US20030153621A1 - Use of 13-hode as a regulator of vascular biocompatibility and an inhibitor of cell hyperplasia - Google Patents

Use of 13-hode as a regulator of vascular biocompatibility and an inhibitor of cell hyperplasia Download PDF

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US20030153621A1
US20030153621A1 US10/257,010 US25701003A US2003153621A1 US 20030153621 A1 US20030153621 A1 US 20030153621A1 US 25701003 A US25701003 A US 25701003A US 2003153621 A1 US2003153621 A1 US 2003153621A1
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hode
pharmaceutical composition
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Michael Buchanan
David Horrobin
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Definitions

  • This invention relates to the regulation of vascular endothelium biocompatibility, as well as to the inhibition of vessel wall (VW) cell and other types of cell hyperplasia following vessel wall (VW) dysfunction and/or injury.
  • this invention relates to dietetic and pharmaceutical preparations of 13-hydroxyoctadeca-9Z, 11E-dienoic acid (13-HODE) and its use to restore vascular endothelial cell biocompatibility, thereby rendering the vasculature less reactive to circulating blood constituents during acute pathophysiological responses and decreasing chronic hyperplasic cell responses during and/or following VW stimulation, dysfunction or injury.
  • Cardiovascular disease is a major cause of morbidity and death in Western societies. It is exacerbated by smoking, hyperlipidemia, hypertension and diabetes. Over the last 40 years, our society has taken multiple steps to reduce cardiovascular disease such as promoting a healthier lifestyle, particularly in regard to smoking and diet. Nonetheless, each year, there are >600,000 percutaneous transluminal coronary angioplasty (PTCA) and surgically invasive procedures, e.g. coronary artery bypass grafting (CABG) in N. America alone, performed in cardiovascular disease patients to improve (cardio)vascular blood flow. While these procedures are beneficial to many patients, the benefits are finite and short-lived, and VW stenosis will reoccur. (RITA Trial Participants.
  • PTCA percutaneous transluminal coronary angioplasty
  • CABG coronary artery bypass grafting
  • restenosis occurs in 25-30% of patients within 6 months of PTCA despite acute heparin treatment, followed by continuous aspirin (ASA) treatment ⁇ oral anticoagulants throughout the 6 month post PTCA period.
  • Heparin is given to accelerate thrombin inhibition by antithrombin III (ATIII), thereby preventing fibrinogen cleavage to fibrin and subsequent fibrin clot formation;
  • ASA is given to acetylate platelet cyclooxygenase, thereby inhibiting thromboxane A 2 (T ⁇ A 2 ) synthesis which renders platelets less reactive to prothrombotic stimuli; an oral anticoagulant, e.g.
  • coumadin is given to decrease the level of vitamin K-dependent procoagulants, thereby decreasing the amounts of procoagulant substrates available for thrombus formation.
  • the current approach to treat cardiovascular disease is to impair platelet function and/or coagulation as a means to prevent (re)occurrence of heart and blood vessel disease. It does not repair the underlying defect, the latter of which if attempted, might return the patient to a normal healthier state.
  • a treatment process which not only corrects the underlying cause of the disease problem but also prevents its onset, is therefore needed.
  • the present invention which relates to the use of 13-HODE in the regulation of blood cell/W compatability per se, offers a more effective approach than do current antithrombotic therapies to both treating and preventing diseases like cardiovascular disease.
  • Vascular restenosis is thought to occur as a result of a combination of intimal smooth muscle cell (SMC) proliferation, SMC synthesis and secretion of extracellular matrix, and VW remodelling.
  • SMC proliferation per se occurs in response to the mitogenic effects of thrombin generated at the time of VW injury, to platelet-derived growth factor (PDGF) secreted by platelets which adhere at the site of VW injury, and to mitogens secreted by activated endothelial cells (Bocan TMA, Guyton JR.
  • Coats et al agree since there is more SMC-derived collagen (and presumeably more SMCs) in non-stenosed VWs than in stenosed VWs (Coats WD et al. 1997; McGee MP et al. 1995.). The opposite might be expected if hyperplasia was the predominate cause for restenosis. Coats et al suggested that the failure of our current antithrombotic therapy to inhibit restenosis as effectively as expected, is because that therapy focuses predominantly on inhibiting SMC proliferation. These conclusions, however, do not consider the heterogeneity of proliferating SMCs and their capacity to synthesise various matrices (Frid MG et al.
