Drug combination comprising (e)-7-[-4-(4-forfinal) -6-isopropyl-2-[-methyl - (methylsulphonyl)amino]- pyrimidine-5 - yl](3r,5s)-3,5-dihydroxide-6-eeewww acid and an inhibitor, inducer or substrate of p450 isoenzyme-3a4

 

(57) Abstract:

The invention relates to the field of medicine and concerns noninteracting combination of drugs, including inhibitor of HMG-CoA reductase, which is an (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]-pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-eeewww acid or its pharmaceutically acceptable salt, and a drug that is an inhibitor, inducer or substrate of 3A4 isoenzyme of cytochrome P450. The combination is used in the treatment of hyperlipidemia in people taking immunosuppressive chemotherapy. The combination does not cause the patient's adverse reactions, defined by the utilization of the medicinal product by the enzyme P450. 2 C. and 13 C.p. f-crystals, 2 tab.

The invention relates to a non-interacting drug combinations inhibitor of 3-hydroxy-3-methylglutaryl (HMG-COA) coenzyme A(HMG-CoA) reductase, which is (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-eeewww acid or its pharmaceutically acceptable salt (hereinafter called “agent”) and medicines, which represents either the inductor, the inhibitor, the treatment of hyperlipidemia in humans, undergoing immunosuppressive chemotherapy. A preferred combination includes agent and vibraty the drug, and the invention relates also to the use of such combinations in the treatment of hyperlipidemia in mammals and to pharmaceutical preparations containing such a combination, which are intended for use in therapy of this kind.

Hypercholesterolemia is a one of the very serious risk factors for atherosclerosis, which is associated with lesions of coronary arteries (including the development of angina, myocardial infarction and mortality), vascular stroke (including cerebrovascular attacks and temporary ischemic stroke and peripheral arterial occlusive disease. There are several types of hypercholesterolemia. The severity of hypercholesterolemia may have an impact on therapy, but in General it is considered that any reduction of cholesterol level in blood plasma leads to reducing the risk of development of these pathologies. Improving diet and increasing physical activity are essential first steps, which are required to continue, even if assigned to drug therapy, despite the in to conduct the drug therapy of hypercholesterolemia. There are special guidelines for the treatment of hypercholesterolemia, for example, the leadership of the American Heart associahion (American Heart Association) (AHA) (Anon, 1988), Updated table of Sheffield (Heart (1998) 80 Supp. 2 S1-S29) and the Recommendations of the group of the European society of cardiology (Pyorala 1994).

Inhibitors of HMG-CoA reductase inhibitors are most often prescribed for the treatment of hypercholesterolemia. In the case of inhibition stage speed control, is cholesterol biosynthesis, and these agents effectively reduce the concentration in the blood plasma atherogenic particles that contain cholesterol, such as low-density lipoprotein (LDL) and lipoprotein very low density lipoproteins (VLDL's). Partial inhibition of cholesterol synthesis in the liver causes positive regulation of the level of LDL receptors-X in the membranes of the liver, which are responsible for the release of blood stream from LDL-X. in Addition, it is believed that reduced the level of cholesterol synthesis in the liver leads to a moderate decrease in the secretion of the liver lonp-X particles. Clinical trials conducted with some inhibitors of HMG-COA reductase, for example, in the framework of the Nordic research programme simvastatin (Scandinavian Simvastatin Survival Study) confirmed that the use of t the systematic destruction of blood vessels. Currently available on the pharmaceutical market of various inhibitors of HMG-COA reductase collectively known as “statins”.

Despite the impressive results of the use of statins in the treatment, in some cases it is possible to achieve just results, significantly below the optimum, especially in the case of treatment of more severe forms of hypercholesterolemia. Such a result may be associated with a reversible increase in levels of liver transaminases at high doses of statins, as well as differences in the effectiveness of different statins. 0.8% of patients in the treatment of low doses of atorvastatin were found clinically significant increase (i.e. more than 3 times the excess of the upper limit of normal (ULN)) level of alanine aminotransferase (ALT) in the serum, and with increasing doses of atorvastatin (LipitorTM(LipitorTM))] specified percentage also increased [according to the European annotations according to the characteristics of the product (APH (SmPC)). In all cases, the observed effect was dose dependent and reversible. In General, cases of ALT elevations are influenced from the point of view limits the possibility of increasing doses of statins, but not limited to further enhance the efficiency of the drug.

Among the side effects, in addition to the General known for statins blagopri is assured with a characteristic increase creatinkinase (QC) index more than 10 times the upper limit of normal (ULN). Specified adverse effects not considered as a dose-related, and, in addition, there are other side effects that are potentially more serious and, therefore, cause more problems. In severe cases, may develop rhabdomyolysis, for life threatening condition, which may in some cases be accompanied by renal insufficiency. The frequency of occurrence of the high rate QC (i.e., more than 10 ULN - 2 cases for at least 1 week without symptoms = myositis in accordance with the criteria FDA) for statins is 3.1% (APH for atorvastatin). In particular, myopathy and rhabdomyolysis associated with statin in combination with gemfibrozil, Niacin, cyclosporine, or erythromycin (Hunninghake H., et al. Current Opinion in Lipidology (1992), 3, 22-28), which are substrates for 3A4 isoenzyme of cytochrome P450. The increased level of side effects in case the combination of a statin with any one drug of the above can be attributed to the interaction of drugs in combination, associated with the metabolism of most statins, which are determined in the same agent isoenzyme 3A4 cyto is on a statin, which is also metabolized under the action of P450-3A4, the probability of occurrence of the considered above side effects increases. The increase in the number of adverse reactions, such as the defeat of muscles is most likely, with increased levels of statins in muscle cells, leading to inhibition processes farnesiana and geranylgeranylation muscle proteins. Elevated levels of statins can be caused by any tool that affects P450-3A4. Therefore, all currently available on the pharmaceutical market latinovich drugs have a warning that in some cases it is not recommended and even contraindicated use them with drugs that are metabolized by P450-3A4.

