WO2009080301A1

WO2009080301A1 - Treatment and prevention of ischaemic cerebral lesions and cerebrovascular cognitive impairment using a treatment regimen consisting of dipyridamole and an angiotensin ii receptor blocker in patients with previous stroke

Info

Publication number: WO2009080301A1
Application number: PCT/EP2008/010897
Authority: WO
Inventors: Lutz Hilbrich; Wolfgang Eisert; Thomas Machnig
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2007-12-21
Filing date: 2008-12-19
Publication date: 2009-07-02

Abstract

The invention relates to a method of treatment or prevention of a condition selected from dementia and cerebral cognitive impairment, preferably due to white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain, in a patient in need thereof, e.g. in patients with previous stroke or in elderly patients, comprising administering a therapeutically effective amount of dipyridamole (DIP) in combination with an angiotensin Il receptor blocker (ARB) and, preferably, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipidlowering agents such as the statins to the patient.

Description

Treatment and prevention of ischaemic cerebral lesions and cerebrovascular cognitive impairment using a treatment regimen consisting of dipyridamole and an angiotensin Il receptor blocker in patients with previous stroke

Field of the Invention

This invention relates to a method of treatment and prevention of white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain and its clinical correlates of signs and symptoms of cognitive dysfunction (vascular cognitive impairment). Thereby, the invention specifically addresses the synergistic effects shown to be present with a treatment regimen that contains diypridamole in any galenic formulation or preparation and an ARB (angiotensin Il receptor blocker). It is suitable for patients who are prone to develop this kind of pathological condition, as an example patients with previous stroke. The invention describes a specific treatment regimen that comprises a therapeutically effective amount of dipyridamole (DIP) in combination with an (ARB) and, preferably, in combination with a drug selected from other anti-platelet agents. The treatment regimen can be used in combination with other drugs commonly used in these type of patients, such as lipid- lowering agents.

Background of the Invention

White matter lesions in the brain are known to be important locus for tissue damage in vascular cognitive impairment (Cerebral White Matter Abnormalities and Lifetime Cognitive Change: A 67-Year Follow-Up of the Scottish Mental Survey of 1932," Ian J. Deary, Ph.D., FRCPE, University of Edinburgh; and Steven A. Leaper, BSc; Alison D. Murray, FRCR, FRCP; Roger T. Staff, Ph.D.; and Lawrence J. Whalley, M.D., FRCPsych, University of Aberdeen; Psychology and Aging, Vol. 18, No. 1.). The spectrum of ischemic white matter lesions histopathologically represents focal and diffuse lesions, the most common form being the combination of both, in varying proportions. It is believed that focal lesion results from the acute reaction to regional ischemia, while the diffuse white matter lesion represents the adjustment to altered perfusional and physiological conditions within the tissue (E. Englund; Neuropathology of White Matter Lesions in Vascular Cognitive Impairment; Cerebrovascular Diseases 2002; 13: 11-15).

White matter changes are detected with high frequency by neuroimaging techniques such as Magnetic Resonance Imaging in aged subjects with cerebrovascular risk factors or diseases and in cognitively impaired patients (J. T. O'BRIEN, R. WISEMAN, E. J. BURTON, B. BARBER, K. WESNES, B. SAXBY, and G. A. FORD; Cognitive Associations of Subcortical White Matter Lesions in Older People; Ann. N.Y. Acad. ScL, November 1 , 2002; 977(1): 436 - 444). Cerebral white matter lesions are known to be strongly associated with age and duration of uncontrolled hypertension. Higher severity of periventricular white matter lesions have been proven to increase the risk of dementia (Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM.; Cerebral white matter lesions and the risk of dementia; Arch Neurol. 2004 Oct;61(10): 1503-4.) The aim of ongoing clinical investigations within the PRoFESS trial are to investigate possible treatment strategies to prevent and to treat cognitive impairment associated with white matter lesions in the brain. The PRoFESS trial is a multi-national, double- blind, double-dummy, active and placebo controlled, randomized study with a 2 x 2 factorial design. It compares the efficacy and safety of a combination of Dipyridamole and ASA, marketed as Aggrenox^® , to clopidogrel, and in the second arm telmisartan (marketed as Micardis^®) to placebo in the prevention of recurrent stroke. The 2x2 factorial study design offers the opportunity to study the contribution of each of the study drugs tested (telmisartan or Dipyridamole + ASA) and the effect of combining them. The invention relates to the observed overall clinical effects on vascular cognitive impairment associated with changes in the white matter lesions and the relative contributions of the drugs concerned in that specific combination.

Dipyridamole {2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido[5,4-d]pyrimidine}, closely related substituted pyrimido-pyrimidines and their preparation have been described in e.g. U.S. Patent 3,031 ,450. DIP was introduced as a coronary vasodilator in the early 1960s. It is also well known having platelet aggregation inhibitor properties due to the inhibition of adenosine uptake. Subsequently, DIP was shown to reduce thrombus formation in a study of arterial circulation of the brain in a rabbit model. These investigations led to its use as an antithrombotic agent; it soon became the therapy of choice for such applications as stroke prevention, maintaining the patency of coronary bypass and valve-replacement, as well as for treatment prior to coronary angioplasty.

