TW200522965A - Novel pharmaceutical combination comprising pyrimido-pyrimidine in combination with one other active component for treatment and prevention of fibrin-dependent microcirculation disorders - Google Patents

Abstract

A pharmaceutical combination for use in the treatment of the human or non-human animal body for treating or preventing fibrin-dependent microcirculation disorders associated with progressive dysfunction of small-sized vessels selected from the group consisting of: microcirculation disorders caused by metabolic diseases where vascular damages are involved selected from diabetic angiopathy, diabetic microangiopathy, diabetic gangrene, diabetic retinopathy, diabetic neuropathy or ulcus cruris, microcirculation disorders caused by inflammatory reactions, morbus crohn, microcirculation disorders caused by autoinnune diseases selected from autoimmune chronic-active hepatitis, idiopathic hepatitis, primary-biliary cirrhosis or autoimmune associated multiple sclerosis, peripheral microcirculation disorders, Raynaud's disease, tinnitus or sudden loss of hearing, microcirculation disorders associated with increased cell fragmentation, tumor diseases or thrombotic- thrombocytopenic purpura, and, as further indications, nephrosclerosis, prerenal hypertension, haemolytic-uremic syndrome, arterial hypertension, vascular dementia, Sudeck's disease, central-veneous thrombosis of the eye, homocystine-induced vasculopathy, ischemic or coronary heart diseases, prevention of myocardial infarction or reinfarction and treatment or prevention of atherosclerosis, comprising a daily dosage of 25 to 450 mg of a pyrimido- pyrimidine selected from dipyridamole, mopidamol and the pharmaceutically acceptable salts thereof and further comprising one other active component selected from acetylsalicalic acid (ASA) orally in a daily dosage of 10 to 30 mg, clopidogrel, ticlopidine and the pharmaceutically acceptable salts thereof, fibrinogen receptor antagonists, heparin, heparinoids and antithrombins, ACE inhibitors, Angiotensin II antagonists, Ca- antagonists and lipidlowering agents.

Description

200522965 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to the treatment of fibrin-dependent microcirculation using dipyramodine or muppyramine as the active ingredient. , Adjust to improve the circulation, and used to make the equivalent. ^ Search for the composition of two adamo or molapoda use. [Prior art] One p ratio σ amo {2,6-di (diethanolamine- 胺 4, 讧 -piperidinepyrimido [5,4-d] when pyrimidine 丨, a closely related substituted pyrimido y 2 Φ ^ and Its wither products have been disclosed in, for example, U.S. Patent 3,031,45. The related substituted pyrimido-pyrimidines and their preparations have been disclosed in, for example, Yingliu μ Profit-seeking Case 1,051,218. Mometamo {2,6-bis (diethanolamine) such as Chenkou Dingkou and Ding Yangyang =. In the early i960s, Er_Mo was used as a coronary arterial dilator. "Platelet agglutination also inhibits the intake of feed acids It is well-known for its characteristics. Next, in the study of cerebral arterial circulation in rabbit models, dipbitamol can reduce blood test formation. This 4b epilogue is divided into Dougan, N, and N inches to guide its use as an antithrombotic agent. : It will soon become applied to stroke prevention, maintenance of coronary artery bypass and valve-replacement non-closing, and treatment before coronary angioplasty. Further, in the European Stroke Prevention Month, the European Stroke 2 (the European Stroke

Prevention Study 2, ESPS 9 · Shan, 2, Journal of Neuroscience (j Neurol Sci〇1996; 143: 1-13; Neurology i99s. Yi r iy98, 51: 17-19) Prove that Dipycla is used alone Mo's treatment can be as effective as reducing low-dose aspirin to reduce the risk of stroke, and the combined therapy of dipylamo and aspirin ^ lin is more than twice as effective as aspirin alone.

