WO2019038316A1 - Pharmaceutical composition for the prevention and/or treatment of cardiovascular and osteoarticular diseases - Google Patents
Pharmaceutical composition for the prevention and/or treatment of cardiovascular and osteoarticular diseases Download PDFInfo
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- WO2019038316A1 WO2019038316A1 PCT/EP2018/072623 EP2018072623W WO2019038316A1 WO 2019038316 A1 WO2019038316 A1 WO 2019038316A1 EP 2018072623 W EP2018072623 W EP 2018072623W WO 2019038316 A1 WO2019038316 A1 WO 2019038316A1
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Classifications
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/32—Burseraceae (Frankincense family)
- A61K36/324—Boswellia, e.g. frankincense
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- 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
Definitions
- the present invention refers to a pharmaceutical composition
- a pharmaceutical composition comprising an association of Vitamin D, Isoflavones and Policosanols useful for the treatment of cardiovascular disease, particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization thanks to the synergistic action of its components.
- Cardiovascular diseases are the main cause of mortality of developed and developing countries. In Europe, cardiovascular diseases are still responsible of 4 millions of deads per year and, despite in recent times there was a reduction in the number of deaths, they still represent the main cause of mortality. Coronary heart disease, alone, are responsible for at least 1.8 millions of deads per year, which represent 20% of the total number of deads in Europe (N. Townsend, M. Nichols, P. Scarborough, and M. Rayner, "Cardiovascular disease in Europe - Epidemiological update 2015," Eur. Heart J., vol. 36, no. 40, pp. 2696-2705, 2015).
- cardiovascular risk From epidemiological studies several factors of cardiovascular risk, among which: hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycaemia have been identified.
- Hyperlipidemias and reduced levels of HDL are a consequence of several factors correlated with each other, which can be either of behavioural or environmental type, genetic (mutations of genes codifying for lipoproteins) or metabolic (diabetes mellitus or other conditions able to affect blood levels of lipoproteins) (L. Brunton, J. Lazo, and K. Parker, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Eleventh Edition. McGraw Hill Professional, 2005).
- Hypercholesterolemia, hypertriglyceridemia and low blood concentration of HDL are the main cause of atherosclerosis and atherosclerosis-associate diseases, such as angina pectoris, myocardial infarction, cerebrovascular diseases and peripheral vascular diseases (arterial and venous occlusion).
- angina pectoris myocardial infarction
- cerebrovascular diseases cerebrovascular diseases
- peripheral vascular diseases arterial and venous occlusion
- LDL low density lipoproteins
- Hypertriglyceridemia is a cardiovascular risk factor less important than hypercholesterolemia. Moderately high levels of triglycerides are part of the metabolic syndrome, which includes insulin-resistance, obesity, hypertension, low level of HDL and an increased cardiovascular risk (already mentioned L. Brunton, J. Lazo, and K. Parker, page. 933).
- Hypertension is the most common cardiovascular disease. It is defined as a constant increase of blood pressure exceeding values of 140/90 mmHg: this criterion characterises a kind of patients whose risk of cardiovascular diseases associated with blood pressure is sufficiently high to deserve medical attention.
- the incidence of hypertension increases with age: about 50% of people between 60 and 69 years suffer from it and the incidence further increases in subjects over 70 years. High blood pressure is able to lead to a left ventricle hypertrophy. Accordingly, hypertension is the main cause of ictus and a risk factor for coronary heart diseases, myocardial infraction and heart and kidney failure (already mentioned L. Brunton, J. Lazo, and K. Parker, page 845).
- the pathogenesis of atherosclerosis begins with a damage to the vascular endothelium, which can be induced by oxidised LDL, free radicals, hypertension, diabetes, genetic alterations, high levels of homocysteine or by microorganisms. These damages create an alteration in the endothelial homeostasis, followed by an increase in vascular permeability, vasoconstriction, coagulation and trigger an inflammatory response. If the inflammatory response is not able to neutralize the etiological agent, the consequence is the increase in the proliferation of smooth muscular cells and the migration of macrophages (derived from monocytes) and T- lymphocytes (E. A. Kaperonis, C. D. Liapis, J. D.
- monocytes and lymphocytes T are recalled to the tunica intima, by chemotactic factors such as MCP-1 (monocyte chemoattractant protein-1 ) protein. From studies on knock-out mice was shown that this protein is crucial from the very first phases of the atherogenesis process (L. Gu et al., "Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.," Mol. Cell, vol. 2, no. 2, pp. 275-281 , 1998).
- the M-CSF factor is able to stimulate the differentiation in macrophages and the lipid ingestion (already mentioned E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou; J. J. Boyle, "Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture.," Curr. Vase. Pharmacol., vol. 3, no. 1 , pp. 63-68, 2005).
- MSRa and CD36 also known as MSRb
- MSRb scavenger receptors for oxidised LDL
- the consequence consists in the conversion of macrophages in foam cells, which accumulate in tunica intima, generating the primary atherosclerotic lesions, namely lipid striae.
- Atherosclerosis can have two effects at vascular level: it can produce, for example, a thickening of the wall of coronary arteries, which causes stable angina.
- Atheromatous plaque can break, which causes acute coronary artery diseases, unstable angina, myocardial infraction and sudden death (already mentioned E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou).
- the pathologic calcification of cardiovascular structures can be associated with a series of pathologies, such as kidney failure, diabetes, hypercholesterolemia and others cardiovascular diseases.
- Vascular calcification is mainly characterized by the deposition of apatite crystals in the wallsb of blood vessels, myocardium and cardiac valves.
- the deposits of calcium can occur at different levels of the vessel: the calcification of tunica intima is associated with atherosclerotic lesions (J. L. Hunt et al., "Bone formation in carotid plaques: a clinicalpathological study," Stroke, vol. 33, no. 5, pp. 1214-1219, 2002; A. P. Burke, A. Taylor, A. Farb, G. T. Malcom, and R. Virmani, "Coronary calcification: insights from sudden coronary death victims.," Zeitschrift fur Kardiologie, vol. 89 Suppl 2, no. 2.
- tunica media also known as Monckeberg Medial Sclerosis
- calcification of tunica media is associated with vascular tightening and atherosclerosis occurring with age, diabetes and kidney failure (M. E. Edmonds, N. Morrison, J. W. Laws, and P. J. Watkins, "Medial arterial calcification and diabetic neuropathy,” Br Med J (Clin Res Ed), vol. 284, no. 6320. pp. 928-930, 1982).
- vascular calcification can lead to devastating organ dysfunction.
- the calcification of cardiac valve occluders is one of the main cause of the valve malfunctioning.
- calcification of the vascular tunica media is responsible for the calcific uremic arteriolopathy, a condition associated with a high mortality rate.
- vascular calcification of the tunica media in medium to large sized arteries causes the tightening thereof, with a reduction in the vascular compliance.
- the consequences of the decreased elasticity of these arteries are increased heart rate, arterial hypertension, increased heart work and left ventricular hypertrophy, as well as a reduction in coronary perfusion.
- Calcification of the vascular media is therefore a major risk factor for coronary artery diseases and cardiovascular events, mainly in patients with type 1 diabetes and in patients with end stage renal disease (ESRD) (C. M. Giachelli, "Vascular calcification mechanisms," J Am Soc Nephrol, vol. 15, no. 12, pp. 2959-2964, 2004).
- CVD cardiovascular diseases
- Blood vessels normally express mineralization inhibitors, such as pyrophosphatase and matrix GLA protein (MGP): loss in the expression of these inhibitor proteins leads to mineralization of the vessel and to an increase in mortality.
- MGP matrix GLA protein
- a2-HS fetuin/glycoprotein is one of the main inhibitors of the deposition of apatite crystals in the vessel and reduced levels of fetuin are associated with an increase in mortality for cardiovascular events.
- Osteogenesis process can further contribute to vascular calcification, as shown by the presence of osteopontin, osteocalcin, BMP2, matrix vesicles and the formation of bone and cartilage in the vascular lesion.
- the cells present in the vessel can undergo differentiation leading them to assume the phenotype of osteoblasts and chondrocytes.
- vascular smooth muscle cells can lead to the formation of apoptotic bodies and debris deriving from necrosis which serve as crystallization germs for apatite.
- the skeleton is the main support structure of our body and constitutes also a protected environment for the hematopoietic activity. It is formed by a mineralized matrix and a cellular compartment with high activity.
- the skeleton is divided in appendicular skeleton, or peripheral, and axial skeleton, or central, associated with different turnover rates.
- the appendicular skeleton constitutes about 80% of bone mass and it is prevalently made up of compact bones.
- the axial part instead, is prevalently made up of spongy bones, with a significant trabecular portion and a thin cortex.
- Osteoporosis a degenerative disorder of the skeleton, is a condition characterized by a poor bone mineral density (osteopenia) and by a weakening of the bone architecture, leading to a weakening of the bone structure and to an increase in the risk of fractures in case of trauma (NIH, F. I. Komarov, I. N. Bkarev, and A. I. SmolianitskiT, "Consensus Development Panel on Osteoporosis prevention, diagnosis, and therapy," Jama, vol. 285, no. 6, pp. 785-95, 2001 ).
- NIH bone mineral density
- F. I. Komarov I. N. Bkarev
- A. I. SmolianitskiT "Consensus Development Panel on Osteoporosis prevention, diagnosis, and therapy," Jama, vol. 285, no. 6, pp. 785-95, 2001 ).
- Hip fractures are among the most severe consequences of osteoporosis, leading to a reduced activity in everyday life, a reduction of life quality and to an increase in mortality (C. Holroyd, C. Cooper, and E. Dennison, "Epidemiology of osteoporosis.,” Best Pract. Res. Clin. Endocrinol. Metab., vol. 22, no. 5, pp. 671-85, 2008).
- osteoporosis As the average age of the world's population is constantly rising, osteoporosis has become an important problem of public health. It affects individuals belonging to all ethnical groups and the number of persons affected by this pathology is about 200 millions in the world. Osteoporosis mainly occurs in elderly individuals, but rarely it can occur also in younger individuals, due to hormone dysfunctions (J. Aaseth, G. Boivin, and O. Andersen, "Osteoporosis and trace elements - An overview," J. Trace Bern. Med. Biol. , vol. 26, no. 2-3, pp. 149-152, 2012.; D. Cech, "Prevention of osteoporosis: From infancy through older adulthood," Hong Kong Physiother. J., vol. 30, no. 1 , pp. 6-12, 2012).
- Bone fractures contribute to significantly increase the mortality in elderly population. Their frequency increases exponentially with age, so that a fracture in at least one woman in 3 and a man in 6, in the last ten years of life is observed (O. Oliver, D., Griffiths, R., Roche, J., Sahota, "Hip fracture,” Clin. Evid. (Online)., vol. 2007, no. 10, pp. 589-609, 2007).
- the consequences of bone fractures are particularly severe and 50% of persons incur in permanent disability, from 15 to 25% need a long period of rehabilitation, whereas from 10 to 20% of affected persons dies in the first year of life (S. R. Cummings, D. M. Black, and S. M.
- Osteoporosis can be classified in primary and secondary osteoporosis (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1662).
- Primary osteoporosis in turn can be subdivided in type I osteoporosis, caused by the lack of estrogens during menopause and characterized by loss of trabecular bone and in type II osteoporosis, characterized by loss of cortical and trabecular bone and caused by the inefficiency of bone remodelling, protracted for a long period of time, lack of nutrients with diet and activation of parathyroid hormone.
- Secondary osteoporosis can be caused by a systemic disease or by the use of drugs, such as glucocorticoids and phenytoin.
- the best therapeutic strategy consists in eliminating the pathology that caused it or suspending the pharmacological treatments that caused it.
- the pharmacological treatments can be similar (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1662).
- Interventions can be classified in non-pharmacological and pharmacological (S. H. Telia and J. C. Gallagher, "Prevention and treatment of postmenopausal osteoporosis," Journal of Steroid Biochemistry and Molecular Biology, vol. 142. NIH Public Access, pp. 155-170, Jul-2014).
- the main objectives of pharmacological therapy are the prevention of fractures, maintenance or increase of bone mineral density and an improvement in physical conditions.
- Osteoporosis treatments aim to reduce the bone resorption rate (antiresorptive therapy) or to promote formation thereof (anabolic therapy) (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1670).
- Non-pharmacological interventions are the following:
- vitamin D Use of vitamin D.
- the recommended dose of this vitamin is 800 Ul (corresponding to 20 ⁇ g): a meta-analysis has shown the efficacy of this dose of vitamin D, associated with the use of calcium (H. A. Bischoff-Ferrari, W. C. Willett, J. B. Wong, E. Giovannucci, T. Dietrich, and B. Dawson-Hughes, "Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.," JAMA, vol. 293, no. 18, pp. 2257-64, 2005).
- Pharmacological interventions of osteoporosis are the following:
- Hormone replacement therapy It is considered the first line treatment in the prevention of fractures in woman up to 5 years from the beginning of menopause.
- the best therapeutic approach consists in the use of doses of estrogens, with or without the association with progestins, for a period of 6 months, in order to rapidly reduce bone resorption, mostly occurring in the first 3-4 years of menopause.
- this therapy was widely used, but after the publication of the study WHI (Women's Health Initiative) in 2001 (J. E. Rboneuw et al. , "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.," JAMA, vol. 288, no. 3, pp. 321-33, Jul.
