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WO2008143879A2 - Complément de vitamine e destiné à réduire les risques d'événements cardio-vasculaires chez des individus souffrant de diabète sucré et à génotype hp 2-2 - Google Patents

Complément de vitamine e destiné à réduire les risques d'événements cardio-vasculaires chez des individus souffrant de diabète sucré et à génotype hp 2-2 Download PDF

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WO2008143879A2
WO2008143879A2 PCT/US2008/006157 US2008006157W WO2008143879A2 WO 2008143879 A2 WO2008143879 A2 WO 2008143879A2 US 2008006157 W US2008006157 W US 2008006157W WO 2008143879 A2 WO2008143879 A2 WO 2008143879A2
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composition
compound
vitamin
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aryl
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WO2008143879A3 (fr
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Andrew Levy
Noah Berkowitz
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Rappaport Family Institute for Research in the Medical Sciences
Synvista Therapeutics Inc
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Rappaport Family Institute for Research in the Medical Sciences
Synvista Therapeutics Inc
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    • G—PHYSICS
    • G06—COMPUTING OR CALCULATING; COUNTING
    • G06F—ELECTRIC DIGITAL DATA PROCESSING
    • G06F1/00—Details not covered by groups G06F3/00 - G06F13/00 and G06F21/00
    • G06F1/24—Resetting means

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  • This invention is directed to methods and compositions of determining the benefit of therapy using vitamin - E for the treatment of cardiovascular events in individuals with diabetes melitus based on their Haptoglobin phenotype and the treatment of the cardiovascular events using vitamin-E based on the haptoglobin phenotype.
  • High dose antioxidant therapy may only provide benefit to individuals who suffer from particularly high levels of oxidative stress.
  • the invention provides a method of determining prognosis for a diabetic subject having a cardiovascular complication, to benefit from supplementation of vitamin - E, comprising the step of obtaining a biological sample from the subject; and determining the subject's haptoglobin allelic genotype, whereby a subject expressing the Hp-2-2 genotype will benefit from supplementation of vitamin - E
  • the invention provides a method of treating, or inhibiting or suppressing or reducing symptoms associated with a diabetic subject having a cardiovascular complication, comprising the step of contacting the subject with an effective amount of a composition comprising glutathione peroxidase or its isomer, metabolite, and/or salt therefore, and vitamin - E, thereby treating vascular complication.
  • the invention provides a composition for treating a cardiovascular complication in a subject comprising: a therapeutically effective amount of a composition comprising glutathione peroxidase or its isomer, metabolite, and/or salt therefore and vitamin - E.
  • FIG. 1 shows Participants flow chart
  • This invention relates in one embodiment to methods and in another embodiment, to compositions for determining the benefit of therapy using vitamin - E for the treatment of cardiovascular events in individuals with diabetes melitus based on their Haptoglobin phenotype and the treatment of the cardiovascular events using vitamin-E based on the haptoglobin phenotype
  • the haptoglobin (Hp) genotype helps to identify patients with high levels of oxidative stress and who will benefit from antioxidant therapy with vitamin E.
  • the Hp gene is polymorphic with two common classes of alleles denoted 1 and 2. It was demonstrated that the Hp 2 allele protein product is an inferior antioxidant compared to the Hp 1 allele protein product. These differences in antioxidant protection are profoundly accentuated in the diabetic state resulting in a marked relative increase in oxidative stress in Hp 2 transgenic mice and Hp 2-2 individuals with DM.
  • Hp 2-2 DM individuals have been shown to have as much as a 500% increase in cardiovascular events as compared to Hp 1-1 and Hp 2-1 DM individuals.
  • vitamin E provides cardiovascular benefit to DM individuals with the Hp 2-2 genotype.
  • a method of determining prognosis for a diabetic subject having a cardiovascular complication, to benefit from supplementation of vitamin - E comprising the step of obtaining a biological sample from the subject; and determining the subject's haptoglobin allelic genotype, whereby a subject expressing the Hp-2-2 genotype will benefit from supplementation of vitamin - E.
  • vitamin E is added to foods in one of its more chemically stable forms, e.g., .alpha.-tocopher ⁇ l acetate (also known as .alpha.-tocopheryl acetate).
  • vitamin E the alcohol and ester forms of synthetic racemic (rac) vitamin E and the alcohol and ester forms of natural (RRR) vitamin E
  • rac racemic
  • RRR alcohol and ester forms of natural
  • the vitamin E is selected from the group consisting of alpha, beta, gamma and delta tocopherols, alpha, beta, gamma and delta tocotrienols, and combinations thereof.
  • the alpha tocopherol group is selected from the group consisting of synthetic (all-rac) and natural (RRR) alpha-tocopherols, alpha-tocopheryl acetates, and alpha-tocopheryl succinates.
  • the Hp 2-2 genotype is associated with a markedly increased incidence of cardiovascular disease in the setting of DM.
  • Hp 2-2 Apo E ⁇ ' ⁇ mice have increased atherosclerotic plaque macrophage content, iron and oxidation as compared to Hp 1-1 Apo E ⁇ mice.
  • reverse cholesterol transport is impaired in Hp 2-2 DM mice.
  • the antioxidant function of Hp is due to its ability to neutralize hemoglobin which is capable of generating the highly reactive hydroxyl radical. Micro-hemorrhages resulting in liberation of extravascular extracorpuscular hemoglobin are of increased frequency and severity in diabetic atherosclerosis.
  • the Hp 1-1 protein is superior to the Hp 2-2 protein in protecting against extracorpuscular hemoglobin as a result of its better ability to prevent release of heme from the Hp-hemoglobin complex and to promote uptake of the Hp-hemoglobin complex via the macrophage CD 163 receptor.
  • Haptoglobin is inherited by two co-dominant autosomal alleles situated on chromosome 16 in humans, these are HpI and Hp2. There are three phenotypes HpI-I , Hp2-1 and Hp2-2.
  • Haptoglobin molecule is a tetramer comprising of four polypeptide chains, two alpha and two beta chains, of which alpha chain is responsible for polymorphism because it exists in two forms, alpha-1 and alpha-2.
  • HpI- 1 is a combination of two alpha-1 chains along with two beta chains.
  • Hp2-1 is a combination of one ⁇ - 1 chain and one alpha-2 chain along with two beta chains.
  • Hp2-2 is a combination of two ⁇ -2 chains and two beta chains.
  • HpI-I individuals have greater hemoglobin binding capacity when compared to those individuals with Hp2-1 and Hp2-2.
  • the gene differentiation to Hp-2 from Hp-I resulted in a dramatic change in the biophysical and biochemical properties of the haptoglobin protein encoded by each of the 2 alleles.
  • the gene differentiation to Hp-2 from Hp-I resulted in a dramatic change in the biophysical and biochemical properties of the haptoglobin protein encoded by each of the 2 alleles.
  • the haptoglobin phenotype of any individual, 1-1, 2-1 or 2-2 is readily determined in one embodiment, from 10 ⁇ l of plasma by gel electrophoresis.
  • antioxidant therapy may be beneficial in specific subgroups with increased oxidative stress.
  • Oxidative Stress refers in one embodiment to a loss of redox homeostasis (imbalance) with an excess of reactive oxidative species (ROS) by the singular process of oxidation. Both redox and oxidative stress are associated in another embodiment, with an impairment of antioxidant defensive capacity as well as an overproduction of ROS.
  • the methods and compositions of the invention are used in the treatment of complications or pathologies resulting from oxidative stress in subjects.
  • activated neutrophils and tissue macrophages use an NADPH cytochrome b-dependent oxidase for the reduction of molecular oxygen to superoxide anions.