  • the restenosis rate in those patients is>4 ⁇ 's the restenosis rate in PTCA patients who do not require a stent (Antoniucci D et al. 1998).
  • the treatment of PTCA patients who require a stent also differs significantly from the treatment of PTCA patients who do not require a stent (Antoniucci D et al. 1998). These differences are likely to affect subsequent outcome, both at the basic and the clinical end point levels. It is more likely that the relative roles of SMC hyperplasia and VW remodelling in restenosis varies depending on the type of injury and the type of the antithrombotic therapy use.
  • the VW is nonthrombogenic and, therefore, biocompatable with the circulating blood.
  • Injured veins and arteries express tissue factor in both their media and intima. This expression increases over time after injury. Tissue factor expression is minimal in uninjured VWs (Channon KM et al. 1997). Tissue factor expression is enhanced further by PMNs and/or monocyte/macrophages, which invade the injury site. This enhancement is dependent on PMN and/or monocyte/macrophage CD18 integrin expression (Channon KM et al. 1997; McGee MP et al. 1995).
  • VW tissue factor expression activates prothrombin, which is widely distributed throughout VW tissue rich in SMCs (McBane RD et al. 1997). Thrombin upregulates endothelial cell PDGF receptor expression, thereby facilitating SMC proliferation (Grandaliano G et al. 1998; DiCorleto PE, Bowen-Pope DF. 1983), and platelet activation. Activated platelets secrete TxA 2 (which is vasoconstrictive), PDGF (which is mitogenic for SMCs) and procoagulants, which exacerbate coagulation (Pakala R et al. 1997). Platelet-related factor Xa/Va activity bound to the injured VW also renders it highly thrombogenic.
  • ASA antiplatelet therapy per se reduces SMC hyperplasia.
  • ASA is beneficial in reducing the risks of stroke, myocardial infarction and transient ischemic attacks in patients with a variety of cardiovascular diseases.
  • the overall risk reduction with ASA is only 25% (Aspirin Trialists' Collaboration. 1994). While this risk reduction is statistically significant, the reduction is modest at best.
  • ASA may benefit only certain subgroup of patients (Buchanan MR, Brister SJ. 1995; Grotemeyer K-H et al. 1993; Grotemeyer KH. 1991). This may be due, in part, to the wide variation in platelet responsiveness to assorted stimuli after ASA ingestion (Mueller MR et al. 1997). The effect of ASA is also finite and has little benefit after 2 years (Aspirin Trialists' Collaboration. 1994).
  • 13-HODE is produced in various cells and tissues of the body, particularly by vascular endothelial cells in healthy vessel walls and by dermal epithelial cells. 13-HODE is formed by the action of an enzyme known as 15-lipoxygenase on the dietary essential fatty acid, linoleic acid. The first step is oxidation of the linoleic acid to give 13-hydroperoxyoctadeca-9Z, 11E-dienoic acid (13-HODE). This is then reduced to 13-HODE. 13-HODE is an important signal transduction molecule which is short-lived and whose synthesis is activated by a variety of different stimuli (Buchanan MR et al.
  • 13-HODE which is an oily liquid can be incorporated in much the same way as its parent fatty acid, linoleic acid, into a range of complex molecules including phospholipids and triglycerides (Spiteller G. 1998; Fang X et al. 1999). 13-HODE which is not incorporated into complex lipids is rapidly metabolized by hydrogenation and beta-oxidation (Bronstein JC, Bull AW. 1993; Hecht, Spiteller G. 1998).
  • Streber's patent describes the use of 13-HODE and other related fatty acids to inhibit aromatase enzymes, which convert androgens to estrogens.
  • the purpose of the treatment is to act on any disease, which is induced by estrogen such as breast cancer, and possibly some types of benign prostatic hyperplasia.
  • all of the evidence provided in Streber's patent is based on data obtained in vitro. There are no experiments, which demonstrate that that invention actually works in vivo.
  • Streber does not provide any details regarding the methods of administration or any practical details as to how the materials might be formulated (although it is stated that ‘tablets or capsules or dragees’ may be used).
  • the daily dose specified ranges from 100 to 1,000 mg, preferably in the 200 to 500 mg range.
  • endogenous VW 13-HODE plays an important role in regulating VW biocompatibility under both healthy and thrombogenic situations.