Almost all drugs are metabolized to some extent in the human body, mainly with the formation of less soluble in the lipid compound that with easier kidneys or liver bile. The liver is the main site where is the metabolism of drugs, and so many of the enzymes involved in the metabolisation of those or other medicinal substances, are contained in high concentration in the endoplasmic re which covers a large class of enzymes, involved in the metabolisation of medications, representing a family of isoenzymes localized in liver microsomes. The metabolism of most widely used medicinal substances are six specific P450 isoenzymes, namely: P450-1A2, 2S9, 2C19, 2D6, 2E1 and 3A4.

The main disadvantage of the currently used “superstation” - atorvastatin is that it is metabolized by enzymes of the class of cytochrome P450, in particular isoenzyme 3A4, which may cause drug interactions with other drugs that are inducers, inhibitors or substrates of the same enzyme P450, which is involved in the metabolisation of atorvastatin. While all statins are the first generation also are metabolized by cytochrome P450. However, the level b of pravastatin low enough that we can consider it as less susceptible to clinically relevant drug interactions. In this regard, despite the lower efficiency of pravastatin when using it in acceptable doses, at the present time for the purpose of reducing hypercholesterolemia, when the likelihood of drug interactions unacceptably high, use this prep is sulfonyl)-amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-eneva acid or its pharmaceutically acceptable salt, calcium salt of which is shown below, hereinafter called the agent is a statin, which belongs to the class of substances which have now become known as “superstation”.

The specified agent disclosed in the application for the European patent, publication No.052 11471 and (Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444), as an inhibitor of HMG-COA reductase, which is the main rate-limiting enzyme in the biosynthesis of cholesterol. Describes the use of an agent for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.

The agent is not metabolized by cytochrome P450-3A4 and in this regard shall not be the potential drug interactions, which is peculiar to modern “superstation”, for example, atorvastatin, or any other currently available for application to the statin.

Based on the foregoing, the authors present as the object of the invention noninteracting drug combination comprising an inhibitor of HMG-CoA reductase, which is an agent, and the medicinal substance, which is an inducer, inhibitor or substrate of cytochrome P450, in particular isoenzyme 3A4.

Another object of the invention is prednaznachennogo for use in combination therapy using drugs, which is an inhibitor, inducer or substrate of P450, in particular, its isoenzyme 3A4.

Another object of the present invention is the use of drugs, representing an inhibitor, inducer or substrate of P450, in particular, its isoenzyme 3A4, to obtain a medicinal product intended for use in combination therapy with the use of an inhibitor of HMG-CoA reductase, which represents the agent.

Another object of the present invention is a pharmaceutical composition comprising the agent, drug, representing an inhibitor, inducer or substrate of P450, in particular, its isoenzyme 3A4, and a pharmaceutically acceptable diluent, carrier or adjuvant.

Another object of the present invention is a pharmaceutical package comprising a first drug, representing the agent, and the second drug representing an inhibitor, inducer or substrate of P450, in particular, its isoenzyme 4.

The term “P450 inducer” refers to a drug that increases the rate at which the enzyme P450, in particular, its isoenzyme 3A4, inactivation of the enzyme P450 or increase the level of transcription of the P450.

The term “P450 inhibitor” refers to a drug that reduces the rate at which the enzyme P450, in particular, its 3A4 isoenzyme that metabolizes the substrate, for example, by reducing the activity of the enzyme P450 or decrease in the level of transcription of the P450.

The term “P450 substrate” refers to a drug which is metabolized by the P450 enzyme, in particular, its isoenzyme 3A4.

The term “non-interacting drug combination” means a combination of medications which does not cause the development of adverse reactions in patients using the combination defined in utilization of the medicinal product by the enzyme P450, in particular, its isoenzyme 3A4. It is believed that in some situations, drug interactions can still occur between two such members of the combination of drugs through a different mechanism that is not associated with the metabolism of drugs, such as impact on the degree of absorption of drugs.

Whether this drug for a P450 enzyme, inhibitor, inducer or substrate, can easily be defined using existing in this region the step of radiolabelled drugs to hepatocytes or microsome assay hepatocytes or selection of a P450 enzyme with the introduction of its in the methods of analytical separation, for example, by HPLC, followed by identification of the formation of the metabolite. In the present description discloses specific procedure for such testing.

In the context of the present description, the term “combination” means that either the agent and drug combinations are entered together in the same pharmaceutical dosage forms, or the agent and the drug are entered separately. In the case of separate introduction of the components of the combination specified introduction can be carried out either simultaneously or sequentially.

It was discovered that the agent is not metabolized to a significant extent isoenzymes 1A2, 2S9, 2C19, 2D6 and 3A4 main cytochrome P450. And this was another aspect of the invention.

Preferred noninteracting combination according to the present invention include those in which the agent is combined with medicine that is involved in the process of lowering cholesterol levels and is also an inhibitor, inducer or substrate of P450-3A4. Examples include fibrates, such as bezafibrat, clofibrate, ciprofibrate, fenofibrate and gemfibrozil (preferably fenofibrate), Niacin. The particular VA is performance communications noninteracting combination according to the present invention include those in which the agent is combined with medicine that is used in the treatment of cardiovascular conditions and is also an inhibitor, inducer or substrate of P450-3A4. Examples include digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil and warfarin.

Preferred noninteracting combination according to the present invention include those in which the agent is combined with cyclosporine and/or tacrolimus (FK506) and could therefore be used in the treatment of patients with elevated cholesterol levels, and who are preparing to transplant or have been subjected to such operations in the recent past. Specific options for implementing this aspect of the invention described below.