  • fibroblasts are also be stimulated to produce ROS in response to pro-inflammatory cytokines.
  • prolonged production of high levels of ROS cause severe tissue damage.
  • high levels of ROS cause DNA mutations that can lead to neoplastic transformation. Therefore and in one embodiment, cells in injured tissues such as glial cells and neurons, must be able to protect themselves against the toxic effects of ROS.
  • ROS-detoxifying enzymes have an important role in epithelial wound repair.
  • the glutathione peroxidase mimetics provided in the compositions and compounds provided herein, replace the ROS detoxifying enzymes described herein.
  • ROS reactive oxygen species
  • H2O2 hydrogen peroxide
  • OY superoxide anion
  • NO nitric oxide
  • SO 2 singlet oxygen
  • FRSEs Endogenous free radical scavenging enzymes
  • SOD superoxide dismutase
  • GPX glutathione peroxidase
  • catalase catalase
  • SOD catalyses the dismutation of OY to H 2 O 2 and molecular oxygen (O 2 ), resulting in selective O 2 " scavenging.
  • GPX and catalase independently decompose H 2 O 2 to H 2 O.
  • ROS is released from the active neutrophils in the inflammatory tissue, attacking DNA and/or membrane lipids and causing chemical damage, including in one embodiment, to healthy tissue.
  • H2O2 is reduced into hydroxyl radical (OH), which is one of the highly reactive ROS responsible in one embodiment for initiation of lipid peroxidation of cellular membranes.
  • organic peroxide-induced lipid peroxidation is implicated as one of the essential mechanisms of toxicity in the death of hippocampal neurons.
  • an indicator of the oxidative stress in the cell is the level of lipid peroxidation and its final product is MDA.
  • the level of lipid peroxidation increases in inflammatory diseases, such as meningitis in one embodiment.
  • the compounds provided herein and in another embodiment are represented by the compounds of formula I-X, are effective antioxidants, capable of reducing lipid peroxidation, or in another embodiment, are effective as antiinflammatory agents.
  • a subject expressing the Hp-2-2 genotype will benefit from supplementation of vitamin - E, is effected by a signal amplification method, whereby said signal amplification method is PCR, LCR (LAR), Self-Sustained Synthetic Reaction (3SR/NASBA), Q-Beta (Q ⁇ ) Replicase reaction, or a combination thereof.
  • a signal amplification method is PCR, LCR (LAR), Self-Sustained Synthetic Reaction (3SR/NASBA), Q-Beta (Q ⁇ ) Replicase reaction, or a combination thereof.
  • the signal amplification methods provided herein which in another embodiment, can be carried out using the systems provided herein, may amplify a DNA molecule or an RNA molecule.
  • signal amplification methods used as part of the present invention include, but are not limited to PCR, LCR (LAR), Self-Sustained Synthetic Reaction (3SR/NASBA) or a Q-Beta (Q.beta.) Replicase reaction.
  • PCR Polymerase Chain Reaction
  • PCR refers in one embodiment to a method of increasing the concentration of a segment of target sequence in a mixture of genomic DNA without cloning or purification. This technology provides one approach to the problems of low target sequence concentration.
  • This process for amplifying the target sequence involves the introduction of a molar excess of two oligonucleotide primers which are complementary to their respective strands of the double-stranded target sequence to the DNA mixture containing the desired target sequence. The mixture is denatured and then allowed to hybridize. Following hybridization, the primers are extended with polymerase so as to form complementary strands. The steps of denaturation, hybridization (annealing), and polymerase extension (elongation) can be repeated as often as needed, in order to obtain relatively high concentrations of a segment of the desired target sequence.
  • the length of the segment of the desired target sequence is determined by the relative positions of the primers with respect to each other, and, therefore, this length is a controllable parameter. Because the desired segments of the target sequence become the dominant sequences (in terms of concentration) in the mixture, in one embodiment, they are said to be "PCR-amplified.” 0
  • Ligase Chain Reaction (LCR or LAR): The ligase chain reaction [LCR; referred to, in another embodiment as “Ligase Amplification Reaction” (LAR)] has developed into a well-recognized alternative method of amplifying nucleic acids.
  • LCR four oligonucleotides, two adjacent oligonucleotides which uniquely hybridize to one strand of target DNA, and a complementary set ofs adjacent oligonucleotides, which hybridize to the opposite strand are mixed in one embodiment and DNA ligase is added to the mixture. Provided that there is complete complementarity at the junction, ligase will covalently link each set of hybridized molecules.
  • LCR LCR-independent background signal
  • the self-sustained sequence replication reaction (3SR) refers in one embodiment, to a transcription-based in vitro amplification system that can exponentially amplify RNA sequences at a uniform temperature.
  • the amplified RNA is utilized in certain embodiments, for mutation detection.
  • an oligonucleotideo primer is used to add a phage RNA polymerase promoter to the 5' end of the sequence of interest.
  • the target sequence undergoes repeated rounds of transcription, cDNA synthesis and second-strand synthesis to amplify the area of interest.
  • 3SR to detect mutations is kinetically limited to screening small segments of DNA (e.g., 200-300 base pairs).
  • Q-Beta (Q ⁇ .) Replicase In one embodiment of the method, a probe which recognizes the sequence of interest is attached to the replicatable RNA template for Q ⁇ . replicase. A previously identified major problem with false positives resulting from the replication of unhybridized probes has been addressed through use of a sequence-specific ligation step. However, available thermostable
  • DNA ligases are not effective on this RNA substrate, so the ligation must be performed by T4 DNA ligase at low temperatures (37 0 C). This prevents the use of high temperature as a means of achieving specificity as in the LCR, the ligation event can be used to detect a mutation at the junction site, but not elsewhere.
  • reaction conditions reduce the mean efficiency to 85%, then the yield in those 20 cycles will be only 1.85 20 , or 220,513 copies of the starting material.
  • a PCR running at 85% efficiency will yield only 21 % as much final product, compared to a reaction running at 100% efficiency.
  • a reaction that is reduced to 50% mean efficiency will yield less than 1% of the possible product.
  • PCR has yet to penetrate the clinical market in a significant way.
  • LCR LCR must also be optimized to use different oligonucleotide sequences for each target sequence.
  • both methods require expensive equipment, capable of precise temperature cycling.
  • nucleic acid detection technologies such as in studies of allelic variation, involve not only detection of a specific sequence in a complex background, but also the discrimination between sequences with few, or single, nucleotide differences.
  • One method of the detection of allele- specific variants by PCR is based upon the fact that it is difficult for Taq polymerase to synthesize a DNA strand when there is a mismatch between the template strand and the 3' end of the primer.
  • An allele-specific variant may be detected by the use of a primer that is perfectly matched with only one of the possible alleles; the mismatch to the other allele acts to prevent the extension of the primer, thereby preventing the amplification of that sequence.
  • This method has a substantial limitation in that the base composition of the mismatch influences the ability to prevent extension across the mismatch, and certain mismatches do not prevent extension or have only a minimal effect.
  • the methods and systems provided herein for providing a prognosis for a diabetic subject to benefit from supplementation of vitamin - E comprising the steps of: obtaining a biological sample from a subject; determining the Haptoglobin (Hp) genotype in the biological sample that is effected by a direct detection method such as a cycling probe reaction (CPR), or a branched DNA analysis, or a combination thereof in other embodiments.
  • a direct detection method such as a cycling probe reaction (CPR), or a branched DNA analysis, or a combination thereof in other embodiments.
  • the direct detection method according to one embodiment is a cycling probe reaction (CPR) or a branched DNA analysis.
