JP2020143037A - Therapeutic pharmaceutical composition for heart failure associated with diabetes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine effective for treating heart failure associated with diabetes. The present invention relates to a pharmaceutical composition containing a xanthine oxidase inhibitor for the prevention and / or treatment of heart failure associated with diabetes. According to the present invention, it becomes possible to prevent and / or treat heart failure associated with diabetes, particularly HFpEF, which has been difficult to improve the prognosis with conventional therapeutic agents. [Selection diagram] Fig. 1

Description

The present invention relates to a pharmaceutical composition containing a xanthine oxidase inhibitor for the prevention and / or treatment of heart failure associated with diabetes.

The number of cases of heart failure with diabetes is increasing, and the rate of heart failure with diabetes in Japan is said to reach 30% (JCARE-CARD, Non-Patent Document 1). In particular, diabetes is a major promoter of heart failure with preserved Ejection Fraction (HFpEF), which presents a left ventricular ejection fraction of ≥50%, and the number of diabetic patients with HFpEF. Is steadily increasing.

Basic treatment with ACE inhibitors, angiotensin II receptor blockers, β-blockers, etc. for heart failure with reduced left ventricular ejection fraction (heart failure with reduced Ejection Fraction, HFrEF) There are drugs, but no drug has been clearly shown to be effective for HFpEF. Therefore, treatment for HFpEF associated with diabetes is based on treatment for diabetes and load-relieving therapy aimed at reducing the symptoms of heart failure.

The complication of heart failure in diabetes has a significantly poor prognosis and causes great social loss in both medical and economic terms. Therefore, the development of a drug effective for the prevention or treatment of heart failure associated with diabetes, particularly HFpEF, is awaited.

In recent years, research on the effectiveness of uric acid production inhibitors for heart failure has been advanced in heart failure patients with high serum uric acid levels. Hyperuricemia is a common comorbidity in heart failure patients, suggesting a link between serum uric acid levels and prognosis in heart failure patients.

Non-Patent Document 2 reports that administration of the uric acid production inhibitor allopurinol to patients with high uric acid levels in heart failure reduced the mortality rate due to heart failure. However, in the subsequent EXACT-HF trial (Non-Patent Document 3), although allopurinol lowered the uric acid level, no improvement in prognosis was observed, and its effectiveness for heart failure has been denied.

Tsutsui et al., Circ. J. 2006; 70: 1617-1623. Gotsman et al., J. Cardiac Fail, 2012; 18: 694-701. Givertz et al., Circulation, 2015; 131: 1763-1771.

An object of the present invention is to provide a drug effective for the treatment of heart failure associated with diabetes.

The present inventors have increased myocardial xanthine oxidase activity in a heart failure model with diabetes as compared with heart failure without diabetes, and administer a xanthine oxidase inhibitor to a heart failure model with diabetes. We found that the function was improved, and completed the following invention.

(1) A pharmaceutical composition containing a xanthine oxidase inhibitor for the prevention and / or treatment of heart failure associated with diabetes.
(2) The pharmaceutical composition according to (1), wherein the heart failure associated with diabetes is HFpEF.
(3) The pharmaceutical composition according to (1) or (2), wherein the xanthine oxidase inhibitor is topiroxostat.

According to the present invention, it becomes possible to prevent and / or treat heart failure associated with diabetes, particularly HFpEF, which has been difficult to improve the prognosis with conventional therapeutic agents.

It is a graph which shows the xanthine oxidase activity in the left ventricular myocardium at the time of baseline (FIG. 1A) and at the time of pressure loading (FIG. 1B) of the pressure-loaded OLETF rat administered with the xanthine oxidase inhibitor. It is a graph which shows the hypoxanthine content (FIG. 2A) and xanthine content (FIG. 2B) in the left ventricular myocardium of a pressure-loaded OLETF rat. It is a graph which shows the hemodynamic data of the pressure-loaded OLETF rat to which the xanthine oxidase inhibitor was administered. It is a graph which shows the myocardial ATP content of the pressure-loaded OLETF rat to which the xanthine oxidase inhibitor was administered.

A first aspect of the present invention relates to a pharmaceutical composition containing a xanthine oxidase inhibitor for the prevention and / or treatment of heart failure associated with diabetes.

Xanthine oxidase is a type of xanthine oxidoreductase that generates active oxygen species, and is the oxidation of hypoxanthine to xanthine (hypoxanthine + H ₂ O + O ₂ → xanthine + H ₂ O ₂ ) and the oxidation of xanthine to uric acid (xanthine + H _2). O + O ₂ → Uric acid + H ₂ O ₂ ) is an enzyme that catalyzes.