O: \ 97 \ 97879.DOC 200522965 ratio. There are several mechanisms to inhibit thrombosis. Early studies have shown that it inhibits the uptake of an endogenous effective antithrombotic compound, adenylate. It has also been shown that dipyridamole inhibits cyclic AMp phosphodiesterase and therefore increases intracellular AMP. The laboratory model simulates the complex physiology of blood vessels and shows that the vascular system is not a passive pipe. After the blood vessel is injured, the complex detection and balance system interacts with the blood production to protect its integrity. Therefore, the endothelial cell produces a strong agglutination inhibitor, prostacyclin. Normal endothelial cells are non-thrombotic and prevent platelet adhesion. Different stimulants promote the release of endothelial-driven relaxation factor (EDRF), which can inhibit platelet adhesion and suspicion. On the same day, the increase in cGMp in the cells after administration of the confirmation compound showed that it could relax smooth muscle cells. Therefore, the endothelium can inhibit thrombosis through two separate mechanisms, one is through stigmadin and c-AMP, and the other is through EDRp ^ c_GMp. Dipyridamole does not enhance the antithrombotic mechanisms of these two vessel walls, in addition to adenylate-controlling potency. It stimulates prostacyclin production by increasing the intracellular cAMp concentration, and enhances the potent anti-thrombus nitric oxide system by increasing cGMP. Ipihamol also has antioxidant properties (free radical biomedicine (Fkc RacHc · Bl0 · · Med ·) 1995; 18: 239-247) can contribute to the antithrombotic effect. When LDL is oxidized, it is recognized by macrophage clearance receptors, which is considered to be an essential step in the development of arteriosclerosis. (Annual Rev. Med. 1992; 43: 219-25). In experimental liver cirrhosis, it was found that the inhibition of free radical formation by dipyridamole can inhibit fibrosis (liver science 996; 24: 855_864) and the amino acid nucleus O: \ 97 \ 97879.DOC -10- 200522965 gallic acid Nephropathy can inhibit oxygen free radicals and proteinuria in experimental animals (European Journal of Clinical Research (Eur · J · Clin · Invest.) 1998; 28: 877-883; Renal Physiol.) 1984; 7: 218- 226). Inhibition of fat peroxidation is also observed in human non-neoplastic lung tissue (Gen. Pharmacol. 1996; 27: 855-859). Mopatam is known to have antithrombotic and additional anti-metastatic properties. [Summary of the invention] It is surprisingly found that σ 荅 mo and Mo Pbitamo are effective in protecting the operation of the golden tube wall, and therefore strongly influence the parental interaction of the fibrin pathway in the blood vessel wall and the coagulation system, resulting in stimulation The need for fibrin aggregation after clot formation is reduced. It is known that when the prothrombinase complex is localized to negatively charged cell membrane phospholipids, it is significantly transformed into more active so that vascular injury accelerates fibrin aggregation. By stabilizing the cell membrane, less negatively charged phosphodiserine can be exposed to the outer layer of the cell membrane, which provides fewer opportunities for the prothrombinase complex to bind to the phosphate, thus preventing the prothrombinase complex from operating its complete conversion The rate converts pro-thrombin to thrombin, which is responsible for converting fibrinogen to fibrin. Increased platelet adhesion and fibrin accumulation are the basic pathways involved in clot formation. Moreover, the time course of these two pathways is shown to be essentially different (Thromb. Haemost. 1993; 69 (Abstract): 569), which proves that the two mechanisms are not closely integrated as expected. In fact, dipymodazole and morphodamol are known to act as platelet aggregation inhibitors, and the newer discovery indicates that these two agents can be used as blood fibers in addition to their ability to stabilize the cell wall cell membrane.

O: \ 97 \ 97879.DOC -11-200522965 Inhibitor of protein aggregation regulation. This effect is particularly important for small blood vessels or microvessels because the ratio of blood vessel wall surface area to blood volume is high, and it provides new research directions for the treatment and prevention of fibrin-dependent microcirculation. Therefore, di Pitamo and Moetamo have the potential to treat a variety of diseases including progressive medium and small-sized vascular disorders. For larger blood vessels and short-term treatment situations or prevention of acute conditions, it is generally believed that dipylamotol vasodilator activity is more important. Dipyridamole is known to be used as a stress tester by short-term high-dose II. Bitamo infusion makes blood

The tube lags behind self-regulation and thus appears disproportionately perfused. By nuclear development or ultrasound cardiac dynamics, this may increase less in the later-stage and narrow areas and greater increase in healthy areas. During the long-term oral treatment of blood polymerisation, the concentration of diammonium and related glandular acid increased for more than several hours, allowing the self-regulating system to have a compensatory effect, so in the "stress test" state: The acid concentration reached a peak in four minutes. The treatment according to the present invention found that it can provide a continuous effect on small blood vessels and therefore continuously improve microcirculation.