  • cycling probe reaction The cycling probe reaction (CPR) (Duck et al., BioTech., 9: 142, 1990), uses a long chimeric oligonucleotide in which a central portion is made of RNA while the two termini are made of DNA. Hybridization of the probe to a target DNA and exposure to a thermostable RNase H causes the RNA portion to be digested. This destabilizes the remaining DNA portions of the duplex, releasing the remainder of the probe from the target DNA and allowing another probe molecule to repeat the process. The signal, in the form of cleaved probe molecules, accumulates at a linear rate. While the repeating process increases the signal, the RNA portion of the oligonucleotide is vulnerable to RNases that may carried through sample preparation.
  • a subject expressing the Hp-2-2 genotype will benefit from supplementation of vitamin - E, is effected by at least one sequence change, which employs in one embodiment a restriction fragment length polymorphism (RFLP analysis), or an allele specific oligonucleotide (ASO) analysis, a Denaturing/ Temperature Gradient Gel Electrophoresis
  • RFLP analysis restriction fragment length polymorphism
  • ASO allele specific oligonucleotide
  • Restriction fragment length polymorphism For detection of single-base differences between like sequences, the requirements of the analysis are often at the highest level of resolution. For cases in which the position of the nucleotide in question is known in advance, several methods have been developed for examining single base changes without direct sequencing. For example, if a mutation of interest happens to fall within a restriction recognition sequence, a change in the pattern of digestion can be used as a diagnostic tool (e.g., restriction fragment length polymorphism [RFLP] analysis).
  • RFLP restriction fragment length polymorphism
  • MCC Mismatch Chemical Cleavage
  • RFLP analysis suffers from low sensitivity and requires a large amount of sample.
  • RFLP analysis is used for the detection of point mutations, it is, by its nature, limited to the detection of only those single base changes which fall within a restriction sequence of a known restriction endonuclease.
  • the majority of the available enzymes have 4 to 6 base-pair recognition sequences, and cleave too frequently for many large-scale DNA manipulations (Eckstein and Lilley (eds.), Nucleic Acids and Molecular Biology, vol. 2, Springer- Verlag, Heidelberg, 1988). Thus, it is applicable only in a small fraction of cases, as most mutations do not fall within such sites.
  • Allele specific oligonucleotide can be designed to hybridize in proximity to the mutated nucleotide, such that a primer extension or ligation event can bused as the indicator of a match or a mis-match.
  • Hybridization with radioactively labeled allelic specific oligonucleotides also has been applied to the detection of specific point mutations (Conner et al., Proc. Natl. Acad. Sci., 80:278-282, 1983). The method is based on the differences in the melting temperature of short DNA fragments differing by a single nucleotide.
  • DGGE/TGGE Denaturing/Temperature Gradient Gel Electrophoresis
  • the fragments to be analyzed are "clamped” at one end by a long stretch of G-C base pairs (30-80) to allow complete denaturation of the sequence of interest without complete dissociation of the strands.
  • the attachment of a GC “clamp" to the DNA fragments increases the fraction of mutations that can be recognized by DGGE (Abrams et al., Genomics 7:463-475, 1990). Attaching a GC clamp to one primer is critical to ensure that the amplified sequence has a low dissociation temperature (Sheffield et al., Proc. Natl. Acad. Sci., 86:232- 236, 1989; and Lerman and Silverstein, Meth.
  • TGGE temperature gradient gel electrophoresis
  • SSCP Single-Strand Conformation Polymorphism
  • the SSCP process involves denaturing a DNA segment (e.g., a PCR product) that is labeled on both strands, followed by slow electrophoretic separation on a non-denaturing polyacrylamide gel, so that intra-molecular interactions can form and not be disturbed during the run.
  • a DNA segment e.g., a PCR product
  • This technique is extremely sensitive to variations in gel composition and temperature.
  • a serious limitation of this method is the relative difficulty encountered in comparing data generated in different laboratories, under apparently similar conditions.
  • Dideoxy fingerprinting (ddF): The dideoxy fingerprinting (ddF) is another technique developed to scan genes for the presence of mutations (Liu and Sommer, PCR Methods Appli., 4:97, 1994).
  • the ddF technique combines components of Sanger dideoxy sequencing with SSCP. A dideoxy sequencing reaction is performed using one dideoxy terminator and then the reaction products are electrophoresed on nondenaturing polyacrylamide gels to detect alterations in mobility of the termination segments as in SSCP analysis.
  • ddF is an improvement over SSCP in terms of increased sensitivity
  • ddF requires the use of expensive dideoxynucleotides and this technique is still limited to the analysis of fragmenls of the size suitable for SSCP (i.e., fragments of 2O0-3OU bases for optimal detection of mutations).
  • Determination of a haptoglobin phenotype may, as if further exemplified in the Examples section that hereinbelow, may be accomplished directly in one embodiment, by analyzing the protein gene products of the haptoglobin gene, or portions thereof. Such a direct analysis is often accomplished using an immunological detection method.
  • the methods and systems provided herein for providing a prognosis for development of a diabetic subject to benefit from supplementation of vitamion - E comprising the steps of: obtaining a biological sample from a subject; determining the Haptoglobin (Hp) genotype in the biological sample by an immunological detection method, such as is a radio-immunoassay (RlA) in one embodiment, or an enzyme linked immunosorbent assay (ELISA), a western blot, an immunohistochemical analysis, or fluorescence activated cell sorting (FACS), or a combination thereof in other embodiments.
  • an immunological detection method such as is a radio-immunoassay (RlA) in one embodiment, or an enzyme linked immunosorbent assay (ELISA), a western blot, an immunohistochemical analysis, or fluorescence activated cell sorting (FACS), or a combination thereof in other embodiments.
  • Immunological detection methods are fully explained in, for example, "Using Antibodies: A Laboratory Manual” (Ed Harlow, David Lane eds., Cold Spring Harbor Laboratory Press (1999)) and those familiar with the art will be capable of implementing the various techniques summarized hereinbelow as part of the present invention. All of the immunological techniques require antibodies specific to at least one of the two haptoglobin alleles. Immunological detection methods suited for use as part of the present invention include, but are not limited to, radio-immunoassay (RIA), enzyme linked immunosorbent assay (ELISA), western blot, immunohistochemical analysis, and fluorescence activated cell sorting (FACS).
  • RIA radio-immunoassay
  • ELISA enzyme linked immunosorbent assay
  • FACS fluorescence activated cell sorting
  • Radioimmunoassay In one version, this method involves precipitation of the desired substrate, haptoglobin in this case and in the methods detailed hereinbelow, with a specific antibody and radiolabeled antibody binding protein (e.g., protein A labeled with I.sup.125) immobilized on a precipitable carrier such as agarose beads. The number of counts in the precipitated pellet is proportional to the amount of substrate.
  • a specific antibody and radiolabeled antibody binding protein e.g., protein A labeled with I.sup.125
  • a precipitable carrier such as agarose beads.
  • the number of counts in the precipitated pellet is proportional to the amount of substrate.
  • a labeled substrate and an unlabelled antibody binding protein are employed. A sample containing an unknown amount of substrate is added in varying amounts. The decrease in precipitated counts from the labeled substrate is proportional to the amount of substrate in the added sample.
  • Enzyme linked immunosorbent assay This method involves fixation of a sample (e.g., fixed cells or a proteinaceous solution) containing a protein substrate to a surface such as a well of a microtiter plate. A substrate specific antibody coupled to an enzyme is applied and allowed to bind to the substrate. Presence of the antibody is then detected and quantitated by a colorimetric reaction employing the enzyme coupled to the antibody. Enzymes commonly employed in this method include horseradish peroxidase and alkaline phosphatase. If well calibrated and within the linear range of response, the amount of substrate present in the sample is proportional to the amount of color produced. A substrate standard is generally employed to improve quantitative accuracy.