Xanthine oxidase is an enzyme that functions in the final stage of the purine metabolic pathway from purines to uric acid, and inhibitors of this enzyme, that is, xanthine oxidase inhibitors, are clinically used as uric acid-lowering drugs mainly by suppressing uric acid production. It is used as a target.

As mentioned above, the efficacy of the xanthine oxidase inhibitor allopurinol for heart failure has been denied. The present inventors have newly found that the xanthine oxidase activity of the myocardium and its substrates hypoxanthine and xanthine are increased in the heart failure model with diabetes as compared with the heart failure without diabetes. , It was derived that among heart failure, heart failure complicated with diabetes is suitable for treatment with xanthine oxidase inhibitor. Xanthine oxidase activity is enhanced in the myocardium of diabetic patients as compared with healthy subjects, and it is presumed that a large amount of reactive oxygen species are generated along with this to damage the myocardium. It is considered that a xanthine oxidase inhibitor can prevent and / or treat heart failure particularly associated with diabetes by reducing the generation of this reactive oxygen species and suppressing myocardial injury.

In the present invention, any substance known to have an activity of inhibiting xanthine oxidase can be used as a xanthine oxidase inhibitor, but its safety and effectiveness as a xanthine oxidase inhibitor are guaranteed. From this point of view, it is preferable to use a xanthine oxidase inhibitor that has already been clinically used. Examples of such xanthine oxidase inhibitors include purine base analog inhibitors having a purine skeleton, such as allopurinol, and non-purine type inhibitors having no purine skeleton, such as febuxostat and topiroxostat. it can.

The pharmaceutical composition of the present invention can prevent and / or treat heart failure associated with diabetes by administering it to a subject in need thereof. Specifically, by administering the pharmaceutical composition of the present invention to a subject who has developed heart failure associated with diabetes, it is possible to treat heart failure complicated with diabetes. In addition, by administering the pharmaceutical composition of the present invention to a subject having diabetes but not developing heart failure, it is possible to prevent heart failure associated with diabetes.

As shown in the examples described below, it has been confirmed that xanthine oxidase inhibitors improve not only left ventricular contractility but also left ventricular diastolic function in a heart failure model complicated with diabetes. Therefore, the pharmaceutical composition of the present invention is effective for the prevention and / or treatment of HFpEF associated with diabetes as well as HFrEF associated with diabetes.

As used herein, prophylaxis and / or treatment includes all medically acceptable types of prophylactic and / or therapeutic interventions aimed at curing, transient remission or prevention of disease, etc. That is, prevention and / or treatment of heart failure associated with diabetes includes medically acceptable interventions for various purposes, including delaying or stopping the progression of heart failure associated with diabetes, preventing the onset or preventing recurrence, and the like. To do.

The subject in the present invention means any animal capable of developing heart failure associated with diabetes, preferably an individual mammal, for example, a primate such as a human or a chimpanzee, or a rodent such as a mouse, a rat, a guinea pig, or a hamster. It is an individual such as a dentate, an artiodactyl such as a cow, a goat, or a sheep, an artiodactyl such as an horse, an individual such as a rabbit, a dog, or a cat, and more preferably an individual human.

The pharmaceutical composition of the present invention contains an effective amount of a xanthine oxidase inhibitor. As used herein, "effective amount" means an amount that is effective in preventing and / or treating heart failure associated with diabetes. Such an effective amount is appropriately adjusted depending on the severity of heart failure associated with diabetes, the patient and other medical factors.

In a preferred embodiment of the pharmaceutical composition of the present invention, the effective amount of the xanthine oxidase inhibitor, in the case of oral administration, is 0.1 to 1000 mg, preferably 0.5 to 500 mg, more preferably 1 to 1 to 1 kg of the body weight of the individual to be administered. It is 200 mg, and in the case of parenteral administration, it is 0.01 to 100 mg, preferably 0.05 to 50 mg, and more preferably 0.1 to 20 mg per 1 kg of the body weight of the administered individual. Pharmaceutical compositions containing these effective amounts of xanthine oxidase inhibitors can be administered once or in multiple doses daily or intermittently.

In the present invention, the form of the pharmaceutical composition is arbitrary, but oral preparations (tablets, capsules, powders, granules, fine granules, pills, suspensions, emulsions, liquids, syrups, etc.) and injections. Parenteral preparations such as agents and drip agents can be mentioned as preferable examples.

The pharmaceutical compositions of the present invention are drugs or buffers other than the above-mentioned active ingredients, antioxidants, preservatives, proteins, hydrophilic polymers, amino acids, chelating agents, nonionic surfactants, excipients, stables. It may contain pharmaceutically acceptable components such as an agent and a carrier. Pharmaceutically acceptable ingredients are well known to those skilled in the art, and those skilled in the art can use the ingredients described in the 17th revised Japanese Pharmacopoeia and other standards within the range of normal practicability, depending on the form of the formulation. Can be appropriately selected and used.