- Bisphosphonates The pharmacological activity consists in the suppression of bone turnover, in the prevention of bone loss and in the protective effect towards bone architecture, which derive from their adhesion to bone surfaces and the inhibition of the farnesyl pyrophosphate synthase enzyme, required for the formation of osteoclasts cytoskeleton, thus inhibiting bone resorption.
- the main bisphosphonates are alendronate, risedronate, ibandronate and zoledronic acid.
- Vitamin D is particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization thanks to the synergistic action of its components.
- an object of the present invention is a pharmaceutical composition comprising an association of Vitamin D, Isoflavones and Policosanols useful for the treatment of cardiovascular diseases, particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization.
- the pharmaceutical composition object of the present invention can optionally contain other active components selected from boswellic acids, curcumin e vitamin K.
- additional components can be present all together in the composition object of the present invention or one of the additional components can be present alone or again two additional components can be present, for example boswellic acids and curcumin, boswellic acids and vitamin K, curcumin and vitamin K.
- the components of the association according to the present invention are all known components, widely used in therapy.
- a promising prevention strategy consists in vitamin D supplementation (see the already mentioned H.A. Bischoff-Ferrari, W.C. Willett, J.B. Wong, E. Giovannucci, T. Dietrich and B. Dawson-Hughes).
- Vitamin D plays an essential role in calcium homeostasis (L. L. Brunton, L. John S, and P. K. L, GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, XI. McGraw-Hill, 2006). Vitamin D is to be considered a real hormone, since our organism is able to synthetized it, but only in ideal conditions the synthetize amount is sufficient, therefore it has to be taken with diet.
- Cholecalciferol and metabolites thereof are able to reduce blood cholesterol by different mechanisms. Cholecalciferol is able to induce the formation of HDL on cellular lines of liver cancer (HepG2), through the induction of cholesterol efflux mediated by the membrane transporter ATB-binding cassette-A1 (ABCA1 ).
- liver receptor X of the ABC-A1 transporter and promotes the cholesterol efflux from THP-1 monocyte cells.
- macrophage polarization with formation of macrophages M2 which produce a minor amount of TNF-a, I L-1 ⁇ and IL-6.
- CYP27A1 sterol 27-hydroxylase
- CYP27A1 increases the levels of 27-hydroxycholesterol, which in turn is able to induce the expression of liver receptors X, ABCA1 and ABCG1 increasing the efflux of cholesterol from foam cells
- the mechanism of action consists in a reduction in the activation by JNK (c-Jun N-terminal kinase) of PPAR- ⁇ receptors, a reduction in the expression of CD36 protein (which binds oxidised lipoproteins) and reduces the uptake of oxidised LDL (J. Oh et al., "1 ,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.," Circulation, vol. 120, no. 8, pp. 687-98, Aug. 2009).
- Another effect of calcitriol administration is the reduction of systolic pressure induced by fructose, but in this case the mechanism of action is unknown (C. L. Chou, C. Y. Pang, T. J. F. Lee, and T. C. Fang, "Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats," PLoS One, vol. 10, no. 3, pp. 1- 19, 2015).
- a clinical study has evaluated the effect of a 75 ⁇ g (3000 IU) per die administration of cholecalciferol for 20 week.
- HRT hormone replacement therapy
- Phytoestrogens such as isoflavones, and in particular soy isoflavones, have been characterized as naturally occurring selective modulators of estrogens receptor, with beneficial effects on the bone similar to those of raloxifen.
- soy isoflavones The relation between soy isoflavones and bone tissue was studied for less than ten years. Data of numerous in vivo studies have shown how soy isoflavones have conservative effects on the bone, with retention of bone mass following ovariectomy. In a clinical study, in menopausal women treated with soy proteins added with isoflavones, a reduction in bone mineral loss was observed. Epidemiological studies have shown that women that consume large quantities of soy have a lower risk of osteoporosis than women that consume a normal occidental diet. Accordingly, many menopausal women consume phytoestrogens to maintain the bone mineral density, as they are associated with significantly lower side effects than steroid hormones.
- isoflavones have led to a reduction in urinary DPD by 23% with respect to the basal level.
- the effect of isoflavones on the bone mineral density is achieved with a dose of isoflavones higher than 75 mg/die.
- Soy isoflavones are able to inhibit the bone loss induced by osteoporosis, but can likewise inhibit the process of vascular calcification. In both cases, the mechanism of action is based on the interaction with the RANK/RANKL/OPG system (M. K. Osako et al., "Estrogen inhibits vascular calcification via vascular RANKL system: Common mechanism of osteoporosis and vascular calcification," Circ. Res., vol. 107, no. 4, pp. 466-475, 2010).
- RANKL Receptor Activator of Nuclear Factor ⁇ B)-Ligand
- OPG osteoprotegerin
- the main role of the RANKL protein is to stimulate the osteoclastic activity and inhibit the osteoblastic activity.
- Osteoprotegerin is a soluble protein able to link the RANKL protein, thereby preventing it from interacting with the RANK receptor and preventing its effects which lead to an increase in bone resorption.
- RANKL is also able to induce the vascular calcification: a study has shown that its mechanism consists in the regulation of the Bone Morphogenetic Protein-2 (MGP-2) protein and it is counteracted by the action of estrogens in a dose-dependent manner (see the already mentioned M. K. Osako et al.).
- MGP-2 Bone Morphogenetic Protein-2
- mice devoid of OPG develop a severe osteoporosis deriving from the marked increase in the differentiation of osteoclasts, as well as a deep calcification of vascular tunica media.
- a high bone resorption and the vascular calcification of arteriae was observed (N. Bucay et al., " ⁇ losteoprotegerin ⁇ -deficient mice develop early onset osteoporosis and arterial calcification," Genes Dev. , vol. 12, no. 12, pp. 1260-1268, 1998).
- CWHIS Controlled Women's Health Initiative Study
- Policosanols are a mixture of long chain primary alcohols, which usually contains 66% of octacosanol ((CH 3 -CH 2 (26)-CH 2 -OH), 12% of triacontanol and 7% of esacosanol; the remaining 15% of the mixture is constituted by minor components, such as tetracosanol, eptacosanol, nonacosanol, dovtriacontanol and tetratriacontanol. They are mainly extracted from cane sugar (Saccharum officinarum) but also from rice (Oryza sativa) and beeswax.
- cane sugar Sacharum officinarum
- rice Oryza sativa
- Policosanols seem to cause a reduction in the synthesis and an increase in the degradation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, enzyme that catalyses the limiting step of the cholesterol biosynthesis. This is, therefore, a mechanism different from that of statins, which act as competitive inhibitors of this enzyme. Policosanols have also shown the ability to improve the metabolism of LDL lipoproteins, increasing the link, capture and degradation thereof by human fibroblasts.
- molecular "pathways" on which policosanols act include the increase in liver levels of Acyl-CoA and levels of AMP, to activate the AMP kinase and inactivate HMG-CoA reductase.
- Policosanols intake is also known to inhibit LDL oxidation, with consequent prevention of the formation of atheromatous plaques.
- a recent Chinese study has shown that a combination of policosanols and atorvastatin in patients with atherosclerosis leads to a reduction of PCSK9 levels, whose expression is induced by statins, as well as to a reduction of total cholesterol and triglycerides, indicating an effect of policosanols on the lipid composition.
- Another important passage in the process of atherosclerosis is the proliferation of vascular smooth muscle cells (VSMC). In preclinical studies carried out on rabbits, it was shown that policosanols reduce the formation of neointima: this indicate a reduction of the VSMC proliferation.
- policosanols Another mechanism of action of policosanols, very important in the prevention of cardiovascular risk, is the reduction of platelet aggregation. This action seem to derive from the inhibition of thromboxane B2 synthesis, while there seems to be no action on prostacyclin.
- Several studies have shown the dose-dependent inhibition of platelet aggregation induced by several experimental substances. It has been shown that policosanols, at a dose of 20 mg/die, present a greater efficacy as antiplatelet agents compared with 100 mg/die of acetylsalicylic acid.
- policosanols administered at a dose of 10-20 mg/die can lead to a reduction in LDL cholesterol up to 30%, a reduction comparable to that obtained with low doses of statins.
- policosanols lowered LDL cholesterol by 33% in normocholesterolemic patients and by 24% in hypercholesteremic patients.
- normocholesterolemic patients a slight increase in HDL cholesterol is also observed, while in dyslipidemic patients an average increase of 17% in HDL is observed, as demonstrated in seven clinical studies.
- a statistically significant decrease in cholesterol was observed even at very low doses (2 mg/die).
- the maximum decrease in cholesterol levels is observed at doses of 5-20 mg/die, whereas higher doses do not further improve cholesterol levels.
- the 40 mg/die dose is also able to reduce triglyceride levels.
- Boswellic acids are the main secondary metabolites of frankincense, a resin produced by plants of the genus Boswellia, having anti-inflammatory and antitumor activity.
- Some clinical trials have shown the efficacy of preparations based on Boswellia in the treatment of inflammatory diseases, such as osteoarthritis, rheumatoid arthritis, chronic inflammatory bowel diseases, but also in the treatment of asthma and cancer (H. Ammon, "Boswellic acids in chronic inflammatory diseases," Planta Med., 2006; D. Poeckel and O. Werz, "Boswellic acids: biological actions and molecular targets.," Curr. Med. Chem., vol. 13, no. 28, pp. 3359-69, Jan. 2006).
- 3-0-acetyl-1 1-ketoboswellic acid is able to interfere with different pathways, among which that of NF-kB (T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet, "Acetyl-boswellic acids inhibit lipopolysaccharide- mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases.," J. Immunol. , vol. 174, no. 1 , pp. 498-506, Jan. 2005) and that of MAP (mitogen-activated protein) kinase ( D. Poeckel and O.
- NF-kB T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet, "Acetyl-boswellic acids inhibit lipopolysaccharide- mediated TNF-alpha induction in monocytes by direct interaction with IkappaB
- mPGES-1 type 1 Prostaglandin E2
- the PGES prostaglandin E synthase
- PGE2 is an enzyme involved in the last step of the biosynthetic pathway of PGE2, which consists in the conversion of PGH2, whose synthesis is catalysed by cyclooxygenase, in PGE2.
- pro-inflammatory stimuli such as lnterleukin-1 ⁇ (IL- ⁇ ⁇ ) and lipopolysaccharide (LPS).
- mPGES-1 receives prostaglandin H2 preferentially by COX-2 enzyme, since the two enzymes are co-expressed and co-localized and that their expression can be induced by pro-inflammatory stimuli. Inflammation, pain and fever can be induced by PGE2 deriving from the overexpression of this enzyme (B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson, "Membrane prostaglandin E synthase-1 : a novel therapeutic target.," Pharmacol. Rev., vol. 59, no. 3, pp. 207-224, 2007).
- Inhibition of mPGES-1 may be effective in the treatment of inflammatory diseases, hyperalgesia induced by prostaglandin E2 and in case of fever.
- All boswellic acids have a good inhibitory activity on mPGES-1 , however, ⁇ -boswellic acid has proved to be one of the most active, with a IC50 of 10 ⁇ in assays on A549 intact cells (U. Siemoneit, A. Koeberle, A. Rossi, F. Dehm, M. Verhoff, S. Reckel, T. J. Maier, J. Jauch, H. Northoff, F. Bernhard, V. Doetsch, L. Sautebin, and O.
- Boswellic acids are among the most potent natural occurring inhibitors of mPGES-1 and have chemical-physical characteristics that make them potentially useful in the treatment of infections even when administered via transdermal route.
- a study carried out on inflammation models has shown that the administration of boswellic acids via topic/transdermal route has led to the same effect of an administration via systemic route, which demonstrates a good systemic adsorption of these active ingredients also via topical route (S. Singh, A. Khajuria, S. C. Taneja, R. K. Johri, J. Singh, and G. N. Qazi, "Boswellic acids: A leukotriene inhibitor also effective through topical application in inflammatory disorders.," Phytomedicine, vol. 15, no. 6-7, pp. 400-7, Jun. 2008).
- boswellic acids through the skin can be further increased by the complexation with phosphatidylcholine.
- Another strategy for further increasing the bioavailability of boswellic acids is by using proniosomes (dehydrated forms of niosomes, vesicles constituted by non-ionic surfactants, which have a better penetration ability with respect to others vesicles (G. V Radha, T. S. Rani, and B. Sarvani, "A review on proniosomal drug delivery system for targeted drug action.,” J. basic Clin. Pharm., vol. 4, no. 2, pp. 42-8, 2013), which should substantially increase the boswellic acids bioavailability with respect to oral administration (boswellic acids are very lipophilic and undergo first pass metabolism) (M. Mehta and M. Garg, "Proniosomal Gel: A Promising Drug Carrier for Boswellic Acids," J. Med. Sci., vol. 15, no. 3, pp. 130-134, Mar. 2015).
- boswellic acids can be potentially useful for the prevention or treatment of vascular calcification.
- Vitamin K is a term associated with a family of vitamins characterized by different molecular structures.
- Vitamin K 1 phytoquinone
- K2 menanquinon
- vitamins K 3 , K 4 and K 5 have synthetic origin.
- Calcification of the vascular tunica media is strongly related with age and is characterized by dense layers of calcium crystals in the centre of media, aligned along the elastic lamina.
- MGP matrix Gla protein
- Numerous studies have shown the involvement of this protein in the processes of vascular calcification.
- the vascular smooth muscle cells (VSMC) are the prevalent cells in tunica media and are able to express MGP protein.
- the mechanism of MGP protein in the inhibition of vascular calcification is largely unknown.