  • Western blot This method involves separation of a substrate from other protein by means of an acrylamide gel followed by transfer of the substrate to a membrane (e.g., nylon or PVDF). Presence of the substrate is then detected by antibodies specific to the substrate, which are in turn detected by antibody binding reagents.
  • Antibody binding reagents may be, for example, protein A, or other antibodies. Antibody binding reagents may be radiolabeled or enzyme linked as described hereinabove. Detection may be by autoradiography, colorimetric reaction or chemiluminescence. This method allows both quantitation of an amount of substrate and determination of its identity by a relative position on the membrane which is indicative of a migration distance in the acrylamide gel during electrophoresis.
  • Immunohistochemical analysis This method involves detection of a substrate in situ in fixed cells by substrate specific antibodies.
  • the substrate specific antibodies may be enzyme linked or linked to fluorophores. Detection is by microscopy and subjective evaluation. If enzyme linked antibodies are employed, a calorimetric reaction may be required.
  • Fluorescence activated cell sorting FACS: This method involves detection of a substrate in situ in cells by substrate specific antibodies. The substrate specific antibodies are linked to fluorophores. Detection is by means of a cell sorting machine which reads the wavelength of light emitted from each cell as it passes through a light beam. This method may employ two or more antibodies simultaneously.
  • determining the haptoglobin phenotype of an individual may be effected using any suitable biological sample derived from the examined individual, including, but not limited to, blood, plasma, blood cells, saliva or cells derived by mouth wash, and body secretions such as urine and tears, and from biopsies, etc.
  • the effectiveness of the compounds provided herein derive from special structural features of the heterocyclic compounds provided herein.
  • having a large number of electrons in the ⁇ orbital overlap around the transition metal incorporated allows the formation of ⁇ -bonds and the donation of an electron to terminate free radicals formed by ROS.
  • the glutathione peroxidase mimetic used in the method of inhibiting or suppressing free radical formation, causing in another embodiment, lipid peroxidation and inflammation is the product of formula (I):
  • GPx cellular GPx
  • gastrointestinal GPx extracellular GPx
  • phospholipid hydroperoxide GPx GPXl
  • cGPx represents a major cellular defense against toxic oxidant species.
  • Peroxides including hydrogen peroxide (H 2 O 2 ), are one of the main reactive oxygen species (ROS) leading to oxidative stress.
  • H 2 O 2 is continuously generated by several enzymes (including superoxide dismutase, glucose oxidase, and monoamine oxidase) and must be degraded to prevent oxidative damage.
  • the cytotoxic effect of H 2 O 2 is thought to be caused by hydroxyl radicals generated from iron-catalyzed reactions, causing subsequent damage to DNA, proteins, and membrane lipids.
  • GPx or its pharmaceutically acceptable salt, its functional derivative, its synthetic analog or a combination thereof, is used in the methods and compositions of the invention.
  • the glutathione peroxidase is represented by formula I:
  • the compound of formula (II) refers to benzisoselen-azoline or -azine derivatives represenetd by the following general formula:
  • R 10 hydrogen; lower alkyl;aralkyl or substituted aralkyl; aryl or substituted aryl;.
  • Alkyl refers to monovalent alkyl groups preferably having from 1 to about 12 carbon atoms, more preferably 1 to 8 carbon atoms and still more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like.
  • the term “lower alkyl” refers to alkyl groups having 1 to 6 carbon atoms.
  • Alkyl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 14 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl, and the like.
  • Aryl refers in another embodiment, to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl).or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
  • such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, aminocarbonyl, alkoxycarbonyl, aryl, carboxyl, cyano, halo, hydroxy, nitro, trihalomethyl and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; --NO 2 ; --CN; — CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH
  • the glutathione peroxidase or its isomer, metabolite, and/or salt therefore, used in the methods and compositions provided herein is an organoselenium compound.
  • organoselenium refers in one embodiment to organic compound comprising at least one selenium atom.
  • Preferred classes of organoselenium glutathione peroxidase mimetics include benzisoselenazolones, diaryl diselenides and diaryl selenides.
  • compositions and methods of treating cardiovascular complication in a diabetic subject comprising organoselenium compounds, thereby increasing endogenous anti-oxidant ability of the cells, or in another embodiment, scavenging free radicals causing apoptosis of cardiovascular organs and tissues and their associated pathologies.
  • compositions for treating a 5 cardiovascular complication in a subject comprising: a therapeutically effective amount of a composition comprising glutathione peroxidase or its isomer, metabolite, and/or salt therefore and vitamin — E.
  • the glutathione peroxidase or its isomer, metabolite, and/or salto therefore used in the compositions and methods provided herein is represented by the compound of formula III:
  • X is O or NH
  • M is Se or Te n is 0-2
  • Ri is oxygen; and o forms an oxo complex with M;or
  • a 4-7 member ring group refers to a saturated cyclic ring. In another embodiment the 4-7 member ring group refers to an unsaturated cyclic ring. In another embodiment the 4-7 member ring group refers to a heterocyclic unsaturated cyclic ring. In another embodiment the 4-7 member ring group refers to a heterocyclic saturated cyclic ring. In one embodiment the 4-7 member ring is unsubstituted.
  • substituent groups may be attached via single or double bonds, as appropriate, as will be appreciated by one skilled in the art.
  • alkyl as used throughout the specification and claims may include both “unsubstituted alkyls” and/or “substituted alkyls", the latter of which may refer to alkyl moieties having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone.
  • such substituents may include, for example, a halogen, a hydroxyl, an alkoxyl, a silyloxy, a carbonyl, and ester, a phosphoryl, an amine, an amide, an imine, a thiol, a thioether, a thioester, a sulfonyl, an amino, a nitro, or an organometallic moiety.
  • a halogen a hydroxyl, an alkoxyl, a silyloxy, a carbonyl, and ester
  • a phosphoryl an amine, an amide, an imine, a thiol, a thioether, a thioester, a sulfonyl, an amino, a nitro, or an organometallic moiety.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amines, imines, amides, phosphoryls (including phosphonates and phosphines), sulfonyls (including sulfates and sulfonates), and silyl groups, as well as ethers, thioethers, selenoethers, carbonyls (including ketones, aldehydes, carboxylates, and esters), - CF 3 , and -CN.
  • substituents may be applied.
  • cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls, carbonyl-substituted alkyls, CF3, and CN.
  • alkyls alkenyls, alkoxys, thioalkyls, aminoalkyls, carbonyl-substituted alkyls, CF3, and CN.
  • substituents may be applied.
  • the compound of formula III, used in the compositions and methods provided herein, is represented by any one of the following compounds or their combinations:
  • the glutathione peroxidase or its isomer, metabolite, and/or salt therefore used in the compositions and methods provided herein is represented by the compound of formula IX:
  • the compound represented formula (IX) is represented by the compound of formula X:
  • the compounds represented by formula I-X mimic the in-vivo activity of glutathione peroxidase.
  • the term “mimic” refers, in one embodiment to comparable, identical, oro superior activity, in the context of conversion, timing, stability or overall performance of the compound, or any combination thereof.
