WO2012116996A1 - Traitement du vieillissement artériel par l'inhibiteur de raas - Google Patents

Traitement du vieillissement artériel par l'inhibiteur de raas Download PDF

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Publication number
WO2012116996A1
WO2012116996A1 PCT/EP2012/053378 EP2012053378W WO2012116996A1 WO 2012116996 A1 WO2012116996 A1 WO 2012116996A1 EP 2012053378 W EP2012053378 W EP 2012053378W WO 2012116996 A1 WO2012116996 A1 WO 2012116996A1
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pharmaceutical composition
composition according
treatment
angiotensin
months
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PCT/EP2012/053378
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English (en)
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Mišo ŠABOVIC
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Farmicom Pharmaceutical Company D.O.O.
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Priority to EP12706831.0A priority Critical patent/EP2680831A1/fr
Publication of WO2012116996A1 publication Critical patent/WO2012116996A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose for use in the prevention, reduction or reversal of arterial aging in apparently healthy subjects.
  • the pharmaceutical composition according to the invention is also useful in decreasing the occurrence of cardiovascular disorders in apparently healthy subjects.
  • Ageing (British English) or aging (American English) is the accumulation of changes in an organism or object over time. Ageing in humans refers to a multidimensional process of physical, psychological and social change. Ageing is defined as the gradual biological impairment of normal function, probably as a result of changes made to cells, molecules and tissues/morphological components. These changes have a direct impact on the functional ability of organs such as for example the heart, brain, kidney and lungs, biological systems such as for example the nervous, digestive and reproductive system and ultimately the organism as a whole. Although ageing affects the whole body the consequences of ageing are related to the involved organ or system. The ageing of arteries produces the most detrimental consequences of ageing. Ageing causes progressive decline in physiological arterial functions and morphology.
  • Aged arteries generate changes in hemodynamic that importantly contribute to the development of cardiovascular diseases.
  • aged arteries are more susceptible for the development of certa i n cond itions such as atherosclerosis.
  • arterial ageing substantially contributes to the development of cardiovascular diseases such as for example, myocardial infarction, stroke, dementia, kidney failure, hypertension and similar.
  • ageing specifically arterial ageing, is one of most important risk factors for development of cardiovascular diseases. It is widely believed that ageing per se is not a modifiable risk factor. This conclusion does not necessarily apply to the arterial ageing, however. Cardiovascular diseases remain the leading cause of morbidity and mortality in developed countries despite current preventive strategies.
  • Arterial ageing is characterised by alterations in cel ls, matrix, and biomolecules present in the arterial wall. Arterial ageing is a foundation for the initiation and progression of cardiovascular diseases. Although arterial ageing literary starts immediately after birth, it seems that important age- related changes occur at middle age. In this period (approximately between 20-65 years) age-related changes gradually and continuously progress.
  • Basic representative functional and morphological age-related arterial changes are for example endothelial dysfunction, vascular smooth muscle cell proliferation/invasion/secretion, matrix fragmentation, collagenisation and glycation that result in typical age related changes such as for example increased arterial stiffness and decreased arterial wall elasticity.
  • Age- associated arterial wall phenotype creates a microenvironment enriched with reactive oxygen species and inflammatory molecules.
  • angiotensin II signalling molecules control and facilitate the processes producing age-related arterial changes.
  • Age-related arterial changes are cl inically si lent, but as described above may lead to development of cardiovascular diseases. Targeting arterial ageing as soon as valuable can reduce the incidence/occurence and progression of said cardiovascular diseases.
  • Arterial aging is a result of gradual changes of morphological (i.e. structural) and functional properties of the arterial wall.
  • the arterial wall consists of three layers: intima, media and adventia.
  • the most inner part of the arterial wall is endothelium (a part of intima), which is directly exposed to the blood in the artery lumen.
  • endothelium a part of intima
  • endothelial function functional property
  • H. -Y.Lee et al. disclose that arterial walls stiffen with age and that this aging process in the arterial tree is heterogeneous, with distal arteries not exhibiting these stiffening changes, which is different from the atherosclerotic process (H.-Y. Lee et a l . , Circulation Journal 2010; 94; 2258-2262).
  • renin-angiotensin-aldosterone system plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure.
  • renin which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.
  • renin When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to form the decapeptide angiotensin I.
  • vascular endothelium particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (All), although many other tissues in the body (heart, brain, vascular) also can form All.
  • Renin inhibitors are antihypertensive drugs that inhibit the first and rate- limiting step of RAAS. Since the 1970s scientists have been trying to develop potent inhibitors with acceptable oral bioavailability. The first and second generations faced problems like poor bioavailability and lack of potency. The third generation is non-peptidic renin inhibitors with acceptable oral bioavailability and potency for clinical use in the treatment of hypertension.
  • Angiotensin-converting enzyme (ACE) inhibitors produce vasodilation by inhibiting the formation of angiotensin II.
  • This vasoconstrictor is formed by the proteolytic action of renin (released by the kidneys) acting on circulating angiotensinogen to form angiotensin I.
  • Angiotensin I is then converted to angiotensin II by angiotensin converting enzyme.
  • ACE inhibitors also break down bradykinin (a vasodilator substance). Therefore, ACE inhibitors, by blocking the breakdown of bradykinin, increase bradykinin levels, which can contribute to the vasodilator action of ACE inhibitors.
  • ACE inhibitors are used primarily to treat hypertension, they may also be prescribed for cardiac failure, diabetic nephropathy, renal disease, systemic sclerosis, left ventricular hypertrophy and other disorders. ACE inhibitors are often used in conjunction with a diuretic in treating hypertension and heart failure.
  • Angiotensin I I receptor antagonists also known as angiotensin receptor blockers (ARBs), AT1 -receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system.
  • ARBs are receptor antagonists that block type 1 angiotensin I I (AT1 ) receptors on bloods vessels and also in other tissues as arterial wall and heart muscle. ARBs act on the surface and inside arterial wall.
  • Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory substances should suppress the expression induction of inflammatory functional proteins such as enzyme participating in the production of chemical mediator of various cytokines and inflammation, as well as suppress information transfer in cells participating in activation, and/or suppress the action expression by chemical mediator of various cytokines and inflammation.
  • An antioxidant is known as a molecule that can neutralize free radicals by accepting or donating an electron to eliminate the unpaired condition. Typically this means that the antioxidant molecule becomes a free radical in the process of neutralizing a free radical molecule to a non-free-radical molecule. But the antioxidant molecule will usually be a much less reactive free radical than the free radical neutralized. Therefore, an antioxidant inhibits the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions that damage cells. Antioxidants terminate oxidation chain reactions by removing free radical intermediates, and inhibit other oxidation reactions.
  • Angiotensin II receptor antagonists and their therapeutically benefits for the primary indication are well known from the state of the art, for example numerous previous studies have shown that the angiotensin II receptor antagonist in therapeutic doses are effective in treatment of hypertension and cardiovascular disorders.
  • the additional combinations with anti-inflammatory agents and/or antioxidants are known to be of certain treatment value for example for cardiovascular prevention (Antonpoulos AA et al. Recent Pat Cardiovasc Drug Disc 2009;4: 76-87).