  • VW cell thrombogenicity varies inversely with VW 13-HODE levels in both animals and humans. Therefore, increasing endogenous levels of 13-HODE in both animals and humans results in a decrease in VW cell thrombogenicity (Weber E et al. 1990; Bertomeu M-C et al. 1990; Brister SJ et al. 1990; Buchanan MR, Brister SJ. 1994); and a decrease in platelet/VW interactions following injury. (Weber E et al. 1990; Bertomeu M-C et al. 1990; Buchanan MR, Brister SJ. 1994); and
  • 13-HODE down regulates the ability of the vitronectin receptor to recognise its ligands, thereby decreasing its adhesivity for vitronectin, fibronectin and fibrin(ogen) (Buchanan MR et al. 1998).
  • PK protein kinases
  • MAP kinase mitogen-activated PK
  • VW cAMP increased VW linoleic acid turnover and subsequent VW 13-HODE synthesis, which, in turn, was associated with decreased platelet/VW interactions at the time of injury (Weber E et al. 1990).
  • the Persantine treatment inhibited SMC hyperplasia 4 weeks after VW injury. Platelet function in these animals was unchanged.
  • Inflammation has been recognized as an integral part, of the thrombotic process as early as 1939 (Mallory GA et al. 1939), yet it is not considered in the rationale for our current antithrombotic therapies.
  • monocytes/macrophages and PMNs express the integrin CD11/CD18 (ICAM), and they release cytokines when activated (Peracchia R et al. 1997; Yasukawa H et al. 1997; Turek JJ et al.
  • Macrophages interacting with the injured vessel wall, accumulate lipid, leading to the formation of a more complex atherosclerotic lesion (Ross R. 1993; Post MJ et al. 1994). Blocking monocyte/macrophage ICAM expression reduces VW hyperplasia significantly (Golino P et al. 1997; Nageh MR et 1997; Natori S et al. 1997). Others have found that radiation ( 90 Sr/Y or 192 Ir) at doses, which selectively impair monocyte/macrophage function also, decreases VW hyperplasia in both rodent and rabbit models (Rubin P et al. 1998; Panek RL et al. 1997; Williams DO.
  • PMNs may attenuate the vessel wall thrombogenicity by providing a source of 13-HODE at the site of blood cell/VW interactions at the time of VW injury (Buchanan MR. 1989; Buchanan MR et al. 1993). Others have argued that PMN-derived oxygen radicals promote ischemia-related damage (Shen J et al. 1996), but this has not been linked to long-term hyperplasia. PMNs also secrete a nitric oxide-like factor, which inhibits platelet function and vasoconstriction (Cerletti C et al. 1992).
  • Monocytes/macrophages normally do not synthesize 13-HODE (Shen J et al. 1996; Shen J et al. 1995). Interestingly however, Shen et al upregulated 15-lipoxygenase in differentiated macrophages and found that 13-HODE synthesis increased. This increase was associated with decreased macrophage lipid accumulation. Fan et al also found that macrophages enriched with linoleic and gamma linolenic acids (substrates for 13-HODE and PGE 1 , respectively), stimulate intracellular SMC cAMP which, in turn, decreases SMC proliferation (Fan YY et al. 1997).
  • 13-HODE inhibits PAF (platelet activating factor)-induced PMN and monocyte/macrophage degranulation and ICAM expression (Cerletti C et al. 1992), thereby preventing further integrin-dependent cell cell and cell ligand interactions.
  • PAF platelet activating factor
  • This invention relates to a method of reducing or inhibiting cell and vessel wall hyperplasia and restoring vessel wall biocompatibility, comprising administering to an animal or human in need of such treatment an amount of 13-hydroxyoctadeca-9Z, 11E-dienoic acid (13-HODE) effective to reduce or inhibit vessel wall thrombogenicity wherein the compound is administered orally.
  • 13-HODE 13-hydroxyoctadeca-9Z, 11E-dienoic acid
  • This invention also relates to the method described above wherein the pharmaceutical composition comprises 13-HODE either in its free form, or with a pharmaceutically acceptable carrier, auxiliary or excipient.
  • the carrier, auxiliary or excipient may be mono-, di- or triglyceride oil, corn, sunflower, safflower, cottonseed, grape seed, olive, evening primrose, borage, fish body and fish liver oils, or an ester of a fatty acid containing 16-26 carbon atoms and one or more double bonds.
  • the ester may be ethyl-eicosapentaenoic (ethyl-EPA), oleic, linoleic, alpha-linoleic, stearidonic, gamma-linolenic, dihomogammalinolenic, arachidonic, docosapentaenoic or docosahexaenoic (DHA).