  • Biologically active derivatives or analogs of the proteins described herein include in one embodiment peptide mimetics. These mimetics can be based, for example, on the protein's specific 5 amino acid sequence and maintain the relative position in space of the corresponding amino acid sequence. These peptide mimetics possess biological activity similar to the biological activity of the corresponding peptide compound, but possess a "biological advantage" over the corresponding amino acid sequence with respect to, in one embodiment, the following properties: solubility, stability and susceptibility to hydrolysis and proteolysis.
  • Methods for preparing peptide mimetics include modifying the N-terminal amino group, the C- terminal carboxyl group, and/or changing one or more of the amino linkages in the peptide to a non- amino linkage. Two or more such modifications can be coupled in one peptide mimetic molecule.
  • Other forms of the proteins and polypeptides described herein and encompassed by the claimed s invention include in another embodiment, those which are "functionally equivalent.” In one embodiment, this term, refers to any nucleic acid sequence and its encoded amino acid which mimics the biological activity of the protein, or polypeptide or functional domains thereof in other embodiments.
  • the composition further comprises a carrier, excipient, lubricant, flow aid, processing aid or diluent, wherein said carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof.
  • the composition further comprises a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetner, a film forming agent, or any combination thereof.
  • the compositions provided herein are used for the treatment of ao cardiovascular condition in a diabetic subject, may be present in the form of suspension or dispersion form in solvents or fats, in the form of a nonionic vesicle dispersion or else in the form of an emulsion, preferably an oil-in-water emulsion, such as a cream or milk, or in the form of an ointment, gel, cream gel, sun oil, solid stick, powder, aerosol, foam or spray.
  • the composition is a particulate composition coated with a polymer (e.g., poloxamers or poloxamines).
  • compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral.
  • the pharmaceutical composition is administered parenterally, paracancerally, transmucosally,o transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneal, or intracranially.
  • the compositions and methods provided herein permit direct application to the site where it is needed. In the practice of the methods provided herein, it is contemplated that virtually any of the compositions provided herein can be employed.
  • compositions of this invention may be in the form of a pellet, a tablet, a capsule, a solution, a suspension, a dispersion, an emulsion, an elixir, a gel, an ointment, a cream, or a suppository.
  • the composition is in a form suitable for oral, intravenous, intraaorterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration.
  • the composition is a controlled release composition.
  • the composition is an immediate release composition.
  • the composition is a liquid dosage form.
  • the composition is a solid dosage form.
  • compositions provided herein are suitable for oral, intraoral, rectal, parenteral, topical, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, intradural, intraocular, intrarespiratory, nasal inhalation or a combination thereof.
  • the step of administering the compositions provided herein, in the methods provided herein is carried out as oral administration, or in another embodiment, the administration of the compositions provided herein is intraoral, or in another embodiment, the administration of the compositions provided herein is rectal, or in another embodiment, the administration of the compositions provided herein is parenteral, or in another embodiment, the administration of the compositions provided herein is topical, or in another embodiment, the administration of the compositions provided herein is epicutaneous, or in another embodiment, the administration of the compositions provided herein is transdermal, or in another embodiment, the administration of the compositions provided herein is subcutaneous, or in another embodiment, the administration of the compositions provided herein is intramuscular, or in another embodiment, the administration of the compositions provided herein is intranasal, or in another embodiment, the administration of the compositions provided herein is sublingual, or in another embodiment, the administration of the compositions provided herein is buccal, or in another embodiment, the administration of the compositions provided herein is intradural, or in another
  • the term "pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • the nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I are prepared in another0 embodiment, from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,s pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2- hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, b- hydroxybutyric, salicylic, galactaric and
  • Suitable pharmaceutically-acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, 0 sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, in another embodiment, the appropriate acid or base with the compound. 5 [00098]
  • the term "pharmaceutically acceptable carriers” includes, but is not limited to, may refer to 0.01-0. IM and preferably 0.05M phosphate buffer, or in another embodiment 0.8% saline.
  • Such pharmaceutically acceptable carriers may be in another embodiment aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esterso such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • the level of phosphate buffer used as a pharmaceutically acceptable carrier is between about 0.01 to about 0.1 M, or between about 0.01 to about 0.09M in another embodiment, or between about 0.01 to about 0.08M in another embodiment, or between about 0.01 to about 0.07M in another embodiment, or between about 0.01 to about 0.06M in another embodiment, or between about 0.01 to about 0.05M in another embodiment, or between about 0.01 to about 0.04M in another embodiment, or between about 0.01 to about 0.03M in another embodiment, or between about 0.01 to about 0.02M in another embodiment, or between about 0.01 to about 0.015 in another embodiment.
  • the compounds of this invention may include compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al., 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by the administration of such polymer- compound abducts less frequently or in lower doses than with the unmodified compound.
  • water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene
  • compositions used in one embodiment in the methods provided herein can be prepared by known dissolving, mixing, granulating, or tablet- forming processes.
  • active ingredients, or their physiologically tolerated derivatives in another embodiment such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders such as acacia, cornstarch, gelatin, with disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • binders such as acacia, cornstarch, gelatin
  • disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil. Preparations can be effected both as dry and as wet granules.
  • the active ingredients or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other auxiliaries.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • composition described in the embodiments provided herein can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient.
  • An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • compositions described herein which are used in another embodiment, in the methods provided herein, further comprise a carrier, an excipient, a lubricant, a flow aid, a processing aid or a diluent.
  • the active agent is administered in another embodiment, in a therapeutically effective amount.
  • the actual amount administered, and the rate and time-course of administration, will depend in one embodiment, on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage, timing, etc., is within the responsibility of general practitioners or specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington's Pharmaceutical Sciences.
  • targeting therapies may be used in another embodiment, to deliver the active agent more specifically to certain types of cell, by the use of targeting systems such as antibodies or cell specific ligands.
  • Targeting may be desirable in one embodiment, for a variety of reasons, e.g. if the agent is unacceptably toxic, or if it would otherwise require too high a dosage, or if it would not otherwise be able to enter the target cells.
  • compositions of the present invention are formulated in one embodiment for oral delivery, wherein the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegratingo agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavoring agent, such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder as gum tragacanth, acacia, cornstarch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegratingo agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or
  • elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.
  • the active compounds may be incorporated into sustained-release, pulsed release, controlled release or postponed release preparations and formulations.
  • Controlled or sustained release compositions include formulation in lipophilic depots
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • the composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgeryo 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249: 1527-1533 (1990).
  • compositions are in one embodiment liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl., acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid,
  • buffer content
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
  • particulate compositions coated with polymers e.g., poloxamers or poloxamines.
  • Other embodiments of the compositions of the invention incorporate particulate forms, protective coatings, protease inhibitors, or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal, and oral.
  • compositions of this invention comprise one or more, pharmaceutically acceptable carrier materials.
  • the carriers for use within such compositions are biocompatible, and in another embodiment, biodegradable.
  • the formulation may provide a relatively constant level of release of one active component. In other embodiments, however, a more rapid rate of release immediately upon administration may be desired.
  • release of active compounds may be event-triggered. The events triggering the release of the active compounds may be the same in one embodiment, or different in another embodiment. Events triggering the release of the active components may be exposure to moisture in one embodiment, lower pH in another embodiment, or temperature threshold in another embodiment.
  • the formulation of such compositions is well within the level of ordinary skill in the art using known techniques.
  • Illustrative carriers useful in this regard include microparticles of poly(lactide-co-glycolide), polyacrylate, latex, starch, cellulose, dexlran and the like.
  • Other illustrative postponed-release carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysaccharide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound, such as phospholipids.
  • the amount of active compound contained in one embodiment, within a sustained release formulation depends upon the site of administration, the rate and expected duration of release and the nature of the condition to be treated suppressed or inhibited.