Preferred patients, which may be a combination according to the present invention, include those who suffer from myopathy or rhabdomyoma, or those who had a history of myopathy or rhabdomyolysis during treatment with an inhibitor of HMG-COA reductase, which is metabolized by P450 3A4, such as atorvastatin, simvastatin and lovastatin.

Other aspects of the present invention include the above objects in use cases is that one day, other specific ranges of dosages, which are also independent aspects of the present invention include (as appropriate for use) the following ranges: from 10 to 80 mg per day, from 10 to 60 mg per day, from 10 to 40 mg per day, from 5 to 40 mg per day, from 5 to 20 mg per day, from 10 to 20 mg per day, from 20 to 60 mg per day, from 20 to 40 mg daily and 40 to 60 mg per day. Specific dosages are 5, 10, 20, 40 and 80 mg / day. Especially good for starting treatment in these methods, the dose of the agent is from 5 to 10 mg per day, and in particular the dose of 10 mg per day.

Substrates for P450-3A4 include: acetaminophen, Aldrin, Atlantans, amiodarone, astemizole, benzphetamine, budenoside, carbamazepine, cyclophosphamide, cyclosporine, Dapsone, digitoxin, diltiazem, diazepam, erythromycin, etoposide, flutamide, hydroxyarginine, ifosfamide, imipramine, lanzoprazol, lidocaine, locatedin, losartan, lovastatin, midazolam, nifedipine, omeprazole, quinidine, rapamycin, retinoic acid, steroids, tacrolimus, teniposide, theophylline, toremifene, triazolam, troleandomycin, verapamil, warfarin, zatosetron and zonisamide.

Inhibitors of P450-3A4 include clotrimazole, levonorgestrel, gestodene, Itraconazole, ketoconazole, is-3A4 include: carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, sulfadimidine, sulfinpirazon and triacetoneamine.

Examples of other inducers, inhibitors or substrates of P450 include those compounds listed in Drug Metabolism Reviews (1997) Vol.29, Issue 1+2, pp.413-580; Rendic, S. and Di Carlo, F. J., "Human cytochrome P450 enzymes. A status report summarising their reactions, substrates, inducers and inhibitors").

Depending on the desired degree of cholesterol reduction may be injected dose of the agent in the range from 5 to 80 mg / day and in any number of different standard dosage forms. The dosage of the medicinal component, which is an inducer, inhibitor or substrate P45-3A4, consistent with those recommended for each of the medications are available in the pharmaceutical market. While any person with an average level of knowledge in this field are able to successfully combine the dose of the agent with the drug, which is an inducer, inhibitor or substrate P45-3A4, because there is no interaction, defined P45-3A4, and there is no need to make any adjustments.

The range of dosages and the above doses are independent objects of the present invention.

Predil)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-enoeou acid (shown in Fig.1).

Experimental part

The following experiment is conducted to determine the in vitro path metabolic transformation [14S]-labeled agent in human hepatocytes, as well as to identify specific P450 isoenzymes involved in the metabolism of [14S]-labeled agent, if such takes place, and amenable to study. This experiment involves the study of the effect of selected chemical inhibitors of P450 (see table 1) on the metabolism of [14S]-labeled agent.

Experimental methods

(1) the Metabolism of [14S]-labeled agent in human hepatocytes

[14S]-labeled agent (1 μm or higher concentrations, if required by the corresponding sensitivity analysis method) incubated with hepatocytes in culture obtained from two donors of human organs. Incubation of the cultures stopped by ethanol at time 0 and after 6, 24 and 48 hours of incubation and stored at about-20C until used in the analytical procedure. Metabolic competence of hepatocytes confirmed at certain time points of incubation when determining their ability to metabolize [14S]-ethoxycoumarin (/P>After incubation of [14S]-ZD4522 with hepatocytes determine metabolic profiles using the method of high performance liquid chromatography (HPLC). The ability of hepatocytes to metabolize [14S]-ethoxycoumarin confirmed by using HPLC method.

The results of the assessment

The obtained results were evaluated by the following items:

(1) Evaluate metabolize whether applied human hepatocytes [14S]-labeled agent.

(2) Quantify the amount of each metabolite formed.

(2) the Enzymes involved in the metabolism of the agent.

[14S]-labeled agent (at the appropriate concentration) is incubated with microsomes from human liver in the absence and in the presence of selected P450 inhibitors (see tab.1). Similarly, they also incubation of [14S]-labeled agent with individual P450 isoenzymes produced by heterologous expression. The incubation is stopped by the addition of an appropriate organic solvent. Using the method of HPLC obtain metabolic profiles inkubiruemykh connections.

Evaluation of the received data

The data floor is ery metabolism of [14S]-labeled agent.

(b) Compare the ability of selective P450 inhibitors to reduce the metabolism of [14S]-labeled agent to determine isoenzyme(s) involved(them) in the metabolism of [14S]-labeled agent.

Assess the ability of the individual expressed isoforms of P450 metabolizing [14S]-labeled agent for the same purpose: to determine isoenzyme(s) P450 involved(s) in the metabolism of [14S]-labeled agent.

(C) These data obtained in vitro, can be used for the purpose of prediction of the pharmacokinetics of the agent in the population and the likely effect on the pharmacokinetics of the agent at its joint application with known inhibitors/inducers of P450.

It was shown that the agent is not exposed to significant metabolize whole hepatocytes, and that it is inhibited by sulfaphenazole and omeprazole.

The application for the treatment of hyperlipidemia and associated conditions in patients after transplantation who receive immunosuppressive therapy

It is known that the two usually used to weakening of the human immune system drug cyclosporine and tacrolimus (formerly known as FK506) are metabolized citehr abolism any other medicines, which is metabolized by the P450-3A4. Accordingly, in cases where the prescribed immunosuppressive therapy, such as with the use of cyclosporine and tacrolimus (especially cyclosporine), the physician should exercise caution in respect of any other treatments that may be assigned to the patient in combination with the specified(and) above vehicle(s).

