, L. W., Qiao, J. H., Lenten, B. J. V., Lusis, A. J. & Reue, K. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J. Clin. Invest. 99, 1906-1916 (1997)).
  • apo A-IV a plasma protein
  • Over-expression of either human or mouse apo A-IV (a plasma protein) in transgenic mice confers significant protection against diet-induced atherosclerosis in cholesterol-fed animals (Duverger, N., Tremp, G., CaiUaud, J. M., et al. Protection against atherogenesis in mice mediated by human apolipoprotein AIV. Science 273, 966-968 (1996); Cohen, R D., CasteUani, L. W., Qiao, J. H., Lenten, B. J. V., Lusis, A J. & Reue, K. Reduced aortic lesions and elevated high density Upoprotein levels in transgenic mice overexpressing mouse apoUpoprotein A-IV. J. Clin. Invest.
  • Atherosclerosis is the presence of oxidized lipids in lipoproteins and in the lesions (Chisolm LTI, G. M. & Penn, M. S. in Atherosclerosis and coronary artery disease (eds Fuster, V., Ross, R. & Topol, EJ.) Vol. 1, 129-149 (Lippincott-Raven, Philadelphia, 1996); Ralph, J. A. & Heinecke, J. W. The role of oxidized lipoproteins in atherogenesis. Free Radic. Biol. Med 20, 707-727 (1996)). In this study, we assessed the role of apoA-IV in protecting against lipid oxidation.
  • apo A-IV The ability of apo A-IV to prevent LDL oxidation was further compared with that of apoE by monitoring the formation of conjugated dienes.
  • the addition of 2.5 ⁇ g/ml of apo A-IV increased the lag time of Cu 2+ -induced conjugated diene formation in LDL by 3 -fold and 5 ⁇ g/ml of apo A-IV totaUy aboUshed conjugated diene formation.
  • rat and human apoE (20 ⁇ g/ml) increased the lag time of Cu 2+ - induced conjugated diene formation in LDL by only 1.3- and 1.5-fold, respectively (Fig. 2).
  • apoA-IV may play an important role in preventing the oxidation of lipoproteins in vivo.
  • many antioxidants exist in nature apo A-IV is unique because: (i) unlike exogenous anti-oxidants such as a-tocopherol, ascorbate and b- carotene, apoA-IV is synthesized in the body and thus is a natural antioxidant; (ii) apoA- IV's production by the intestine is directly correlated with fat intake; and (in) apo A-IV is amphipathic and is distributed in lipoprotein-bound and lipoprotein-free forms in circulation.
  • LDL oxidation was also determined by the formation of conjugated dienes (Kleinveld, H. A., Hak-Lemmers, H. L. M., Stalenhoef, A. F. H. & Demacker, P. N. M. Improved measurement of low-density-lipoprotein susceptibility to copper-induced oxidation: Application of a short procedure for isolating low-density lipoprotein. Clin. Chem. 38, 2066-2072 (1992)).
  • LDL (50 ⁇ g/ml) was oxidized using 10 ⁇ M CuSO at 30°C in a quartz cuvette and absorbance readings at 234 nm were taken every 5 min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte à un procédé et à un dispositif permettant d'inhiber l'oxydation de lipides. Conformément à la présente invention, on a fabriqué un certain nombre de nouveaux peptides suppresseurs de l'oxydation des lipides, à partir d'apolipoprotéine A-IV. Ces peptides présentent des propriétés d'inhibition de l'oxydation des lipides et peuvent, lorsqu'ils sont administrés par voie orale ou intraveineuse, servir à réduire l'athérosclérose. Etant donné que ces peptides comprennent des parties spécifiques de la protéine apo A-IV native, leur administration à des sujets humains ne devrait pas poser de problèmes d'immunogénicité.
EP99914142A 1998-03-31 1999-03-25 Peptides antioxydants Withdrawn EP1068239A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8013198P 1998-03-31 1998-03-31
US80131P 1998-03-31
PCT/US1999/006580 WO1999050286A2 (fr) 1998-03-31 1999-03-25 Peptides antioxydants