Furthermore, the European Stroke Prevention Study 2 (ESPS-2; J Neurol Sci. 1996; 143: 1-13; Neurology 1998; 51 : 17-19) proved that treatment by DIP alone was as effective as low-dose aspirin in the reduction of stroke risk, and combination therapy with DIP and aspirin was more than twice as effective as aspirin alone.

DIP appears to inhibit thrombosis through multiple mechanisms. Early studies showed that it inhibits the uptake of adenosine, which was found to be a potent endogenous anti-thrombotic compound. DIP was also shown to inhibit cyclic AMP phosphodiesterase, thereby increasing intracellular c-AMP.

DIP also has antioxidant properties (Free Radic. Biol. Med. 1995; 18: 239-247) that may contribute to its antithrombotic effect. When oxidized, low density lipoproteins become recognized by the scavenger receptor on macrophages, which is assumed to be the necessary step in the development of atherosclerosis (Ann. Rev. Med. 1992; 43: 219-25).

The inhibition of free radical formation by DIP has been found to inhibit fibrinogenesis in experimental liver fibrosis (Hepatology 1996; 24: 855-864) and to suppress oxygen radicals and proteinuria in experimental animals with aminonucleoside nephropathy (Eur. J. Clin. Invest. 1998; 28: 877-883; Renal Physiol. 1984; 7: 218-226). Inhibition of lipid peroxidation also has been observed in human nonneoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859).

Angiotensin Il (ANG II) plays a major role in pathophysiology, especially as the most potent blood pressure increasing agent in humans. ANG Il antagonists therefore are suitable for treating elevated blood pressure and congestive heart failure in a mammal. Examples of ANG Il antagonists are described in EP-A-O 502 314, EP-A- 0 253 310 , EP-A-O 323 841 , EP-A-O 324 377, US-A-4,355,040 and US-A-4,880,804 . Specific ANG Il antagonists are sartans such as candesartan, eprosartan, irbesartan, losartan, telmisartan or valsartan, furthermore olmesartan and tasosartan. The ARB telmisartan, obtainable on the market under the trade name Micardis®, is represented by the chemical name 4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol- 2-yl)-benzimidazol-1-ylmethyl]-biphenyl-2-carboxylic acid the following structure:

It is known that ANG II, besides its blood pressure increasing effect, additionally features growth promoting effects contributing to left ventricular hypertrophy, vascular thickening, atherosclerosis, renal failure and stroke. Bradykinin, on the other hand, exerts vasodilating and tissue protective actions, as disclosed for instance by W. Wienen et al.: Antihypertensive and renoprotective effects of telmisartan after long term treatment in hypertensive diabetic (D) rats, 2nd. Int. Symposium on Angiotensin Il Antagonism, February 15-18, 1999, The Queen Elizabeth Il Conference Center, London, UK, Book of Abstracts, Abstract No. 50.

Losartan and irbesartan provide a renoprotective effect found within first clinical trials, as disclosed for instance by S. Andersen et al.: Renoprotective effects of angiotensin Il receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney lnt 57 (2), 601-606 (2000).

ARBs selectively block the ATi receptor, leaving the AT₂ receptor, which plays a role in anti-growth and tissue regenerative actions, unopposed. Completed clinical trials with ARBs appear to display similar blood pressure reducing and tissue protective effects as with ACE inhibitors, as disclosed for instance by D. H. G. Smith et al.: Once- daily telmisartan compared with enalapril in the treatment of hypertension, Adv. Ther 1998, 15: 229-240, and by B.E. Karlberg et al.: Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension, J Hypertens 1999, 17: 293-302.

EP-A-1 013 273 discloses the use of ATi receptor antagonists or AT₂ receptor modulators for treating diseases associated with an increase of ATi receptors in subepithelial area or increase of AT₂ receptors in the epithelia, especially for treatment of several lung diseases.

In WO 01/30353 is disclosed that fibrin-dependent microcirculation disorders can be treated by DIP, for example microcirculation disorders caused by metabolic diseases, inflammatory reactions or autoimmune diseases, furthermore peripheral microcirculation disorders or microcirculation disorders associated with increased cell fragmentation.

Furthermore, WO 02/085331 discloses that NO-dependent microcirculation disorders can be treated by DIP, due to the activity as free radical scavenger.

WO 02/34248 discloses a method for increasing tissue perfusion with blood by coadministration of an agent that increases cGMP synthesis and an agent that inhibits cGMP degradation in the cells of the blood vessel walls or in blood cells, e.g. by coadministration of a statin and DIP.