Often immunosuppressive therapy is used before transplantation in humans, during this operation, or after it. In particular, in the case of heart transplant physician may also decide to carry out patient therapy with statins to reduce the risk of future coronary heart disease, vascular stroke, peripheral arterial occlusive disease or peripheral vascular disease, especially in patients with elevated cholesterol levels or in patients with normolipidemia, but who have other risk factors associated with heart disease. In particular, in the special group of patients (patients with human transplants) patients have a high risk of atherosclerosis in transplanted organs in a threatening manner and in a short period of time, partially associated with surgical povrezhdeniem immunosuppressive therapy. Hyperlipidemia is a common condition after transplantation, even in patients who have not had hyperlipidemia before transplantation and the incidence of it is 60-80% of the number of recipients.

It is known that some immunosuppressive drugs, such as steroids, cyclosporine and tacrolimus, raise the level of cholesterol in the blood of patients (Wierzbicki AS (1999) IJCP 53 (1) 54-59). In addition, cyclosporine and tacrolimus may increase the levels of fibrinogen and lipoproteins in a patient, which contributes to the progression of atherosclerosis in patients after transplantation (Hohaye H., Clin. Transplant (1997) 11, 225-230 and Hilbrands LB, J. Am. Soc. Nephrol (1995) 5, 2073-2081). The unusually fast-paced atherosclerosis occurs in approximately 20% of patients after transplantation of the heart through 1 year after surgery and at 40-65% in 5 years (G. Chang et al. American Heart Journal(1998), 136(2), 329-334). There is evidence that such rapidly developing atherosclerosis causes coronary heart disease (CHD) 1-18% of patients 1 year after transplantation in heart and in 20-50% of patients after 3 years (Erdoes LS. J. Vasc. Surg. (1995) 22, 434-440). It was shown that lovastatin, pravastatin and simvastatin lower cholesterol in patients after operations, transplantati the patients 1 year after transplantation and significantly reduced the incidence of rejection hemodynamic body. Due to the low incidence of serious drug interactions when conducting immunosuppressive therapy with pravastatin, this tool is a drug of first choice in the treatment of patients after transplantation. However, as noted above, pravastatin did not reduce the level of lipid/cholesterol to the same extent as, for example, atorvastatin.

Found that this agent is extremely effective in the treatment of hypercholesterolemia in patients after transplantation, and that the specified agent is not metabolized by the 3A4 isoenzyme of cytochrome P450. Thus, it was shown using the agent in a clinical trial that the agent may, at normal doses be administered to patients when conducting immunosuppressive therapy without the development of clinically significant adverse effects associated with the simultaneous use of an agent and immunosuppressive(s) of drug(s) and, in addition, it achieves a higher degree of cholesterol reduction than it had been previously, for example, when using pravastatin.

In this regard, the authors suggest, as a first object of the invention, a method of conducting a safe therapy, excluding drugs is himioteramii, includes introduction to the patient the specified agent. A specific group of patients undergoing immunosuppressive treatment and who may benefit from treatment according to the present invention, include those who:

1) suffering from primary (type IIA) hypercholesterolemia (LDL-L135 and TG<200);

3) refer to patients with established CHD or other disease with atherosclerotic lesion, such as peripheral vascular disease (BPS), vascular shock or occlusion of peripheral arteries;

4) patients with a high risk of developing coronary heart disease or another disease with atherosclerotic lesion, such as described in the present description, in connection with the combination of risk factors. The term “high risk” is defined in Recommendation of Second Joint Task Force of European and other Societies on Coronary Prevention, Wood, D. et al. European Heart Journal, Atherosclerosis and Journal of Hypertension, 1998 as the absolute risk of developing CHD, constituting 20% in 10 years or more than 20% when extrapolated to age 60 years. Has the patient or does not have a high risk can be identified by the maps accompanying the above recommendations, which are included in the present opiskelijalle pressure 180 mm Od or higher and total cholesterol concentration in blood plasma 7 mmol/l or higher, will be classified as a patient with a high degree of risk. Similarly can be used and other guidelines containing recommendations for reducing risk factors;

a) JAMA, June 16, 1993, Vol. 629, No.23, pages 3015-3023 - "Summary of the NCEP Adult Treatment Panel II Report" - in particular Fig.1 pages 3018-3019, which is incorporated into this description by reference.

b) Post Graduate Medical Journal, 1993, 69 (811): 359-369 - "Management of hyperlipidaemia: guidelines of the British Hyperlipidaemic Association" - in particular, table V and table VI, which is included in the present description by reference.

C) Heart, 1998, 80 Supplement 2: S1-S29 - "Joint British recommendations on prevention of coronary heart disease in clinical practice" - in particular Fig.1 pages S4-S5, which is incorporated into this description by reference.

g) The Lancet, 1995, December 2, Vol 346, 1467-1471 - Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease" - in particular the table on page 1468, which is incorporated into this description by reference.

5) refer to patients with diabetes type I and II;

6) refer to patients who are preparing for heart transplants have been found transplantation.

Statin therapy is conducted with the aim of achieving the patient receiving immunosuppressive hee is of flight data (reported) (intravascular ultrasonography);

2) reduce LDL-X at least 30, 40 or 50%;

3) maintain or increase the level of HDL-X at least 5, 10 or 15%;

4) achieve change any of the above option is better than the use of pravastatin in the same dose and for the same period of time.