  • all the above mentioned references are silent on the effect on arterial ageing.
  • prior art does not teach or even does not give any hint that a subtherapeutic daily dose of these drugs is sufficient and efficient for prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • WO 2005/072696 discloses the use of ACE (angiotensin-converting enzyme) inhibitors and/or angiotensin II receptor antagonists for the improving and/or maintaining the skin tone and for the treatment of skin ageing. The application is silent on the effect of said active substances on arterial ageing.
  • ACE angiotensin-converting enzyme
  • WO 2006/105806 discloses the composition comprising four or more active agents, namely a statin, a compound suppressing angiotensin production or activity and anti-inflammatory agent and at least one antioxidant used for prevention and/or treatment of ageing process.
  • the application provides comparative data on a positive effect towards cell growth and cell reproduction when using the composition comprising all four above mentioned active agents. However, the application is silent on the impact of said combination on arterial ageing and it does not provide any data when one or more active agent is omitted from the composition.
  • Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These effects maybe related or unrelated to the primary mechanism of action of the drug, and they are usually unexpected.
  • the objects of the present invention are surprisingly achieved by providing a pharmaceutical composition comprising at least one renin-angiotensin- aldosterone system inhibitor in a subtherapeutic daily dose in the prevention, reduction or reversal of arterial aging in apparently healthy subjects. More specifically, the present invention relates to the pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant and combinations thereof for use in the prevention, reduction or reversal of arterial aging in apparently healthy subjects.
  • An advantage of said pharmaceutical composition is a new approach for prevention of cardiovascular diseases.
  • the pharmaceutical combinations according to the present invention are also useful in decreasing the occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is directed to a pharmaceutical composition composition comprising at least one renin-angiotensin- aldosterone system inhibitor in a subtherapeutic daily dose, in the prevention, reduction or reversal of arterial aging in apparently healthy subjects.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose for use in decreasing the occurrence of cardiovascular disorders in apparently healthy subjects.
  • arterial aging refers to changes, in particular gradual changes of morphological (i.e. structural) and functional properties of the arterial wall.
  • arterial aging exclusively refers to changes, in particular gradual changes of the morphological properties of the arterial wall.
  • the morphological properties of the arterial wall are preferably to be understood as the stiffness properties of arteries.
  • arterial stiffness can be determined on the basis of the parameters pulse wave velocity (PWV) and ⁇ -stiffness.
  • PWV pulse wave velocity
  • Arterial stiffness is presently most adequately described by the parameter pulse wave velocity (PWV).
  • the PWV is calculated from measurements of pulse transit time and the distance traveled by the pulse between two recording sites.
  • the PWV is measured on elastic arteries such as aorta, carotid artery, iliac artery, femoral artery.
  • PWV represents the speed of pulse transmission through the arterial three. The stiffer the arteries are, the faster is the pulse transmission and consequently the higher is the PWV.
  • the PWV can be easily and reproducibly measured using an ultrasound apparatus such as Aloka ProSound Alpha 10 apparatus with a high resolution eTracking system.
  • the ultrasound apparatus is equipped with software for automatic determination of arterial stiffness parameters through the analysis of pulse waves.
  • Other widely- used devices as Sphygomocor®, Compylor® and similar devices can also be used for PVW calculation.
  • the ⁇ -stiffness is also a parameter being a measure for arterial stiffness. It describes the local arterial stiffness. Accordingly, the determination of ⁇ - stiffness is a method for measuring stiffness from artery diameter and mutation width by the beating and blood pressure.
  • ⁇ -stiffness is measured using a common carotid artery using an ultrasound apparatus such as Aloka ProSound Alpha 10 apparatus with a high resolution eTracking system.
  • the ultrasound apparatus is equipped with software for automatic determination of arterial stiffness parameters through the analysis of pulse waves.
  • the functional properties of the arterial wall are preferably characterized by the endothelial function of the arterial wall.
  • Endothelial function can be assessed with a variety of methods.
  • the most widely used method is the measurement of flow mediated dilatation (FMD) of brachial artery after short-term ischemia induced by sphygmomanometer inflation. Consequently, reactive hyperemia, which is dependent on endothelial function, occurs and brachial artery dilates.
  • FMD flow mediated dilatation
  • the present difference between the diameter measured after hyperemia and the basal diameter is taken as FMD.
  • FMD is used invasively with high- resolution ultrasound machines/systems; the measurements could be performed manually or automatically (as in the case when Aloka ProSound Alpha 10 apparatus is used).
  • arterial aging preferably means that arterial aging in these subjects is not caused or accelerated by any extrinsic influence such as hypertension, metabolic syndrome, diabetes etc..
  • Figure 1 of the article by Lee et al. wherein the causes of arterial aging are presented (H.-Y. Lee et al. , Circulation Journal 2010; 94; 2258-2262).
  • arterial aging of "apparently healthy subjects” is preferably based on the structural change of the arteries with aging caused e.g. by longstanding arterial pulsation in the central artery, which has a direct effect on the structural matrix proteins, collagen and elastin in the arterial wall, disrupting muscular attachments and causing elastin fibers to fatigue and fracture. Further, accumulation of advanced glycation endproducts (AGE) on the proteins alters their physical properties and causes stiffness of the fibers in "apparently healthy subjects” . Sti ll further, the calcium content in the arterial wall increases with age in "apparently healthy subjects", which also contribute to arterial aging (H.-Y. Lee et al. , Circulation Journal 201 0; 94; 2258-2262).
  • AGE advanced glycation endproducts
  • Appendix healthy subjects are subjects, which have a low cardiovascular risk.
  • An "apparently healthy subject” according to the present invention having a low cardiovascular risk exhibits a Framingham Risk Score for coronary heart disease (CHD) (10-year risk) of 10% or less, preferably 8% or less, more preferably 5% or less.
  • CHD coronary heart disease
  • the Fram ingham Risk Score for the CHD is calculated on the basis described in "The third report of the National Cholesterol Education Program (NCEP) Expert panel on Detection, Eval uation and Treatment of H igh B lood Cholesterol in Adults (Adu lt Treatment Panel III), Circulation 2002; 106: 3143-3421 .
  • NCEP National Cholesterol Education Program
  • the calculation of the Framingham Risk Score for a coronary heart disease (CHD) (10-year risk) is based on the ATP III page of the NHLBI Web site (www.nhlbi.nih.gov/guidelines/cholesterol) referenced at page 3229 of said article.
  • the algorithm underlying the calculation of the Fram ingham risk equation in these calculators has been described by Anderson KM et al. in "An updated coronary risk profile. A statement for health professionals", Circulation (1991 ), 83:356-362.
  • the Framingham risk score for the CHD (10 years) the risk for coronary heart diseases such as myocardial infarction and death is assessed.
  • an apparently healthy man has a Framingham Risk Score for the CHD of 10% or less, preferably 8% or less, more preferably 5% or less and an apparently healthy woman has a Framingham Risk Score for the CHD of 10% or less, preferably 8% or less, more preferably 5% or less.
