US20060166948A1 - Compositions comprising vitamin k for treating or preventing age-related stiffening of arteries - Google Patents

Compositions comprising vitamin k for treating or preventing age-related stiffening of arteries Download PDF

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US20060166948A1
US20060166948A1 US10/525,591 US52559105A US2006166948A1 US 20060166948 A1 US20060166948 A1 US 20060166948A1 US 52559105 A US52559105 A US 52559105A US 2006166948 A1 US2006166948 A1 US 2006166948A1
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vitamin
composition according
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arteries
age
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Cees Vermeer
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Nattopharma ASA
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VITAK BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention concerns the use of vitamin K and derivatives thereof to prevent or treat a reduction in elasticity and distensibility of the vasculature, and thereby to lower blood pressure and prevent cardiovascular disease.
  • Vitamin K is an essential component of the diet. It was first identified as an element needed to prevent haemorrhaging by activating blood-clotting factors. Natural K-vitamers are menadione-derivatives differing from each other in the polyisoprenoid side chain attached to the 3-position of the ring structure. Vitamin K can be provided in the diet by dark green, leafy vegetables (K 1 or phylloquinone), and by fermented foods such as cheese and curd (K 2 or menaquinone). K 2 vitamins are also synthesized in the small intestine by resident symbiotic bacteria. Vitamin K is also needed for carboxylation of two bone matrix proteins necessary for normal bone metabolism.
  • arteriosclerosis is a disease of the arteries characterized by inflammation, macrophage invasion, foam cell formation, intima thickening, accretion of cholesterol, and formation of an atherosclerotic plaque.
  • the onset of atherosclerosis is invariably in the large arteries such aorta and coronary arteries. In more advanced stages one may see plaque rupture leading to sudden vascular occlusion, myocardial infarction and cerebrovascular accident (infarction of the brain).
  • vascular stiffening due to loss of elasticity of the arteries.
  • Vascular stiffening is associated with ageing, diabetes mellitus and renal dysfunction; it is the result of degradation of the elastic lamellae in the tunica media resulting in loss of elasticity.
  • the onset of vascular stiffening is generally seen in the smaller vessels, from extends to the larger arteries. This will lead to increased blood pressure, vascular widening, and in later stages to rupture of (mainly the small) arteries and capillaries.
  • the present patent application relates to the effect of vitamin K on vascular stiffening. Studies have shown that also on a molecular level age-related stiffening of the arteries can be distinguished from arteriosclerotic/atherosclerotic calcification.
  • age-related stiffening is a process which originates in the tunica media, and is not associated with inflammation. It is believed that age-related stiffening occurs as a result of deposition of minerals around the elastic fibres of the tunica media, followed by degradation of the elastin structure. After deterioration of the elastin, the elastic properties of the artery depend on collagen, which is much less flexible.
  • vitamin K is a useful therapeutic measure to prevent the development of cardiovascular disease conditions including hypertension, left ventricular hypertrophy, congestive heart failure, myocardial infarction, stroke, Mönckeberg's sclerosis and coronary heart disease.
  • the invention provides use of a composition comprising vitamin K or a derivative thereof, optionally together with vitamin D or a derivative thereof, in the manufacture of a medicament or nutritional formulation for treating or preventing age-related stiffening of arteries.
  • the invention provides use of a composition comprising vitamin K or a derivative thereof, optionally together with vitamin D or a derivative thereof, in the manufacture of a medicament or nutritional formulation for treating or preventing an age-related decrease in compliance and/or distensibility of arteries and/or an age-related increase in pulse pressure.
  • the invention provides use of a composition comprising vitamin K or a derivative thereof, optionally together with vitamin D or a derivative thereof, in the manufacture of a medicament or nutritional formulation for treating or preventing any of: hypertension, left ventricular hypertrophy, congestive heart failure, myocardial infarction, stroke, Mönckeberg's sclerosis, and coronary heart disease.
  • the invention provides a composition for promoting healthy arteries, comprising vitamin K or a derivative thereof, and optionally vitamin D or a derivative thereof, and one or more additional components selected from: polyphenols, vitamin C, vitamin E (tocopherols and/or tocotrienols), L-Arginine, phytosterols, antihypertensive peptides, soluble fibers (e.g. guar, pectin), omega-3, omega-6 and/or omega-9 fatty acids, carnitine, taurine, coenzyme Q10, creatine, folic acid, folates, magnesium, potassium, vitamin B6, and vitamin B12.