As another object of the invention, which is defined by the fact that the agent is not metabolized to a significant extent by P450 isoenzymes, is considered more secure than was the case previously, the introduction of the patients in the course of immunosuppressive therapy combinations vibrate and agent. As noted above, the joint introduction of fibrate and statin previously was associated with a high incidence of rhabdomyoma and myopathy. In addition, fibrate drugs interact with cyclosporine due to the fact that both of these tools are metabolized by the same P450 isoenzyme. In this regard, the use of statin and fibrates of the drug in combination with immunosuppressive therapy was contraindicated because of risk of serious drug interactions (Hunnighake 1992, Wanner C. Kidney Int. (1995) 52 (suppl.), S60-S62; and S. Katznelson Contributions Nephrol. (1997) 120, 97-104). However, if it were possible, it would be desirable and statins, in this regard, their combined pharmacological action is complementary from the point of view of reducing the effect and, in addition, decreases the likelihood of developing coronary heart disease and other above mentioned diseases associated with atherosclerotic plaques. On this basis, the possibility of combining agent, which is not metabolized by the P450-3A4, with vibrator and immunosuppressive therapy can be seen as an additional opportunity to reduce further the level of cholesterol in these patients than it had been before, and more secure than it could be done previously with the introduction of statin, fibrate and immunosuppressive tools.

It is believed that fibrate drugs act through peroxisomal receptor - activator of proliferation (PPAR-) and affect gene activation of many genes involved in the formation of atheroma. In patients taking fibrate drugs, there is a more balanced distribution of padmakshi LDL (decrease lonp and increasing HDL), low LDL and triglyceride levels as well as, as well as some improvement associated with normalization of insulin sensitivity. Examples fibrotic funds include bezafibrat, ciprofibrate, fenofibrate and gemfibrozil.

Diseases and conditions may be prescribed immunosuppressive therapy include, in addition to the above organ transplantation, autoimmune diseases, including rheumatic disorders such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and other autoimmune disorders, such as idiopathic thrombocytic purpura, autoimmune hemolytic anemia, and acute glomerulonephritis.

The agent may be injected at the same time as immunosuppressive chemotherapy, or if not at the same time, then after a short period of time after immunosuppressive therapy, for example, on the same day, for 6, 3, 2 or 1 hour.

The agent can be administered in accordance with the desired effect of reducing the level of cholesterol in the range from 5 to 80 mg / day in any number of standard dosage forms, preferably in the form of a single injection per day. The ideal is a single daily dose of 10, 20 and 40 mg, the Preferred doses are 20 and 40 mg per day, taken in the form of the receive those funds, which are metabolized by the liver enzymes such as P450-3A4, and, most likely, will not cause drug interactions with the agent. Examples of such funds include the above cyclosporine and tacrolimus, and corticosteroids, which are also metabolized in the liver. Examples of corticosteroids include prednisone (especially widely used in the case of organ transplantation). Preferably at least one immunosuppressive funds if they use more than one, is a cyclosporine or tacrolimus, preferably cyclosporine.

Example

Following non-limiting example refers to a clinical trial and are given to illustrate embodiments of the above aspect of the invention.

Plan tests

The real test (see tab.2) is a multicenter, randomized, double-blind study with the inclusion of a parallel group. During the period of time from 1 to 4 weeks after surgery, patients are distributed randomly into groups receiving either agent or pravastatin for 52 weeks. Patients begin the of up to a dose of 20 mg. By the time 4 of the visit and subsequent visits, the researcher has the right to increase the dose of each medication 40 mg during the period of optional titration. Patients who titrated dose of 40 mg may be transferred at the discretion of the researcher again at a dose of 20 mg in the reverse titration.

Plan tests

* In the case of patients who have to point 4 of the visit tolerated dose of 20 mg agent or pravastatin, at the discretion of the researcher, this dose was titrated up to 40 mg

** The randomization should be performed within 4 weeks after transplantation of the heart, and patients should not receive surgery or any other treatment aimed at reducing the level of lipids.

Inclusion criteria of patients in the test:

(1) underwent heart transplantation is not more than 4 weeks prior to randomization;

(2) have a concentration of TG on an empty stomach <4.52 Mall/l (400 mg/DL)

Exclusion criteria patients from trials

Any one of the criteria from the above list is sufficient to exclude the patient from the test:

(1) the use of any other drugs that reduce cholesterol, or the product is esni serious consequences after taking other inhibitors of HMG-CoA reductase or hypersensitivity reactions to them;

(3) pregnant women, women breast feeding, or women who may potentially be pregnant, if they are not used means of chemical or mechanical contraception or have a positive result pregnancy test (analysis of human chorionic gonadotropin (HCG, -HCG);

(4) are also excluded patients who, within 5 years prior to randomization, had a history of diabetic ketoacidosis;

(5) uncompensated hypothyroidism, defined by exceeding the ULN thyroid-stimulating hormone (TSH) is more than 1.5 times the time of the visit 2, or patients who within the preceding three months were subjected to substitution therapy with thyroid hormone;

(6) use of other medications that disclosed in more detail below, with the exception of immunosuppressants and diazepam;

(7) abuse in this period of alcohol or drugs;

(8) liver disease or dysfunction in the acute phase, which is determined by the rise time 2 visit 1.5 times ULN following liver tests: ALT, ACT or bilirubin level;

(9) over time 2 visit > 3 times QC syvorotki history of cancer and who, according to the researcher, have more than minimal risk of relapse;

(12) participation in other programs drug trials in less than 4 weeks prior to the allocation of patients to groups in this study;

(13) patients, distributed in groups in a double-blind test, but then got out, again not included;

(14) a serious or unstable medical or psychological condition that, in the opinion of the investigator, will adversely impact the degree of safety or successful participation of the patient in the test;

(15) patients receiving cycle hormone replacement therapy (HT), cycle oral contraceptive therapy (PCT), injections of progesterone depot, or patients who began a course of acyclic GT or PCT within the last 3 months.