- the VSMC apoptosis leads to the formation of negatively charged apoptotic bodies that, if not duly phagocyted, can serve as crystallization germs for crystals of hydroxyapatite.
- MGP protein is synthetized at a relatively low speed, however in the arteries of diabetic patients a low expression of this protein is observed, suggesting its involvement in the prevention of vascular calcification.
- the crucial role of vitamin K in the inhibition of vascular calcification has become evident after an in vivo study that provided for the administration of vitamin K antagonists. After the administration of these compounds for 6 weeks, a severe calcification of the tunica media of arteriae was observed. The replacement of these compounds with high doses of vitamin K has induced a significant regression of the calcification grade, of about 37%.
- Vitamin K In recent times the attention on Vitamin K is growing a lot, because of its potential use in the inhibition of vascular calcification. In a recent pilot study, it has been shown that the administration of menanchinon-7 for 6 weeks leads to a significant reduction in the amount of inactive Vitamin K-dependent proteins (VKDP), PIVKA-II factor (Protein Induced by Vitamin K Absence of Antagonism-Factor II), non-carboxylate osteocalcin and non-carboxylate MGP. Further studies will be necessary to determine whether these effects of vitamin K can be relevant for the reduction of the mortality resulting from vascular calcification. The presence of microcalcification in atheromatous plaques is a factor able to destabilize the plaque and lead to its break. The MGP protein was shown to be effective in the prevention of arteriae microcalcification.
- vitamin K is an essential cofactor in the carboxylation and activation of the MGP protein, the supplementation of this vitamin may lead to an inhibition of processes of vascular calcification, with a following reduction in the risk of mortality.
- Curcuma longa is a plant that has been used for thousands of years in Chinese traditional medicine for the treatment of several types of diseases (S. Shishodia, G. Sethi, and B. B. Aggarwal, "Curcumin: Getting back to the roots,” in Annals of the New York Academy of Sciences, 2005, vol. 1056, no. 1 , pp. 206-217).
- Curcumin is the main secondary metabolite of Curcuma, having numerous pharmacological activities, such as anti-inflammatory, antioxidant, immunomodulatory, antitumor and neuro-protective activity (G. R. Pillai, A. S. Srivastava, T. I. Hassanein, D. P. Chauhan, and E. Carrier, "Induction of apoptosis in human lung cancer cells by curcumin," Cancer Lett, vol. 208, no. 2, pp. 163-170, May 2004; K. H. Reeta, J. Mehla, and Y. K. Gupta, "Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats," Eur. J.
- Curcumin has several mechanisms of action, but the main one consists in modulating the expression of numerous proteins, among which pro-inflammatory cytokines (TNF- a, IL-8, I L- 1 ⁇ , IL-6) (J.-W. Cho, K.-S. Lee, and C.-W. Kim, "Curcumin attenuates the expression of IL-1 beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets.," Int. J. Mol. Med. , vol. 19, no. 3, pp.
- Curcumin has shown its efficacy in the reduction of lipid peroxidation and blood levels of cholesterol in numerous studies carried on humans and rodents (K. K. Soudamini, M. C. Unnikrishnan, K. B. Soni, and R. Kuttan, "Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin," Indian J. Physiol. Pharmacol., vol. 36, no. 4, pp. 239-243, Oct. 1992; K. B. Soni and R. Kuttan, "Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers," Indian J. Physiol. Pharmacol. , vol. 36, no. 4, pp. 273-275, Oct. 1992).
- curcumin is able to improve the accumulation of cholesterol in macrophages, due to a reduced uptake of oxidised LDL and to an increased efflux thereof. Moreover, this molecule is able to induce a down regulation of SR-A (scavenger receptor class A) protein acting on proteolysis mediated by ubiquitin-proteasome-calpain and to increase the expression of ABCA1 (ATP-binding cassette A1 ) transporter, acting on the LXRa (calmodulin-liver X receptor a) receptor.
- SR-A scavenger receptor class A
- ABCA1 ATP-binding cassette A1
- curcumin modules the production of SR-A, ABCA1 , ABCG1 and SR-BI in aortas of apoE-/- mice, in which it delays the progression of atherosclerosis (J. F. Zhao et al, "Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis," Mol. Nutr. Food Res. , vol. 56, no. 5, pp. 691-701 , 2012).
- the action on LXRa receptor should also allow for an increase in the genic expression of CYP7A1 cytochrome, which is involved in the biosynthesis of biliary acids starting from cholesterol.
- Thongnopnua "Effect of different curcuminoid supplement dosages on total In Vivo antioxidant capacity and cholesterol levels of healthy human subjects," Phyther. Res., vol. 25, no. 1 1 , pp. 1721-1726, Nov. 201 1 ).
- the composition object of the present invention comprises the association of Vitamin D, Isoflavones and Policosanols, and optionally one, two or three additive components selected among boswellic acids, curcumin and vitamin K, in admixture with a suitable pharmaceutically acceptable carrier.
- Suitable pharmaceutically acceptable carriers are those commonly known to the man skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders, tablets, capsules, etc.
- said pharmaceutically acceptable carriers can consist of diluents (for example calcium phosphate dibasic, lactose, microcrystalline cellulose and cellulose derivatives), thickeners (for example gums hydroxypropylmethylcellulose and others cellulose derivatives), sweeteners (for example sorbitols, mannitols and others polyols, acesulfame K, aspartame, cyclamates, saccharine, sucralosio), lubricants (for example magnesium stearate, stearic acid, waxes), dispersants, surfactants (for example Sodium lauryl sulphate and polysorbates), flavouring agents, adsorbents (for example silica gel, talc, starch, bentonite, kaolin), glidants and
- composition object of the present invention is preferably a solid pharmaceutical composition for oral use, even more preferably a tablet.
- composition object of the present invention comprises Vitamin D, Isoflavones and Policosanols and optionally also one or more components selected among boswellic acids, curcumin and vitamin K.
- Vitamin D is present in an amount between 0.1 ⁇ g and 1000 ⁇ g, preferably between 1 ⁇ g and 100 ⁇ g, even more preferably between 5 ⁇ g and 50 ⁇ g.
- Isoflavones are present in an amount between 1 mg and 200 mg, preferably between 10 mg and 120 mg, even more preferably between 50 and 100 mg.
- Isoflavones are preferably used as extracts from a plant of the genus Glycine and are commercially available.
- the dry extract from Glycine Max (L.) Merr. marked by Nutraceutica srl, which is a mixture of soy isoflavones (40%) and genistein (36%).
- Policosanols are present in an amount between 0.1 mg and 200 mg, more preferably between 1 mg and 100mg, even more preferably between 10 mg and 50 mg.
- Policosanols are preferably used as a powder obtained by extraction of the waxy coating of sugar cane. Policosanols are a mixture of superior primary aliphatic alcohols whose main component is octacosanol. Policosanols usable in the composition object of the present invention are commercially available, for example by Farmalabor srl (powder - policosanols 98% - octacosanol 60%).
- Boswellic acids are in an amount between 1 mg and 500 mg, more preferably between 10 mg and 250 mg, even more preferably between 25 mg and 150 mg.
- Curcumin if present, is in an amount between 1 mg and 1000 mg, preferably between 10 mg and 1000 mg, even more preferably between 20 mg and 300 mg. Curcumin is preferably used as an extract from a plant belonging to the Zingiberaceae family. An extract particularly suitable for the compositions object of the present invention is that marked as Curcuma Fitosoma (Meriva Indena).
- curcumin is meant to comprise also derivatives with analogous activity such as curcuminoids.
- Vitamin K if present, is in an amount between 1 ⁇ g and 5000 ⁇ , preferably between 20 ⁇ g and 200 ⁇ , even more preferably between 50 and 100 ⁇ .
- compositions object of the present invention are particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and increasing bone mineralization thanks to the synergic activity of the components thereof.
- a further object of the present invention is a pharmaceutical composition
- a pharmaceutical composition comprising the association of Vitamin D, Isoflavones and Policosanols, and optionally one, two or three additional components selected among boswellic acids, curcumin and vitamin K, in admixture with a suitable pharmaceutically acceptable carrier for use in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization.
- the inventors are of the opinion that the synergic effect of the association Vitamin D, Isoflavones and Policosanols, according to the present invention, derives from the following activities of the components of the association.
- Isoflavones act as agonists of the estrogen receptor. The activation of these receptors is associated with, among others, an increase in the expression of osteoprotegerin. This protein is able to bind the RANK-L (Receptor activator of nuclear factor kappa-B ligand) protein, preventing the binding with the RANK (Receptor activator of nuclear factor kappa-B) receptor.
- RANK-L Receptor activator of nuclear factor kappa-B ligand
- the interaction RANK-L/RANK at the level of vascular smooth muscle cells may lead to the expression of BMP-2 (Bone morphogenetic protein 2) protein, which induce the vascular calcification process, with osteoblastogenic differentiation and deposit of hydroxyapatite crystals in the vascular tunica media and to the inhibition of the expression of MGP protein (Matrix Gla Protein), which has the opposite effect and inhibits the calcification process.
- BMP-2 Bis morphogenetic protein 2
- MGP protein Mestrix Gla Protein
- Vitamin D Low doses of Vitamin D can induce the process of vascular calcification.
- the administration of Vitamin D can inhibit this phenomenon.
- Policosanols inhibit the synthesis of cholesterol, acting on the expression of HMG- CoA reductase. This leads to a reduction of cholesterol levels in the hepatocyte, an increase in the expression of LDL receptors and the following reduction in blood levels of LDL.
- Isoflavones acting on the estrogen receptor, stimulate osteoblasts proliferation and cause osteoclasts apoptosis. In this manner they prevent bone reabsorption and stimulate mineralization.
- Vitamin D enhances the absorption of calcium and phosphate at intestinal level. These minerals are crucial for the process of bone mineralization. In addition it is involved in the secretion of parathyroid hormone, which is able to stimulate bone proliferation.
- composition object of the present invention was evaluated with the following experimental protocol.
- VSMC vascular smooth muscle cells
- the synergic activity of the components of the present invention cab be evaluated in in vitro and/or in vivo models of osteoporosis.
- in vivo experiments can measure the proliferation of osteoblasts by colorimetric test (such as MTT) or the differentiation of osteoclasts; they can also evaluate the activity of the alkaline phosphatase following the addition of the components to be tested either individually or in combination.
- colorimetric test such as MTT
- differentiation of osteoclasts can also evaluate the activity of the alkaline phosphatase following the addition of the components to be tested either individually or in combination.
- bone mineralization can be evaluated in vitro by spectrophotometric tests using suitable reactants such as, for example, alizarin.
- the synergic activity of the components of the present invention against osteoporosis can also be evaluated by means of in vivo tests on animals experimentally reproducing the disease conditions through ovariectomy or others methods accepted by the scientific literature. Then, bone fragility and densitometry can be evaluated through specific devices and/or by assessing blood levels of biochemical markers.
- the association of substances of the present invention has a synergic activity on the metabolism of cholesterol. Said action is evaluated by suitable experimental tests able to induce hypercholesterolemia in animals, for example, by the administration of a specific diet with a high fat content. After developing the model and administering the substances either individually or in combination, the specific lipoprotein (HDL, LDL, VLDL) and triglycerides levels and/or other parameters involved in lipid metabolism are evaluated.
- HDL, LDL, VLDL specific lipoprotein
- triglycerides levels and/or other parameters involved in lipid metabolism are evaluated.
- Daily doses are meant to be administered in a suitable oral dosage form and divided in one or more dosage units such as a tablet.
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Abstract
A pharmaceutical composition comprising a synergic association of Vitamin D, Isoflavones and Policosanols and optionally one, two or three additional components selected among boswellic acids, curcumin and vitamin K for the treatment of cardiovascular diseases, in particular for reducing the process of vascular calcification and cholesterol levels and for increasing bone mineralization is described.
Description
"Pharmaceutical composition for the prevention and/or treatment of cardiovascular and osteoarticular diseases"
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DESCRIPTION
The present invention refers to a pharmaceutical composition comprising an association of Vitamin D, Isoflavones and Policosanols useful for the treatment of cardiovascular disease, particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization thanks to the synergistic action of its components.
Background of the invention
Hypercholesterolemia
Cardiovascular diseases are the main cause of mortality of developed and developing countries. In Europe, cardiovascular diseases are still responsible of 4 millions of deads per year and, despite in recent times there was a reduction in the number of deaths, they still represent the main cause of mortality. Coronary heart disease, alone, are responsible for at least 1.8 millions of deads per year, which represent 20% of the total number of deads in Europe (N. Townsend, M. Nichols, P. Scarborough, and M. Rayner, "Cardiovascular disease in Europe - Epidemiological update 2015," Eur. Heart J., vol. 36, no. 40, pp. 2696-2705, 2015).
As regards the combination of risk factors, in some cases it was found that the combination of more factors leads to an increase in mortality less relevant than might be expected. In other cases, instead, as in the combination between diabetes and hypertension, the risk of cardiovascular events significantly increases (R. C. Turner et al., "Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23)," Bmj, vol. 316, no. 7134, pp. 823-828, 1998).
From epidemiological studies several factors of cardiovascular risk, among which: hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycaemia have been identified.