  • compositions of the invention are administered in conjunction with one or more therapeutic agents.
  • agents are in other embodiments, age spots removing agents, keratoses removing agents, analgesics, anesthetics, antiacne agents, antibacterial agents, antiyeast agents, antifungal agents, antiviral agents, antiburn agents, antidandruff agents, antidermatitis agents, antipruritic agents antiperspirants, antiinflammatory agents, antihyperkeratolytic agents, antidryskin agents, antipsoriatic agents, antiseborrheic agents, astringents, softeners, emollient agents, coal tar, bath oils, sulfur, rinse conditioners, foot care agents, hair growth agents, powder, shampoos, skin bleaches, skin protectants, soaps, cleansers, antiaging agents, sunscreen agents, wart removers, vitamins, tanning agents, topical antihistamines, hormones, vasodilators and retinoids.
  • compositions described herein are used in the methods described herein. Accordingly and in another embodiment, provided herein is a method of treating a cardiovascular condition in a diabetic subject, comprising: contacting said subject with an effective amount of a composition comprising glutathione peroxidase or its isomer, metabolite, and/or salt therefore.
  • the term "administering” refers to bringing a subject in contact with the compositions provided herein.
  • the compositions provided herein are suitable for oral administration, whereby bringing the subject in contact with the composition comprises ingesting the compositions.
  • bringing the subject in contact with the composition will depend on many variables such as, without any intention to limit the modes of administration; the hemorrhagic event treated, age, pre-existing conditions, other agents administered to the subject, the severity of symptoms, location of the affected are and the like.
  • provided herein are embodiments of methods for administering the compounds of the present invention to a subject, through any appropriate route, as will be appreciated by one skilled in the art [000116]
  • the methods provided herein, using the compositions provided herein further comprise contacting the subject with one or more additional agent, which is not
  • the one or more additional agent not glutathione peroxidase or its isomer, metabolite, and/or salt therefore, nor vitamin - E is an aldosterone inhibitor.
  • the additional agent is an angiotensin-converting anzyme.
  • the additional agent is an antioxidant.
  • the additional agent is an angiotensin receptor ATj blockecr
  • the additional agent is an angiotensin II receptor antagonist.
  • the additional agent is a calcium channel blocker.
  • the additional agent is a diuretic.
  • the additional agent is digitalis.
  • the additional agent is a beta blocker.
  • the additional agent is a statin.
  • the additional agent is a cholestyramine or in another embodiment, the is additional agent is a combination thereof.
  • statins refers to a family of compounds that are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, 2 o the rate-limiting enzyme in cholesterol biosynthesis.
  • HMG-CoA reductase inhibitors in one embodiment, statins reduce plasma cholesterol levels in various mammalian species.
  • Statins inhibit in one embodiment, cholesterol biosynthesis in humans by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A (“HMG-CoA”) reductase enzyme.
  • HMG- 2S CoA reductase catalyzes in another embodiment, the conversion of HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol.
  • Decreased production of cholesterol causes in one embodiment, an increase in the number of LDL receptors and corresponding reduction in the concentration of LDL particles in the bloodstream. Reduction in the LDL level in the bloodstream reduces the risk of coronary artery disease.
  • Statins used in the compositions and methods of the invention are lovastatin (referred to as mevinolin in one embodiment, or monacolin-K in another embodiment), compactin (referred to as mevastatin in one embodiment, or ML-236B in another embodiment), pravastatin, atorvastatin (Lipitor) rosuvastatin (Crestor) fluvastatin (Lescol), simvastatin (Zocor), cerivastatin.
  • the statin used as one or more additional therapeutic agent is any one of the statins described herein, or in another embodiment, in combination of statins. A person skilled in the art would readily recognize that the choice of statin used, will depend on several factors, such as in certain embodiment, the underlying condition of the subject, other drugs administered, other pathologies and the like.
  • the additional agent may be an anti-dyslipidemic agent such as (i) bile acid sequestrants such as, cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivatives, of a cross-linked dextran; ColestidTM; LoCholestTM; and QuestranTM, and the like; (ii) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and ZD-4522, and the like; (iii) HMG-CoA synthase inhibitors; (iv) cholesterol absorption inhibitors such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, vytorin, and the bile acid sequestrant
  • agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW 7647, BM 170744, LY518674; and other fibric acid derivatives, such as AtromidTM, LopidTM and TricorTM, and the like;
  • FXR receptor modulators such as GW 4064, SR 103912, and the like;
  • LXR receptor such as GW 3965, T9013137, and XTCO 179628, and the like;
  • lipoprotein synthesis inhibitors such as niacin;
  • bile acid reabsorption inhibitors such as BARI 1453, SC435, PHA384640, S892.1,
  • agonists such as GW 501516, and GW 590735, and the like;
  • triglyceride synthesis inhibitors such as GW 501516, and GW 590735, and the like;
  • MTTP microsomal triglyceride transport
  • inplitapide such as inplitapide, LAB687, and CP346086, and the like;
  • transcription modulators such as squalene epoxidase inhibitors;
  • squalene epoxidase inhibitors such as low density lipoprotein (LDL) receptor inducers;
  • platelet aggregation inhibitors such as GW 501516, and GW 590735
  • MTTP microsomal triglyceride transport
  • niacin receptor agonists such as GW 501516, and GW 590735, and the like.
  • the additional agent administered as part of the compositions, used in the methods provided herein is an anti-hypertensive agents such as (i) diuretics, such as thiazides, including chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics, such as bumetanide, ethacrynic acid, furosemide, and torsemide; potassium sparing agents, such as amiloride, and triamterene; and aldosterone antagonists, such as spironolactone, epirenone, and the like; (ii) beta-adrenergic blockers such as acebutolol, atenolol, betaxoioi, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, es
  • diuretics such as
  • Combinations of anti- obesity agents and diuretics or beta blockers may further include vasodilators, which widen blood vessels.
  • vasodilators useful in the compositions and methods of the present invention include, but are not limited to, hydralazine (apresoline), clonidine (catapres), minoxidil (loniten), and nicotinyl alcohol (roniacol).
  • RAAS renin-angiotensin-aldosterone system
  • RAAS renin-angiotensin-aldosterone system
  • secretion of the enzyme renin from the juxtaglomerular cells in the kidney activates in another embodiment, the renin-angiotensin- aldosterone system (RAAS), acting on a naturally-occurring substrate, angiotensinogen, to release in another embodiment, a decapeptide, Angiotensin I.
  • Angiotensin converting enzyme cleaves in one embodiment, the secreated decapeptide, producing an octapeptide, Angiotensin II, which is in another embodiment, the primary active species of the RAAS system.
  • Angiotensin II stimulates in one embodiment, aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, stimulating vasopressin secretion, causing a positive cardiac inotropic effect or modulating other hormonal systems in other embodiments.
  • the angiotensin converting enzyme (ACE) inhibitor used in the methods and compositions of the invention is captopril, cilazapril, delapril, enalapril, fentiapril, fosinopril, indolapril, lisinopril, perindopril, pivopril, quinapril, ramipril, spirapril, trandolapril, zofenopril or a combination thereof.
  • a representative group of ACE inhibitors consists in another embodiment, of the following compounds: AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL- 242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, I5B2, indolapril, ketomethylureas, KRI-1 177, KRI-1230, L-681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS-41 , nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH-0399, ROO-91 1 , RS-10085-197, RS-2039, RS 5139
  • aldosterone antagonist and “aldosterone receptor antagonist” refer to a compound that inhibits the binding of aldosterone to mineralocorticoid receptors, thereby blocking the biological effects of aldosterone.