Several publications report platelet aggregation inhibitory activity of ARBs, e.g. M. Monton et al., "Comparative effects of angiotensin Il AT-1-type receptor antagonists in vitro on human platelet activation" in: Journal of Cardiovascular Pharmacology, Vol. 35 (6), 906-913 (2000) discloses different platelet inhibition by losartan, irbesartan, valsartan, and telmisartan;

S. Chlopicki et al., "Antiplatelet action of losartan involves TXA2 receptor antagonism but not TXA2 synthase inhibition" in: Journal of Physiology and Pharmacology, Vol. 51 (4), 715-722 (2000); W. Buczko et al., " Studies on the antithrombotic action of AT1 receptor antagonists", in: Medical Science Monitor 2001 , Poland, VoI 7(4), 600-605 (2001); J.I. Guerra-Cuesta et al., "Effect of losartan on human platelet activation" in : Journal of Hypertension, Vol. 17 (3) , 447-452 (1999);

WO 01/82858 discloses platelet aggregation inhibitory activity of losartan, irbesartan and valsartan, furthermore, WO 03/094915 (Novartis) discloses that ARBs possess platelet aggregation inhibitory activity and thus are suitable for treatment of several conditions which can be influenced by platelet inhibition. This reference is focusing on valsartan and its metabolite valeryl 4-hydroxy valsartan.

EP-1 197 226 (Takeda) discloses a method for preventing the recurrence of cerebrovascular disorders and of the troubles following such disorders, e.g. mental disorders, by administering an ARB such as candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, olmesartan or tasosartan.

WO 2004-071385 discloses a method of preventing ischemic stroke or reducing the risk of primary or secondary ischemic stroke using dipyridamole in combination with acetylsalicylic acid (ASA) and an angiotensin Il antagonist.

US 05-0038003-A1 discloses a method of treating and preventing vascular events and circulatory disorders using dipyridamole in combination with acetylsalicylic acid (ASA) and an angiotensin Il antagonist.

WO 2004/069254 discloses a method of treating or preventing MMP-9-dependent disorders, e.g. vascular syndromes or diseases, atherosclerotic damages, arthritic conditions, inflammatory reactions, autoimmune reactions or proliferative diseases, using dipyridamole or mopidamole, optionally in combination with a platelet aggregation inhibitor, a fibrinogen receptor antagonist, heparin, an ACE inhibitor, an Angiotensin Il antagonist, a Ca-antagonist or a statin. WO 2004-093881 discloses a method of treatment of disorders caused by elevated thrombin or elevated thrombin receptor expression, e.g. thromboembolic disease vascular syndromes, or proliferative diseases, using dipyridamole or mopidamole, optionally in combination with platelet aggregation inhibitors, fibrinogen receptor antagonists, heparin, ACE inhibitors, Angiotensin Il antagonists, Ca-antagonists or lipid-lowering agents such as the statins.

Summary of the Invention

The invention is based on the PRoFESS clinical trial testing the combination of an ARB and a dipyridamole + ASA combination using a 2X2 factorial study design. It has been observed in several clinical studies that an antihypertensive treatment with an ARB can prevent the progression of dementia (J Birns and L Kalra. Blood pressure and vascular cognitive impairment: the debate continues. Journal of Human Hypertension (2006) 20, 1-3). The combination of ASA + DIP is known to prevent the recurrence of a stroke event after a first stroke ((ESPS-2; J Neurol Sci. 1996; 143: 1- 13; Neurology 1998; 51 : 17-19 and ). It has now been shown unexpectedly that DIP+ASA when administered in combination with an ARB provides an unexpected efficacy in the prevention or treatment of dementia and vascular cognitive impairment, particularly associated with white matter lesions in persons in need thereof, especially in the elderly who are at risk for a recurrent stroke event. These effects can be expained due to the unique vascular protective effects of dipyridamole on cerebrovascular vessels combined with the potential cerebroprotective effects of an ARB exerted on the the AT-2-receptor.

The superior efficacy of the methods according to the invention may be based on synergistic actions or overadditive effects of the antithrombotic, antioxidant, organoprotective, tissue-protective and vasculoprotective properties of the components of the combined treatment regimen of an ARB and a DIP containing antiplatelet treatment regimen. These effects are seen on background medication typically prescribed in patients who are at risk for stroke, such a statins and medications to treat diabetes. This finding provides a rationale also for combination treatment together with other antithrombotic agents, such as platelet aggregation inhibitors, e.g. acetylsalicalic acid (ASA)₁ clopidogrel or ticlopidine or the pharmaceutically acceptable salts thereof, or for combination treatment using additional cardiovascular therapies such as treatment with lipid-lowering agents.

According to a first aspect the present invention provides a method of treatment or prevention of a condition selected from dementia and cerebral cognitive impairment, preferably due to white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain, in a patient in need thereof, e.g. in patients with previous stroke or in elderly patients, comprising administering a therapeutically effective amount of dipyridamole (DIP) in combination with an angiotensin Il receptor blocker (ARB) and, preferably, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid-lowering agents such as the statins to the patient. Symptoms of dementia are defined e.g. in Pschyrembel, edition 259, Walter de Gruyter, Berlin, New York, 2002, page 345, being incorporated by reference. A preferred embodiment of the inventive method is a ternary combined treatment regime wherein DIP, an ARB, preferably telmisartan, and one platelet aggregation inhibitor, preferably ASA, are administered to the patient, without any additional active drug.