  • the parameters included in the Framigham risk score for a CHD are as follows: gender, age, total cholesterol level, HDL cholesterol level, smoking, systolic blood pressure and untreated/treated hypertension.
  • An apparently healthy subject having a low cardiovascular risk does preferably not have a (manifested) cardiovascular disorder. More preferably, the apparently healthy subject does not have diabetes.
  • the apparently healthy subject does not have a (manifested) cardiovascular disorder and in addition does not have disorders which importantly influence the functional capacity of different tissues/organs or the whole body.
  • cardiovascular disorder refers to a cardiovascular disorder or cardiovascular event such as for example ischemic heart disease, carotid and intracerebral artery disease, peripheral arteria l d isease, aortic aneurism and the l ike , and any combinations thereof.
  • CVD refers to myocardial infarction, stroke, dementia, critical limb ischemia, aortic aneurism and any combinations thereof, more preferably to myocardial infarction, stroke, vascular dementia and any combinations thereof.
  • the term "subtherapeutic daily dose" in the context of the at least one renin-angiotensin-aldosterone system inhibitor relates to a dose, which does not substantially lower the blood pressure.
  • the systolic blood pressure is not lowered by more than 15%, preferably not more than 10% by a subtherapeutic dose according to the present invention.
  • the diastolic blood pressure is not lowered by more than 15%, preferably not more than 10%.
  • the recommended daily therapeutic dose for a renin-angiotensin-aldosterone system inhibitor is typically in the range of 20 mg to 320 mg.
  • the recommended therapeutic daily dose is in the range of 40 mg to 320 mg.
  • the recommended therapeutic daily dose is in the range of 25 mg to 100 mg.
  • pharmaceutically acceptable salts includes any and all non-toxic, salts of the disclosed compounds. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts and basic salt.
  • the pharmaceutically acceptable salts include, but are not limited to metal salts, such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metals, such as calcium salt, magnesium salt and the like, organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like, inorganic acid salts, such as hydrochloride, hydrobromide, phosphate, sulphate and the like, organic acid salts such as citrate, lactate, tartrate, m aleate, fum arate, m andelate , acetate , d ich loroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the
  • Acid addition salts can be formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, and the like.
  • Basic salts can be formed by mixing a solution of the particular compound of the present invention and a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
  • the term "daily dose" of the pharmaceutically active ingredient(s) corresponds to the total amount of said active/the actives that is/are administered to a subject per day.
  • the daily dose can be administered in any suitable frequency such as in a once-a-day dosage or alternatively in a divided dosage, e.g. twice-a-day dosage or dosages which have to be administered 3 or 4 times a day.
  • residual improvement refers to a change in the improvement of a parameter as measured after a certain time period (e.g. a rest period) in relation to the improvement achieved after a treatment period. The residual improvement after said time period is given as a percentage of the initial improvement (measured e.g. after determination of the treatment).
  • the FM D at beginning of the treatment was 1 % .
  • the FM D measured after a treatment period was 4 % (improvement 300%) and the FMD measured after a rest period following the treatment period was 3%, leading to a residual improvement of 67%.
  • the term "substantially”, if not defined otherwise in the context it is used, means that the value following the term may diviate ⁇ 10%, preferably ⁇ 5%.
  • treatment period is defined as the time period in which a subject is adm inistered the daily dosis of the pharmaceutical composition according to the present invention.
  • rest period is defined as the time period in which a subject is not administered the pharmaceutical composition of the present invention.
  • Figure 1 Changes expressed in percentage of A) flow mediated dilation (FMD), B) ⁇ -stiffness of carotid artery and pulse wave velocity (PVW) and in placebo and treated group after 1 month (30 days) of treatment (Example 1 )
  • Figure 2 Beneficial arterial characteristics (expressed in percentage of the effect achieved after 1 month (30 days) of treatment) that still persist 5, 7 and 8 months after discontinuation of treatment according to Example 1 (Example 2)
  • Figure 3 Effect of the treatment according to Example 1 and Example 2 on "biological" arterial ageing (Example 3)
  • Figure 4 Values of flow mediated dilation (FMD), ⁇ -stiffness of carotid artery and pulse wave velocity (PVW) in placebo and treated group after 1 month (30 days) of treatment (Example 4)
  • Figure 5 Beneficial arterial characteristics (expressed in percentage of the effect achieved after 1 month (30 days) of treatment) that still persist 3, 8 and 10 months after discontinuation of treatment according to Example 4 (Example 5)
  • Figure 6 Changes expressed in percentage of flow mediated dilation (FMD), ⁇ -stiffness of carotid artery and pulse wave velocity (PVW) of treated group after 1 month (30 days) (1 . intervention) and after a 2. intervention (treatment for 1 month - 30 days) after a 12-months rest period. Subjects of the 2.
  • FMD flow mediated dilation
  • PVW pulse wave velocity
  • One embodiment of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose, for use in decreasing the occurrence of cardiovascular disorders in apparently healthy subjects.
  • the inventor believes that the prevention, reduction or reversal of arterial ageing, as evidenced for example by the reduction achieved by the pharmaceutical composition according to the present invention in the PVW and the ⁇ -stiffness will lead to a decrease in occurrence of cardiovascular disorders in apparently healthy subjects.
  • the decrease in occurrence of the cardiovascular disorder may be indicated e.g. by the difference in the 10 year risk factor for CHD diseases (Framingham Heart Study) calculated for the chronological age before the beginning of the treatment and the one calculated after the treatment using the calculated biological age.
  • the at least one renin-angiotensin-a l doste rone i n h i b itor of th e pharmaceutical composition of the present invention may be selected from the group consisting of renin inhibitor, angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist and combinations thereof.
  • the at least one renin- angiotensin-aldosterone system inhibitor is an angiotensin II receptor antagonist.
  • angiotensin II receptor antagonist is selected from the group consisting of azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, and any pharmaceutically acceptable salts or esters and any combinations thereof.
  • the angiotensin II receptor antagonist is selected from the group consisting of azilsartan, losartan, olmesartan, candesartan, valsartan, telmisartan, and any pharmaceutically acceptable salts or esters, and combinations thereof, even more preferably the angiotensin II receptor antagonist is selected from the group consisting of azilsartan, losartan, candesartan, valsartan, telmisartan, and any pharmaceutically acceptable salts or esters, and combinations thereof, even more preferably the angiotensin II receptor antagonist is selected from the group consisting of losartan, valsartan, telmisartan, and any pharmaceutically acceptable salts or esters, and combinations thereof, or losartan, valsartan, and any pharmaceutically acceptable salts or esters, and combinations thereof.
  • angiotensin II receptor antagonist is valsartan or any pharmaceutically acceptable salt thereof, preferably valsartan.