  • antagonists include partial antagonists and in another embodiment full antagonists.
  • the term “full antagonist” refers to a compound that evokes the maximal inhibitory response from the Aldosterone, even when there are spare (unbound) Aldosterone present.
  • the term “partial antagonist” refers to a compound does not evoke the maximal inhibitory response from the androgen receptor, even when present at concentrations sufficient t ⁇ saturate the androgen receptors present.
  • the aldosterone antagonists used in the methods and compositions of the present s invention are in one embodiment, spirolactone-type steroidal compounds.
  • the term "spirolactone-type" refers to a structure comprising a lactone moiety attached to a steroid nucleus, such as, in one embodiment, at the steroid "D" ring, through a spiro bond configuration.
  • a subclass of spirolactone-type aldosterone antagonist compounds consists in another embodiment, of epoxy-steroidal aldosterone antagonist compounds such as eplerenone.
  • o spirolactone-type antagonist compounds consists of non-epoxy-steroidal aldosterone antagonist compounds such as spironolactone.
  • the invention provides a composition comprising an aldosterone antagonist, its isomer, functional derivative, synthetic analog, pharmaceutically acceptable salt or combination thereof; and a glutathione peroxidase or its isomer, functional derivative, synthetic analog, pharmaceutically acceptable salt or combination thereof,s wherein the aldosterone antagonist is epoxymexrenone, or eplerenone, dihydrospirorenone, 2,2;6,6- diethlylene-3oxo-17alpha-pregn-4-ene-21 , 17-carbolactone, spironolactone, 18-deoxy aldosterone, 1 ,2- dehydro-18-deoxyaldosterone, RU28318 or a combination thereof in other embodiments.
  • the antioxidants include small-molecule antioxidants ando antioxidant enzymes.
  • Suitable small-molecule antioxidants include, in another embodiment, hydralazine compounds, glutathione, vitamin C, vitamin E, cysteine, N-acetyl-cysteine, .beta.- carotene, ubiquinone, ubiquinol-10, tocopherols, coenzyme Q, and the like.
  • Suitable antioxidant enzymes include in one embodiment superoxide dismutase, catalase, glutathione peroxidase, or a combination thereof.
  • Suitable antioxidants are described more fully in the literature, such as in5 Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Twelfth Edition, Version 12: 1 ,1996.
  • angiotensin II (AH) is one of the most potent endogenous vasoconstrictors known, exerts in one embodiment, stimulation on the release0 of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, (RAAS) by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
  • RAAS renin-angiotensin system
  • the angiotensin II receptor antagonist used in the compositions and methods of the invention is Iosartan, irbesartan, eprosartan, candesartan, valsartan, telmisartan, zolasartin, tasosartan or a combination thereof.
  • angiotensin II receptor antagonists used in the compositions and methods of the invention are in one embodiment biphenyltetrazole compounds or biphenylcarboxylic acid compounds or CS-866, Iosartan, candesartan, valsartan or irbesartan in other embodiments.
  • the angiotensin II receptor antagonists of the compositions and methods used in the present invention are optical isomers and mixtures of said isomers. In one embodiment, hydrates of the above- mentioned compounds are also included.
  • Depolarization triggers in another embodiment, entry of small amounts of Ca 2+ through the L-type Ca + channels located on the cell membrane, which in one embodiment, prompts SR Ca + release by cardiac ryanodine receptors (RyR's), a process termed calcium-induced Ca 2+ release.
  • RyR's cardiac ryanodine receptors
  • activation of the ATP-dependent calcium pump recycles cytosolic Ca 2+ into the SR to restore sarcomere relaxation.
  • Ca + channel blockers inhibits the triggering of sarcomer contraction and modulate increase in cystolic pressure.
  • calcium channel blockers are amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, clentiazem, diltiazen, efonidipine, fantofarone, felodipine, isradipine, lacidipine, lercanidipine, manidipine, mibefradil, nicardipine, nifedipine, nilvadipine, nisoldipine, nitrendipine, semotiadil, verapamil, and the like.
  • Suitable calcium channel blockers are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, Twelfth Edition, Version 12: 1 , 1996; and on STN Express, file phar and file registry, which can be used in the compositions and methods of the invention.
  • the ⁇ -blocker used in the compositions and methods of the invention is propanalol, terbutalol, labetalol propranolol, acebutolol, atenolol, nadolol, bisoprolol, metoprolol, pindolol, oxprenolol, betaxolol or a combination thereof.
  • angiotensin II receptor blocker ARB refers in one embodiment to a pharmaceutical agent that selectively blocks the binding of All to the ATi receptor.
  • ARBs provide in another embodiment, a more complete blockade of the RAAS by preventing the binding of All to its primary biological receptor (All type 1 receptor [ATi]).
  • the ARB used in the methods and compositions of the invention is candesartan, eprosartan, irbesartan losartan, olmesartan, telmisartan, valsartan or a combination thereof.
  • a diuretic is used in the methods and compositions of the invention.
  • the diuretic is chlorothiazide, hydrochlorothiazide, mehtylclothiazide, chlorothalidon, or a combination thereof.
  • the additional agent used in the compositions provided herein is a non-steroidal anti-inflammatory drug (NSAID).
  • NSAID is sodium cromoglycate, nedocromil sodium, PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists.
  • the NSAID is ibuprofen; flurbiprofen, salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, indomethacin, sulindac, etodolac, tolmetin, ketorolac, diclofenac, naproxen, fenoprofen, ketoprofen, oxaprozin, piroxicam, celecoxib, and rofecoxiband a pharmaceutically acceptable salt thereof.
  • the NSAID component inhibits the cyclo-oxygenase enzyme, which has two (2) isoforms, referred to as COX-I and COX-2. Both types of NSAID components, that is both non-selective COX inhibitors and selective COX-2 inhibitors are useful in accordance with the present invention.
  • compositions comprising an additional agent that is not glutathione peroxidase or its isomer, metabolite, and/or salt therefore, nor vitamin - E, are used in the therapies effected by the methods provided herein.
  • a method of treating, or inhibiting or suppressing or reducing the symptoms of cardiovascular complication in a diabetic subject comprising the step of obtaining a biological sample from the subject, determining the haptoglobin genotype expressed by the subject, wherein if the subject expresses Hp-2-2 allele, the subject will benefit from a high-dose supplementation of vitamin - E, as well as contacting the subject with a therapeutically effective amount of a GPx mimetic, represented by any one of the compounds of formula I-X or their combination, whereby the cardiovascular complication is cardiovascular death, myocardial infarct, stroke or their combination.
  • the term “treatment” refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly.
  • the term “treating” refers to reducing incidence, or alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis or combination thereof in other embodiments.
  • Treating embraces in another embodiment, the amelioration of an existing condition.
  • treatment does not necessarily result in the complete absence or removal of symptoms. Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition. The alleviation of a condition that results in a more serious condition is encompassed by this term.
  • preventing refers in another embodiment, to preventing the onset of clinically evident pathologies associated with vascular complications altogether, or preventing the onset of a preclinically evident stage of pathologies associated with vascular complications in individuals at risk, which in one embodiment are subjects exhibiting the Hp-2 allele.
  • the determination of whether the subject carries the Hp-2 allele, or in one embodiment, which Hp allele precedes the methods and administration of the compositions of the invention.
  • Cardiovascular disease is the most frequent, severe and costly complication of type 2 diabetes. It is the leading cause of death among patients with type 2 diabetes regardless of diabetes duration.
  • allelic polymorphism contributes to the phenotypic expression of CVD in diabetic subjects.