A further embodiment of the inventive method is a ternary combined treatment regime wherein DIP, an ARB, preferably telmisartan, and one lipid lowering agent, preferably simvastatin or atorvastatin, are administered to the patient, without any additional active drug.

A further embodiment of the inventive method is a quaternary combined treatment regime wherein DIP, an ARB, preferably telmisartan, one platelet aggregation inhibitor, preferably ASA, and one lipid lowering agent, preferably simvastatin or atorvastatin, are administered to the patient, without any additional active drug.

The method of the invention is meant to comprise preventive treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk, as well as, in a second aspect, therapeutic treatment of patients having already developed said condition in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy for prevention or reduction of risk of occurrence of the diseases. Persons in need of the preventive treatment according to the method of the invention may be patients having elevated risk of cerebrovascular events or risk to develop atherosclerosis, e. g. elder patients, diabetic, obese and/or hypertensive patients, smokers, atherosclerotic patients or patients with elevated familiar incidence for dementia or cognitive dysfunction, or for the risk factors mentioned hereinbefore.

In the method according to the invention a pharmaceutical composition is used comprising DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid-lowering agents such as the HMG-CoA reductase inhibitors (HMG CoA RIs), e.g. the statins, adapted for simultaneous, separate or sequential administration. For successive administration the ARB may be given before or after the administration of DIP and any of the optional additional drugs may be given before or after the administration of either the ARB or DIP.

In one embodiment of the method according to the invention a binary pharmaceutical composition is used containing only DIP and an ARB, preferably telmisartan, as actives, optionally together with one or more pharmaceutically acceptable diluents, excipients, carriers or auxiliary compounds known in the art.

In a further embodiment of the method according to the invention a ternary pharmaceutical composition is used containing DIP, an ARB, preferably telmisartan, and one platelet aggregation inhibitor, preferably ASA, as the only actives, optionally together with one or more pharmaceutically acceptable diluents, excipients, carriers or auxiliary compounds known in the art. In a further embodiment of the method according to the invention a ternary pharmaceutical composition is used containing DIP, an ARB, preferably telmisartan, and one lipid lowering agent, preferably simvastatin or atorvastatin, as the only actives, optionally together with one or more pharmaceutically acceptable diluents, excipients, carriers or auxiliary compounds known in the art.

In a further embodiment of the method according to the invention a quaternary pharmaceutical composition is used containing DIP, an ARB₁ preferably telmisartan, one platelet aggregation inhibitor, preferably ASA, and one lipid lowering agent, preferably simvastatin or atorvastatin, as the only actives, optionally together with one or more pharmaceutically acceptable diluents, excipients, carriers or auxiliary compounds known in the art.

Viewed from a second aspect the present invention provides a medicament comprising DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid-lowering agents such as the HMG CoA RIs, e.g. the statins, for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof.

Viewed from a third aspect the present invention provides the use of DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other antiplatelet agents and/or a drug selected from the lipid-lowering agents such as the HMG CoA RIs, e.g. the statins, for the manufacture of a pharmaceutical composition for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof. By this use is meant the preparation of all of the pharmaceutical compositions according to the invention mentioned hereinbefore or below. Detailed Description of the Invention

The invention provides a new and improved approach for preventive and/or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof.

With regard to all aspects of the invention any ARB may be suitable, unless otherwise specified, e.g. the sartans such as candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, olmesartan and tasosartan, preferably telmisartan.

Optional combination with platelet aggregation inhibitors

ASA inhibits aggregation through direct effects on the platelet, in more detail, by irreversibly acetylating platelet cyclooxygenase, thus inhibiting the production of thromboxane, which is strongly thrombotic. In high doses, however, ASA crosses over into endothelial cells (N. Eng. J. Med. 1984; 311 : 1206-1211), where it interrupts the production of prostacyclin, a potent natural inhibitor of platelet aggregation and by-product of the "arachidonic cascade" (N. Engl. J. Med. 1979; 300: 1142-1147). These observations led to the concept of low-dose antiplatelet therapy with ASA to maximize inhibition of thromboxane while minimizing the loss of prostacyclin (Lancet 1981 ; 1 : 969-971 ). In combination with DIP and an ARB, preferably telmisartan, also the low-dose ASA concept is preferred according to the invention. Other platelet inhibiting drugs such as clopidogrel or ticlopidine may be used instead of ASA within the method of the invention.

Optional combination with lipid-lowering agents

Hypertension is often present at the same time as hyperlipidaemia. Both symptoms are regarded as serious risk factors in the development of dementia or cognitive dysfunction, which often lead to adverse cerebrovascular events. High blood cholesterol levels and high blood lipid levels are involved for example in the start of atherosclerosis, a condition characterised by unevenly distributed lipid deposits inside the arteries, including the coronary, carotid, peripheral and cerebral arteries. This irregular lipid distribution is thus characteristic not only for coronary heart damage and cardiovascular diseases but also for cerebrovascular diseases and central ischemic events, the gravity and prevalence of which are also affected by the existence of diabetes, the sex of the person or cigarette smoking.