The equation of Friedewald

LDL-X is calculated using the equation of Friedewald as follows:

In SI units (mmol/l)

LDL-X=Total cholesterol - [HDL-X+Triglycerides/2,2]

In other units are not SI units (mg/DL)

LDL-X=Total cholesterol - [HDL-X+Triglycerides/5]

The absence of coronary artery disease and BPS and 1 or

no risk factors < 160 mg/DL

The absence of coronary artery disease and BPS and 2 or

more risk factors < 130 mg/DL

Clinically significant coronary artery disease and BPS 100 mg/DL

aThe second report of the expert Council on the identification, evaluation and treatment of high cholesterol in adults. Bethesda (MD): national institutes of health, national Institute of heart and lung (National Institutes of Health, National Heart and Lung Institute, 1993, Sep. Report No.93-3095).

NCEP - national training program on reducing the level of cholesterol National Cholesterol Education Program).

The application for the treatment of hyperlipidemia and associated States, with a combination of agent and fibranova drug or Niacin

Myopathy and rhabdomyolysis can occur when using a statin in combination with gemfibrozil, cyclosporine, or erythromycin (HMG CoA reductase inhibitors, Hunninghake, Current Opinion in Lipidology (1992) 3, 22-28), which are substrates of P450 - 3A4. In addition, reports show increased levels of side effects of the introduction fibrate drugs with concomitant statin therapy, such as the syndrome of the type of myositis-flu, which occasionally occurs in patients receiving gemfibrizol contraindicated, as written on the packaging of all commercially available statins and in the United States, and Europe. However, despite the possibility of serious drug interactions, doctors still prescribe combination therapy with statin and fibrates drug patients with complicated hypercholesterolemia, such as patients with familial combined hyperlipidemia, when the risk of serious drug interactions are outweighed by the benefits achieved with this combination therapy. In case of assignment of combination therapy with statin and fibrates drug in patients on a regular basis, typically every 6 weeks to monitor the QC to achieve stable results. When the treatment is stopped if you develop symptoms of muscular lesions in combination with increased activity of QC. However, as indicated on the packaging of the drug LipitorTM(LipitorTM), “there is no guarantee that such control [level QC] will prevent the development of severe myopathy".

The authors found that this agent is extremely effective in the treatment of patients with mixed hyperlipidemia and hyperglyceridemia when combined fibranova drug and agent, and that yasenyukom test, that the specified agent may receive doses be administered to patients who are also taking vibraty the drug, without the development of clinically significant adverse effects associated with the simultaneous use of an agent and fibranova of the drug. In addition, when using agent and fibranova of the drug achieved a higher degree of reduction of lipid levels than was possible previously. The specified combination of the most useful in the case of mixed hyperlipidemia, when there is an increased level and LDL, and HDL, and triglycerides.

Based on the foregoing, the authors suggest, as a first object of the invention, a method of conducting a safe combination therapy, excluding drug interactions, reduction of lipid levels in mammals, including humans, preferably in a patient with mixed form of hyperlipidemia and hypertriglyceridemia, including the introduction of the patient specified agent and fibranova drug or Niacin.

In the context of the present description, the term “combination” or “combination” means that either (1) the agent and vibraty the preparation of this combination are entered together in a single pharmaceutical composition, or (2) the agent and vibraty drug veneno, or sequentially.

In the context of the present description, the term “vibraty drug” encompasses a class of drugs that are grouped based on the structure/activity fibrin acid, such drugs include the following commercially available products: bezafibrat, clofibrate, ciprofibrate, fenofibrate and gemfibrozil, preferably fenofibrate.

A preferred group of patients who should enter the drug combination according to the invention, include those who are already suffering from myopathy or rhabdomyolysis after treatment with statin and/or fibrates drug which is metabolized by the P450-3A4.

Specific groups of patients who may benefit from treatment according to the present invention, include those who:

1) suffer from a combination (type IIb) hypercholesterolemia (typically LDL-CH ml/DL and TG) (mg/DL);

2) suffer from family (type IV and V) hypercholesterolemia;

3) treat patients with hypercholesterolemia, developing in connection with such conditions as:

a) diabetes (type I or type II);

b) nephrotic syndrome;

b) uremia;

d) hyperthyroidism and

5) refer to patients with a high risk of developing coronary heart disease or another disease with atherosclerotic lesion, such as described above in the present description, in connection with the combination of risk factors. The term “high risk” is defined in ("Recommendation of the Second Joint Task Force of European and other Societies on Coronary Prevention, Wood, D. et al. European Heart Journal, Atherosclerosis and Journal of Hypertension, 1998 as the absolute risk of developing CHD, constituting 20% in 10 years or more than 20% when extrapolated to age 60 years. Has the patient or does not have a high risk can be identified by the maps accompanying the above recommendations, which are included in the present description by reference. For example, a male patient aged 40 who smokes and has a systolic pressure of 180 mm Od or higher and total cholesterol concentration in blood plasma 7 mmol/l or above, will be classified as a patient with a high degree of risk. Similarly can be used and other guidelines containing recommendations for reducing risk factors;

a) JAMA, June 16, 1993, Vol. 629, No.23, pages 3015-3023 - "Summary of the NCEP Adult Treatment Panel II Report" - in particular Fig.1 in the article): 359-369 - "Management of hyperlipidaemia: guidelines of the British Hyperlipidaemic Association" - in particular, table V and table VI, which is included in the present description by reference.

C) Heart, 1998, 80 Supplement 2: S1-S29 - "Joint British recommendations on prevention of coronary heart disease in clinical practice" - in particular Fig.1 pages S4-S5, which is incorporated into this description by reference.

g) The Lancet, 1995, December 2, Vol 346, 1467-1471 - Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease" - in particular the table on page 1468, which is incorporated into this description by reference.