  • ethyl-EPA ethyl-eicosapentaenoic
  • oleic oleic
  • linoleic alpha-linoleic
  • stearidonic gamma-linolenic
  • dihomogammalinolenic dihomogammalinolenic
  • arachidonic docosapentaenoic or docosahexaenoic (DHA).
  • This, invention also includes a pharmaceutical composition comprising 13-HODE and a fat-soluble antioxidant, such, as, ascorbyl palmitate, tocopherols, and ascorbic acid in the presence of lecithin.
  • a fat-soluble antioxidant such as, ascorbyl palmitate, tocopherols, and ascorbic acid in the presence of lecithin.
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 13-HODE and an additive selected from the group consisting of aggregants, disaggregants, osmotic pressure regulating salts, buffers, sweeteners, and coloring agents.
  • the pharmaceutical composition or 13-HODE of this invention may be administered in the form of a dietetic composition, or as a formulation selected from the group consisting of tablets, dragees, capsules, granules, suppositories, solutions, suspensions and lyophilized compositions.
  • a pharmaceutical composition as described above wherein the daily dose of 13-HODE is equal to or less than 100 mg is also part of this invention.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising 13-HODE and an omega-3 fatty acid (such as EPA, DHA, or any a derivative of EPA or DHA, such as ethyl-EPA or ethyl-DHA).
  • an omega-3 fatty acid such as EPA, DHA, or any a derivative of EPA or DHA, such as ethyl-EPA or ethyl-DHA.
  • the invention includes a method of correcting the inhibition of endogenous 13-HODE synthesis by omega-3 fatty acids by incorporating 13-HODE into formulations of omega-3 fatty acids.
  • the method and the pharmaceutical composition of 13-HODE of this invention may be used to treat cardiovascular or cerebrovascular disease, inflammatory or autoimmune disease, infection with bacteria, viruses, fungi, or protozoa, respiratory disease, gastrointestinal disease, renal or urinary tract disease, skin disease, neurological or psychiatric disease, disease of the reproductive system, diabetes, syndrome X or any complication of diabetes, diseases associated with overactive protein kinases, and diseases associated with endothelial dysfunction.
  • the method and the pharmaceutical composition of 13-HODE of this invention may also be used to treat and/or prevent cancer or the metastatic spread of cancer.
  • FIG. 1 illustrates the cell free plasma 13-HODE levels in rabbits treated orally with 13-HODE (suspended in corn oil, upper; or EPA, lower) at 100 to 1000 ⁇ g/kg/day on days 1 to 7.
  • FIG. 2 illustrates 13-HODE levels in vessel walls obtained from rabbits treated orally with 0 to 100 ⁇ g/kg/day for 7 days. 13-HODE was suspended in corn oil (upper) or EPA (lower) and given on days 1 to 7.
  • FIG. 3 illustrates the effect of 13-HODE, suspended in corn oil, on increase of vessel wall area of injured vessel walls from rabbits treated orally with 0 or 1000 ⁇ g/kg/day for 7 days.
  • FIG. 4 illustrates cell free plasma 13-HODE levels in rabbits treated orally with 13-HODE (suspended in corn oil upper; or EPA, lower) at 100 to 1000 ⁇ g/kg/day on days 1 to 7.
  • FIG. 5 illustrates effect of 13-HODE, suspended in corn oil (upper) or EPA (lower), on increase of vessel wall area of injured vessel walls from rabbits treated orally with 0 to 1000 ⁇ g/kg/day for 7 days.
  • FIG. 6 illustrates the properties of 13-hydroxyoctadeca-9Z, 11E-dienoic acid (13HODE).
  • the present invention demonstrates a method for reducing or inhibiting vessel wall hyperplasis and restoring vessel wall biocompatability in a mammal or human in need of such treatment, by administering an amount of 13-hydroxyoctadeca-9Z, 11E-dienoic acid (13-HODE) effective to reduce or inhibit vessel wall thrombogenicity.
  • 13-HODE 13-hydroxyoctadeca-9Z, 11E-dienoic acid
  • the present invention also specifically demonstrates the beneficial effects of exogenously administered 13-HODE in animals and humans of vascular response to VW injury, including the prevention and treatment of vessel wall hyperplasia, as well as the facilitation of vessel wall disease regression.
  • 13-HODE is one of the factors, which regulates vessel wall biocompatibility, thereby attenuating untoward blood component/vessel wall interactions. It may do this in several ways, one of which probably is to reduce the expression and activation of the vitronectin receptor.