Hyperlipidemias and reduced levels of HDL are a consequence of several factors correlated with each other, which can be either of behavioural or environmental type, genetic (mutations of genes codifying for lipoproteins) or metabolic (diabetes mellitus or other conditions able to affect blood levels of lipoproteins) (L. Brunton, J. Lazo, and
K. Parker, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Eleventh Edition. McGraw Hill Professional, 2005).
Hypercholesterolemia, hypertriglyceridemia and low blood concentration of HDL are the main cause of atherosclerosis and atherosclerosis-associate diseases, such as angina pectoris, myocardial infarction, cerebrovascular diseases and peripheral vascular diseases (arterial and venous occlusion). The use of drugs able to control blood levels of cholesterol and, in particular, levels of low density lipoproteins (LDL) has led to the reduction of mortality, as several clinical experimentations suggest. For example, in a simvastatin experimentation, a reduction from 30 to 40% of fatal and non-fatal coronary heart diseases and ictus was observed (T. et al Pedersen, Terje; Kjekshus, J; Berg, K; Haghfelt, "Randomised trial of cholesterol lowering in 4444 patients with coronary heart Lancet, vol. 344, no. November, pp. 1383-8, 1994). A 0.6 mmol/L difference in the blood concentration of cholesterol is associated with a 27% relative difference in the risk of coronary heart diseases and this correlation is always observed in a concentration range of cholesterol ranging from 4.0 mmol/L to 9.0 mmol/L (R. Jackson, C. M. M. Lawes, D. A. Bennett, R. J. Milne, and A. Rodgers, "Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk," Lancet, vol. 365, no. 9457, pp. 434-441 , Jan. 2005).
Hypertriglyceridemia is a cardiovascular risk factor less important than hypercholesterolemia. Moderately high levels of triglycerides are part of the metabolic syndrome, which includes insulin-resistance, obesity, hypertension, low level of HDL and an increased cardiovascular risk (already mentioned L. Brunton, J. Lazo, and K. Parker, page. 933).
Hypertension is the most common cardiovascular disease. It is defined as a constant increase of blood pressure exceeding values of 140/90 mmHg: this criterion characterises a kind of patients whose risk of cardiovascular diseases associated with blood pressure is sufficiently high to deserve medical attention. The incidence of hypertension increases with age: about 50% of people between 60 and 69 years suffer from it and the incidence further increases in subjects over 70 years. High blood pressure is able to lead to a left ventricle hypertrophy. Accordingly, hypertension is the main cause of ictus and a risk factor for coronary heart diseases, myocardial infraction and heart and kidney failure (already mentioned L. Brunton, J. Lazo, and K. Parker, page 845).
The pathogenesis of atherosclerosis begins with a damage to the vascular endothelium, which can be induced by oxidised LDL, free radicals, hypertension, diabetes, genetic alterations, high levels of homocysteine or by microorganisms. These damages create an alteration in the endothelial homeostasis, followed by an increase in vascular permeability, vasoconstriction, coagulation and trigger an inflammatory response. If the inflammatory response is not able to neutralize the etiological agent, the consequence is the increase in the proliferation of smooth muscular cells and the migration of macrophages (derived from monocytes) and T- lymphocytes (E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou, "Inflammation and atherosclerosis," Eur. J. Vasc.Endovasc. Surg., vol. 31 , no. 4, pp. 386-393, 2006).
After the adhesion to the vascular endothelium surface, mediated by ICAM-1 and VCAM-1 (but also ELAM, Selectin-P, Selectin-E), monocytes and lymphocytes T are recalled to the tunica intima, by chemotactic factors such as MCP-1 (monocyte chemoattractant protein-1 ) protein. From studies on knock-out mice was shown that this protein is crucial from the very first phases of the atherogenesis process (L. Gu et al., "Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice.," Mol. Cell, vol. 2, no. 2, pp. 275-281 , 1998). Once in contact with tunica intima, the M-CSF factor is able to stimulate the differentiation in macrophages and the lipid ingestion (already mentioned E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou; J. J. Boyle, "Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture.," Curr. Vase. Pharmacol., vol. 3, no. 1 , pp. 63-68, 2005). Moreover this factor is able to increase the expression of scavenger receptors for oxidised LDL, among which MSRa and CD36 (also known as MSRb) (already mentioned J.J. Boyle). The consequence consists in the conversion of macrophages in foam cells, which accumulate in tunica intima, generating the primary atherosclerotic lesions, namely lipid striae.
Within lipid striae the activation lymphocytes T occurs, which promote the migration of smooth muscular cells, by the secretion of cytokines (TNF-β, interferon-γ), fibrogenic mediators and growth factors. The proliferation of smooth muscle generates a dense extracellular matrix, which characterizes the later stages of atherosclerosis (already mentioned E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou).
Atherosclerosis can have two effects at vascular level: it can produce, for example, a thickening of the wall of coronary arteries, which causes stable angina. Otherwise the atheromatous plaque can break, which causes acute coronary artery diseases, unstable angina, myocardial infraction and sudden death (already mentioned E. A. Kaperonis, C. D. Liapis, J. D. Kakisis, D. Dimitroulis, and V. G. Papavassiliou).
Vascular calcification
In the nineteenth century, the pathologist Rudolf Virchow firstly recognised vascular calcification in the pathophysiology of cardiovascular diseases, although he considered it a passive and degenerative phenomenon. In the last 20 years, instead, vascular calcification was recognised as an active and finely regulated process.
The pathologic calcification of cardiovascular structures can be associated with a series of pathologies, such as kidney failure, diabetes, hypercholesterolemia and others cardiovascular diseases.
Vascular calcification is mainly characterized by the deposition of apatite crystals in the wallsb of blood vessels, myocardium and cardiac valves. The deposits of calcium can occur at different levels of the vessel: the calcification of tunica intima is associated with atherosclerotic lesions (J. L. Hunt et al., "Bone formation in carotid plaques: a clinicalpathological study," Stroke, vol. 33, no. 5, pp. 1214-1219, 2002; A. P. Burke, A. Taylor, A. Farb, G. T. Malcom, and R. Virmani, "Coronary calcification: insights from sudden coronary death victims.," Zeitschrift fur Kardiologie, vol. 89 Suppl 2, no. 2. pp. 49-53, 2000), whereas the calcification of tunica media (also known as Monckeberg Medial Sclerosis) is associated with vascular tightening and atherosclerosis occurring with age, diabetes and kidney failure (M. E. Edmonds, N. Morrison, J. W. Laws, and P. J. Watkins, "Medial arterial calcification and diabetic neuropathy," Br Med J (Clin Res Ed), vol. 284, no. 6320. pp. 928-930, 1982).
Vascular calcification can lead to devastating organ dysfunction. In the heart, the calcification of cardiac valve occluders is one of the main cause of the valve malfunctioning. In patients undergoing dialysis, calcification of the vascular tunica media is responsible for the calcific uremic arteriolopathy, a condition associated with a high mortality rate.
Conversely, the vascular calcification deriving from kidney failure, diabetes and atherosclerosis has often been regarded as a benign factor. However, in recent times, experimental evidences have emerged leading to the conclusion that the phenomenon of vascular calcification often increases the problems associated with
atherosclerosis, with an increase in the risk of myocardial infraction and break of the atheromatous plaque, with formation of thrombi and consequent tissue ischemia (P. J. Fitzgerald, T. a Ports, and P. G. Yock, "Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound.," Circulation, vol. 86, no. 1 , pp. 64-70, 1992; G. Puentes et ai, Eds., "H: Estimation of coronary calcium mass using electron beam computed tomography: A promising approach for predicting coronary events?," Circulation, vol. 92, p. 313; W. G. BEADENKOPF, A. S. DAOUD, and B. M. LOVE, "Calcification in the Coronary Arteries and Its Relationship To Arteriosclerosis and Myocardial Infarction.," Am. J. Roentgenol. Radium Ther. Nucl. Med., vol. 92, pp. 865-71 , 1964; G. Sangiorgi et al., "Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: A histologic study of 723 coronary artery segments using nondecalcifying methodology," J. Am. Coll. Cardiol., vol. 31 , no. 1 , pp. 126-133, 1998; J. A. Rumberger, D. B. Simons, L. A. Fitzpatrick, P. F. Sheedy, and R. S. Schwartz, "Coronary artery calcium area by electron- beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study.," Circulation, vol. 92, pp. 2157-2162, 1995). Vascular calcification of the tunica media in medium to large sized arteries causes the tightening thereof, with a reduction in the vascular compliance. The consequences of the decreased elasticity of these arteries are increased heart rate, arterial hypertension, increased heart work and left ventricular hypertrophy, as well as a reduction in coronary perfusion. Calcification of the vascular media is therefore a major risk factor for coronary artery diseases and cardiovascular events, mainly in patients with type 1 diabetes and in patients with end stage renal disease (ESRD) (C. M. Giachelli, "Vascular calcification mechanisms," J Am Soc Nephrol, vol. 15, no. 12, pp. 2959-2964, 2004).
More than half of the deaths in patients with ESRD are due to cardiovascular diseases (CVD). The CVD risk is, in fact, from 20 to 30 times higher in patients with ESRD compared with general population.
In order to explain the pathogenesis process of vascular calcification 4 different mechanisms were proposed (see the already cited CM. Giachelli):
1. Blood vessels normally express mineralization inhibitors, such as pyrophosphatase and matrix GLA protein (MGP): loss in the expression of these inhibitor proteins leads to mineralization of the vessel and to an increase in mortality. a2-HS fetuin/glycoprotein is one of the main inhibitors of the deposition
of apatite crystals in the vessel and reduced levels of fetuin are associated with an increase in mortality for cardiovascular events.
2. Osteogenesis process can further contribute to vascular calcification, as shown by the presence of osteopontin, osteocalcin, BMP2, matrix vesicles and the formation of bone and cartilage in the vascular lesion. In fact, the cells present in the vessel can undergo differentiation leading them to assume the phenotype of osteoblasts and chondrocytes.
3. In menopausal women, the increased turnover of the bone can lead to the release in the blood flow of crystallization germs for apatite which, once reached the vascular wall, might cause the deposition of circulating calcium and phosphate.
4. The death of vascular smooth muscle cells can lead to the formation of apoptotic bodies and debris deriving from necrosis which serve as crystallization germs for apatite.
In all cases, high blood level of calcium and phosphate represent a crucial etiological agent in the process of vascular calcification. Numerous in vitro studies, on animals and humans, have explained the role of these ions in the process of vascular calcification. In fact, it was shown that an increase in the concentration of inorganic phosphate in cellular cultures of vascular smooth muscle cells is associated with the deposition of apatite crystals in the extracellular matrix and the phenotypic change of said cells, with a reduction of genes specific for smooth muscular cells and an increase in the expression of genes involved in bone differentiation, among which osteocalcin, osteopontin and Runx2 (see the already mentioned CM. Giachelli). Also calcium is associated with the predisposition for vascular calcification, because on the one hand it increases mineralization and on the other it increases phosphate absorption by vascular smooth muscle cells, with exacerbation of the previously described mechanisms.
Currently, pharmacological treatments effective in the prevention of vessel calcification and, as a consequence, in the reduction of mortality caused by cardiovascular events do not exist (see the already mentioned CM. Giachelli):
1. Since high levels of calcium and phosphate can predispose to vascular calcification, a possible therapeutic strategy consists in reducing the absorption of these ions at intestinal level. Most used are phosphorus chelating agent not containing calcium, such as sevelamer, for the reduction of hyperphosphatemia.
The efficacy of this treatment in the reduction of mortality in dialysis patients is, however, modest.
2. An alternative is represented by antihypertensive agents. In a clinical study, the use of nifedipine has led to a bigger slowdown in the progression of vascular calcification in hypertensive patients than diuretics. Moreover, it was observed that the vascular calcification of tunica media and the consequent tightening of vessels can led to the development of hypertension.
Osteoporosis
The skeleton is the main support structure of our body and constitutes also a protected environment for the hematopoietic activity. It is formed by a mineralized matrix and a cellular compartment with high activity.
The skeleton is divided in appendicular skeleton, or peripheral, and axial skeleton, or central, associated with different turnover rates. The appendicular skeleton constitutes about 80% of bone mass and it is prevalently made up of compact bones. The axial part, instead, is prevalently made up of spongy bones, with a significant trabecular portion and a thin cortex.
Osteoporosis, a degenerative disorder of the skeleton, is a condition characterized by a poor bone mineral density (osteopenia) and by a weakening of the bone architecture, leading to a weakening of the bone structure and to an increase in the risk of fractures in case of trauma (NIH, F. I. Komarov, I. N. Bkarev, and A. I. SmolianitskiT, "Consensus Development Panel on Osteoporosis prevention, diagnosis, and therapy," Jama, vol. 285, no. 6, pp. 785-95, 2001 ). Hip fractures are among the most severe consequences of osteoporosis, leading to a reduced activity in everyday life, a reduction of life quality and to an increase in mortality (C. Holroyd, C. Cooper, and E. Dennison, "Epidemiology of osteoporosis.," Best Pract. Res. Clin. Endocrinol. Metab., vol. 22, no. 5, pp. 671-85, 2008).
As the average age of the world's population is constantly rising, osteoporosis has become an important problem of public health. It affects individuals belonging to all ethnical groups and the number of persons affected by this pathology is about 200 millions in the world. Osteoporosis mainly occurs in elderly individuals, but rarely it can occur also in younger individuals, due to hormone dysfunctions (J. Aaseth, G. Boivin, and O. Andersen, "Osteoporosis and trace elements - An overview," J. Trace Bern. Med. Biol. , vol. 26, no. 2-3, pp. 149-152, 2012.; D. Cech, "Prevention of
osteoporosis: From infancy through older adulthood," Hong Kong Physiother. J., vol. 30, no. 1 , pp. 6-12, 2012).