  • angiotensin II receptor antagonist is losartan or any pharmaceutically acceptable salt thereof, preferably losartan potassium.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not substantially change the systolic blood pressure in a subject.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not substantially change the diastolic blood pressure in a subject.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not lower the systolic blood pressure in a subject by more than 15%, preferably more than 10%, more preferably more than 6%, most preferably more than 4%.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not lower the systolic blood pressure in a subject by more than 15%, preferably more than 10%, more preferably more than 6% , most preferably more than 4%, when administered for at least 10 days, preferably at least 14 days, more preferably at least 1 month.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not lower the diastolic blood pressure in a subject by more than 15%, preferably more than 10%, more preferably more than 8%, most preferably more than 5%.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone system inhibitor does not lower the diastolic blood pressure in a subject by more than 15%, preferably more than 10%, more preferably more than 8%, most preferably more than 5%, when administered for at least 10 days, preferably at least 14 days, more preferably at least 1 month.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone inhibitor is between 1 and 50%, preferably between 1 and 25% of the daily recommended therapeutic dose for the primary medical indication of said active.
  • the subtherapeutic daily dose of the renin-angiotensin-aldosterone inhibitor is preferably between 1 and 75 mg, between 1 and 60 mg, between 1 and 50 mg, between 1 and 45 mg, between 1 and 40 mg, and/or between 1 and 25 mg.
  • the daily dose of the renin-angiotensin- aldosterone inhibitor is selected from 10, 15, 20, 25, or 30 mg.
  • the renin-angiotensin- aldosterone is valsartan or any pharmaceutically acceptable salts or esters thereof, and the subtherapeutic daily dose is between 1 and 75 mg, preferably between 1 and 60 mg, more preferably between 1 and 50 mg, still more preferably between 1 to 40 mg, most preferably between 10 to 30 mg, particularly preferably 20 mg.
  • the renin-angiotensin- aldosterone is telmisartan or any pharmaceutically acceptable salts or esters thereof, and the subtherapeutical dose thereof is between 1 to 40 mg, preferably between 1 to 20 mg, most preferably 20 mg.
  • the renin-angiotensin- aldosterone is losartan or any pharmaceutically acceptable salts or esters thereof, and the subtherapeutical dose thereof is between 1 to 40 mg, preferably between 1 to 30 mg, more preferably 20 mg and most preferably 12,5 mg.
  • the present invention is directed to a pharmaceutical compostion comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose for use in the prevention, reduction or reversal of arterial aging in apparently healthy subjects.
  • An apparently healthy subject having a low cardiovascular risk exhibits a Framingham Risk Score for a CHD (10-year risk) of 10% or less, preferably 8% or less, more preferably 5% or less as defined above.
  • the apparently healthy subject does not have a (manifested) cardiovascular disorder.
  • the apparently healthy subject does not have a (manifested) cardiovascular disorder and in addition does not have disorders which importantly influence the functional capacity of different tissues/organs or the whole body.
  • cardiovascular disorder (CVD) refers to a cardiovascular disorder or cardiovascular event such as for example ischemic heart disease, carotid and intracerebral artery disease, peripheral arterial disease, aortic aneurism and the like, and any combinations thereof.
  • CVD refers to myocardial infarction, stroke, dementia, critical limb ischem ia, aortic aneurism and any combinations thereof, more preferably to myocardial infarction, stroke, vascular dementia and any combinations thereof.
  • the apparently healthy subject is a mammal, preferably a human subject.
  • the pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose is useful for treatment for a period for at least one week, at least two weeks, preferably between 2 weeks and 3 months, more preferably between 2 weeks and 2 months, and more preferably between 2 weeks and 1 month, and most preferably after treatment for 1 month (e.g. 30 or 31 days).
  • the flow-mediated dilatation of brachial artery (FMD) after a period of treatment, preferably after 1 month of treatment, compared to the beginning of the treatment is increased.
  • the FMD increases by at least 25%, preferably at least 50%, more preferably at least 100%, still more preferably at least 125%, most preferably at least 150%, particularly preferably 156.0 % after a treatment period, preferably 1 month of treatment, compared to the beginning of the treatment.
  • a decrease of the pulse- wave velocity (PWV) after a period of treatment, preferably after 1 month of treatment, compared to the beginning of the treatment is achieved.
  • the PWV decreases by at least 1 %, preferably at least 3%, more preferably at least 5%, most preferably at least 7%, particularly preferably 7.2 % after a treatment period, preferably 1 month of treatment compared to the beginning of the treatment.
  • the ⁇ -stiffness of carotid artery after a period of treatment, preferably after 1 month of treatment, com pared to the beginning of the treatment is decreased.
  • the ⁇ -stiffness decreases by at least 3% , preferably at least 5%, more preferably at least 10%, and most preferably at least 13%%, particularly preferably 13.7 % after a treatment period, preferably 1 month of treatment, compared to the beginning of the treatment.
  • the effect on arterial aging may be determ ined by measuring the difference in the parameters of the pulse-wave velocity (PVW) and the ⁇ -stiffness of carotid artery after a treatment period, preferably 1 month of treatment compared to the beginning of the treatment.
  • PVW pulse-wave velocity
  • the effect achieved by a pharm aceutically active substance is usually determined by the presence of a therapeutically effective concentration of said active in the blood.
  • the half-life time (t-i /2 ) in the blood plasma is an important factor which influences the period of time for which efficacy of a dosis regimen may be observed.
  • the half-life time for valsartan is about 6.0 hours and for losartan about 1 .5-2 hours, Therefore, it can be expected that a pharmaceutical effect can only be maintained as long as the pharmaceutically active substance is administered on a regular basis, e.g. on a daily basis, twice-a-days-basis, or the like. This is also reflected by the treatment schedule of the primary indications of the renin-angiotensin- aldosterone system inhibitors.
  • the use of the pharmaceutical composition according to the present invention comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose allows for an exceptionally long term persistence of the improvements achieved for the arterial characteristics after discontinuation of the treatment resulting in long term improvement of arterial wall properties such as the arterial ageing. This improvement is reflected for example by the residual of the improvement compared to the beginning of the treatment.
  • the phenomenon is described in the present invention by the term "rest period”.
  • the term “activity during drug-free period” is used.
  • the two terms “rest period” and “activity during drug-free period” are used interchangeably.
  • the reduction or reversal of arterial aging after a period of treatment persists in a substantial amount the for at least 1 month, preferably at least 3 months, more preferably at least 5 months, still more preferably at least 7 months, 8 months, most preferably at least 10 months, particularly preferably for approximately at least 12 months after discontinuation of the treatment.
  • the residual improvement of the PVW is at least 5%, preferably at least 10%, more preferably at least 15%, still more preferably at least 20%, most preferably at least 25% based on the decrease of the PVW after a period of treatment. In one aspect of this embodiment, after discontinuation of the treatment for at least 3 months the residual improvement of the PVW is at least 5% , preferably at least 1 0% , more preferably at least 15%, still more preferably at least 20%, most preferably at least 25% based on the decrease of the PVW after a period of treatment.
  • the residual improvement of the PVW is at least 5%, preferably at least 10%, more preferably at least 15%, still more preferably at least 20%, most preferably at least 25% based on the decrease of the PVW after a period of treatment.
  • the residual improvement of the PWV is at least 2%, preferably at least 4%, more preferably at least 6%, most preferably at least 8%, particularly preferably 9.9% based on the decrease of the PWV after a period of treatment.