  • the methods and compositions of the invention are used in the treatment of CVD in diabetic subjects.
  • MI myocardial infarct
  • an individual who was formerly diagnosed as having severe, stable or unstable angina pectoris can be diagnosed as having had a small
  • myocardial infarct refers to the death of a certain segment of the heart muscle (myocardium), which in one embodiment, is the result of a focal complete blockage in one of the main coronary arteries or a branch thereof.
  • subjects which were formerly diagnosed as having severe, stable or unstable angina pectoris are treated according to the methods or in another embodiment with the compositions of the invention, upon determining these subjects carry the Hp-2 allele and are diabetic.
  • ischemia-reperfusion injury refers in one embodiment to a list of events including: reperfusion arrhythmias, microvascular damage, reversible myocardial mechanical dysfunction, and cell death (due to apoptosis or necrosis). These events may occur in another embodiment, together or separately.
  • Oxidative stress, intracellular calcium overload, neutrophil activation, and excessive intracellular osmotic load explain in one embodiment, the pathogenesis and the functional consequences of the inflammatory injury in the ischemic- reperfused myocardium.
  • the route of administration in the step of contacting in the methods of the invention, using the compositions described herein is optimized for particular treatments regimens. If chronic treatment of cardiovascular complications is required, in one embodiment, administration will be via continuous subcutaneous infusion, using in another embodiment, an external infusion pump. In another embodiment, if acute treatment of vascular complications is required, such as in one embodiment, in the case of miocardial infarct, then intravenous infusion is used.
  • compositions provided herein are administered in conjunction with other therapeutical agents.
  • agents that can be used in combination with the compositions of the invention are agents used to treat diabetes such as insulin and insulin analogs (e.g. LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH.sub.2 ; biguanides: metformin, phenformin, buformin; .alpha.2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glimepiride, repaglinide, meglitinide; other insulin secretagogues: linogliride, A-4166; glita
  • insulin and insulin analogs
  • compositions of the invention are pramlintide acetate (Symlin.TM.), AC2993, glycogen phosphorylase inhibitor and nateglinide. Any combination of agents can be administered as described hereinabove.
  • subject refers in one embodiment to a mammal including a human in need of therapy for, or susceptible to, a condition or its sequelae.
  • the subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, and mice and humans.
  • subject does not exclude an individual that is normal in all respects.
  • Hp phenotyping was performed in the Hp core laboratory on hemoglobin-enriched serum by polyacrylamide electrophoresis An Hp phenotype (Hp 1-1 , Hp 2-1 or Hp 2-2) is obtained using this method in over 98% of individuals with a reproducibility of greater than 99%. 26
  • This method provides a signature banding pattern for each of the three possible Hp phenotypes with which we have demonstrated 100% correspondence to the three possible Hp genotypes of identical nomenclature as determined by PCR
  • Individuals with Hp 2-2 were approached by their primary care physician and consented to participate in the treatment phase of the study. Only after signing this second ICF were patients provided with a medication bottle to begin the treatment phase of the study.
  • DM individuals with the Hp 2-2 genotype providing consent for the treatment phase of the study were randomly allocated to receive either placebo or vitamin E (natural source d-alpha tocopherol) at a dose of 400 IU per day for the duration of the study.
  • Placebo pills were identical to vitamin E pills except that they contained no vitamin E. Pills were supplied in bottles identical in appearance having only the participant's enrollment number on the bottle. Treatment allocation was blinded for all study participants, physicians and the study staff. All treatment decisions regarding routine care remained at the discretion of the patient's primary care physician. Assessment of S compliance was based on telephone interviews.
  • a computer generated randomization list was used to assign individuals to the twoo treatment groups. At the site of study drug manufacture all medication bottles were labeled with a number in accordance with the computer generated randomization key. A medication bottle number was assigned to potential participants in the study coordination center after receiving formal documentation from the Hp core laboratory that an individual was Hp 2-2. The coordination center then assigned that individual the next available bottle number in sequence and that bottle was sent tos the patient's primary care clinic where it was to be distributed by the primary physician only after the individual consented to participate in the treatment phase of the study and signed the second ICF. A large number of Hp 2-2 patients who underwent randomization declined to sign the second ICF and therefore never received the study medication.
  • Cardiovascular death was defined as either (1) unexplained death due to ischemic cardiovascular disease occurring within 24 hours after the onset of symptoms or (2) death from myocardial infarction or stroke within 7 days after the myocardial infarction or stroke.
  • Myocardial infarction was defined by the typical rise and fall of serum markers of myocardial necrosis (CK-MB or troponin) with at least one of the following: (a) typical ischemic symptoms; (b) development of pathologic Q-waves on the ECG; (c) ECG changes diagnostic of ischemia.
  • 27 Stroke 5 was defined as a neurologic deficit lasting more than 24 hours. Prespecified secondary endpoints were: total mortality, hospitalization for congestive heart failure, and coronary revascularization.
  • Hp 2-2 individuals who were assigned a medication bottle number by the study coordination center but refused to enter the treatment phase of the study were not included in the treatment group analysis and as they were never provided with or treated with the study medication.
  • Figure 1 provides a flow diagram of the trial comparing vitamin E versus placebo in individuals with the Hp 2-2 genotype and DM.
  • Hp genotype was obtained on 3044 individuals with the distribution: Hp 1 -1 285 (9.4%); Hp 2-1 1248 (41.0%); Hp 2-2 151 1 (49.6%).
  • Hp 1-1 and Hp 2-1 individuals were excluded from randomization but were followed in a registry for primary and secondary endpoints.
  • 151 1 DM individuals identified as Hp 2-2 527 were excluded from the treatment phase of the study due to either closure of the randomization phase of the study or due to a refusal to sign consent to participate in the treatment phase of the study. These 527 DM individuals were also followed in the registry.
  • a total of 984 Hp 2-2 DM individuals were randomized and treated with vitamin E (505) or placebo (479).
  • Creatinine (umol/1) 0.9 (0.3) 0.9 (0.3)
  • Metformin 323 (64.0) 284 (59.2) *p 0.02 increased statin use in placebo group. No other significant differences between groups in any other variable.

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Abstract

Méthodes et compositions permettant de déterminer l'avantage procuré par la prise de vitamine E pour le traitement d'événements cardio-vasculaires chez des individus souffrant de diabète sucré sur la base de leur phénotype d'haptoglobine et pour un tel traitement par la vitamine e E sur la base du phénotype d'haptoglobine.
PCT/US2008/006157 2007-05-14 2008-05-14 Complément de vitamine e destiné à réduire les risques d'événements cardio-vasculaires chez des individus souffrant de diabète sucré et à génotype hp 2-2 Ceased WO2008143879A2 (fr)

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US10/748,177 2003-12-31
US11/798,488 US20080044399A1 (en) 2000-04-20 2007-05-14 Vitamin E supplementation for reducing cardiovascular events in individuals with DM and the Hp 2-2 genotype
US74817707 2007-05-14

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US10058542B1 (en) 2014-09-12 2018-08-28 Thioredoxin Systems Ab Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith

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US7608393B2 (en) * 2000-04-20 2009-10-27 Rappaport Family Institute For Research In The Medical Sciences Methods of predicting a benefit of antioxidant therapy for prevention of cardiovascular disease in hyperglycemic patients

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US10058542B1 (en) 2014-09-12 2018-08-28 Thioredoxin Systems Ab Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith
US11013730B1 (en) 2014-09-12 2021-05-25 Thioredoxin Systems Ab Composition comprising selenazol or thiazalone derivatives and silver and method of treatment therewith

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