The endothelium can provide maintenance of local perfusion of the vessels by several separate mechanisms, one being the local vasodilatation mediated by prostacyclin and Nitric Oxide (NO, also described in literature as EDRF). The benefit of enhancing endothelial NO synthesis by HMG CoA RIs has been described in US Patent No. 5,968,983 and WO 00/56403. It is known that several lipid-lowering agents such as HMG CoA RIs, e.g. the statins, provide an increase of cellular Nitric oxide (NO) production at doses below the typical dose to lower serum lipids but sufficient to still enhance eNOS (endothelial nitric oxide synthetase) in cells of the vasculature. Lipid lowering therapy combined with potent platelet aggregation inhibitors for inhibiting the formation of thrombotic occlusions and for reducing the risk of occurrence of cardiovascular and cerebrovascular events is already disclosed in WO 98/11896. These findings provide a rationale for combining administration of DIP andan ARB such as telmisartan with the administration of a lipid lowering agent in the method of the invention, optionally together with administration of a platelet aggregation inhibitor.

Lipid lowering agents which can be used within the method of the invention may be HMG CoA RIs. The term HMG-CoA reductase inhibitor is intended to include all pharmaceutically acceptable salt, ester and lactone forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters and lactone forms is included within the scope of this invention. Suitable HMG CoA RIs are the statins, e.g. Atorvastatin, Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Dalvastatin, Compactin, Rosuvastatin and Mevastatin. Preferred statins are Simvastatin and Atorvastatin.

Preferably the lipid lowering agent is administered in a therapeutical dose effective to lower elevated serum lipids. HMG CoA RIs known to upregulate expression of eNOS in a subtherapeutical dose (referring to the lipid lowering effect) may be administered in sub- or therapeutical doses. Formulations and dosages: DIP

In the method of the invention any of the oral DIP retard, instant or the parenteral formulations on the market may be used, the retard formulations being preferred, for instance those available under the brand name Persantin^®, or, already in combination with ASA the formulations available under the brand name Asasantin^® or Aggrenox^®. Suitable DIP retard formulations are disclosed in EP-A-0032562, instant formulations are disclosed in EP-A-0068191 and combinations of ASA with DIP are disclosed in EP-A-0257344 which are incorporated by reference.

In the method according to the invention a plasma level of DIP of about 0.2 to 5 μmol/L, preferably of about 0.5 to 2 μmol/L or particularly of about 0.8 to 1.5 μmol/L may be maintained. DIP can be administered orally in a daily dosage of 50 to 750 mg, preferably 100 to 500 mg, most preferred 200 to 450 mg, for instance 200 mg twice a day. For long-term treatment it may be of advantage to administer repeated doses such as a dose of 25 mg DIP retard or any other instant release formulation several times a day. For parenteral administration DIP could be given in a dosage of 0.5 to 5 mg/kg body weight, preferably 1 to 3.5 mg/kg body weight, during 24 hours as slow i.v. infusion (not faster than 0.2 mg/min).

Formulations and dosages: ARBs

Several ARBs are already on the market and can be used for administration, e.g. Micardis^®, Lorzaar^®, Cozaar^®, Lortaan^®, Losaprex^®, Neo-Lotan^® or Oscaar^®, Approvel^®, Karvea^®, Diovan^®, Atacand^®, Blopress^® and Teveten^®.

The ARB may be administered in a daily dosage of 10 mg (or 0.143 mg/kg, based on a person of 70 kg) to 500 mg (7.143 mg/kg) orally and of about 20 mg (0.286 mg/kg) parenterally, preferably of 20 mg (0.286 mg/kg) to 200 mg (1.429 mg/kg) orally. Particularly preferred is an oral daily dosage of 40 mg (0.571 mg/kg) to 100 mg (1.143 mg/kg). For instance, the ARB is selected from candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, olmesartan, tasosartan and administered orally in a total daily dosage of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg in single dosage units. The total daily dose may be administered once a day in a single dosage unit, or in the alternative, as a sum of subdoses, twice or trice a day.

Pharmaceutical compositions according to the invention comprise an ARB in the dosage units mentioned hereinbefore, optionally together with one or more pharmaceutically acceptable diluents and/or carriers.

Formulations and dosages: ARBs / telmisartan

In the method of the invention telmisartan (brand name Micardis^®) may be used in its free acid form, in the form of a pharmaceutically acceptable salt or as a polymorph thereof, using for instance the dosages disclosed in Rote Liste^®2003, Editio Cantor Verlag Aulendorf, Germany, or in Physician's Desk Reference, 57 edition, 2003, or an equivalent thereof. Preferably, telmisartan is administered orally in a daily dosage of 10 to 200 mg, e.g. in a daily dosage of 20, 40, 80 or 160 mg, more preferred in a daily dosage of 40 to 160 mg, most preferred 60 to 100 mg, for example 20, 40 or 80 mg once a day.