  • additional components selected from: polyphenols, vitamin C, vitamin E (tocopherols and/or tocotrienols), L-Arginine, phytosterols, antihypertensive peptides, soluble fibers (e.g. guar, pectin), omega-3, omega-6 and/or omega-9 fatty acids, carnitine, taurine,
  • composition for promoting healthy arteries which comprises: 0.5-1.5 mg vitamin K; 5-10 ⁇ g vitamin D; 450-550 mg Calcium; 7-12 mg Zinc; and 100-200 mg Magnesium.
  • kits comprising Vitamin K or a derivative thereof, and optionally vitamin D or a derivative thereof and a medicament, for simultaneous, separate or sequential administration, wherein said medicament is selected from the group consisting of: anticoagulants, antithrombotics, fibrinolytics, antihypertensives, diuretics, antianginals, hypolipidaemic agents, beta-blockers, ACE inhibitors, cardiac glycosides, phosphodiesterase inhibitors, anti-arrhythmics, and calcium antagonists.
  • FIG. 1 shows how the Distensibility Coefficient (DC) varies over a 3 year study period when placebo, Vitamin D (MD) and Vitamins K plus D (MDK) are administered to a group of postmenopausal women.
  • DC Distensibility Coefficient
  • FIG. 2 shows how the Compliance Coefficient (CC) varies over a 3 year study period when placebo, Vitamin D (MD) and Vitamins K plus D (MDK) are administered to a group of postmenopausal women.
  • CC Compliance Coefficient
  • the black bar represents the baseline measurement (100%), and the shaded bars are the % change relative to baseline after 3 years.
  • This invention provides the first form of directed therapy for reducing age-related arterial stiffening (as distinct from stiffening due to atherosclerosis).
  • Arterial elastic properties (compliance and distensibility) deteriorate with age.
  • the severity of this downward trend was found to be significantly reduced in a group of menopausal women who regularly consumed a supplement of vitamin K (plus Vitamin D) over the course of 3 years. These women were selected for the study on the basis of criteria which included a lack of evidence of atherosclerotic disease and low risk factors for the disease.
  • vitamin K and derivatives refers to one or more compounds of Formula 1′, and/or their pharmaceutically or nutritionally acceptable salts, here R may be any covalently linked organic group including polyisoprenoid residues, esters, ethers, thiol adducts, etc. and especially the compounds thereof of Formula 2: in which n is an integer from 1 to 12; and in which the broken lines indicate the optional presence of a double bond.
  • Sources of vitamin K which can be used according to the present invention include the following: phylloquinone from natural sources such as vegetable extracts, fats and oils, synthetic phylloquinone, synthetic vitamin K 3 (menadione), different forms of vitamin K 2 : synthetic MK-4, MK-5, MK-6, MK-7, MK-8, MK-9, MK-10, MK-11, MK-12 and MK-13, natto (food prepared from fermented soy-bean, rich in MK-7), and other fermented foods or dairy products.
  • the dose of vitamin K useful in performing the invention is not restricted but varies depending on, for example, the age of the subject and the degree of risk of developing arterial stiffening.
  • Current AI values or Adequate Intakes are 120 ⁇ g for men and 90 ⁇ g for women.
  • Benefits may be derived by selecting dosages higher than the AI values, particularly in population groups where vitamin K deficiencies are common, for instance among postmenopausal women.
  • suitable dosages may lie in the range 10 to 1000 ⁇ g, more preferably 50 to 500 ⁇ g, and most preferably 100 to 200 ⁇ g vitamin K/day.
  • daily dosage may vary between 0.5 to 50 ⁇ g/kg body weight/day, preferably 0.75 to 25 ⁇ g/kg body weight/day, more preferred 1 to 15 ⁇ g/kg body weight/day.
  • Vitamin D is included together with vitamin K in the composition used in the clinical study, and may play a role in supporting the function of vitamin K in preventing arterial stiffening.
  • Any form of natural or synthetic vitamin D may be employed, including vitamin D 1 , vitamin D 2 (calciferol), vitamin D 3 (cholecalciferol) and vitamin D analogues (e.g. alfacalcidol, dihydrotachysterol, calcitriol).