  • abnormalities of vessel wall biocompatibility are associated with a remarkable number of illnesses, including infections, cardiovascular, problems of many types, as well as to problems relating to inflammation, fibrosis and loss of normal metabolic control (Valiance et al. 1997), and tumour cell metastasis.
  • vascular endothelial cells are activated, leading to the loss of the normal vascular permeability barrier, expression of leukocyte adhesion molecules, change in VW surface thromboreactivity, the production of a wide range of cytokines and the upregulation of HLA antigens (Hunt BJ, Jurd KM.).
  • a wide range of illnesses may be caused or exacerbated by endothelial cell activation and damage.
  • the present invention through the regulation of endothelial function in a favourable direction by 13-HODE, will therefore have a desirable effect in a wide variety of diseases encompassing almost every aspect of medicine.
  • the administration of exogenous 13-HODE in this invention is able to compensate for any suppression of endogenous 13-HODE synthesis which can occur as a result of administration of omega-3 fatty acids such as alpha-linoleic acid, docoapentaenoic acid and particularly EPA and docosahexaenoic acid (DHA) (Miller and Ziboh, as above).
  • omega-3 fatty acids such as alpha-linoleic acid, docoapentaenoic acid and particularly EPA and docosahexaenoic acid (DHA) (Miller and Ziboh, as above).
  • EPA and DHA have many desirable actions but sometimes the clinical results of administering EPA and DHA are less favourable than expected, as in the case with attempts to prevent reocclusion after angioplasty (Cairns et al, as above).
  • the co-administration of 13-HODE with EPA or DHA or other omega-3 fatty acids is therefore of particular value.
  • composition according to the present invention can be formulated for administration orally.
  • the composition may be in the form of tablets, capsules, suspensions, emulsions and solutions,
  • Formulations for oral use include tablets, which contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients.
  • the excipients may be, for example, inert diluents, such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch or alginic acid; binding agents, for example, starch, gelatin, or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants etc.
  • the tablets may be uncoated or they may coated by known techniques, optionally to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl momostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as chewing tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the acitve ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • the acitve ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Powders, dispersible powders or granules suitable for preparation of an aqueous suspension by addition of water are also convenient dosage forms of the present invention.
  • Formulation as a suspension provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersion or wetting agents are, for example, naturally-occurring phosphatides, as e.g. lecithin, or condensation products of ethylene oxide with e.g. a fatty acid, a long chain aliphatic alcohol or a partial ester derived from fatty acids and a hexitol or hexitol anhydrides, for example, polyoxyethylene stearate, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate etc.
  • Suitable suspending agents are, for example, sodium carboxymethylcellulose, methylcellulose, sodium alginate etc.
  • the pharmaceutically acceptable carriers or excipients may include emulsifying agents, antioxidants, buffering agents, preservatives, humectants, penetration enhancers, chelating agents, gelforming agents, ointment bases, perfumes and skin protective agents.
  • emulsifying agents are naturally occurring gums, e.g. gum acacia or gum tragacanth, naturally occurring phosphatides, e.g. soybean lecithin and sorbitan monooleate derivatives.
  • antioxidants are butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof and cysteine.
  • preservative are parabens and benzalkonium chloride.
  • humectants are glycerin, propylene glycol, sorbitol and urea.
  • penetration enhancers are propylene glycol, DMSO, triethanoiamine, N,N-dimethylacetamide, N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof, tetrahydrofurfuryl alcohol and Azone.RTM.
  • chelating agents are sodium EDTA, citric acid and phosphoric acid.
  • gel forming agents are Carbopol, cellulose derivatives, bentonit, alginates, gelatin and PVP.
  • ointment bases examples include beeswax, paraffin, cetyl palmitate, vegetable oil, sorbitan esters of fatty acids (Span), polyethyleneglycols and condensation products between sorbitan esters of fatty acids and ethylene oxide, e.g. polyoxyethylene sorbitan monooleate (Tween).
  • Span sorbitan esters of fatty acids
  • Tween polyoxyethylene sorbitan monooleate
  • Dietetic compositions of the present invention may be made up in the form of emulsions, for example, sauces, mayonnaise or margarine.
  • One embodiment of the invention relates to the administration of a pharmaceutical composition, in conjunction with a pharmaceutically acceptable carrier, for the therapeutic effects, which are discussed below.