Pharmaceutical compositions according to the invention comprise telmisartan in the dosage units mentioned hereinbefore, optionally together with one or more pharmaceutically acceptable diluents and/or carriers. Especially preferred pharmaceutical compositions comprise telmisartan in an amount of about 80 mg in a single dosage unit, optionally together with one or more pharmaceutically acceptable diluents and/or carriers.

Formulations and dosages: Platelet aggregation inhibitors / ASA With respect to ASA any of the oral formulations on the market may be used. Reference is made to Rote Liste^®2003, Editio Cantor Verlag Aulendorf, Germany, or to Physician's Desk Reference, 57 edition, 2003. This component of the medication may be administered orally in a daily dosage of 10 to 200 mg, preferably 25 to 100 mg, most preferred 30 to 75 mg, for instance 25 mg twice a day.

Cantor Verlag Aulendorf, Germany, or in Physician's Desk Reference, 57 edition, 2003, and may contain from 25 mg to 500 mg, preferably from 75 mg to 375 mg, and most preferably from 75 mg to 150 mg of clopidogrel. For example, the formulation may contain 25 mg, 50 mg, 75 mg, 150 mg, 250 mg, or 500 mg of clopidogrel. Oral administration may be in one or divided doses of two, three, or four times daily. A single daily dose is preferred. Clopidogrel is on the market under the brand names Plavix^® and Iscover^®.

Formulations and dosages: Platelet aggregation inhibitors / Ticlopidine Suitable oral formulations of ticlopidine are disclosed in Rote Liste^®2003, Editio Cantor Verlag Aulendorf, Germany, or in Physician's Desk Reference, 57 edition, 2003, and may contain from 25 mg to 600 mg, preferably from 100 mg to 400 mg, and most preferably from 200 mg to 300 mg of ticlopidine. For example, the formulation may contain 25 mg, 50 mg, 75 mg, 150 mg, 250 mg, or 500 mg of ticlopidine. Oral administration may be in one or divided doses of two, three, or four times daily. A single daily dose is preferred.

Formulations and dosages: HMG CoA RIs /statins

Dosage information for HMG CoA RIs is well known in the art, since several HMG- CoA Rl's are on the market. In particular, the daily dosage amounts of the HMG-CoA reductase inhibitor may be the same or similar to those amounts which are employed for anti-hypercholesterolemic treatment or, in the alternative, may be in a subtherapeutical dose refering to the lipid lowering effect. Regarding formulations and dosages of specific HMG-CoA Rl's reference is made to Rote Liste^®2003, Editio Cantor Verlag Aulendorf, Germany, or in Physician's Desk Reference, 57 edition, 2003.

Preferably, the oral dosage amount of a HMG-CoA Rl is from about 1 to 200 mg/day, and more preferably from about 5 to 160 mg/day. However, dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors as noted above. Also, the dosage amount of HMG-CoA reductase inhibitor needed to achieve the desired effect will be affected by the dosage amount and potency of other components of the medication according to the invention, e.g. the platelet aggregation inhibitor which may be employed in the combined therapy. An HMG-CoA Rl which has sufficiently greater potency may be given in sub-milligram daily dosages. Oral administration may be in single or divided doses of two, three, or four times daily, although a single daily dose of the HMG-CoA Rl is preferred.

The daily dosage amount for simvastatin may be may be in the range of from about 0.625 mg (or 0.009 mg/kg of body weight, based on a person weighing 70 kg; all following relative amounts are based on a 70 kg person) to about 450 mg (6.43 mg/kg) by oral route, about 20 mg (0.286 mg/kg) by parenteral route and preferably in a dosage of about 1.25 mg (0.018 mg/kg) to about 80 mg (1.428 mg/kg) by oral route. Particularly preferred is an oral daily dose of about 2.5 mg (0.036 mg/kg), about 5 mg (0.071 mg/), about 10 mg (0.143 mg/kg), about 20 mg (0.286 mg/kg), about 40 mg (0.571 mg/kg), about 80 mg (1.142 mg/kg), or about 160 mg (2.284 mg/kg), or, especially to start with, an oral daily dose of about 10 mg by oral route.

Formulations of simvastatin may contain 2.5-40 mg, preferably 5, 10, 15, 20, 25, 30, 35 or 40 mg of the drug, or an equivalent thereof, if a salt is used.

Simvastatin {2,2-dimethyl-butanoic acid, 1 ,2,3,7,8,8a-haxahydro-3,7-dimethyl-8-[2- tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl-1-naphthalenyl ester} is described in EP 0 033 538 und US 4 444 784 and is marketed under the brand name Zocor^®.