It was found that dipyramob and mapomob have significant inhibitory activity on fibrin aggregation via the vascular wall and cell membrane stabilization potency. They also provide a rationale for combination therapy to incorporate other antithrombotic agents such as platelet aggregation inhibitors such as acetamidine = Salicylic acid (ASA), clopidate. mail. Or chlorophene bites or pharmaceutically acceptable salts thereof, fibrinogen receptor antagonists (Abciximab, RDGS_skin bond, synthetic intravenous or oral fibrinogen antagonist 'For example, vadafiben (palpitate, lafradafiban or a pharmaceutically acceptable salt thereof), heparin

O: \ 97 \ 97879.DOC -12- 200522965 (heparin) and heparin or antithrombin, or additional cardiovascular therapies for combination therapy such as the use of ACE inhibitors, angiotensin π antagonists, calcium-antagonists Or lipid-lowering agents such as statins. ASA inhibits agglutination by directly acting on platelets, and more specifically, it inhibits the production of powerful thromboxane (thromboxane) by irreversibly acetylating platelet cyclooxygenase. However, aspirin penetrates into endothelial cells at high doses (New England Journal of Medicine (N. Eng. L Med. 1984, 311 · 12G6) 2U), interrupts natural and effective platelet aggregation inhibitors and acts as a biological Acrylic acid series (arachldonic cascade) n byproduct _ prostacyclin production. (New England Journal of Medicine 1979; 300: ιΐ42_ιΐ47). These observations have led to the concept of low-dose ASA anti-platelet therapy to increase blood test inhibition to a higher level while minimizing prostacyclin loss (Lancet 1981; 1: 969_971). According to the present invention, the concept of humor or morphamol and low-dose ASA is preferred. The present invention provides a method for treating human or non-human animal body, preferably mammal, for treating or preventing fibrin-dependent microcirculation or a disease state including microcirculation. The method comprises administering An effective dose with the animal body selected from the group consisting of dipyridamole, molpyramid and pharmaceutically acceptable salts thereof, preferably dipyridamole, and in combination with one or more other antithrombotic agents as needed Pharmaceutical composition. Another aspect of the present invention provides the use of spermidines selected from the group consisting of Ertamo, Mometamo, and pelvis, acceptable use of pyridine, preferably dipyramid, and optionally combined with-or a variety of other anti- Blood preparation, and treatment of human or non-human animal body, preferably mammal, for the treatment or prevention of fibrin

O: \ 97 \ 97879.DOC -13-200522965 Dependent microcirculation disease or packet eight G 3 ring attack and cracking method. Medical composition in a disability state

[Embodiment J The invention provides a new research direction for the treatment and prevention of culvert maladjusted fibrin eggs self-propelled and small-sized blood, including the administration of puppets, the combination of pharmaceutically acceptable salts, An effective agent for fibrin-dependent microcirculation products. The diseases include pathogenesis or medium or small V :: fibrin deposition leading to various clinical records. It is known that hematoemia f disorder enters the red ring disease. However, inflammation and diabetes mellitus will cause the release of the microcirculation inflammation site. Θ The microcirculation disease is caused by the release of bleeding fibrinogen from the fiery niches of the tissue. Progressive — Caused by an autoimmune response. V- is a microcirculation disorder. It may also be a solution to the "fibrin-dependent microcirculation disease" symptoms. Microcirculation disorders that cause damage to blood vessels in this area with non-limited metabolic diseases include, for example, diabetic angioplasty, especially diabetes Microangioplasty, 7 such as diabetic gangrene, diabetic retinopathy, diabetic neuropathy, or calf ulcers, microcirculation disorders caused by inflammatory reactions, such as morbus crohn (local ileitis) caused by autoimmune diseases Microcirculation, autoimmune k-active hepatitis (idiopathic hepatitis), primary biliary, ten sclerosis, or (autoimmune-related) multiple sclerosis, peripheral microcirculation,

O: \ 97 \ 97879.DOC -14- 200522965 Such as Raynaud's disease, tinnitus, or sudden hearing loss, covering microcirculation disorders that increase cell disruption, such as tumor disease or thrombocytopenic purpura (TTP) ), Or further symptoms, nephrosclerosis, prerenal hypertension, hemolytic uremic syndrome (HUS), arterial hypertension, vascular dementia, Alzheimer's disease (Sudeck's disease) Central venous thrombosis, ischemic optic neuropathy, homocysteine-induced vascular disease, A deficiency or coronary heart disease, prevention of myocardial infarction or reinfarction, and treatment or prevention of arteriosclerosis. Fibrin-dependent microcirculation " symptoms also include compatible cardiomyopathy. Therefore, the present invention is provided to a person in need of such treatment, such as suffering from ischemic or coronary artery disease, a method for improving myocardial blood flow supply, and preventing myocardial infarction or reinfarction. In addition, the present invention also provides a method for treating or preventing arteriosclerosis.