Bone fractures contribute to significantly increase the mortality in elderly population. Their frequency increases exponentially with age, so that a fracture in at least one woman in 3 and a man in 6, in the last ten years of life is observed (O. Oliver, D., Griffiths, R., Roche, J., Sahota, "Hip fracture," Clin. Evid. (Online)., vol. 2007, no. 10, pp. 589-609, 2007). The consequences of bone fractures are particularly severe and 50% of persons incur in permanent disability, from 15 to 25% need a long period of rehabilitation, whereas from 10 to 20% of affected persons dies in the first year of life (S. R. Cummings, D. M. Black, and S. M. Rubin, "Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women.," Arch. Intern. Med., vol. 149, no. 149, pp. 2445-2448, 1989; R. G. Cumming, "Epidemiology of osteoporosis and osteoporotic fractures," Aust. Prescr., vol. 20, no. SUPPL. 3, pp. 13-17, 1997; J. Magaziner et al., "Recovery From Hip Fracture in Eight Areas of Function," J. Gerontol., vol. 55, no. 9, pp. M498-M507, 2000; S. R. Cummings, S. M. Rubin, and D. Black, "The future of hip fractures in the United States: Numbers, Costs, and Potential Effects of Postmenopausal Estrogen," ClinOrthop, vol. 252. pp. 163-166, 1990). Medical expenses associated with osteoporosis are very high and constantly rising: in United States there has been a rise from 7.2 billions of dollars per year in 1990 to about the current 16 billions of dollars (see the already mentioned S. R. Cummings, S. M. Rubin, and D. Black).
Osteoporosis can be classified in primary and secondary osteoporosis (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1662).
Primary osteoporosis in turn can be subdivided in type I osteoporosis, caused by the lack of estrogens during menopause and characterized by loss of trabecular bone and in type II osteoporosis, characterized by loss of cortical and trabecular bone and caused by the inefficiency of bone remodelling, protracted for a long period of time, lack of nutrients with diet and activation of parathyroid hormone.
Secondary osteoporosis can be caused by a systemic disease or by the use of drugs, such as glucocorticoids and phenytoin.
In the case of secondary osteoporosis, the best therapeutic strategy consists in eliminating the pathology that caused it or suspending the pharmacological treatments that caused it. In any case, since both primary and secondary osteoporosis
are characterized by bone mineral loss, the pharmacological treatments can be similar (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1662).
Interventions can be classified in non-pharmacological and pharmacological (S. H. Telia and J. C. Gallagher, "Prevention and treatment of postmenopausal osteoporosis," Journal of Steroid Biochemistry and Molecular Biology, vol. 142. NIH Public Access, pp. 155-170, Jul-2014). The main objectives of pharmacological therapy are the prevention of fractures, maintenance or increase of bone mineral density and an improvement in physical conditions. Osteoporosis treatments aim to reduce the bone resorption rate (antiresorptive therapy) or to promote formation thereof (anabolic therapy) (see the already mentioned L. Brunton, J. Lazo, and K. Parker, p. 1670).
Non-pharmacological interventions are the following:
Changes to the diet and lifestyle, with an increase in the weekly physical activity, the reduction of smoking, which can be detrimental for bone health and the reduction of the consumption of alcoholic beverages the use of which, besides damaging the bone structure, is associated with an increased risk of falls;
Calcium supplementation. Lots of menopausal women take inadequate amounts of calcium with diet and in several studies it has been shown the usefulness of the administration of this element. A study has shown a minor incidence of fractures in women following a daily supplementation of calcium (R. L. Prince, A. Devine, S. S. Dhaliwal, and I. M. Dick, "Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women.," Arch. Intern. Med., vol. 166, no. 2006, pp. 869-875, 2006).
Use of vitamin D. The recommended dose of this vitamin is 800 Ul (corresponding to 20 μg): a meta-analysis has shown the efficacy of this dose of vitamin D, associated with the use of calcium (H. A. Bischoff-Ferrari, W. C. Willett, J. B. Wong, E. Giovannucci, T. Dietrich, and B. Dawson-Hughes, "Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials.," JAMA, vol. 293, no. 18, pp. 2257-64, 2005). Pharmacological interventions of osteoporosis are the following:
Hormone replacement therapy. It is considered the first line treatment in the prevention of fractures in woman up to 5 years from the beginning of
menopause. The best therapeutic approach consists in the use of doses of estrogens, with or without the association with progestins, for a period of 6 months, in order to rapidly reduce bone resorption, mostly occurring in the first 3-4 years of menopause. For years this therapy was widely used, but after the publication of the study WHI (Women's Health Initiative) in 2001 (J. E. Rboneuw et al. , "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.," JAMA, vol. 288, no. 3, pp. 321-33, Jul. 2002) its use is decreased. From this study emerged that the use of hormone replacement therapy leads to an increase in the risk of cardiovascular events and risk of breast cancer, which indicates that the risks of this therapy widely outweigh the benefits (see the already mentioned J. E. Rboneuw et al.). Bisphosphonates. The pharmacological activity consists in the suppression of bone turnover, in the prevention of bone loss and in the protective effect towards bone architecture, which derive from their adhesion to bone surfaces and the inhibition of the farnesyl pyrophosphate synthase enzyme, required for the formation of osteoclasts cytoskeleton, thus inhibiting bone resorption. The main bisphosphonates are alendronate, risedronate, ibandronate and zoledronic acid. The efficacy of the use of these drugs was demonstrated in several studies (D. M. Black et al., "Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long- term Extension (FLEX): a randomized trial.," JAMA : the journal of the American Medical Association, vol. 296, no. 24. pp. 2927-2938, 2006; J.-Y. Reginster et al., "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group," Osteoporos Int, vol. 1 1 , no. 1 , pp. 83-91 , 2000; D. Black, P. Delmas, and R. Eastell, "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis," N. Engl. J. Med. , vol. 356, no. 18, pp. 1809-1822, 2007; D. M. Black, I. R. Reid, and S. Boonen, "Black DM et al The Effect of 6 Versus 9 Years of Zoledronic Acid Treatment in Osteoporosis A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PF.pdf," J Bone Min. Res, vol. 2012, no. 27, p. 243, 2006; I. C. Chesnut et al., "Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis," J Bone
Min. Res, vol. 19, no. 8, pp. 1241-1249, 2004), however these drugs present several serious usage restrictions. Bioavailability is very limited (about 1 %) and, after the administration, the patient is required to stay in supine position to avoid gastroesophageal reflux which can be induced by them. The intravenous administration, instead, is associated with the insurgence of acute phase reactions. Another side effect of bisphosphonates is musculoskeletal pain. Other rarer side effects are hypocalcaemia, ocular inflammation and an increase in the risk of atypical femoral fractures and mandibular osteonecrosis (see the already mentioned S.H. Telia and J.C. Gallagher).
- Thiazide diuretics. They are able to reduce renal excretion of calcium, which can be associated with a reduction in bone loss. The effect is very limited. Denosumab. Monoclonal antibody that acts by binding RANKL protein which, interacting with RANK protein, can enhance bone resorption.
Teriparatide. Parathyroid hormone analogous.
There is still the need of a therapeutic treatment effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization, without the above described drawbacks.
Now it has been surprisingly found that an association of Vitamin D, Isoflavones and Policosanols is particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization thanks to the synergistic action of its components.
Detailed description of the invention
Therefore, an object of the present invention is a pharmaceutical composition comprising an association of Vitamin D, Isoflavones and Policosanols useful for the treatment of cardiovascular diseases, particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization.
The pharmaceutical composition object of the present invention can optionally contain other active components selected from boswellic acids, curcumin e vitamin K. These additional components can be present all together in the composition object of the present invention or one of the additional components can be present alone or again two additional components can be present, for example boswellic acids and curcumin, boswellic acids and vitamin K, curcumin and vitamin K.
The components of the association according to the present invention are all known components, widely used in therapy.
Vitamin D
Given the high prevalence, severity and the high costs associated with fractures caused by osteoporosis, the need of a preventive strategy which is secure and effective is felt. A promising prevention strategy consists in vitamin D supplementation (see the already mentioned H.A. Bischoff-Ferrari, W.C. Willett, J.B. Wong, E. Giovannucci, T. Dietrich and B. Dawson-Hughes).
Vitamin D plays an essential role in calcium homeostasis (L. L. Brunton, L. John S, and P. K. L, GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, XI. McGraw-Hill, 2006). Vitamin D is to be considered a real hormone, since our organism is able to synthetized it, but only in ideal conditions the synthetize amount is sufficient, therefore it has to be taken with diet.
In a meta-analysis the efficacy of calcium and vitamin D administration was evaluated in 7 clinical studies (see the already mentioned H.A. Bischoff-Ferrari, W.C. Willett, J.B. Wong, E. Giovannucci, T. Dietrich and B. Dawson-Hughes). The meta-analysis involved 9820 treated patients, with an average age of 79 years and among which 68% was female. The dose of vitamin D was 400 Ul (International Units)/die in 2 studies and from 700 to 800 Ul/die in the remaining 5 studies; the daily assumption of calcium was between 500 and 1200 mg/die.
In the clinical studies providing for the administration of 700-800 Ul of vitamin D per die, a high risk of 0.74 (95% CI, 0,61 -0,88) to incur in hip fracture was observed, therefore, the likelihood of a bone fracture was reduced by 26%. In the clinical studies providing for the administration of 400 Ul/die of vitamin D, instead, a RR of 1 .15 was observed, from which it can be derived that this daily dose of vitamin D might be not effective in reducing the risk of hip fracture. As regards the risk of non-vertebral fractures, instead, an RR of 0.77 (95% CI, 0,68-0,87) was observed in the studies with a dose of 700-800 Ul/die, with a reduction of fracture risk by 23% (see the already mentioned H.A. Bischoff-Ferrari, W.C. Willett, J.B. Wong, E. Giovannucci, T. Dietrich and B. Dawson-Hughes).
Cholecalciferol and metabolites thereof (25-hydroxycholecalciferol and 1 ,25- dihydroxycholecalciferol) are able to reduce blood cholesterol by different mechanisms. Cholecalciferol is able to induce the formation of HDL on cellular lines
of liver cancer (HepG2), through the induction of cholesterol efflux mediated by the membrane transporter ATB-binding cassette-A1 (ABCA1 ).
1 ,25-dihydroxycholecalciferol (calcitriol) increases the expression of liver receptor X, of the ABC-A1 transporter and promotes the cholesterol efflux from THP-1 monocyte cells. In addition is able to act on macrophage polarization, with formation of macrophages M2 which produce a minor amount of TNF-a, I L-1 β and IL-6.
Finally, 1 ,25-dihydroxycholesterol is able to induce the expression of CYP27A1 cytochrome, through the JNK kinases pathway (c-Jun N-terminal kinases) dependent on the calcitriol receptor (VDR). CYP27A1 (sterol 27-hydroxylase) increases the levels of 27-hydroxycholesterol, which in turn is able to induce the expression of liver receptors X, ABCA1 and ABCG1 increasing the efflux of cholesterol from foam cells (K. Yin et al., "Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine.," Arterioscler. Thromb. Vase. Biol., vol. 35, no. 1 1 , pp. 2432-42, Nov. 2015).
An in vitro study on macrophages collected from subjects belonging to 4 control groups (with or without hypertension, with or without diabetes, with or without vitamin D deficiency), has shown how calcitriol is able to inhibit the formation of foam cells in macrophages collected from diabetic obese patients, reducing the uptake of acetylated and oxidised LDL. In non-diabetic patients, the reduction in the formation of foam cells is definitely less significant. Moreover, the removal of vitamin D from the culture medium is associated with a bigger formation of foam cells after the addition of oxidised and acetylated LDL. The mechanism of action consists in a reduction in the activation by JNK (c-Jun N-terminal kinase) of PPAR-γ receptors, a reduction in the expression of CD36 protein (which binds oxidised lipoproteins) and reduces the uptake of oxidised LDL (J. Oh et al., "1 ,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.," Circulation, vol. 120, no. 8, pp. 687-98, Aug. 2009).
Another effect of calcitriol administration is the reduction of systolic pressure induced by fructose, but in this case the mechanism of action is unknown (C. L. Chou, C. Y. Pang, T. J. F. Lee, and T. C. Fang, "Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats," PLoS One, vol. 10, no. 3, pp. 1- 19, 2015).
A clinical study has evaluated the effect of a 75μg (3000 IU) per die administration of cholecalciferol for 20 week. In patients having a normal vitamin D3 intake before the study, the administration of cholecalciferol has led to a non-significant reduction of pressure. Instead, in patients that before the study had a low blood concentration (<32 ng/ml) of Vitamin D3, a very slight reduction of pressure by 4/3 mmHg was observed (T. Larsen, F. H. Mose, J. N. Bech, A. B. Hansen, and E. B. Pedersen, "Effect of cholecalciferol supplementation during winter months in patients with hypertension: a randomized, placebo-controlled trial.," Am. J. Hypertens. , vol. 25, no. 1 1 , pp. 1215- 22, Nov. 2012).
Several cohort and control-case studies have shown in some cases a correlation between low blood concentrations of vitamin D and increased cardiovascular risk. For example a follow-up study on patients without previously cardiovascular problems and a vitamin D deficiency (hydroxycalciferol concentrations <15 ng/mL) has shown a twofold increase in the likelihood of myocardial infraction. Another study on patients with even lower (<10 ng/mL) blood levels of hydroxycalciferol has shown a hazard ratio of outbreak of a cardiovascular event of 1.85, with respect to patients with normal vitamin D levels. Finally another study has demonstrated an increased risk of hypertension from 3 to 6 times greater in patients with reduced levels of vitamin D. The problem is that studies often show contrasting results, above all with regard to the correlation between vitamin D and the development of hypertension. Therefore, it is not possible to say with certainty that vitamin D supplementation can modify blood pressure (S. E. Judd and V. Tangpricha, "Vitamin D Deficiency and Risk for Cardiovascular Disease," Am. J. Med. Sci. , vol. 338, no. 1 , pp. 40-44, 2009).