The daily dosage amount for atorvastatin may be may be in the range of from about 1.25 mg (or 0.018 mg/kg of body weight, based on a person weighing 70 kg; all following relative amounts are based on a 70 kg person) to about 450 mg (6.43 mg/kg) by oral route, about 20 mg (0.286 mg/kg) by parenteral route and preferably in a dosage of about 2.5 mg (0.036 mg/kg) to about 80 mg (1.428 mg/kg) by oral route. Particularly preferred is an oral daily dose of about 5 mg (0.071 mg/kg), about 10 mg (0.143 mg/kg), about 20 mg (0.286 mg/kg) or about 40 mg (0.571 mg/kg) or, especially to start with, an oral daily dose of about 10 mg by oral route.

For example, the daily oral dosage of atorvastatin calcium may be in the range of from about 1 mg to 160 mg, and more particularly from 5 mg to 80 mg, including dosage amounts of 10 mg, 20 mg and 40 mg.

Formulations of atorvastatin may contain 2.5-40 mg, preferably 5, 10, 15, 20, 25, 30, 35 or 40 mg of the drug, or an equivalent thereof, if a salt is used.

Atorvastatin is described in EP 0 247 633 and US-4 681 893. Polymorphs of atorvastatin are described in WO-97/03958, WO-97/03959, EP-O 848 704 and EP- 1 148 049. Salts of atorvastatin (monopotassium salt, monosodium salt, calcium salt, magnesium salt, zinc salt and meglumine) are described in EP-O 409 281 and US- 5 273 995. Atorvastatin hemicalcium salt {[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ- dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1 H-pyrrol-1 -heptan- oic acid hemicalcium salt) is marketed under the brand names Lipitor^®, Zarator^® and Sortis^®.

The daily dosage amount for lovastatin may be may be in the range of from about 1 to 100 mg, including dosage amounts of 10 mg, 20 mg, 40mg and 80 mg.

The daily dosage amount for fluvastatin sodium may be may be in the range of from about 10 to 100 mg, including dosage amounts of 20 mg, 40mg and 80 mg.

The daily dosage amount for pravastatin sodium may be may be in the range of from about 1 to 50 mg, including dosage amounts of 10 mg, 20 mg, and 40 mg. The daily dosage amount for rosuvastatin calcium sodium may be may be in the range of from about 1 to 50 mg, including dosage amounts of 10 mg, 20 mg, and 40 mg.

Ratios of daily closes:

Telmisartan and DIP may be administered in an oral daily dose ratio of telmisartan : DIP = 1 : 100 to 50 : 100 (based on weight), preferably 5 : 100 to 25 : 100, or, most preferred, 10 : 100 to 20 : 100.

Specific embodiments:

A specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day and telmisartan administered orally 20, 40 or 80 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and ASA administered orally 25 mg once or twice a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and clopidogrel administered orally 75 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and ticlopidine hydrochloride administered orally 250 mg (correspoding to 219,6 mg of ticlopidine) once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and simvastatin administered orally 5, 10 or 20 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and atorvastatin administered orally 5, 10 or 20 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, ASA administered orally 25 mg once or twice a day, and simvastatin administered orally 5, 10 or 20 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, ASA administered orally 25 mg once or twice a day, and atorvastatin administered orally 5, 10 or 20 mg once a day.

A further specific method of treatment or prevention according to the invention comprises the combination of DIP administered orally 200 mg twice a day, telmisartan administered orally 20, 40 or 80 mg once a day, and rosuvastatin calcium administered orally 5, 10 or 20 mg once a day.

The medicament for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof according to the invention is meant to comprise a fixed dose combination comprising the active ingredients in one formulation together as well as

a kit of parts comprising (a) a first containment containing a pharmaceutical composition comprising a therapeutically effective of DIP; and

(b) a second containment containing a pharmaceutical composition comprising a therapeutically effective of an ARB, preferably telmisartan; and, optionally,

(c) a third containment containing a pharmaceutical composition comprising a therapeutically effective of a drug selected from other antiplatelet agents; and/or optionally,

(d) a further containment containing a pharmaceutical composition comprising a therapeutically effective amount of a drug selected from lipid-lowering agents such as the statins.

The active agents employed in the instant combination therapy can be administered in oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.

The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions. Typical injectable formulations include solutions and suspensions.

The active compounds can be administered orally, bucally, parenterally, by inhalation spray, rectally or topically, the oral administration being preferred. Parenteral administration may include subcutaneous, intravenous, intramuscular and in- trasternal injections and infusion techniques. The active drugs can be administered in admixture with pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a nontoxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methyl cellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reducing. and non-reducing sugars, magnesium stearate, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like. For oral administration in liquid form, the drug components can be combined with non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring and flavoring agents can also be incorporated into the mixture. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms. Other suitable components include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth or alginates, carboxymethylcellulose, polyethylene glycol, waxes and the like. The active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Viewed from a different aspect the present invention provides the use of DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other antiplatelet agents and/or a drug selected from the lipid-lowering agents such as the statins, for the manufacture of a pharmaceutical composition for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof. By this use is meant the preparation of all the above-mentioned pharmaceutical compositions according to the invention. With respect to all aspects of the invention the following combinations are preferred, especially in the oral dosages indicated hereinbefore:

• DIP and telmisartan,

• DIP, telmisartan and ASA (most preferred embodiment)