  • the residual improvement of the PWV is at least 0.5%, preferably at least 1 %, more preferably at least 1 .5%, most preferably at least 2%, even more preferably 2.5% based on the decrease of the PWV after a period of treatment.
  • the residual improvement of the ⁇ -stiffness is at least 5%, preferably at least 10%, more preferably at least 15%, and most preferably at least 20% based on the decrease of the ⁇ -stiffness after a period of treatment.
  • the residual improvement of the ⁇ -stiffness is at least 5%, preferably at least 10%, more preferably at least 15%, and most preferably at least 20% based on the decrease of the ⁇ -stiffness after a period of treatment.
  • the residual im provement of the ⁇ - stiffness is at least 5%, preferably at least 10%, more preferably at least 1 5%, and most preferably at least 20% based on the decrease of the ⁇ - stiffness after a period of treatment.
  • the residual improvement of the ⁇ -stiffness is at least 1 %, preferably at least 3%, more preferably at least 5%, and most preferably at least 8%, particularly preferably 9.9% based on the decrease of the ⁇ -stiffness after a period of treatment.
  • the residual im provement of the ⁇ - stiffness is at least 0.5%, preferably at least 1 %, more preferably at least 1 .5%, and most preferably at least 2% based on the decrease of the ⁇ - stiffness after a period of treatment.
  • the residual im provement of the FM D is at least 1 5% , preferably at least 25%, more preferably at least 35%, most preferably at least 45% based on the increase of the FMD after a period of treatment. In one aspect of this embodiment, after discontinuation of the treatment for at least 3 months the residual improvement of the FMD is at least 15%, preferably at least 25%, more preferably at least 35%, most preferably at least 45% based on the increase of the FMD after a period of treatment.
  • the residual improvement of the FMD is at least 15%, preferably at least 25%, more preferably at least 35%, most preferably at least 45% based on the increase of the FMD after a period of treatment.
  • the residual improvement of the FMD is at least 1 0% , preferably at least 1 5% , more preferably at least 20% , most preferably at least 25%, even more preferably at least 30%, particularly preferably 30.4% based on the increase of the FM D after a period of treatment.
  • the residual improvement of the FMD is at least 1 %, preferably at least 3%, more preferably at least 5%, most preferably at least 6% based on the increase of the FMD after a period of treatment.
  • the pharmaceutical composition according to the present invention for use in the prevention, reduction or reversal of arterial aging is applied in a repeated intervention cycle comprising at least one treatment-period followed by at least one rest-period.
  • the intervention cycle is preferably repeated at least once, more preferably 2, 3, 4 or 5 times.
  • the treatment-period may last at least one week, at least two weeks, preferably between 2 weeks to 3 months, more preferably between 2 weeks and 2 months, still more preferably between 2 weeks and 1 month (e.g. 30 or 31 days).
  • the rest-period may be at least 1 day, preferably at least 1 week, more preferably at least 1 month, more preferably at least 3 months, still more preferably at least 4 months, more preferably at least 6 months, most preferably at least 8 months, particularly preferably approximately 10 or 12 months.
  • the pharmaceutical composition according the present invention comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose may comprise one or more further active agents, preferably selected from the group consisting of an anti-inflammatory agent, an antioxidant, and combinations thereof.
  • the anti-inflammatory agents and/or the antioxidants may be selected from the group defined below.
  • the pharmaceutical composition may further comprise an anti-inflammatory agent and an antioxidant, with the proviso that the pharmaceutical composition is not vitamin C and/or vitamin E.
  • the pharmaceutical composition does not comprise vitamin C and/or vitamin E. In one embodiment of the present invention, the pharmaceutical composition does not comprise fluvastatin or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the pharmaceutical composition may further comprise an anti-inflammatory agent, but not comprising an antioxidant.
  • the pharmaceutical composition may comprise an antioxidant and an anti-inflammatory agent, wherein the anti-inflammatory agent is not acetylsalicylic acid.
  • the pharmaceutical composition may further comprise an antioxidant, but not comprising an anti- inflammatory agent.
  • the pharmaceutical composition may further comprise an anti-inflammatory agent and/or an antioxidant.
  • the anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid and resveratrol.
  • the antioxidant is coenzyme Q10 or any analogue thereof.
  • the anti-inflammatory agent is acetylsalicylic and the antioxidant is coenzyme Q10.
  • acetylsalicylic acid is present in the pharmaceutical composition according to the present invention it is present in an amount, which corresponds to a weight ratio of acetylsalicylic acid and renin-angiotensin- aldosterone system inhibitor of from 15: 1 to 1 :2, preferably 10: 1 to 2.5: 1 , more preferably 6:1 to 4: 1 , most preferably 5:1 .
  • the pharmaceutical composition comprises acetylsalicylic acid in a daily dose of between 1 to 200 mg, preferably 50 to 150 mg, most preferably 100 mg.
  • coenzyme Q 1 0 is present in the pharm aceutical com position according to the present invention it is present in an amount which corresponds to a weight ratio of acetylsalicylic acid and renin-angiotensin- aldosterone system inhibitor of from 15: 1 to 1 :2, preferably 10: 1 to 2.5: 1 , more preferably 6: 1 to 4: 1 , most preferably 5: 1 .
  • the pharmaceutical composition comprises coenzyme Q10 in a daily dose of 1 to 200 mg, preferably 50 to 150 mg, most preferably 100 mg.
  • the pharmaceutical composition comprises valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40 mg, preferably between 10 to 30 mg, most preferably 20 mg, and acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form.
  • the pharmaceutical composition comprises valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40 mg, preferably between 10 to 30 mg, most preferably 20 mg, and acetylsalicylic acid in a daily dose between 1 to 200 mg, preferably 50 to 150 mg, most preferably 100 mg and/or coenzyme Q10 1 to 200 mg, preferably 50 to 1 50 mg, most preferably 1 00 mg.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects
  • one intervention-cycle is repeated at least 3, 4 or 5 times.
  • One intervention-cycle may consist of one treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month and one rest-period lasting approximately 12 months, preferably between 6 and 12 months.
  • the present invention relates to the pharmaceutical composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form.
  • the present invention relates to the pharmaceutical composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical composition
  • the pharmaceutical composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • Further embodiments of the invention relate to the pharmaceutical composition according to present invention further comprising one or more pharmaceutically acceptable excipient.
  • One of the embodiment of the present invention is the pharmaceutical composition comprising at least one renin-angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the pharmaceutical combination composition according to the present invention provides beneficial effect by substantially improving both functional characteristics such as for example endothelial function measured by flow- mediated dilatation of brachial artery (FMD) and morphological characteristics such as for example stiffness and elasticity of arteries measured by pulse-wave velocity (PVW) and ⁇ -stiffness of carotid artery.
  • FMD flow- mediated dilatation of brachial artery
  • PVW pulse-wave velocity
  • ⁇ -stiffness of carotid artery It is important to emphasize the similarity between the terms morphological or structural which are used to describe the same characteristics by different authors but basically disclosed the same characteristics of arterial wall. All three above mentioned methods are standard and generally widely accepted methods for estimation of functional and morphological characteristics of arteries.