Another review reports numerous epidemiological studies which correlate low blood concentrations of 25-hydroxycholecalciferol to an increased cardiovascular risk (hypertension, myocardium infraction, ictus, angina pectoris, etc.). Values of relative risk and OD, vary a lot from study to study, but in all cases there is an even minimum increase of cardiovascular events in case of vitamin D deficiency (J. M. Geleijnse, "Vitamin D and the prevention of hypertension and cardiovascular diseases: a review of the current evidence.," Am. J. Hypertens., vol. 24, no. 3, pp. 253-262, 201 1 ).
In a more recent clinical study on 200 participants with hypertension and low blood level of vitamin D3, 2800UI of cholecalciferol were administered in order to evaluate the effect thereof on the cardiovascular risk. The result was that a significant correlation between vitamin D deficiency and blood pressure and cardiovascular
events does not exist. However, after therapy with this vitamin, an increase of blood triglycerides was observed (S. Pilz et al., "Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.," Hypertension, vol. 65, no. 6, pp. 1 195-1201 , 2015).
Isoflavones
The prevalence of age-related bone loss is greater in women than in men and, in 25- 30% of elderly women, this process leads to serious orthopaedic problems (H. G. Bone et al., "Alendronate and estrogen effects in postmenopausal women with low bone mineral density," J. Clin. Endocrinol. Metab., vol. 85, no. 2, pp. 720-726, 2000). Natural or surgical menopause is associated with an initial phase, lasting about 10 years, of rapid loss of bone mineral density, followed by a period of less deterioration of the skeleton (E. F. Eriksen and B. L. Langdahl, The Pathogenesis of Osteoporosis, vol. 48, no. 5. Bone Miner, 1997). The deficiency of ovarian hormones deriving from menopause entails an increase in the speed of bone turnover and causes an imbalance between bone resorption and formation thus leading to an acceleration in bone loss (J. Verhaeghe et al., "Effects of recombinant human growth hormone and insulin-like growth factor-l, with or without 17 beta-estradiol, on bone and mineral homeostasis of aged ovariectomized rats.," J. Bone Miner. Res., vol. 1 1 , no. 1 1 , pp. 1723-1735, 1996).
Although the best treatment for osteoporosis remains controversial, the most logical approach consists in associating an antiresorptive agent to generate a regression in bone remodelling and an agent able to stimulate osteoblastic proliferation, in order to enhance the process of bone formation. Among antiresorptive agents currently available in therapy, hormone replacement therapy (HRT) is probably the most effective treatment, as it was shown that this therapy can either reduce the bone mineral loss, or reduce the risk of fractures, including hip fracture.
Phytoestrogens, such as isoflavones, and in particular soy isoflavones, have been characterized as naturally occurring selective modulators of estrogens receptor, with beneficial effects on the bone similar to those of raloxifen.
There are numerous experimental evidences in support of soy isoflavones efficacy in the prevention and in the treatment of osteoporosis.
The relation between soy isoflavones and bone tissue was studied for less than ten years. Data of numerous in vivo studies have shown how soy isoflavones have conservative effects on the bone, with retention of bone mass following ovariectomy.
In a clinical study, in menopausal women treated with soy proteins added with isoflavones, a reduction in bone mineral loss was observed. Epidemiological studies have shown that women that consume large quantities of soy have a lower risk of osteoporosis than women that consume a normal occidental diet. Accordingly, many menopausal women consume phytoestrogens to maintain the bone mineral density, as they are associated with significantly lower side effects than steroid hormones. In a meta-analysis the effect of Isoflavones in the prevention of bone mineral loss was evaluated (P. Wei, M. Liu, Y. Chen, and D. C. Chen, "Systematic review of soy isoflavone supplements on osteoporosis in women," Asian Pac. J. Trop. Med., vol. 5, no. 3, pp. 243-248, 2012). The daily intake of soy Isoflavones for a period from 1 month to 2 years has led to a statistically significant increase of the bone mineral density, by 54% (95 CI: 13% to 94%, P<0.001 ) compared to placebo. The percentage change combined in urinary BAD with respect to the basal was 26%. In addition, isoflavones have led to a reduction in urinary DPD by 23% with respect to the basal level. The effect of isoflavones on the bone mineral density is achieved with a dose of isoflavones higher than 75 mg/die.
Soy isoflavones are able to inhibit the bone loss induced by osteoporosis, but can likewise inhibit the process of vascular calcification. In both cases, the mechanism of action is based on the interaction with the RANK/RANKL/OPG system (M. K. Osako et al., "Estrogen inhibits vascular calcification via vascular RANKL system: Common mechanism of osteoporosis and vascular calcification," Circ. Res., vol. 107, no. 4, pp. 466-475, 2010).
In the bone, RANKL (Receptor Activator of Nuclear Factor κ B)-Ligand) and OPG (osteoprotegerin) are expressed in osteoclastic cells. The main role of the RANKL protein is to stimulate the osteoclastic activity and inhibit the osteoblastic activity. Osteoprotegerin, is a soluble protein able to link the RANKL protein, thereby preventing it from interacting with the RANK receptor and preventing its effects which lead to an increase in bone resorption. RANKL is also able to induce the vascular calcification: a study has shown that its mechanism consists in the regulation of the Bone Morphogenetic Protein-2 (MGP-2) protein and it is counteracted by the action of estrogens in a dose-dependent manner (see the already mentioned M. K. Osako et al.).
Mice devoid of OPG develop a severe osteoporosis deriving from the marked increase in the differentiation of osteoclasts, as well as a deep calcification of vascular tunica
media. Similarly to knock-out mice for osteoprotegerin, a high bone resorption and the vascular calcification of arteriae was observed (N. Bucay et al., "{losteoprotegerin}-deficient mice develop early onset osteoporosis and arterial calcification," Genes Dev. , vol. 12, no. 12, pp. 1260-1268, 1998).
Estrogens regulate the bone metabolism inducing the osteoclasts apoptosis and the OPG expression by osteoclasts. Moreover, estrogens are able to inhibit the progression of vascular lesions, to enhance favourable alterations in lipoprotein metabolism and control the adhesion molecules that contribute to the inflammatory response in vessels.
In CWHIS (Controlled Women's Health Initiative Study) study, carried out on menopausal women aged between 50 and 59 years treated with a long-term estrogenic therapy have shown reduced levels of arteriae vascular calcification than women that received a placebo (J. E. Manson et al., "Estrogen therapy and coronary- artery calcification.," N. Engl. J. Med., vol. 356, no. 25, pp. 2591-2602, 2007).
Policosanols
Policosanols are a mixture of long chain primary alcohols, which usually contains 66% of octacosanol ((CH3-CH2(26)-CH2-OH), 12% of triacontanol and 7% of esacosanol; the remaining 15% of the mixture is constituted by minor components, such as tetracosanol, eptacosanol, nonacosanol, dovtriacontanol and tetratriacontanol. They are mainly extracted from cane sugar (Saccharum officinarum) but also from rice (Oryza sativa) and beeswax.
Numerous studies, on animals and humans, have shown that the consumption of policosanols can improve the lipid profile, with a reduction in the concentration of LDL cholesterol and an increase in concentration of HDL cholesterol. In addition to the improvement activity of the lipid profile, they are able to reduce platelet aggregation, to reduce the proliferation of vascular smooth muscle cells and to improve the symptoms of cardiovascular disorders.
Policosanols seem to cause a reduction in the synthesis and an increase in the degradation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, enzyme that catalyses the limiting step of the cholesterol biosynthesis. This is, therefore, a mechanism different from that of statins, which act as competitive inhibitors of this enzyme. Policosanols have also shown the ability to improve the metabolism of LDL lipoproteins, increasing the link, capture and degradation thereof by human fibroblasts.
Although their mechanism of action have not yet been fully identified, a group of American researchers proposed that molecular "pathways" on which policosanols act include the increase in liver levels of Acyl-CoA and levels of AMP, to activate the AMP kinase and inactivate HMG-CoA reductase.
Policosanols intake is also known to inhibit LDL oxidation, with consequent prevention of the formation of atheromatous plaques. A recent Chinese study has shown that a combination of policosanols and atorvastatin in patients with atherosclerosis leads to a reduction of PCSK9 levels, whose expression is induced by statins, as well as to a reduction of total cholesterol and triglycerides, indicating an effect of policosanols on the lipid composition. Another important passage in the process of atherosclerosis is the proliferation of vascular smooth muscle cells (VSMC). In preclinical studies carried out on rabbits, it was shown that policosanols reduce the formation of neointima: this indicate a reduction of the VSMC proliferation.
Another mechanism of action of policosanols, very important in the prevention of cardiovascular risk, is the reduction of platelet aggregation. This action seem to derive from the inhibition of thromboxane B2 synthesis, while there seems to be no action on prostacyclin. Several studies have shown the dose-dependent inhibition of platelet aggregation induced by several experimental substances. It has been shown that policosanols, at a dose of 20 mg/die, present a greater efficacy as antiplatelet agents compared with 100 mg/die of acetylsalicylic acid.
The majority of the studies on policosanols refer to the treatment of patients with hypercholesterolemia. In all these clinical studies, significant reductions in total (TC) (8-23%), LDL (1 1.3-27.5%), LDL/HDL (15.3-38.3%) and TC/HDL (9.1 -30.5%) cholesterol were observed.
The administration of policosanols, at a dose of 10-20 mg/die can lead to a reduction in LDL cholesterol up to 30%, a reduction comparable to that obtained with low doses of statins. In either brief (<12 weeks) or long term (up to 2 years) randomized clinical trials, controlled with placebo and in double-blind, policosanols lowered LDL cholesterol by 33% in normocholesterolemic patients and by 24% in hypercholesteremic patients. In normocholesterolemic patients, a slight increase in HDL cholesterol is also observed, while in dyslipidemic patients an average increase of 17% in HDL is observed, as demonstrated in seven clinical studies.
Two clinical studies, carried out on 300 post-menopausal women have shown the efficacy of policosanols in reducing hypercholesterolemia. In both the studies, an
initial 5 mg dose of polycosanols was used which was augmented (after 8 weeks in a study and 12 weeks in another study) to 10 mg/die for another treatment period of the same duration as the previous. At the end of the treatment period with the 5 mg/die dose, a reduction in total cholesterol (13-20%), LDL cholesterol (17-18%), LDL/HDL ratio (17-17.2%) and TC/HDL ratio (16.3-16.7%) and, in one of the two studies, a 16.5% increase of HDL cholesterol was observed. At the end of the treatment period with the 10 mg/die dose, a further decrease in TC, LDL, LDL/HDL and TC/HDL values, by 17-20%, 25-28%, 27-30% and 21 -27% respectively was observed.
A statistically significant decrease in cholesterol was observed even at very low doses (2 mg/die). The maximum decrease in cholesterol levels is observed at doses of 5-20 mg/die, whereas higher doses do not further improve cholesterol levels. The 40 mg/die dose is also able to reduce triglyceride levels.
Boswellic acids
Boswellic acids are the main secondary metabolites of frankincense, a resin produced by plants of the genus Boswellia, having anti-inflammatory and antitumor activity. Some clinical trials have shown the efficacy of preparations based on Boswellia in the treatment of inflammatory diseases, such as osteoarthritis, rheumatoid arthritis, chronic inflammatory bowel diseases, but also in the treatment of asthma and cancer (H. Ammon, "Boswellic acids in chronic inflammatory diseases," Planta Med., 2006; D. Poeckel and O. Werz, "Boswellic acids: biological actions and molecular targets.," Curr. Med. Chem., vol. 13, no. 28, pp. 3359-69, Jan. 2006).
Different mechanisms have been proposed for the action of boswellic acids on inflammation. For example, 3-0-acetyl-1 1-ketoboswellic acid is able to interfere with different pathways, among which that of NF-kB (T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet, "Acetyl-boswellic acids inhibit lipopolysaccharide- mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases.," J. Immunol. , vol. 174, no. 1 , pp. 498-506, Jan. 2005) and that of MAP (mitogen-activated protein) kinase ( D. Poeckel and O. Werz, "Boswellic acids: biological actions and molecular targets.," Curr. Med. Chem., vol. 13, no. 28, pp. 3359-69, Jan. 2006). In addition, it was demonstrated the ability of boswellic acids to interact with 5-lipoxigenasis (5-LOX) (H. Safayhi, T. Mack, J. Sabieraj, M. I. Anazodo, L. R. Subramanian, and H. P. Ammon, "Boswellic acids: novel, specific, non-redox inhibitors of 5-lipoxygenase.," J. Pharmacol. Exp. Ther., vol. 261 , no. 3, pp. 1 143-6,
Jun. 1992) and with cyclooxygenase isoform 1 (COX-1 ) (U. Siemoneit, B. Hofmann, N. Kather, T. Lamkemeyer, J. Madlung, L. Franke, G. Schneider, J. Jauch, D. Poeckel, and O. Werz, "Identification and functional analysis of cyclooxygenase- 1 as a molecular target of boswellic acids.," Biochem. Pharmacol., vol. 75, no. 2, pp. 503- 13, Jan. 2008). These activities, however, have been only demonstrated in vitro and at present there are no in vivo studies in support to the pharmacological relevance of these mechanisms of action (U. Siemoneit, A. Koeberle, A. Rossi, F. Dehm, M. Verhoff, S. Reckel, T. J. Maier, J. Jauch, H. Northoff, F. Bernhard, V. Doetsch, L. Sautebin, and O. Werz, "Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.," Br. J. Pharmacol., vol. 162, no. 1 , pp. 147-62, Jan. 201 1 ).