Latinova therapy is conducted with the aim of achieving the patient receiving vibraty drug or Niacin:

1) reduce LDL-X at least 30, 40, 50, 60, 70 or 80%;

2) maintain or increase the level of HDL-X at least 5, 10 or 15%;

3) reduction of triglycerides by at least 10, 20, 30 or 40%.

The combination of fibrate or Niacin and agent can be administered in separate dosage forms, which the patient takes, either simultaneously or sequentially, alternatively, it can be combined dosage form. The combination of fibrate and the agent may provide additive or synergistic effect on snii patients.

In addition, there may be used a combination of Niacin and agent, either as a separate dosage forms, the patient may be taken simultaneously or sequentially or as a combined dosage forms. And the combination of fibrate and agent may also have an additive or synergistic effect on the reduction of LDL-X, for maintaining or increasing the content of HDL-X or to reduce the level of triglycerides in the blood of patients.

The definition of the injected dose of the agent is the responsibility of the attending physician, which makes it based on the severity of the disease, age, weight and sex of the patient. This, however, there is evidence of typical doses that range from 5 to 80 mg / day when administered orally, preferably as a single daily administration of the drug in tablet form.

The magnitude of the injected dose fibranova drug or Niacin also selects the attending physician, taking into account all of the factors mentioned above, as well as specific tools.

In the case of clofibrate (such as (Atromid-S®)) typical dose is a daily dose of 20-30 mg/kg body weight in the form of 2 or 3 separate doses taken orally after a meal.

If bezafibrate in the evening or in the morning.

If fenofibrate (such as Lipantil®) typical dosage is a single dose of 200 mg or triple dose of 62 mg, taken daily with a meal.

In the case of gemfibrozil (such as Lopid®) typical dosage is an oral dose of 600 mg, taken twice a day.

If ciprofibrate (such as Modalim®) typical dosage is a single oral dose of 100 mg.

In the case of Niacin (Niaspan®), composition with slow release, which is the preferred characteristic, the dose is 500 mg, which is taken daily in 1-4 reception, preferably two or three times a day.

Preferred vibratrim drug is fenofibrate.

Preferably the agent is administered to a patient receiving Niacin daily dose of from 10 mg to 40 mg

A specific object of the present invention illustrated by the following non-limiting example.

Objectives

The main objective

The main purpose of testing is to assess the joint effect of the introduction of the agent and fenofibrate on the pharmacokinetics and agent, and fenofibrate.

Secondary CEIA was constant clinical supervision.

Plan tests

The trial is a randomized, uncontrolled, with 3-s ' intersection and an open-label study conducted in a single center.

Volunteers receive in the distribution in random order 3 courses of treatment:

10 mg of the agent once a day for 7 days;

- fenofibrate (LipantilTM(LipantilTM)) 3 times on 67 mg daily for 7 days;

agent (10 mg once daily) and fenofibrate (LipantilTM(LipantilTM) 67 mg, daily), taken in combination for 7 days.

Between each treatment period is a break of at least 3 weeks (21 days).

Inclusion criteria

For inclusion in the test volunteers must meet the following criteria:

- men aged from 18 to 65 years;

- normal values of the clinical examination, including medical history, the results of resting ECG and 24-hour ambulatory ECG (if such a study was not conducted within the last 12 months)

- negative screening results for surface antigen of hepatitis b virus and antibodies to hepatitis C and normal indicators PR desirable weight (Metropolitan Height and Weight Tables).

Exclusion criteria of the trials

Volunteers should be excluded from the study if at least one of the following criteria:

- the use of any therapies, including abuse of various drugs;

- welcome another new chemicals within 4 months prior to testing (new feature is defined as a connection that has not been submitted for resolution to use on the market);

- participation in another trial within 3 months prior to this test, with the exception of non-invasive tests, which were not used the medication;

- any acute illness within 2 weeks prior to the test;

any clinically significant abnormalities in clinical chemical analysis, analysis of blood or urine. In addition, the following parameters should not exceed the upper limit of normal: total bilirubin, ALT, AST, KK.

risk (in the understanding of the researcher) migrate through the blood or other body fluids, agents that cause acquired immunodeficiency syndrome (AIDS), hepatitis b or hepatitis C;

- certain or suspected presence of an individual who stennie means, it has a structure similar to that agent or related statins or fibrates or related fibrate drugs;

- a history of or currently, diseases of the gastrointestinal tract, liver, gallbladder or kidney disease or other conditions that interfere with the absorption, distribution, metabolism or excretion of drugs;

- a history of the syndrome Gilbert;

- if participation in the test will require the volunteer return more than 1350 ml of blood within 12 months before the end of the test;

- excessive alcohol consumption, defined as the maximum intake per week over 28 units (1 unit equals half a pint of beer or a measure of spirits);

- admission for treatment in the preceding 3 months of any drug, which is characterized proven potential hepatotoxicity (e.g., halothane gas);

clinical opinion of the investigator or treating physician volunteers that volunteer should not participate in the test.

Restrictions on volunteers

You want volunteers:

- refrain from taking any means (including medications the morning dose of fenofibrate in each test period, if this is not agreed by the researcher;

- during the night (from midnight) before each day of testing did not take night of food and eat only a light Breakfast on arrival on test 1 to day 7 in each of the study periods;

- refrain from driving a car, riding a bike, use machinery (drills, grinding mechanisms, sharps and other) within 24 hours after the first dose on day 7 tests in each period;

to stay up to 24 hours after the first dose on day 7 tests in each period;

- refrain from Smoking, consumption of grapefruit, grapefruit juice, beverage or food products containing licorice or caffeine (such as coffee, tea, cocoa, chocolate and Cola) from midnight before 1 day of testing before the expiration of 72 hours after the last dose of the agent or morning dose of fenofibrate in each of the test periods;

- to refrain from taking alcoholic beverages within 96 hours to 1 day trial and before the expiration of 72 hours after the last dose of the agent or morning dose of fenofibrate in each of the test periods;

- to refrain from physical activity within 96 h is as in each of the test periods;

- refrain from potentially hazardous activities in the period from the moment of receiving the first dose of the agent or fenofibrate to a medical examination after the test;

- refrain from donating blood throughout the trial and for 3 months after the last dose under test.