O: \ 97 \ 97879.DOC 200522965 has deducted a pyrimidine sigmamo, mapodamol or its pharmaceutically acceptable salts can be used alone or in combination with other antithrombotic agents to treat I fibrin- Dependent microcirculation. ratio. Mo or Mo said that the plasma concentration of tamo should be maintained at about to 5 micromoles / liter compared to about 0.4 to 5 micromoles / liter, especially about 0.5 to 2 micromoles / liter or about 0.8. To 1_5 micromoles / liter. This effect can be achieved by using any commercially available tamo oral delayed, immediate or parenteral formulation, preferably a delayed formulation, such as the commercially available brand name Pensa Bite (p⑽Ca⑧) Or, in combination with a dose of ASA, the following commercially available AsaSantin (R) or Aggrenox (R) preparations are used. The dipyrmolium chitin type formula has been disclosed in the European patent case Ep_A_⑼M%], that is, the 亇 1 formula is disclosed in the European patent case Ep-A_〇68i9l and the combination of ASA and dipyramoline is disclosed in the mentioned manner In European patent case EP_A_ 0257344. Mortalox is also available as oral delayed, immediate, or parenteral formulations, such as those disclosed in UK patent case Gb 1,051,218 or mentioned in European patent case Ep-A _〇, 10,898, preferably a slow-acting formula. Dipyramob or morpyromo can be administered orally at a daily dose of 25 to 45 mg, preferably 50 to 240 mg, and most preferably 75 to 200 mg. For long-term treatment, it is advisable to administer repeated doses such as 25 mg dipyramob retarder I or any other immediate release formulation three or four times daily. Dipylamotol can be administered parenterally, at a dose of 0.5 to 5 mg / kg body weight, preferably 1 to 3.5 by slow intravenous infusion (not more than 0.2 mg / min) over a 24-hour period. Mg / kg body weight.

O: \ 97 \ 97879.DOC -16- 200522965 The combination of dipamo or mopamo with low-dose AS A can be administered orally in combination with 10 to 30 mg of ASA and 50 to 300 mg of dipamo or Mo Ye Diao σ 'Mo' is preferably 480 to 2 4 0 克 2 p ratio π 荅 Mo or Cap 卩 σ 荅 Mo, for example, the weight ratio is between 1 to 5 and 1 to 12, the best is The weight ratio is! More than 8, for example 25 mg AS A and 200 mg dipyramod or mopendimo. Other antithrombotic compounds can be administered from 0.1 to 10 times, preferably from 0.3 to 50 times, and most preferably from 0.3 to 2.0 times the clinically described dose (e.g. Rote LiSte®) 1999, · Vadafil 贲, Lavaldife 贲 · · European patent EP-A-0483 667), combined with dipyramod or mapodamo daily dose of 450 mg, preferably 50 to 240 mg, most It is preferably 75 to 200 mg. Any combination of ACE inhibitors known to be used in combination therapy with dipyramob or morphamol and ace inhibitors, such as benazepril, caputo, capt 〇pril), sirona, ceronapril, enalapril, fosinópdl, imidapril, iisinopril, Moses Moexipril, quinapril, ramipril, trandolapril or perindOprii, using known techniques, such as As described by Roth Liszt⑧ 999, the editing center is in Editio Cantor Verlag Aulendorf. Combining therapy with dipidamod or mapodamod and angiotensin π antagonists 'Related techniques are known to be applicable to any angiotensin Η antagonist', such as cantons such as can (jesartan), Eprosartan, irbesartan, sarsartan, telmisartan, valsartan, olsarsar O: \ 97 \ 97879.DOC -17- 200522965 olmesartan, or tassartan, using a dose known to the art, such as described by Roth Liszt® 1999, with the editorial center in Arandorf. Combine The combination of dipyridamole or morphamol and calcium antagonists is used in the treatment, and any calcium antagonist is known to be applicable in related arts, such as nifedipine, nitripine, nisol Nisoldipine, nilvadipine, isadipine, adipine, felodipine, or lacidipine, using doses known to the art, such as Roth Liste 1999 As mentioned, the editorial center is in Arandorf. Combining therapy with dipyramod or morphamol and statin, the relevant techniques are known to be applicable to 'statin' (for example, Rovastatin (10 complete, simvastatin)) Known doses for related techniques, such as described by Rot Liszt® 1999, with Arandorf as the editorial center. It is worth noting that microcirculation that increases cell disruption, as mentioned above, especially accelerates fibrin accumulation due to potential free The cell membrane region activates the prothrombinase complex. These microcirculation disorders, such as tumor diseases or thrombotic thrombocytopenia, are more preferred for treatment using high-dose diatamo or mupida ηamo. It means dipymodam or The plasma concentration of morphamol is about ο ′ to 5 ^ 0 micromoles / liter, preferably about 0.5 to 20 micromoles / liter, particularly preferably about 0.5 to 10 micromoles / liter, and more preferably Slow intravenous infusion to maintain. In response to these symptoms, the mouth is clear 'Etamo or Mo, compared to. Momo can be administered at a daily dose of about 150 to 800 mg, preferably about 200 to 800 mg, the best outline To _ grams.