• DIP, telmisartan and atorvastatin

• DIP, telmisartan and simvastatin

• DIP, telmisartan and rosuvastatin

• DIP, telmisartan, atorvastatin and ASA

• DIP, telmisartan, simvastatin and ASA

• DIP, telmisartan, rosuvastatin and ASA

Furthermore, all aspects of the invention are meant to comprise telmisartan either in its free acid form, in the form of a pharmaceutically acceptable salt, e.g. the sodium salt, as a polymorph or as the metabolite telmisartan 1-O-acylglucuronide (Drug Metab Dispos 1999 Oct; 27(10): 1143-9). Accordingly, all other drugs of the combinations according to the invention are meant to comprise also any pharmaceutically acceptable salts, polymorphs or active metabolites thereof.

Claims

1. A method of treatment or prevention of a condition selected from dementia and cerebral cognitive impairment, in a patient in need thereof, comprising administering a therapeutically effective amount of dipyridamole (DIP) in combination with an angiotensin Il receptor blocker (ARB) and, preferably, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid-lowering agents such as the statins to the patient.

2. The method of claim 1 , wherein the condition is due to white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain.

3. The method of claim 1 or 2, wherein the patient suffered from a previous stroke.

4. The method of claim 1 , 2 or 3, wherein the patient is an in elderly patient or a patient at risk of recurrent stroke.

5. The method of any of claims 1 to 4, wherein the method is a ternary combined treatment regime wherein DIP, an ARB and one platelet aggregation inhibitor are administered to the patient, without any additional active drug.

6. The method of any of claim 5, wherein the platelet aggregation inhibitor is selected from acetylsalicalic acid (ASA), clopidogrel and ticlopidine.

7. The method of any of claims 1 to 4, wherein the method is a ternary combined treatment regime wherein DIP, an ARB and a lipid-lowering agent such as a statin are administered to the patient, without any additional active drug.

8. The method of any of claim 7, wherein the lipid-lowering agent is selected from atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, dalvastatin, compactin, rosuvastatin and mevastatin.

9. The method of any of claims 1 to 7, wherein the ARB is selected from candesartan, eprosartan, irbesartan, losartan, telmisartan, olmesartan and tasosartan.

9. The method of claim 8, wherein the ARB is, telmisartan.

10. A medicament comprising DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid- lowering agents such as the HMG CoA RIs, e.g. the statins, for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof.

11. The medicament of claim 10, wherein the condition is due to white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain.

12. The medicament of claim 10, wherein the patient suffered from a previous stroke.

13. The medicament of claim 10, 11 or 12, wherein the patient is an in elderly patient or a patient at risk of recurrent stroke.

14. The medicament of any of claims 10 to 13, comprising DIP, an ARB and one platelet aggregation inhibitor.

15. The medicament of any of claim 14, wherein the platelet aggregation inhibitor is selected from acetylsalicalic acid (ASA), clopidogrel and ticlopidine.

16. The medicament of any of claims 10 to 13, comprising DIP, an ARB and a lipid- lowering agent such as a statin.

17. The medicament of any of claim 16, wherein the lipid-lowering agent is selected from atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, dalvastatin, compactin, rosuvastatin and mevastatin.

18. The medicament of any of claims 10 to 17, wherein the ARB is selected from candesartan, eprosartan, irbesartan, losartan, telmisartan, olmesartan and tasosartan.

19. The medicament of claim 18, wherein the ARB is, telmisartan.

20. Use of DIP or a pharmaceutically acceptable salt thereof in combination with an ARB, preferably telmisartan, and, optionally, in combination with a drug selected from other anti-platelet agents and/or a drug selected from the lipid-lowering agents such as the HMG CoA RIs, e.g. the statins, for the manufacture of a pharmaceutical composition for preventive or therapeutic treatment for preventive or therapeutic treatment of dementia and regression of cognitive function in a patient in need thereof.

21. The use of claim 20, wherein the condition is due to white matter lesions as diagnosed by magnetic resonance imaging (MRI) of the brain.

22. The use of claim 20, wherein the patient suffered from a previous stroke.

23. The use of claim 20, 21 or 22, wherein the patient is an in elderly patient or a patient at risk of recurrent stroke.

24. The use of any of claims 20 to 23, comprising DIP, an ARB and one platelet aggregation inhibitor.

25. The use of any of claim 24, wherein the platelet aggregation inhibitor is selected from acetylsalicalic acid (ASA), clopidogrel and ticlopidine.

26. The use of any of claims 20 to 23, comprising DIP, an ARB and a lipid-lowering agent such as a statin.

27. The use of any of claim 26, wherein the lipid-lowering agent is selected from atorvastatin, lovastatin, pravastatin, simvastatin, fluvastatin, dalvastatin, compactin, rosuvastatin and mevastatin.

28. The use of any of claims 20 to 27, wherein the ARB is selected from candesartan, eprosartan, irbesartan, losartan, telmisartan, olmesartan and tasosartan.

29. The use of claim 28, wherein the ARB is, telmisartan.