  • Natural sources of vitamin D include saltwater fish, organ meats, fish-liver oils and egg yolk. Suitable dosages of vitamin D are 2 to 50 ⁇ g/day, preferably 5 to 20 ⁇ g/day, and most preferably about 7 to 10 ⁇ g/day.
  • Vitamin K is conventionally provided in the form of tablets or capsules, i.e. in a pharmaceutical or dietary supplement format.
  • the vitamin K may be compounded with pharmaceutically acceptable carriers, excipients or diluents in the forms of pills, tablets (coated or uncoated), hard or soft capsules, dragées, lozenges, oral solutions, suspensions and dispersions, syrups or sterile parenteral preparations.
  • Suitable excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binding agents such as starch gelatin or acacia; effervescents; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate
  • granulating and disintegrating agents such as cornstarch or alginic acid
  • binding agents such as starch gelatin or acacia
  • effervescents effervescents
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • Vitamin K (optionally together with vitamin D) in a fortified food or beverage product.
  • Preferred nutritional product formats include: juice drinks, dairy drinks, powdered drinks, sports drinks, mineral water, soy beverages, hot chocolate, malt drinks, biscuits, bread, crackers, confectioneries, chocolate, chewing-gum, margarines, spreads, yoghurts, breakfast cereals, snack bars, meal replacements, protein powders, desserts, and medical nutrition tube feeds and nutritional supplements.
  • compositions of the invention may be included in the compositions of the invention, including any of those selected from preservatives, chelating agents, effervescing agents, natural or artificial sweeteners, flavoring agents, coloring agents, taste masking agents, acidulants, emulsifiers, thickening agents, suspending agents, dispersing or wetting agents, antioxidants, and the like.
  • vitamin K and optionally vitamin D
  • other healthy or pharmaceutically active components in a single composition, or in the form of a kit for simultaneous, sequential or separate administration.
  • vitamin K could be provided in conjunction with medicaments selected from anticoagulants such as aspirin or COX-2 inhibitors, antithrombotics, fibrinolytics, antihypertensives, diuretics, antianginals, hypolipidaemic agents including statins, bile acid sequestrants, nicotinic acid derivatives, and fibrates, beta-blockers, ACE inhibitors, cardiac glycosides, phosphodiesterase inhibitors, antiarrhythmics, and calcium antagonists.
  • anticoagulants such as aspirin or COX-2 inhibitors, antithrombotics, fibrinolytics, antihypertensives, diuretics, antianginals, hypolipidaemic agents including statins, bile acid sequestrants, nicotinic acid derivatives, and fibrates, beta-blockers, ACE inhibitors, cardiac glycosides, phosphodiesterase inhibitors, antiarrhythmics, and calcium antagonists.
  • anticoagulants such aspirin or COX-2 inhibitors, antithrombotics
  • bioactive substances for co-administration include: polyphenols, vitamin C, vitamin E (tocopherols and/or tocotrienols), L-Arginine, phytosterols, antihypertensive peptides, soluble fibers (e.g. guar, pectin), omega-3, omega-6 and/or omega-9 fatty acids, carnitine, taurine, coenzyme Q10, creatine, folic acid, folates, magnesium, potassium, vitamin B6, and vitamin B12.
  • vitamin K is effective at limiting age-related stiffness throughout the network of arteries in the body, its therapeutic effect on the body is probably most significant with respect to its influence on the larger elastic arteries of the body, especially the common carotid arteries supplying blood to the neck and head, the aorta, and the renal arteries.
  • vitamin K By reducing arterial stiffening, vitamin K also has the effects of counteracting the sequelae of arterial stiffening, namely hypertension, left ventricular hypertrophy, congestive heart failure, myocardial infarction, stroke and coronary heart disease.
  • Elevated blood pressure or “hypertension” as used herein refers to a blood pressure persistently exceeding 140/90 mmHg (systolic/diastolic).
  • Inclusion criteria were: apparently healthy women, Caucasian, between 50 and 60 years old, and at least 2 years postmenopausal. Exclusion criteria were: use of oral anticoagulants, corticosteroids, hormone replacement therapy, vitamin concentrates or food supplements, and high alcohol consumption (>6 glasses/day). In total 181 women met the criteria for participation and were randomized into the study. Information on cardiovascular risk factors, current health status, medical history, drug use and smoking behaviour was collected before the start of the study. Within this trial participants underwent clinical examinations at 0, 3, 12, 18, 24 and 36 months. The vascular examinations took place at baseline and at the end of the study after 3 years.