Publications (1)

Publication Number Publication Date
EP1068239A2 true EP1068239A2 (fr) 2001-01-17

Family

ID=22155452

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99914142A Withdrawn EP1068239A2 (fr) 1998-03-31 1999-03-25 Peptides antioxydants

Country Status (2)

Country Link
EP (1) EP1068239A2 (fr)
WO (1) WO1999050286A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001278864A1 (en) 2000-06-30 2002-01-30 University Of Cincinnati Peptides with antioxidant and antimicrobial properties
GB2368339B (en) 2000-10-26 2002-09-18 Yissum Res Dev Co Complex incorporating a plurality of antioxidants
WO2003035683A2 (fr) * 2001-10-26 2003-05-01 Uffe Holmskov Proteine tensioactive d et atherosclerose
US11912785B2 (en) 2017-12-06 2024-02-27 Steven W. Bailey Peptide compositions for slowing degradation of vitamin mineral supplements, foods, pharmaceutical and cosmetics

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2686605B1 (fr) * 1992-01-27 1994-03-11 Rhone Poulenc Rorer Sa Nouveaux polypeptides, leur preparation et leur utilisation.
WO1995025749A2 (fr) * 1994-03-22 1995-09-28 Research Corporation Technologies, Inc. Peptides coupe-faim

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9950286A3 *

Also Published As

Publication number Publication date
WO1999050286A2 (fr) 1999-10-07
WO1999050286A3 (fr) 1999-11-18

Similar Documents

Publication Publication Date Title
US20080020983A1 (en) Peptides with antioxidant and antimicrobial properties
US5840688A (en) Eating suppressant peptides
Phelps et al. Cloning and characterization of the mitochondrial phosphate transport protein gene from the yeast Saccharomyces cerevisiae
JP5180074B2 (ja) サイモシンβ４誘導体及びその使用方法
US20090022674A1 (en) Cosmetic or dermatological preparations comprising oligopeptides for lightening the skin of age marks and/or for preventing tanning of the skin, in particular tanning of the skin caused by uv radiation
Zitnik et al. The cloning and characterization of a murine secretory leukocyte protease inhibitor cDNA
KR101092915B1 (ko) 성장인자―유래 펩타이드 및 이의 용도
EP1068239A2 (fr) Peptides antioxydants
CA3034066C (fr) Conjugue de minoxidil et d'un peptide
US6296857B1 (en) Cosmetic or dermatological preparations comprising oligopeptides for lightening the skin of age marks and/or for preventing tanning of the skin, in particular tanning of the skin caused by UV radiation
KR101622524B1 (ko) 안정한 펙시가난 제제
AU2018264739B2 (en) Conjugate of isotretinoin and peptide
US20230181441A1 (en) Trolox-peptide conjugate and use thereof
EP0679659B1 (fr) Polypeptide a inhibition specifique de la cathepsine l
EP1093804A1 (fr) Compositions cosmetiques ou dermatologiques contenant des oligopeptides pour l'eclaircisement de la peau
KR102607534B1 (ko) TATdMt 펩타이드를 포함하는 미백 조성물
KR20180019974A (ko) 지방분해 촉진 효과를 가지는 펩타이드, 및 이의 용도
FR2701955A1 (fr) Facteur de croissance de la famille de l'HARP, procédé d'obtention et applications.
JP4242728B2 (ja) 新規生理活性ペプチド及びその用途
KR20230057931A (ko) 보툴리눔 유래 펩타이드를 포함하는 탈모개선용 조성물
OA19189A (en) Conjugate of Minoxidil and Peptide.
OA19680A (en) Conjugate of Isotretinoin and Peptide.
KR20130032787A (ko) 심혈관 질환 예방 및 치료용 펩타이드 및 이의 용도

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20001025

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20031001