  • renin-angiotensin-aldosterone system (RAAS) inhibitor as used in the present invention can include renin inhibitor, angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor antagonist and any combinations thereof.
  • the renin inhibitor can be aliskiren.
  • ACE inhibitor as used in the present invention can include, but is not limited to, benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, trandolapril, moexipril, quinapril, ramipril and any pharmaceutically acceptable salts or esters thereof.
  • ACE inhibitor can be selected from the group consisting of, but not limited to, perindopril, lisinopril, enalapril, moexipril, ramipril and any pharmaceutically acceptable salts or esters thereof, more preferably it can be selected from the group consisting of, but not limited to, perindopril and ramipril and any pharmaceutically acceptable salts or esters thereof.
  • angiotensin II receptor antagonist as used in the present invention can include, but is not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof.
  • angiotensin II receptor antagonist can be selected from the group consisting of, but not limited to, azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably it can be selected from the group consisting of, but not limited to, losartan, telm isartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably angiotensin I I receptor antagonist is valsartan and telm isartan and any pharmaceutically acceptable salts or esters thereof.
  • angiotensin II receptor antagonist as used in the present invention can further include one or more combination with other active substance such as for example combination with diuretic, preferably thiazide diuretic and more preferably hydrochlorothiazide, combination with calcium channel blockers and any pharmaceutically acceptable salts thereof, such as for example dihydropiridine calcium channel blockers that can be selected from the group consisting of, but not lim ited to, am lodipine, felodipine, lacidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine and any pharmaceutically acceptable salts thereof and any combinations thereof.
  • other active substance such as for example combination with diuretic, preferably thiazide diuretic and more preferably hydrochlorothiazide, combination with calcium channel blockers and any pharmaceutically acceptable salts thereof, such as for example dihydropiridine calcium channel blockers that can be selected from the group consisting of,
  • RAAS inhibitor as used in the present invention can further include one or more combination with other active substance such as for example, but not limited to, combination with diuretic, such as for example thiazide such as for example chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, polythiazide, preferably hydrochlorothiazide and indapamide; loop diuretic such as for example bumetanide, ethacrynic acid, furosemide, torsemide, preferably furosemide and torsemide; K+-sparing diuretic such as for example amioloride, eplerenone, spironolactone, triamterene, preferably eplerenone and spironolactone; and Ca-inhibitors such as for example acetazolamide, dichlorphenamide, methazolamide
  • another object of the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • at least one renin-angiotensin- aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose
  • at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects
  • Another object of the present invention is the pharmaceutical combination composition
  • at least one angiotensin I I receptor antagonist selected from the group consisting of, but not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof
  • Still another object of the present invention is the pharmaceutical com bination com position com prising valsartan or any pharmaceutical ly acceptable salts thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • Still another object of the present invention is the pharmaceutical combination composition
  • anti-inflammatory agent can include, but is not limited to, classic non-steroidal antiinflammatory agents (NSAIDS), such as for example acetylsalicyclic acid, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid, fenoprofen , nabum etone, acetam inophen and any pharm aceutica l ly acceptable salts thereof; COX-2 inhibitors, such as for example nimesulide, flosulid, celecoxib, rofecoxib, parecoxib sodium, valdecoxib, etoricoxib, etodolac, meloxicam and any pharmaceutically acceptable salts thereof; glucocorticoids, such as for example acetyls
  • anti-inflammatory agent can be selected from the group consisting of, but not limited to, acetylsalicyclic acid, ketoprofen, ibuprofen, naproxen, celecoxib, rofecoxib, meloxicam, hydrocortisone, cortisone, prednisone, prednisolone, betamethasone, dexamethasone, resveratrol and any pharmaceutically acceptable salts thereof and/or any analogues, more preferably acetylsalicyclic acid, ibuprofen, celecoxib, hydrocortisone, dexamethasone, resveratrol and any pharmaceutically acceptable salts thereof and/or any analogues of these agents, and even more preferably acetylsalicyclic acid and resveratrol and any pharmaceutically acceptable salts thereof and/or any analogues thereof.
  • the anti-inflammatory agent is present in the pharmaceutical combination composition in the efficient amount
  • antioxidant as used in the present invention can include, but is not lim ited to, butylatedhydroxyanisole, butylatedhydroxytoluene, malic acid, ascorbylpalmitate, sodium ascorbate, sodium metabisulphite, propyl gallate, beta-carotene, ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbic acid-2 -glycoside, ascorbylpalmitate, ascorbyl stearate, a-lipoic acid, glutathione, coenzyme Q10, tocopherol, tocopherol acetate, retinol, retinol palm itate, genistein, quercetin, epigallocatechin, epigallocatechingallate, gallocatechingallate, sylibin, diosmetin, kaempferol, epicatechin, galangin, indolic acid, ⁇ -linolenic acid, l
  • the antioxidant can be selected from the group consisting of, but not lim ited to, ascorbic acid, sodium ascorbyl phosphate, coenzyme Q10, magnesium ascorbyl phosphate, ascorbic acid-2-glycoside, butylatedhydroxyanisole, chlorogenic acid , epigal locatech i ngal late, indol ic acid , a-l i p o i c a c i d a n d a n y pharmaceutically acceptable salts thereof and/or any analogues thereof, more preferably ascorbic acid, sodium ascorbyl phosphate, coenzyme Q10, magnesium ascorbyl phosphate, ascorbic acid-2-glycoside, butylatedhydroxyanisole and any pharmaceutically acceptable salts thereof and/or any analogues thereof and even more preferably coenzyme Q10 and any pharmaceutically acceptable salts thereof and/or any analogue thereof.
  • the antioxidant is present in the pharmaceutical combination composition in the efficient amount to inhibit oxidation.
  • the term subtherapeutic daily dose relates to the dose that does not substantially lower the blood pressure, as defined above therefore the beneficial effects at this dose are attributed solely/purely to the pleiotropic effects of renin-angiotensin-aldosterone system inhibitor.
  • the subtherapeutic daily dose is between 1 and 50%, more preferably between 1 and 25% of daily recommended therapeutic dose for particular active substance.
  • a subtherapeutic daily dose does not produce side-effects which are important limitation of therapeutic dosages particularly for long term usage during which known and still unknown complications or side-effects could occur.
  • subtherapeutic daily dose means between 1 and 40mg if valsartan or any pharmaceutically acceptable salts or esters thereof is used as RAAS inhibitor and between 1 and 20mg if telmisartan or any pharmaceutically acceptable salts or esters thereof is used as RAAS inhibitor.
  • the present invention relates to the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least one renin- angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects
  • the subtherapeutic daily dose is between 1 and 50%, preferably between 1 and 25% of daily recommended therapeutic dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • Another object of the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least renin-angiotensin-aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects
  • the subtherapeutic daily dose is between 1 and 50%, preferably between 1 and 25% of daily recommended therapeutic dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • Another object of the present invention is the pharmaceutical combination composition
  • at least one angiotensin II receptor antagonist selected from the group consisting of, but not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for
  • Another object of the present invention is the pharmaceutical combination composition
  • Another object of the present invention is the pharmaceutical combination composition
  • the term apparently healthy subject according to the present invention relates to a subject having a low cardiovascular risk as defined above.