A potentially interesting mechanism of action is the inhibition of microsomal synthase of type 1 Prostaglandin E2 (mPGES-1 ). The PGES, prostaglandin E synthase, is an enzyme involved in the last step of the biosynthetic pathway of PGE2, which consists in the conversion of PGH2, whose synthesis is catalysed by cyclooxygenase, in PGE2. It has been shown that the mPGES-1 isoforme can be induced by pro-inflammatory stimuli, such as lnterleukin-1 β (IL-Ι β) and lipopolysaccharide (LPS). Moreover, mPGES-1 receives prostaglandin H2 preferentially by COX-2 enzyme, since the two enzymes are co-expressed and co-localized and that their expression can be induced by pro-inflammatory stimuli. Inflammation, pain and fever can be induced by PGE2 deriving from the overexpression of this enzyme (B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson, "Membrane prostaglandin E synthase-1 : a novel therapeutic target.," Pharmacol. Rev., vol. 59, no. 3, pp. 207-224, 2007). Inhibition of mPGES-1 may be effective in the treatment of inflammatory diseases, hyperalgesia induced by prostaglandin E2 and in case of fever. All boswellic acids have a good inhibitory activity on mPGES-1 , however, β-boswellic acid has proved to be one of the most active, with a IC50 of 10 μΜ in assays on A549 intact cells (U. Siemoneit, A. Koeberle, A. Rossi, F. Dehm, M. Verhoff, S. Reckel, T. J. Maier, J. Jauch, H. Northoff, F. Bernhard, V. Doetsch, L. Sautebin, and O. Werz, "Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.," Br. J. Pharmacol., vol. 162, no. 1 , pp. 147-62, Jan. 201 1 ). In in vivo assays on acute inflammation models (carrageenan edema and pleuritis) has shown a good activity at a dosage of 1 mg/kg, comparable to a 5 mg/kg dose of indomethacin (U. Siemoneit, A. Koeberle, A. Rossi, F. Dehm, M. Verhoff, S. Reckel,
T. J. Maier, J. Jauch, H. Northoff, F. Bernhard, V. Doetsch, L. Sautebin, and O. Werz, "Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.," Br. J. Pharmacol., vol. 162, no. 1 , pp. 147-62, Jan. 201 1 ).
Boswellic acids are among the most potent natural occurring inhibitors of mPGES-1 and have chemical-physical characteristics that make them potentially useful in the treatment of infections even when administered via transdermal route. In literature several studies on the efficacy of Boswellia administered via topic route exist. A study carried out on inflammation models (rat ear edema induced by arachidonic acid, carrageenan edema, adjuvant arthritis) has shown that the administration of boswellic acids via topic/transdermal route has led to the same effect of an administration via systemic route, which demonstrates a good systemic adsorption of these active ingredients also via topical route (S. Singh, A. Khajuria, S. C. Taneja, R. K. Johri, J. Singh, and G. N. Qazi, "Boswellic acids: A leukotriene inhibitor also effective through topical application in inflammatory disorders.," Phytomedicine, vol. 15, no. 6-7, pp. 400-7, Jun. 2008).
Another study speaks of the use of a cream containing Boswellia extracts in the treatment of inflammation associated with radiotherapy of breast cancer. In this sense it has shown to be so effective in the treatment of erythema and other symptoms associated with skin inflammations, to allow a reduction in the dosage of glucocorticoids usually employed in the therapy of the radiation damage (S. Togni, G. Maramaldi, A. Bonetta, L. Giacomelli, and F. Di Pierro, "Clinical evaluation of safety and efficacy of Boswellia-based cream for prevention of adjuvant radiotherapy skin damage in mammary carcinoma: a randomized placebo controlled trial.," Eur. Rev. Med. Pharmacol. Sci., vol. 19, no. 8, pp. 1338-44, Apr. 2015).
The absorption of boswellic acids through the skin can be further increased by the complexation with phosphatidylcholine. This leads to the formation of phytosomes containing boswellic acids, which shown an absorption definitely higher than the sole boswellic acids, when administered at the same dose (A. Sharma, N. K. Gupta, and V. K. Dixit, "Complexation with phosphatidyl choline as a strategy for absorption enhancement of boswellic acid.," Drug Deliv., vol. 17, no. 8, pp. 587-95, Nov. 2010). Another strategy for further increasing the bioavailability of boswellic acids is by using proniosomes (dehydrated forms of niosomes, vesicles constituted by non-ionic surfactants, which have a better penetration ability with respect to others vesicles (G.
V Radha, T. S. Rani, and B. Sarvani, "A review on proniosomal drug delivery system for targeted drug action.," J. basic Clin. Pharm., vol. 4, no. 2, pp. 42-8, 2013), which should substantially increase the boswellic acids bioavailability with respect to oral administration (boswellic acids are very lipophilic and undergo first pass metabolism) (M. Mehta and M. Garg, "Proniosomal Gel: A Promising Drug Carrier for Boswellic Acids," J. Med. Sci., vol. 15, no. 3, pp. 130-134, Mar. 2015).
Since one of the mechanisms that can induce the process of calcification is inflammation, the use of boswellic acids can be potentially useful for the prevention or treatment of vascular calcification.
Vitamin K
Vitamin K is a term associated with a family of vitamins characterized by different molecular structures. Vitamin K1 (phylloquinone) is the form synthetized by plants, K2 (menanquinon) is synthetized by bacteria, while vitamins K3, K4 and K5 have synthetic origin.
It has been observed that low daily intake of vitamin K or absorption disorders of this vitamin are associated with a reduced bone density and a higher risk of fracture in elderly persons (S. L. Booth et al , "Associations between vitamin K biochemical measures and bone mineral density in men and women," J. Clin. Endocrinol. Metab., vol. 89, no. 10, pp. 4904-4909, 2004; S. Booth and K. Broe, "Vitamin K intake and bone mineral density in women and men," Am. J. Clin. Nutr., vol. 77, no. 77, pp. 512- 6, 2003; D. Feskanich, P. Weber, W. C. Willett, H. Rockett, S. L. Booth, and G. A. Colditz, "Vitamin K intake and hip fractures in women: a prospective study," Am. J. Clin. Nutr., vol. 69, no. 1 , pp. 74-79, 1999), as well as ad a higher bone turnover in boy in development stage (K. HJ, K. JC, J. Bean, and E. JG, "Vitamin K, bone turnover, and bone mass in girls.," American Journal of Clinical Nutrition, vol. 80, no. 4. pp. 1075-1080, 2004).
A systematic review and a meta-analysis carried out by Cockaine and collaborators, revealed that the supplementation with menanquinon is related to a consistent reduction in the risk of all types of fracture (ORhy = 0.23; 95% confidence interval [CI], 0.12-0.47; ORvertebrai = 0.40; 95% CI, 0.25-0.65; ORnon-vertebrai = 0.19; 95% CI, 0.1 1- 0.35) (Sarah Cockayne, J. Adamson, S. Lanham-New, M. J. Shearer, S. Gilbody, and D. J. Torger, "Vitamin K and the Prevention of Fractures," Arch. Intern. Med., vol. 166, no. 1 , pp. 1256-1261 , 2006). The administration of vitamin K has led to a reduction
in the risk of hip fracture by 6%, vertebral fracture by 13% and non-vertebral fracture by 9%.
Calcification of the vascular tunica media is strongly related with age and is characterized by dense layers of calcium crystals in the centre of media, aligned along the elastic lamina. Among the proteins considered to be expressed in cells involved in vascular calcification, there is the matrix Gla protein (MGP). Numerous studies have shown the involvement of this protein in the processes of vascular calcification. The vascular smooth muscle cells (VSMC) are the prevalent cells in tunica media and are able to express MGP protein. The mechanism of MGP protein in the inhibition of vascular calcification is largely unknown. The VSMC apoptosis leads to the formation of negatively charged apoptotic bodies that, if not duly phagocyted, can serve as crystallization germs for crystals of hydroxyapatite. In healthy arteries, MGP protein is synthetized at a relatively low speed, however in the arteries of diabetic patients a low expression of this protein is observed, suggesting its involvement in the prevention of vascular calcification. Other numerous experimental evidences unequivocally demonstrate that the MGP protein, mainly in its carboxylate form, has the ability to prevent the vascular calcification. The crucial role of vitamin K in the inhibition of vascular calcification has become evident after an in vivo study that provided for the administration of vitamin K antagonists. After the administration of these compounds for 6 weeks, a severe calcification of the tunica media of arteriae was observed. The replacement of these compounds with high doses of vitamin K has induced a significant regression of the calcification grade, of about 37%.
The calcification of media is an important process in the development of atherosclerosis, hypertension and myocardial infarction. In clinical trials on rats treated with Warfarin it has been shown that calcification of tunica media leads to systolic hypertension.
In recent times the attention on Vitamin K is growing a lot, because of its potential use in the inhibition of vascular calcification. In a recent pilot study, it has been shown that the administration of menanchinon-7 for 6 weeks leads to a significant reduction in the amount of inactive Vitamin K-dependent proteins (VKDP), PIVKA-II factor (Protein Induced by Vitamin K Absence of Antagonism-Factor II), non-carboxylate osteocalcin and non-carboxylate MGP. Further studies will be necessary to determine whether these effects of vitamin K can be relevant for the reduction of the mortality resulting from vascular calcification.
The presence of microcalcification in atheromatous plaques is a factor able to destabilize the plaque and lead to its break. The MGP protein was shown to be effective in the prevention of arteriae microcalcification.
Since vitamin K is an essential cofactor in the carboxylation and activation of the MGP protein, the supplementation of this vitamin may lead to an inhibition of processes of vascular calcification, with a following reduction in the risk of mortality.
Curcumin
Curcuma longa is a plant that has been used for thousands of years in Chinese traditional medicine for the treatment of several types of diseases (S. Shishodia, G. Sethi, and B. B. Aggarwal, "Curcumin: Getting back to the roots," in Annals of the New York Academy of Sciences, 2005, vol. 1056, no. 1 , pp. 206-217).
Curcumin is the main secondary metabolite of Curcuma, having numerous pharmacological activities, such as anti-inflammatory, antioxidant, immunomodulatory, antitumor and neuro-protective activity (G. R. Pillai, A. S. Srivastava, T. I. Hassanein, D. P. Chauhan, and E. Carrier, "Induction of apoptosis in human lung cancer cells by curcumin," Cancer Lett, vol. 208, no. 2, pp. 163-170, May 2004; K. H. Reeta, J. Mehla, and Y. K. Gupta, "Curcumin ameliorates cognitive dysfunction and oxidative damage in phenobarbitone and carbamazepine administered rats," Eur. J. Pharmacol., vol. 644, no. 1-3, pp. 106-1 12, Oct. 2010; V. S. Yadav, K. P. Mishra, D. P. Singh, S. Mehrotra, and V. K. Singh, "Immunomodulatory effects of curcumin.," Immunopharmacol. Immunotoxicol., vol. 27, no. 3, pp. 485-497, Jan. 2005). It is one of the most potent natural occurring antiinflammatory agents (G. Yuan, M. L. Wahlqvist, G. He, M. Yang, and D. Li, "Natural products and anti-inflammatory activity," Asia Pac. J. Clin. Nutr., vol. 15, no. 2, pp. 143-152, 2006). In addition it has chemical-physical properties suitable for its distribution at central (being a lipophilic and relatively small molecule, is able to cross the blood-brain barrier) and peripheral nervous system level.
Curcumin has several mechanisms of action, but the main one consists in modulating the expression of numerous proteins, among which pro-inflammatory cytokines (TNF- a, IL-8, I L- 1 β , IL-6) (J.-W. Cho, K.-S. Lee, and C.-W. Kim, "Curcumin attenuates the expression of IL-1 beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets.," Int. J. Mol. Med. , vol. 19, no. 3, pp. 469-474, 2007), apoptotic proteins, NF-kB, COX-2, STAT3, MDA, etc. (S. C. Gupta, S. Patchva, and B. B. Aggarwal, "Therapeutic roles of
curcumin: lessons learned from clinical trials.," AAPS J., vol. 15, no. 1 , pp. 195-218, 2013).
Curcumin has shown its efficacy in the reduction of lipid peroxidation and blood levels of cholesterol in numerous studies carried on humans and rodents (K. K. Soudamini, M. C. Unnikrishnan, K. B. Soni, and R. Kuttan, "Inhibition of lipid peroxidation and cholesterol levels in mice by curcumin," Indian J. Physiol. Pharmacol., vol. 36, no. 4, pp. 239-243, Oct. 1992; K. B. Soni and R. Kuttan, "Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers," Indian J. Physiol. Pharmacol. , vol. 36, no. 4, pp. 273-275, Oct. 1992).