Ready forms of drugs and their storage

Dosage and introduction

Capsule agent or fenofibrate volunteer takes orally with 200 ml of purified water in a sitting position, not slouching.

1 through day 7 in each of the test periods, the volunteers receive one of the following treatments:

110 mg capsule agent between the 830and 930;

- 367 mg capsules fenofibrate:

the 1st capsule take between 830and 930food;

2nd capsule take between 1630and 1730food;

the 3rd capsule take between 2230and the 2330food;

110 mg capsule agent and h mg capsules fenofibrate:

the 1st capsule agent and the 1st capsule fenofibrate take at a time between 830and 930;

2nd capsule fenofibrate take in PI 2330food.

1 through 6 day of each test period the volunteers come into the office and immediately leave after administration of doses of the agent, fenofibrate or combination agent/fenofibrate, whereas in the 7 day trial volunteers stay in the er for 24 hours.

In those test periods when volunteers take fenofibrate for distribution to the appropriate group randomly, they take two doses of fenofibrate home. Volunteers give 1 portion of fenofibrate for adoption, as described above. In addition, volunteers receive timer to set the desired time, in order to guarantee the drug in the desired period of time, as well as a diary to mark the acceptance of the dose. In the case when the volunteers take and agent, and fenofibrate, to the appropriate form of documentation must be attached removable label. The researcher must be confident that all volunteers are properly taking prescribed drugs.

Clinical and laboratory evaluations

The primary point to evaluate

The following parameters are measured as a basic estimate of the positions of:

AUC (0-24) and (Cmaxagent in the presence and in the absence of Venofer is to evaluate

The following parameters are measured as a secondary estimate of the positions of:

tmax, tl/2Cminagent in the presence and in the absence of fenofibrate;

tmax, t1/2Cminfor fenofibrate in the presence and in the absence of the agent, evaluation of security settings: presence of symptoms, blood pressure and heart rate, ECG data, results of clinical chemical analysis, blood analysis and urine analysis.

Pharmaceutical compositions

The following example illustrates, without limiting in any way possible pharmaceutical dosage forms that can be used within the present invention:

The mg capsule

Agent 5,0

Lactose 42,5

Corn starch 20,0

Microcrystalline cellulose 32,0

Pre gelatinizing

starch 3,3

Hydrotalcite 1,1

Magnesium stearate 1,1

Capsules containing 1, 2, 5 or 10 mg of the agent, can be obtained in a similar way using larger or smaller amounts of lactose, respectively, while preserving the overall weight of the form 105 mg.

2. Noninteracting drug combination under item 1, in which the second drug is an inhibitor or inducer of 3A4 isoenzyme of cytochrome P450.

3. Noninteracting drug combination under item 1 or 2, in which these drugs are administered together or each drug administered sequentially.

4. Noninteracting drug combination according to any one of paragraphs.1-3, in which the second drug used to lower cholesterol and it is an inducer, inhibitor or substrate of P450 isoenzyme-3A4.

5. Noninteracting drug combination in p. 4, in which the second drug is selected from bezafibrat, clofibrate, fenofibrate, gemfibrozil and Niacin.

6. Noninteracting drug combination under item 5, in which the second drug is fenofibrate.

7. Noninteracting drug combination according to any one of paragraphs.1-3, in which the second drug used to treat heart with. vzaimodeystviya drug combination under item 7, in which the second drug is selected from digitoxin, diltiazem, losartan, nifedipine, quinidine, verapamil and warfarin.

9. Noninteracting drug combination according to any one of paragraphs.1-3, in which the second drug used for immunosuppressive therapy and it is an inducer, inhibitor or substrate of P450 isoenzyme-3A4.

10. Noninteracting drug combination under item 9, in which the second drug is selected from cyclosporine, tacrolimus and corticosteroid.

11. Noninteracting drug combination according to any one of paragraphs.1-10, in which (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-eeewww acid or its pharmaceutically acceptable salt is used in a dose of 5, 10, 20, 40 or 80 mg once daily.

12. Pharmaceutical composition comprising (E)-7-[4-(4-forfinal)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidine-5-yl](3R,5S)-3,5-dihydroxide-6-eeewww acid or its pharmaceutically acceptable salt, pharmaceutical product, which is an inducer, inhibitor or substrate of P450 isoenzyme-3A4, and t is s on p. 12, in which the second drug is a substrate of P450 isoenzyme-3A4 selected from acetaminophen, Aldrin, AtlantNIRO, amiodarone, astemizole, benzphetamine, budenoside, carbamazepine, cyclophosphamide, cyclosporine, Dapsone, digitoxin, diltiazem, diazepam, erythromycin, etoposide, flutamide, hydroxyarginine, ifosfamide, imipramine, lansoprazole, lidocaine, lofatadine, losartan, lovastatin, midazolam, nifedipine, omeprazole, quinidine, rapamycin, retinoic acid, steroids, tacrolimus, teniposide, theophylline, toremifene, triazolam, troleandomycin, verapamil, warfarin, zatosetron and zonisamide.

14. The pharmaceutical composition according to p. 12, in which the second drug is an inhibitor of the isoenzyme P450-3A4 and is selected from clotrimazole, ethinyl estradiol, gestodene, Itraconazole, ketoconazole, miconazole, diltiazem, naringenin, erythromycin, cyclosporine and triacetoneamine.

15. The pharmaceutical composition according to p. 12, in which the second drug is an inducer of isoenzyme P450-3A4 selected from carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, sulfadimidine, sulfine

 

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