  • the effect of prevention, reduction or reversal of arterial ageing in apparently healthy subjects when using the pharmaceutical combination composition according to the present invention is surprisingly achieved after treatment defined as a treatment- period, that can last for at least 1 week, at least 2 weeks, between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month.
  • the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one renin- angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects in a treatment-period lasting at least 1 week, at least two weeks, between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month.
  • a pharmaceutical combination composition comprising at least one renin- angiotensin-aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflam matory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects in a treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month.
  • renin- angiotensin-aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose
  • at least one other active agent selected from the group consisting of an anti-in
  • Another preferred embodiment of the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one angiotensin II receptor antagonist, selected from the group consisting of, but not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti
  • Another preferred embodiment of the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects in a treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month.
  • telmisartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 20mg and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects in a treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month.
  • the above mentioned objects of the present invention were determined in a double-blind study wherein 40 apparently healthy subjects were randomly assigned to treatment (valsartan 20 mg daily, 1 month - 30 days) or placebo.
  • the main functional and morphological characteristics of arteries were tested by measurement of flow-mediated dilatation of brachial artery (FMD), pulse- wave velocity (PVW) and ⁇ -stiffness of carotid artery once at baseline and after 30 days. All parameters of arterial function were significantly improved after 30 days of treatment: a) FMD increased by 156.0 % (p ⁇ 0.001 ), b) PVW decreased by 7.2 % (p ⁇ 0.01 ) and
  • Said beneficial arterial characteristics were not accompanied by any changes in blood pressure.
  • the inventors observed substantial long term persistence of beneficial arterial characteristics.
  • the beneficial effect on arterial ageing when administering the pharmaceutical com bination com position according to the present invention surprisingly persisted in an substantial amount even approximately 1 month, 3, 4, 5, 6, 7, 8 or 12 months, preferably between 6 and 12 months, after discontinuation of treatm ent.
  • the period without any treatm ent according to the present invention and wherein the beneficial arterial characteristics are still present is named as the rest- period.
  • One of the aims of the rest-period is to prevent the occurrence of 'resistance' to therapy leading to decreased efficacy after certain time. If any inhibitory process is induced by treatment which seems to be logical it would be dim inished during the rest period.
  • still another embodiment of the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising at least one renin-angiotensin- aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects having at least one treatment period and at least one rest period characterised that the rest-period is approximately 1 month, 3, 4, 5, 6, 7, 8 or 12 months, preferably between 6 and 12 months.
  • Another object of the present invention relates to the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least one angiotensin II receptor antagonist, selected from the group consisting of, but not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telm isartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent
  • Another object of the present invention relates to the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects characterised that the rest-period is approximately 1 month, 3, 4, 5, 6, 7, 8 or 12 months, preferably between 6 and 12 months.
  • Another object of the present invention relates to the pharmaceutical combination composition
  • beneficial arterial characteristics was measured after discontinuation of treatment.
  • the beneficial arterial characteristics measured in the same observed group of subjects were still present in substantial amounts even after up to 12 months. For example, after 7 months of discontinuation the beneficial arterial characteristics were still present at the following percentage of initial improvement achieved after 1 month (30 days) of treatment disclosed above: a) FMD still increased by 30.4 %,
  • the present invention relates to a specific, original approach for implementation of the above mentioned obtained beneficial arterial characteristics by the following treatment regime: one treatment-period followed by one rest-period represents, i.e. one intervention-cycle that can be repeated at least 3, 4 or to 5 times.
  • the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one renin- angiotensin-aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects wherein one intervention-cycle is repeated at least 3, 4 or 5 times.
  • Another object of the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflam matory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects wherein one intervention-cycle is repeated at least 3, 4 or 5 times.
  • Another object of the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one angiotensin II receptor antagonist, selected from the grou p cons isti ng of, but not l i m ited to , azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally
  • Another object of the present invention relates to a pharm aceutical combination composition
  • a pharm aceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects wherein one intervention-cycle is repeated at least 3, 4 or 5 times.
  • Another object of the present invention relates to a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising telmisartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 20mg and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects wherein one intervention-cycle is repeated at least 3, 4 or 5 times.
  • the present invention is a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is a pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti- inflam matory agent, an antioxidant or any m ixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is a pharmaceutical combination composition
  • a pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor selected from the group consisting of, but not limited to, renin inhibitor, angiotensin-converting enzyme inhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is a pharmaceutical combination composition
  • at least one angiotensin II receptor antagonist selected from the group consisting of, but not limited to, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any mixture
  • the present invention is a pharmaceutical combination composition
  • valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is a pharmaceutical combination composition
  • telmisartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 20mg and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent, an antioxidant or any mixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least one renin-angiotensin- aldosterone system inhibitor as defined above in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent as defined above, an antioxidant as defined above or any mixtures thereof.
  • the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising at least one angiotensin-ll-receptor blocker as defined above in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an antiinflammatory agent as defined above, an antioxidant as defined above or any mixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and resveratrol or any pharmaceutically acceptable salts thereof and coenzyme Q10 in any pharmaceutically acceptable form.
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and resveratrol or any pharmaceutically acceptable salts thereof.
  • the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and resveratrol or any pharmaceutically acceptable salts thereof.
  • the present invention is the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and coenzyme Q10 in any pharmaceutically acceptable form.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and coenzyme Q10 in any pharmaceutically acceptable form.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg.
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and resveratrol or any pharmaceutically acceptable salts thereof and coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and resveratrol or any pharmaceutically acceptable salts thereof and coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and acetylsalicylic acid for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and resveratrol or any pharmaceutically acceptable salts thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and resveratrol or any pharmaceutically acceptable salts thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose and coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition
  • the present invention is the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a subtherapeutic daily dose for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the present invention is the pharmaceutical combination composition
  • valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40 mg for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • composition according to the present invention may mean that each component is adm inistered to the patient separately in an individual dosage form simultaneously, separately or sequentially in any order.
  • the present invention furthermore relates to a commercial package comprising the pharmaceutical combination composition according to the present invention together with instructions for simultaneous, separate or sequential use.
  • pharmaceutical combination composition according to the present invention may mean that all or just some components of the composition are administered to the subject in the same unit dosage form.
  • the combination of two or more active agents in the same pharmaceutical combination composition provides the additional advantage of reducing the frequency of administration of a dosage, thereby increasing the safety of the therapy and it is more patient friendly.
  • the further object of the present invention relates to the pharmaceutical combination composition
  • the pharmaceutical combination composition comprising a pharmaceutical combination composition according to the present invention together with one or more pharmaceutically acceptable excipient.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or, as the case may be, an animal without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • 'pharmaceutically acceptable excipient means a component of a ph arm aceut ica l prod uct that i s not an active i n g red ient.
  • U sefu l pharmaceutically acceptable excipients of the present invention include, but are not limited to, diluents, disintegrants, binders, lubricants, surfactants, pH modifiers, antiadherants, pigments, colorants and the like, and any combinations thereof.