  • the pharmaceutical composition of 13-HODE is administered orally, and comprises a combination product containing 13-HODE in combination with a carrier from the group consisting of corn, sunflower, safflower, cottonseed, grapeseed, olive, evening primrose, borage, fish body, fish liver oils, ethyl-eicosapentaenoic, oleic, linoleic, alpha-linolenic, stearidonic, gamma-linolenic, dihomogammalinolenic, arachidonic, docosapentaenoic or docosahexaenoic (DHA).
  • a carrier from the group consisting of corn, sunflower, safflower, cottonseed, grapeseed, olive, evening primrose, borage, fish body, fish liver oils, ethyl-eicosapentaenoic, oleic, linoleic, alpha-linolenic, stearidonic
  • the pharmaceutical composition of the present invention comprises a combination product containing 13-HODE in combination with corn oil in a ratio between about 1:3 to about 1:100.
  • a combination product containing 13-HODE in combination with corn oil in a ratio between about 1:3 to about 1:100.
  • 50mg of 13-HODE can be mixed with 450 mg corn oil.
  • the pharmaceutical composition of the present invention comprises a combination product containing 13-HODE in combination with an ester carrier in a ratio of about 1:3 to about 1:100.
  • the pharmaceutical composition of the present invention comprises a combination product containing 13-HODE in combination with an ethyl ester of a 16-26 carbon fatty acid with one or more double bonds, such as ethyl-oleate, ethyl-linolate, ethyl-EPA or ethyl-DHA.
  • the pharmaceutical composition in a further embodiment of the present invention comprises 13-HODE is incorporated into the Sn1 or Sn2 positions of an appropriate phospholipid prior to mixing with a carrier.
  • the pharmaceutical composition comprises 13-HODE and omega-3 fatty acids, like EPA, DHA, derivatives of EPA and DHA, ethyl-EPA and ethyl-DHA.
  • compositions are useful when administered in methods of medical treatment or prophylaxis of a disease, disorder or abnormal physical state associated with abnormalities of vessel wall biocompatibility, including cardiovascular or cerebrovascular, inflammatory or auto-immune, respiratory, gastrointestinal, renal, skin, neurological and psychiatric diseases and cancers.
  • diseases which can be treated or prevented by administering the pharmaceutical composition of the present invention include both Type I, Type II and the precursor Type II diabetes, syndrome X (Cosentino F, Lucher TF. 1998; Steinberg AD. 1997), many types of inflammatory disorders including rheumatoid arthritis and osteoarthritis and autoimmune diseases (Perretti M.
  • endothelial function is impaired by smoking (Motoyama T et al., 1997) in normal people who have a high fat meal (Plotnick GD et al., 1997), and in apparently healthy people who had a low birth weight or who are at risk of cardiac disease (Goodfellow J et al.) Endothelial function is impaired in fit young adults of low birth weight. (Ridker PM et al., 1998) Plasma concentrations of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. (Lancet, 1998).
  • Dosages to be administered depend on individual patient condition, indication of the drug, physical and chemical stability of the drug, toxicity of the desired effect and the chosen route of administration (Robert Rakel, ed., Conn's Current Therapy (1995, W. B. Saunders Company, USA)).
  • 13-HODE is a colourless or very pale yellow oily liquid. Within the body 13-HODE can be metabolized as described earlier or transferred intact between various possible complex lipids including triglycerides, diaglycerides (diacylglycerols), monoglycerides, cholesterol esters and phospholipids of many different types. As a pharmaceutical, 13-HODE may be used as is, or be dissolved in various carriers, or be incorporated into glyceride, ester, phospholipid or other molecules with any appropriate carrier.
  • Glycerides esters of propane diol, ethyl esters and phospholipids to which 13-HODE is co-valently bound and any other molecules or vehicles which can release 13-HODE in a biologically active form within the body all lie within this invention.
  • a real problem is presented by the fact that active daily doses of 13-HODE are in the 50 to 1,000 ⁇ g/kg/day range. The lower end of this range, 100 ⁇ g/kg/day, was shown to be highly biologically active in rabbits. That translates into a 7 mg/day dose for a 70 kg person. Since doses for humans are often considerably lower than doses for animals because of a weight/body surface area scaling, a daily dose of as little as 5 mg or less is really possible. Formulating an oily liquid is such small doses is a problem. It could be absorbed into tabletting materials and tabletted and coated, or micro-encapsulated by methods well known to those skilled in the art.