In a study by Zhao and collaborators, for example, it has been shown that curcumin is able to improve the accumulation of cholesterol in macrophages, due to a reduced uptake of oxidised LDL and to an increased efflux thereof. Moreover, this molecule is able to induce a down regulation of SR-A (scavenger receptor class A) protein acting on proteolysis mediated by ubiquitin-proteasome-calpain and to increase the expression of ABCA1 (ATP-binding cassette A1 ) transporter, acting on the LXRa (calmodulin-liver X receptor a) receptor. Finally, in this study it has been shown that curcumin modules the production of SR-A, ABCA1 , ABCG1 and SR-BI in aortas of apoE-/- mice, in which it delays the progression of atherosclerosis (J. F. Zhao et al, "Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis," Mol. Nutr. Food Res. , vol. 56, no. 5, pp. 691-701 , 2012). The action on LXRa receptor should also allow for an increase in the genic expression of CYP7A1 cytochrome, which is involved in the biosynthesis of biliary acids starting from cholesterol. This effect was demonstrated in vivo, in a study carried out on rats: the administration to rats of a diet comprising 0.1 % p/p of curcumin is associated with a significant increase (p<0.05) in the expression of CYP7A1 and to a significant decrease by 68% in blood levels of LDL cholesterol (M. Kim and Y. Kim, "Hypocholesterolemic effects of curcumin via up-regulation of cholesterol 7a- hydroxylase in rats fed a high fat diet.," Nutr. Res. Pract, vol. 4, no. 3, pp. 191-5, 2010).
Several clinical studies on the use of curcumin has indicated a significant hypolipidemic and antinflammatory effect, as well as an improvement in life quality, either in average aged healthy individuals or in patients with hyperlipidemia, obesity, rheumatoid arthritis, cancer and depressive disorders (see the already mentioned K. B. Soni and R. Kuttan; B. Chandran and A. Goel, "A randomized, pilot study to assess
the efficacy and safety of curcumin in patients with active rheumatoid arthritis," Phyther. Res. , vol. 26, no. 1 1 , pp. 1719-1725, Nov. 2012; K. Pungcharoenkul and P. Thongnopnua, "Effect of different curcuminoid supplement dosages on total In Vivo antioxidant capacity and cholesterol levels of healthy human subjects," Phyther. Res., vol. 25, no. 1 1 , pp. 1721-1726, Nov. 201 1 ).
In a randomized double-blind placebo-controlled clinical study the effect of curcumin administration in patients with metabolic syndrome was evaluated. The 65 patients taking part to the study were divided in 2 groups: the first, of 33 patients, was administered with curcumin at a 650 mg dose, 3 times per die, for a period of 12 weeks, while the second group, of 32 participants, was administered with placebo. After the treatment period, statistically significant reductions in blood concentrations of triglycerides (by 28.8%), total cholesterol (by 9.8%), LDL cholesterol (by 1 1.64%) and non-HDL, as well as an increase by 6.8% in HDL cholesterol were observed (Y.- S. Yang, Y.-F. Su, H.-W. Yang, Y.-H. Lee, J. I. Chou, and K.-C. Ueng, "Lipid-Lowering Effects of Curcumin in Patients with Metabolic Syndrome: A Randomized, Double- Blind, Placebo-Controlled Trial," Phyther. Res., vol. 28, no. 12, pp. 1770-1777, Dec. 2014).
In a preferred embodiment, the composition object of the present invention comprises the association of Vitamin D, Isoflavones and Policosanols, and optionally one, two or three additive components selected among boswellic acids, curcumin and vitamin K, in admixture with a suitable pharmaceutically acceptable carrier.
Suitable pharmaceutically acceptable carriers are those commonly known to the man skilled in the art for the preparation of pharmaceutical compositions for oral administration such as solutions, suspensions, powders, tablets, capsules, etc. By way of non-limiting example, said pharmaceutically acceptable carriers can consist of diluents (for example calcium phosphate dibasic, lactose, microcrystalline cellulose and cellulose derivatives), thickeners (for example gums hydroxypropylmethylcellulose and others cellulose derivatives), sweeteners (for example sorbitols, mannitols and others polyols, acesulfame K, aspartame, cyclamates, saccharine, sucralosio), lubricants (for example magnesium stearate, stearic acid, waxes), dispersants, surfactants (for example Sodium lauryl sulphate and polysorbates), flavouring agents, adsorbents (for example silica gel, talc, starch, bentonite, kaolin), glidants and anti-sticking agents (for example talc, colloidal silica, corn-starch), colorants, antioxidants, binders (for example gums, starch, gelatine,
cellulose derivatives, sucrose, sodium alginate), disaggregants (starch, microcrystalline cellulose, alginic acid, crospovidone), plasticisers (for example ethyl cellulose and others cellulose derivatives, acrylates and methacrylates), thickeners, emulsifiers, humectants, wetting agents, preservatives, chelants and mixtures thereof.
The composition object of the present invention is preferably a solid pharmaceutical composition for oral use, even more preferably a tablet.
The composition object of the present invention comprises Vitamin D, Isoflavones and Policosanols and optionally also one or more components selected among boswellic acids, curcumin and vitamin K.
Vitamin D is present in an amount between 0.1 μg and 1000 μg, preferably between 1 μg and 100 μg, even more preferably between 5 μg and 50 μg.
Isoflavones are present in an amount between 1 mg and 200 mg, preferably between 10 mg and 120 mg, even more preferably between 50 and 100 mg. Isoflavones are preferably used as extracts from a plant of the genus Glycine and are commercially available. For example the dry extract from Glycine Max (L.) Merr., marked by Nutraceutica srl, which is a mixture of soy isoflavones (40%) and genistein (36%). Policosanols are present in an amount between 0.1 mg and 200 mg, more preferably between 1 mg and 100mg, even more preferably between 10 mg and 50 mg. Policosanols are preferably used as a powder obtained by extraction of the waxy coating of sugar cane. Policosanols are a mixture of superior primary aliphatic alcohols whose main component is octacosanol. Policosanols usable in the composition object of the present invention are commercially available, for example by Farmalabor srl (powder - policosanols 98% - octacosanol 60%).
Boswellic acids, if present, are in an amount between 1 mg and 500 mg, more preferably between 10 mg and 250 mg, even more preferably between 25 mg and 150 mg.
Curcumin, if present, is in an amount between 1 mg and 1000 mg, preferably between 10 mg and 1000 mg, even more preferably between 20 mg and 300 mg. Curcumin is preferably used as an extract from a plant belonging to the Zingiberaceae family. An extract particularly suitable for the compositions object of the present invention is that marked as Curcuma Fitosoma (Meriva Indena).
In the present contest, the term curcumin is meant to comprise also derivatives with analogous activity such as curcuminoids.
Vitamin K, if present, is in an amount between 1 μg and 5000 μς, preferably between 20 μg and 200 μς, even more preferably between 50 and 100 μς.
The compositions object of the present invention are particularly effective in reducing the process of vascular calcification, in reducing cholesterol levels and increasing bone mineralization thanks to the synergic activity of the components thereof.
Therefore, a further object of the present invention is a pharmaceutical composition comprising the association of Vitamin D, Isoflavones and Policosanols, and optionally one, two or three additional components selected among boswellic acids, curcumin and vitamin K, in admixture with a suitable pharmaceutically acceptable carrier for use in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization.
Without being bound to a specific theory, the inventors are of the opinion that the synergic effect of the association Vitamin D, Isoflavones and Policosanols, according to the present invention, derives from the following activities of the components of the association.
Reduction of the vascular calcification process.
Isoflavones act as agonists of the estrogen receptor. The activation of these receptors is associated with, among others, an increase in the expression of osteoprotegerin. This protein is able to bind the RANK-L (Receptor activator of nuclear factor kappa-B ligand) protein, preventing the binding with the RANK (Receptor activator of nuclear factor kappa-B) receptor. The interaction RANK-L/RANK at the level of vascular smooth muscle cells, may lead to the expression of BMP-2 (Bone morphogenetic protein 2) protein, which induce the vascular calcification process, with osteoblastogenic differentiation and deposit of hydroxyapatite crystals in the vascular tunica media and to the inhibition of the expression of MGP protein (Matrix Gla Protein), which has the opposite effect and inhibits the calcification process. Isoflavones thus reduce the expression of BMP-2 and increase the expression of MGP, with the following inhibition of the vascular calcification process.
Low doses of Vitamin D can induce the process of vascular calcification. The administration of Vitamin D can inhibit this phenomenon.
Reduction of cholesterol levels
Policosanols inhibit the synthesis of cholesterol, acting on the expression of HMG- CoA reductase. This leads to a reduction of cholesterol levels in the hepatocyte, an
increase in the expression of LDL receptors and the following reduction in blood levels of LDL.
Increase of bone mineralization
Isoflavones, acting on the estrogen receptor, stimulate osteoblasts proliferation and cause osteoclasts apoptosis. In this manner they prevent bone reabsorption and stimulate mineralization.
Vitamin D enhances the absorption of calcium and phosphate at intestinal level. These minerals are crucial for the process of bone mineralization. In addition it is involved in the secretion of parathyroid hormone, which is able to stimulate bone proliferation.
The efficacy of the composition object of the present invention was evaluated with the following experimental protocol.
In order to evaluate the efficacy in the prevention of vascular calcification, calcification of vascular smooth muscle cells was induced with the experimental protocol described by Roman-Garcia and collaborators (P. Roman-Garcia, S. Barrio-Vasquez, J. L. Fernandez-Martin, M. P. Ruiz-Torres e J. B. Cannata-Andia, "Natural antioxidants and vascular calcification: A possible benefit?," J. Nephrol., vol 24, no. 6, pp. 669-672, 201 1 ).
In brief, cultures of VSMC (vascular smooth muscle cells) cells were prepared using a suitable culture medium. The culture media used for the groups of cells of the experiment are the following:
1. Normal culture medium;
2. Culture medium added with calcium (3 mM) and phosphate (2 mM);
3. Culture medium added with calcium (3 mM), phosphate (2 mM) and policosanols; 4. Culture medium added with calcium (3 mM), phosphate (2 mM) and vitamin D;
5. Culture medium added with calcium (3 mM), phosphate (2 mM) and isoflavones;
6. Culture medium added with calcium (3 mM), phosphate (2 mM), policosanols, vitamin D and isoflavones;
7. Culture medium added with calcium (3 mM), phosphate (2 mM) and curcumin; 8. Culture medium added with calcium (3 mM), phosphate (2 mM) and boswellic acids;
9. Culture medium added with calcium (3 mM), phosphate (2 mM) and Vitamin K;
10. Culture medium added with calcium (3 mM), phosphate (2 mM), policosanols, vitamin D, isoflavones, curcumin, boswellic acids and vitamin K.
The mineralization of smooth muscle cells was evaluated using the staining with alizarin and quantified using a suitable experimental protocol (C. A. Gregory, W. G. Gunn, A. Peister e D. J. Prockop, "An Alizarin red-based assay of mineralization by adherent cells in culture: Comparison with cetylpyridinium chloride extraction," Anal. Biochem., col. 329, no. 1 , pp 77-84, 2004).
Genie expression of Cbfa1/RUNX2 and of Mn-superoxide dismutase-2 (SOD-2) was measured by Western blotting, using a standard protocol.
Moreover, the synergic activity of the components of the present invention cab be evaluated in in vitro and/or in vivo models of osteoporosis.
For example, in vivo experiments can measure the proliferation of osteoblasts by colorimetric test (such as MTT) or the differentiation of osteoclasts; they can also evaluate the activity of the alkaline phosphatase following the addition of the components to be tested either individually or in combination.
In addition, also bone mineralization can be evaluated in vitro by spectrophotometric tests using suitable reactants such as, for example, alizarin.
The synergic activity of the components of the present invention against osteoporosis can also be evaluated by means of in vivo tests on animals experimentally reproducing the disease conditions through ovariectomy or others methods accepted by the scientific literature. Then, bone fragility and densitometry can be evaluated through specific devices and/or by assessing blood levels of biochemical markers.
The association of substances of the present invention has a synergic activity on the metabolism of cholesterol. Said action is evaluated by suitable experimental tests able to induce hypercholesterolemia in animals, for example, by the administration of a specific diet with a high fat content. After developing the model and administering the substances either individually or in combination, the specific lipoprotein (HDL, LDL, VLDL) and triglycerides levels and/or other parameters involved in lipid metabolism are evaluated.
Examples
By way of example are now provided some examples of daily doses of active components of the pharmaceutical compositions object of the present invention.
Claims
1 ) A pharmaceutical composition comprising an association of Vitamin D, Isoflavones and Policosanols in admixture with a suitable pharmaceutically acceptable carrier. 2) A pharmaceutical composition according to claim 1 comprising one, two or three additional components selected among boswellic acids, curcumin and vitamin K.
3) A pharmaceutical composition according to claim 1 or 2 in the form of a solid pharmaceutical composition for oral use.
4) A pharmaceutical composition according to claim 3 in the form of tablet.
5) A pharmaceutical composition according to any of the previous claims wherein Policosanols are in an amount between 0.1 mg and 200 mg, Isoflavones are in an amount between 1 mg and 200 mg and Vitamin D is in an amount between 0.1 μg and 1000 μg.
6) A pharmaceutical composition according to any of the previous claims from 2 to 5 wherein, if present, boswellic acids are in an amount between 1 mg and 500 mg, curcumin is in an amount between 1 mg and 1000 mg and vitamin K is in an amount between 1 μg and 5000 μg.
7) Pharmaceutical composition according to any of the previous claims for use in the treatment of cardiovascular and/or osteoarticular diseases.
8) Pharmaceutical composition according to claim 7 for use in reducing the process of vascular calcification, in reducing cholesterol levels and in increasing bone mineralization.
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