  • the pharmaceutical combination composition according to the present invention may be administered to the patient by any known route of administration such as for example peroral (mouth), topical (skin), parenteral (skin or mucous membrane), transmucosal (nasal, buccal/sublingual, vaginal, occular, rectal) or inhalation.
  • the pharmaceutical combination composition according to the present invention may be useful for immediate-, delayed-, modified-, sustained-, extended-, pulsed-, continous- or controlled-release applications.
  • the pharmaceutical combination composition according to the present invention may be prepared by any process known from the state of the art.
  • the pharmaceutical combination composition according to the present invention suitable for peroral administration may take the form of, but is not limited to, solution, suspension, emulsion, tablet, pill, gel, syrup, elixir, capsule, powder, liquid or solid crystal, paste, and the like.
  • the pharmaceutical combination composition according to the present invention suitable for topical administration may take the form of, but are not limited to, cream, gel, liniment or balm, lotion, ointment, ear drops, eye drops, skin patch and the like.
  • the pharmaceutical combination composition according to the present invention suitable for parenteral administration may refer to modes of administration which include, but are not limited to, intradermal, intraosseous, intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the pharmaceutical combination composition according to the present invention suitable for inhalation may take the form of, but is not limited to, aerosol, inhaler, nebulizer, vaporizer and the like.
  • the pharmaceutical combination composition according to the present invention may be in the form of suppositories such as for example rectal or vaginal suppositories.
  • suppositories such as for example rectal or vaginal suppositories.
  • the inventors of the present application surprisingly found out that arterial ageing (in particular typical functional and morphological characteristics of arterial wall that can be measured by standard and widely used methods) can be prevented, reduced or reversed by administering the pharmaceutical combination composition according to the present invention.
  • the achieved beneficial arterial characteristics were not accompanied by the primary action of renin-angiotensin-aldosterone system inhibitor i.e. decrease of blood pressure.
  • the improvement in age-related characteristics in the observed population was achieved already after short- term treatment (for example at least one month) and again, unexpectedly, persists at important level approximately to 12 months after discontinuation of treatment.
  • the unique efficacy profile of said composition of the present invention allows a cyclic treatment consisting of a short term treatment-period followed by a long term rest-period during which beneficial arterial characteristics are still present.
  • a pharmaceutical combination composition comprising at least one renin-angiotensin-aldosterone system inhibitor, selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • renin-angiotensin-aldosterone system inhibitor selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose
  • at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • a pharmaceutical combination composition comprising at least one renin-angiotensin-aldosterone system inhibitor, selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • renin-angiotensin-aldosterone system inhibitor selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose
  • at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • renin-angiotensin-aldosterone system inhibitor is angiotensin II receptor antagonist, selected from the group consisting of, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and
  • angiotensin II receptor antagonist is valsartan or any pharmaceutically acceptable salts.
  • anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid and resveratrol.
  • antioxidant is coenzyme Q10 or any analogues thereof.
  • the pharmaceutical combination composition according to anyone of items 1 to 8 wherein one intervention-cycle consists of one treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month and one rest-period lasting 12 months, preferably between 6 and 12 months.
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form. 1 1 .
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • the pharmaceutical combination composition according to any one of items 1 to 12 further comprising one or more pharmaceutically acceptable excipient.
  • the present invention com prises the following preferred embodiments:
  • a pharmaceutical combination composition comprising at least one renin-angiotensin-aldosterone system inhibitor, selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • renin-angiotensin-aldosterone system inhibitor selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof in a subtherapeutic daily dose
  • at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • a pharmaceutical combination composition comprising at least one renin-angiotensin-aldosterone system inhibitor, selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof i n a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • at least one renin-angiotensin-aldosterone system inhibitor selected from the group consisting of, renin inhibitor, angiotensin-converting enzymeinhibitor and angiotensin II receptor antagonist and any combinations thereof i n a subtherapeutic daily dose and optionally at least one other active agent selected from the group consisting of an anti-inflammatory agent, an antioxidant or any m ixtures thereof for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • renin-angiotensin-aldosterone system inhibitor is angiotensin II receptor antagonist, selected from the group consisting of, azilsartan, losartan, eprosartan, irbesartan, olmesartan, candesartan, valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof, preferably azilsartan, losartan, telmisartan, olmesartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof, more preferably losartan, telmisartan, azilsartan, candesartan and valsartan and any pharmaceutically acceptable salts or esters thereof and even more preferably valsartan and telmisartan and any pharmaceutically acceptable salts or esters thereof.
  • angiotensin II receptor antagonist selected from the group consisting of, azilsartan, losartan, eprosartan, irbes
  • anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid and resveratrol.
  • antioxidant is coenzyme Q10 or any analogues thereof.
  • the pharmaceutical combination composition according to anyone of items 1 to 8 wherein one intervention-cycle consists of one treatment-period lasting between about 2 weeks to about 3 months, preferably between about 2 weeks to about 2 months and more preferably between about 2 weeks to about 1 month and one rest-period lasting 12 months, preferably between 6 and 12 months.
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form. 1 1 .
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in prevention, reduction or reversal of arterial ageing in apparently healthy subjects.
  • the pharmaceutical combination composition comprising valsartan or any pharmaceutically acceptable salts thereof in a daily dose between 1 and 40mg and optionally acetylsalicylic acid, resveratrol and/or coenzyme Q10 in any pharmaceutically acceptable form for use in decreasing occurrence of cardiovascular disorders in apparently healthy subjects.
  • composition according to any one of items 1 to 12 further comprising one or more pharmaceutically acceptable excipient.
  • the pharmaceutical combination composition comprising valsartan (as a representative of angiotensin II receptor antagonist) and following pharmaceutically acceptable excipients microcrystalline cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and iron oxide was used.
  • Table 1 Subject characteristics in the placebo and in the test group
  • BP blood pressure
  • b.p.m. beats per minute
  • Table 5 Improvement on FMD, PWV and ⁇ -stiffness achieved after 1 month of treatment (1 . intervention) and a further 1 month treatment (2. intervention) after a rest period of 12 months

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Abstract

La présente invention concerne une composition de combinaisons pharmaceutiques comprenant au moins un inhibiteur du système rénine-angiotensine-aldostérone, sélectionné dans le groupe comprenant l'inhibiteur de la rénine, l'inhibiteur de l'enzyme de conversion de l'angiotensine et un antagoniste du récepteur de l'angiotensine II dans une dose quotidienne sous-thérapeutique. Ladite composition est conçue pour prévenir et/ou atténuer le vieillissement du corps, et peut être notamment utilisée dans la prévention, l'atténuation ou l'inversion du vieillissement artériel chez des sujets apparemment en bonne santé.
PCT/EP2012/053378 2011-02-28 2012-02-28 Traitement du vieillissement artériel par l'inhibiteur de raas WO2012116996A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
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CN111494366A (zh) * 2019-01-31 2020-08-07 洛阳尚德药缘科技有限公司 二甲基氨基含笑内酯在制备抗衰老药物上的应用

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