O: \ 97 \ 97879.DOC -18- 200522965 Covering microcirculation that increases cell disruption can also be treated by the combination of dipyramod or rubidone σ and mo and ASA in low doses. Tamo or morphamol, as indicated above, is combined with an oral dose of about 0 to 30 mg ASA per day, preferably about 25 mg ASA. In order to study the inhibition of fibrin accumulation by dipyrazole, the following experiments were performed: Studies on the use of radioactively calibrated platelets and fibrinogen in living organisms The radioactively calibrated 99Tc platelets and calibrated fibrin will be used

The original study of the efficacy of Mo and Heparin. Methods such as nuclear and physical methods (Nuclear lnstruments and Meth〇ds in physic

Research ^ 1994 ' 353: 448_452. Place energy_sensitive solid-phase radiographs around the rabbit carotid artery. After balloon induced angioplasty, the adhesion of platelets and fibrinogen was measured for 4 hours. It was found that platelet and fibrinogen adhesion have different time courses. After the damage: no adhesion was detected when radiolabeled platelets were injected for 30 minutes; it was obvious that the endogenous platelets had been attached to the angioplasty site. In contrast, fibrinogen adhesion on the control and treatment groups of animals has not expired even after four hours, so it is pointed out that fibrinogen is regulated by different stimuli or factors at different time points after injury. Qi Yihe reduced the accumulation of both the small plate and fibrinogen. } The treatment with a single pidamo also produces a decrease in blood agglutination, as with heparin, but it is also seen, however, the adhesion to fibrinogen reduces the dipamomo far more than heparin. [Schematic description] Figure 1 is "Platelet plate accumulation after heparin administration (" mild injury ") (infusion:

O: \ 97 \ 97879.DOC -19- 200522965 100U / kg high dose + 2511 / kg / min post-fibrin accumulation ^ Mild θ "〃 Administered with 隹 rod L granule 厪 injury" (Infusion: 100U / Kg + 25U / kg / hour) (below). Jinda d 99 blood every minute after M-shape of the common carotid artery in rabbits: synchronous detection of platen and calibrated avermectin. Control (:: treatment), and (N-6) no longer show rapid platelet increase and fibrinogen increase t after injury. Mingsu __ ^ M (continued remuneration in kilograms, /: dry infusion) showed a decrease in platelet and fibrin adhesion. Measurements showed constant radioactivity without injury. Fig. 2 is the second part of the accumulation of fibrin, platin, and fibrin. "Mo potency (dose: 0.25 mg / kg / hr from the hour before injury)", the above picture is " m TG • platelet accumulation ", T picture is "coffin fibrin accumulation". 0 After treatment with pidamo (0.25 mg / kg followed by 0 4 g / kg / hr), radioactively labeled Acer platelets (99Tc) and fibrin were treated at the angioplasty site. (1231) Shen; Temple. The platelet count is low, but fibrin is broken during the first four hours after angioplasty. The item sticker is almost completely blocked O: \ 97 \ 97879.DOC -20-