  • the most convenient and preferred dosage forms of 13-HODE was to dissolve the 13-HODE into a triglyceride oil carrier or an ester. It was found that corn oil is a particularly useful diluent, and that 13-HODE can be readily and conveniently mixed with corn oil in a ratio, for example, from 1:3 to 1:100.
  • Other triglyceride oils such as vegetable oil, including sunflower, safflower, soy, evening primrose, borage, coconut or palm oil, or cottonseed, rapeseed, olive, fish body or fish liver oils may all be used for this purpose.
  • esters for this purpose are esters of fatty acids with 16-26 carbon atoms and one or more double bonds in the chain.
  • Ethyl ester of EPA was found to be particularly appropriate, but equivalent esters of fatty acids such as oleic, linoleic, alpha-linoleic, stearidonic, gamma-linoleic, dihomogammalinoleic, arachidonic, docosapentaenoic and DHA are all examples of esters which could be useful to carry the 13-HODE.
  • the preparations can then be further processed to give a final dosage form.
  • the oils can be ingested directly, or appropriate antioxidants or flavours can be added, or they can be converted into palatable, flavoured emulsions by the use of emulsifying agents or flavouring well known to those skilled in the art.
  • a particularly valuable dosage form is a soft gelatin or bonded hard gelatin capsule, or a similar capsule made with agar or other appropriate materials.
  • Soybean lipoxygenase is then added at the rate of about 2500 U/litre and the mixture is stirred and regularly, purged with oxygen to keep the DOC at 100%.
  • Octa-deca-9Z, 12Z-dienoic acid, dissolved 1/1 in ethanol is then added at a rate of about 10 g/litre.
  • the reaction is then pressurized with an overblanket of oxygen, and vigorously stirred.
  • the reaction is allowed to proceed, and monitored at 15 minute intervals by ultraviolet analysis and thin layer chromatography analysis to confirm the conversion of the linoleic acid to 13-HODE.
  • the vessel On completion of the reaction, the vessel is flushed with nitrogen and reduced by adding sodium borochydride at the rate of about 3.3 g/litre.
  • the mixture On completion of the reduction process, the mixture is acidified to pH 6 with citric acid.
  • Reverse phase silica (OD53) is then added and stirred and the mixture is allowed to continue to stir overnight under nitrogen at room temperature.
  • the silica absorbs the 13-HODE, which is then recovered by filtering the silica, washing it with water, and then eluting out the product by multiple washing with acetonitrile.
  • the solvent is then washed off and the crude oil is purified by column chromatography with diethyl ester and methylene chloride to yield pure 13-HODE as a viscous pale yellow oily substance. This material can then be formulated as discussed above.
  • corn oil was used because it had previously been found that suspending linoleic acid in corn oil facilitated its selective uptake by the VW (Bertomeu M-C et al. 1990).
  • marine fish oil was used (specifically marine menhaden or 97% pure ethyl eicosapentaenoic (ethyl-EPA)) since marine fish oils such as tuna, sardine or other oils also are suitable to maintain 13-HODE stability.
  • ethyl-EPA was of great interest therapeutically because EPA has many desirable actions other than on the VW endothelium such as the inhibition of platelet aggregation, the lowering of triglyceride levels and the attenuation of inflammation. However, it also can inhibit the formation of endogenous 13-HODE, which might be a possible negative effect (Miller CC, Ziboh, Va. 1990; Gimenez-Arnau A et al. 1997).
  • This inhibitory effect of EPA may help explain why the expected desirable cardiovascular effects of EPA have not been realized in practice. For example, a continuous course of EPA treatment failed to reduce restenosis after occluded coronary arteries had been opened by angioplasty (Cairns JA et al. 1996).
  • New Zealand white rabbits (half males/half females; 2.5-2.9 kg) were used throughout. Rabbits were treated with 100, 400 or 1000 ⁇ g/kg/day of purified 13-HODE suspended in corn oil or ethyl-eicosapentaenoic acid (EPA), or with an equivolume of either suspending vehicle (total volume 1 ml) for 7 days. Serial blood samples were collected before, during and after treatment to assess the levels of 13-HODE in plasma. On day 7, the treatments were stopped. At that time, the rabbits were anaesthetised with a combination of Atravet, Ketamine, Vetrepham and glycopyrolate, given subcutaneously.
  • EPA ethyl-eicosapentaenoic acid
  • Both carotid arteries of anaesthetised rabbits were isolated between 2 temporary ligatures, first by applying the proximal ligature, then allowing the blood to drain from the segment, and then applying the distal ligature.