  • participant groups received a placebo (maltodextrin)
  • the three different types of supplements were similar in appearance and taste, and participants were allowed to choose between a supplement in the form of a tasteless powder (to be mixed with water before intake) or in the form of chocolate-coated tablets with a crunchy malt core. Participants were instructed to take one sachet with powder or three tablets per day during evening hours, preferably after the meal. Also, they were advised to maintain their usual diets and to avoid taking supplements containing either calcium, vitamin D, or vitamin K for two months before and throughout the study. Novartis Consumer Health SA (Nyon, Switzerland) prepared and provided all supplements.
  • the right common carotid artery of each patient was investigated. The same investigator performed all examinations at the start and the end of the study and for each participant several repeated measurements (5-7) are made during one session. Reproducibility was evaluated for assessment of common carotid artery distension and diameter.
  • the primary outcome measures for the purposes of this study were the vessel wall characteristics of the common carotid artery measured with ultrasound (ATL Mark V).
  • IMT intima-media thickness
  • a paired t-test was used to evaluate the change in the vessel wall characteristics over the three years within each group. We considered a level of p ⁇ 0.05 to be statistically significant. For every participant, the percentage change from baseline in all parameters was calculated and the mean change from baseline was calculated per group. Primary outcome analysis consisted of comparison of the change in DC, CC, PP and IMT between the MD-group and placebo and between the MDK-group and placebo. Linear regression analysis was used with the change in vascular parameters relative to baseline as dependent variable and the treatment groups and several covariates as explanatory variables. Baseline values of age, BMI, smoking (yes or no), heart rate and mean arterial pressure were chosen as covariates, because their influence on the change in vascular properties or response to the supplementation could not be excluded.
  • Table 1 details the baseline measurements of each study group.
  • Table 2 summarizes per group the differences between the mean values at baseline and at the end of the study for all vascular parameters with their paired-levels of significance.
  • the DC and CC in the placebo group decreased significantly (by 10% and 6%, respectively).
  • the PP on the other hand, increased by 7%, but the increase did not reach the level of significance.
  • DC decreased significantly (by 7%)
  • CC decreased by 4%, while the PP increased by 6%; however these latter two changes did not reach the level of significance.
  • the DC and CC remained approximately constant over the three year period, the CC even showing a tendency to increase (+3%). The PP remained unchanged throughout the entire study period.
  • FIGS. 1 and 2 illustrate the percentage change in DC and CC respectively of the three groups.
  • the changes in the placebo-relative to the MDK-group remained statistically significant and were: 8.8% decrease of DC (95% Cl: 1.9 to 21.4), 8.6% decrease of CC (95% Cl: 1.8 to 20.3), and 6.3% increase of PP (95% Cl: ⁇ 17.1 to ⁇ 0.7).
  • the MD group who received a vitamin D supplement, failed to show any improvement in measures of vascular wall aging relative to the placebo group. It can be concluded that provision of vitamin D alone is not capable of delivering cardiovascular benefits to postmenopausal women fulfilling the criteria applied in the present study.
  • the MDK group showed significant relative improvements in distensibility, compliance and pulse pressure over the 3 year period of the study.

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Cited By (12)

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US7955418B2 (en) 2005-09-12 2011-06-07 Abela Pharmaceuticals, Inc. Systems for removing dimethyl sulfoxide (DMSO) or related compounds or odors associated with same
US20110293759A1 (en) * 2010-06-01 2011-12-01 Calitoga Llc Nutritional supplement for recovery, repair, and maintenance
US8435224B2 (en) 2005-09-12 2013-05-07 Abela Pharmaceuticals, Inc. Materials for facilitating administration of dimethyl sulfoxide (DMSO) and related compounds
US8480797B2 (en) 2005-09-12 2013-07-09 Abela Pharmaceuticals, Inc. Activated carbon systems for facilitating use of dimethyl sulfoxide (DMSO) by removal of same, related compounds, or associated odors
US8673061B2 (en) 2005-09-12 2014-03-18 Abela Pharmaceuticals, Inc. Methods for facilitating use of dimethyl sulfoxide (DMSO) by removal of same, related compounds, or associated odors
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