Claims (1)

200522965 10. Scope of patent application: 1. A method for treating or preventing fibrin-dependent microcirculation associated with asymptotic dysregulation of small blood vessels selected from the following groups, for human or non-human treatment Animal's medical combination: u selected from the following metabolic diseases caused by the blood vessel index & related microcirculation diabetic angioplasty, diabetic microangioplasty, diabetic gangrene, diabetic retinopathy, diabetic neuropathy or calf Ulcers, microcirculation caused by inflammatory reactions, cohen disease (morbus crohn, local ileitis), microcirculation caused by autoimmune diseases selected from the group consisting of autochronic chronic-active hepatitis, idiopathic hepatitis, Primary-Biliary sclerosis or autoimmune-related multiple sclerosis, peripheral microcirculation, Raynaud (s disease), tinnitus or sudden hearing loss, increase in cell disruption Circulation, tumor disease, or thrombocytopenic purpura, and 'such as further symptoms, renal sclerosis, prerenal hypertensive Hemolytic uremic syndrome, arterial hypertension, vascular dementia, O: \ 97 \ 97879.DOC 200522965 Sudeck's disease, central eye-venous thrombosis, homocysteine-induced Vascular disease, ischemic or coronary heart disease, prevention of myocardial infarction or re-infarction, and treatment or prevention of arteriosclerosis, containing 25 to 450 mg per dose of pyrimidopyrimidine, which is selected from dipyridine. Momo, morphamol, and pharmaceutically acceptable salts thereof, and further comprising an active ingredient selected from the group consisting of acetosalicylic acid (ASA), clopidogrel ), Ticlopidin and its pharmaceutically acceptable salts, fibrinogen receptor antagonists, heparin, heparinoids and antithrombin, ACE inhibitors, angiotensin η antagonists , Calcium-antagonists and lipid-lowering agents. 2. The medical combination according to claim 1, characterized in that the fibrinogen-dependent microcirculation is selected from the group consisting of diabetic angiostomy, diabetic gangrene, diabetic retinopathy, diabetic neuropathy or calf ulcers, Cohen disease, Autoimmune-active hepatitis (idiopathic hepatitis), primary-biliary sclerosis, Reynolds disease, tinnitus or sudden deafness nephrosclerosis, O: \ 97 \ 97879.DOC 200522965 prerenal hypertension , Hemolytic uremic syndrome, Shaddock atrophy, and cysteine-induced vascular disease. 3. The medicinal combination according to claim 1 or 2, which comprises 50 to 300 ¾ g of pyrimido-pyrimidine per oral dose and 10 to 30 mg of acetamidine salicylic acid (ASA) per oral dose. 4. The pharmaceutical combination according to claim 1 or 2, which comprises a combination of pyrimido-pyrimidine and clopidogide or chlorobenzidine. 5. The medicinal combination according to claim 1 or 2, which comprises pyrimido_pyrimidine and selected from benazepril, caputo ... ceronapril, en NariaprH, enaiaprH, fosinopril 'imidaprii, lisinopril, moexipril, quinapril, lamy (Ramipril), trandolapr⑴ or perindopril combined ACE inhibitors. 6 · According to claim 1 or 2 of the pharmaceutical combination, which contains meticulous σ determination and -sigma σ determination and selection From the satan such as candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan ( valsartan), olmesartan and tasosartan angiotensin II antagonist. 7. A pharmaceutical combination according to claim 1 or 2, which comprises a pyrimido-pyrimidine and a compound selected from Shi Xiao Pene nifedipine, nitrendipine, Ni: \ 97 \ 97879.DOC 200522965 Sodium Calcium antagonists of nisoldipine, nilvadipine, isradipine, fedidipine or lacidipine. 8. According to claim 1 or 2 A pharmaceutical combination comprising a pyrimido-pyrimidine and a member selected from the group consisting of lovastatin, simvastatin, pravastatin, and fluvastatin Atorvastatin and atorvastatin and cerivastatin in combination. 9 · The pharmaceutical combination according to any one of claims 1 to 8, characterized in that -Pyrimidine is an oral delayed or immediate or parenteral formulation. O: \ 97 \ 97879.DOC