  • the rabbits were injected intramuscularly with Temgesic to minimize any pain and with 12.5 mg Baytril as an antibiotic, and then allowed to recover.
  • This injury procedure results in endothelial denudation and the exposure of a thrombogenic surface within 1 hour of restoration of blood flow, followed by SMC proliferation and intimal hyperplasia, which plateaus at 4 weeks and which is sustained for ⁇ 12 weeks (Buchanan MR, Brister SJ: 1998; Buchanan MR et al. 1999).
  • Plasma 13-HODE Levels There was a three-fold increase in the plasma 13HODE levels after 7 days of treatment with 100 ⁇ g/kg/day of 13-HODE suspended in corn oil (FIG. 1, upper panel). Increasing the 13-HODE dose to 1,000 ⁇ g/kg/day had no further effect. The plasma 13-HODE levels returned back to almost control levels within 14 to 21 days. Similar results were seen when the 13-HODE was suspended in ethyl-EPA (FIG. 1, lower panel), although the absolute levels of plasma 13-HODE were lower in all treatment levels tested. Notwithstanding, there were no significant differences in the dose-related increases in plasma 13-HODE levels between the two suspending vehicle treatment groups.
  • VW 13-HODE Levels There also was a dose-related increase in VW wall 13-HODE levels in the rabbits treated with 13-HODE suspended in corn oil and measured 28 days after stopping the treatment (FIG. 2, upper panel). These data indicated the VW 13-HODE levels remain elevated despite stopping the treatment. This may be due to the 13-HODE being incorporated into complex lipids as demonstrated by Fang et al (1999).
  • 13-HODE prevents VW hyperplasia effective when administered orally since the 13-HODE will reach the vascular tissue and other tissues in concentrations, which are biologically, active and which restore VW biocompatibility.
  • Triglyceride and ester oils are appropriate vehicles for the 13-HODE.
  • 13-HODE is used in a ratio of between 1:3 and 1:100 or even up to 1:1000 with triglyceride oil, particularly corn oil.
  • triglyceride oil particularly corn oil.
  • 50 mg of 13-HODE could be mixed with 450 mg corn oil in a soft gelatin or bonded hard gelatin capsule, or 5 mg could be mixed with 100 mg of evening primrose oil or any other appropriate oil in similar types of capsules.
  • compositions as in Example 3 are used, but in which the oil is for direct administration as a liquid and is flavoured in an Appropriate way, for example with lemon.
  • compositions as in Example 3 are used, but in which the oil is mixed with water to form a 5 to 40% oil in water emulsion, using an appropriate emulsifier and appropriate flavourings.
  • compositions as in Examples 3-5 are used, but in which the oil is mixed with an ester, particularly an ethyl ester of a 16-18 carbon fatty acid with one or more double bonds.
  • an ester particularly an ethyl ester of a 16-18 carbon fatty acid with one or more double bonds.
  • Ethyl oleate, ethyl-linolate, ethyl-EPA and ethyl-DHA are examples of appropriate carriers for 13-HODE.
  • Binion DG et al. Acquired increases in leucocyte binding by intestinal; microvascular endothelium in inflammatory bowel disease. Lancet 352: 1742-1746, 1998
  • Bocan TMA Guyton JR. Human aortic fibrolipid lesions: progenitor lesions for fibrous plaques, exhibiting early formation of the cholesterol-rich core.
  • Blann AD Endothelial cell damage and the development or progression of atherosclerosis. Clin Sci 97: 119-121, 1999
  • DiCorleto PE Bowen-Pope DF. Cultured endothelial cells produce a platelet-derived growth factor-life protein. Proc Natl Acad Sci USA 80: 1919-1923, 1983
  • Mari I Upregulation of nuclear PKC and MAPkinase during hyperproliferation of guinea-pig epidermis: modulation of 13-HODE. Cell Signalling 10: 143-149, 1998
  • Perretti M Endogenous mediators that inhibit the leukocyte endothelium interaction. TIPS 18: 418-425, 1997

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US20020028848A1 (en) 2002-03-07
US7202276B2 (en) 2007-04-10
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MXPA02009831A (es) 2004-09-06
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WO2001076568A2 (en) 2001-10-18
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TWI287447B (en) 2007-10-01
AU2001250194A1 (en) 2001-10-23
ATE414510T1 (de) 2008-12-15
WO2001076568A3 (en) 2002-09-26
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WO2001076568B1 (en) 2002-10-24
EP1272169B1 (de) 2008-11-19

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