The method of administering the pharmaceutical composition of the present invention is not particularly limited, and is appropriately determined according to the dosage form. In one of the preferred embodiments, the pharmaceutical composition of the present invention is orally or parenterally (intravenously, intraperitoneally, etc.) administered to the living body.

The present invention also provides a method of preventing and / or treating heart failure associated with diabetes, which comprises administering an effective amount of a xanthine oxidase inhibitor to a subject in need thereof. The meaning of each term in the method of prevention and / or treatment is as explained above.

The present invention will be described in more detail with reference to the following examples, but these examples are for the purpose of assisting the understanding of the present invention, and the technical scope of the present invention is not limited thereto.

Example 1 Evaluation of cardiac function improving effect of pressure-loaded type 2 diabetes model rat by xanthine oxidase inhibitor 1) Otsuka Long-Evans-Tokushima fatty rats (OLETF) rat and control Long-Evans-Tokushima, which is a type 2 diabetes model Otsuka rats (LETO) rats (both male, 29-35 weeks old) were divided into two groups, one group (Topi (-)) with only standard diet and the other group (Topi (+)) with 0.5. Topiroxostat (Sanwa Kagaku Co., Ltd.) mixed diet of mg / kg BW / day was fed, and each was bred under standard conditions. On the 14th day after the start of breeding, phenylephrine (Sigma Aldrich) was continuously administered intravenously, the dose was adjusted so that the blood pressure was maintained at 200-230 mmHg, and a catheter with a pressure sensor was inserted into the left chamber to adjust the pressure volume. The curve was analyzed.

2) Hearts were collected from some rats (8 animals / group each) in each group immediately before the start of administration of phenilefurin, which is the baseline, and under a pressure load of 200 mmHg by continuous administration of phenilefurin, and triple quadrupole mass spectrometry. Left chamber using a stable isotope-labeled [ ¹³ C ₂ , ¹⁵ N ₂ ] xanthine as a substrate to detect [ ¹³ C ₂ , ¹⁵ N ₂ ] uric acid using an analyzer (LC-TQMS / MS). Myocardial xanthine oxidase activity was measured (in cooperation with Sanwa Chemical Research Institute). The results are shown in FIG. Myocardial xanthine oxidase activity was higher in OLETF rats than in LETO rats, a tendency that was more pronounced after pressure loading. Administration of topiroxostat reduced xanthine oxidase activity to the same level in both OLETF and LETO rats.

In addition, immediately before the start of administration of phenylephrine, which is the baseline, and after freezing the left ventricular myocardial tissue collected from OLETF rats and LETO rats of Topi (-) in liquid nitrogen under a pressure load of 200 mmHg by continuous administration of phenylephrine. Stored at -80 degrees. After homogenizing the frozen tissue, the contents of hypoxanthine and xanthine were measured using a xanthine / hypoxanthine assay kit (BioVision). The results are shown in FIG. Both hypoxanthine and xanthine were significantly increased in OLETF rats after pressure loading.

3) Immediately before the start of phenilefurin administration at baseline and at the end of pressure-overloaded phenilefrin administration, rats (n = 8 / group) in each group were anesthetized by isoflurane inhalation, and the Millar Mikro-Tip catheter system and MPVS -Pressure-volume relationship analysis was performed using the Ultra pressure volume system, and various hemodynamic data were acquired. LVEDP (left ventricular end-diastolic pressure) and Tau (left ventricular pressure drop time constant) are indicators of left ventricular dilatability, and Ees (end-systolic elastance) are indicators of left ventricular contractility independent of load conditions. is there. Ea / Ees (left heart-arterial coupling; effective arterial elastance / terminal systolic elastance) is an indicator of left ventricular contractility to afterload, with values closer to 1 being more appropriate contraction for afterload. It has the ability and means that the overall cardiovascular efficiency is good.

The results are shown in FIG. LVEDP was comparable between OLETF and LETO rats at baseline. At the time of pressure loading, an increase in LVEDP was observed in both OLETF and LETO rats, and the value was significantly higher in OLETF rats than in LETO rats. It was confirmed that administration of topiroxostat did not change LVEDP in LETO rats and suppressed only the increase in LVEDP in OLETF rats. Tau showed significantly higher values in OLETF rats than in LETO rats at both baseline and pressure loading. It was confirmed that administration of topiroxostat did not change the Tau of LETO rats and reduced the Tau of OLETF rats to the same extent as that of LETO rats.

Ees showed lower values in OLETF rats than in LETO rats at both baseline and pressure loading. It was confirmed that administration of topiroxostat increased Ees in OLETF rats to the same level as in LETO rats. Ea / Ees was significantly higher in OLETF rats than in LETO rats at both baseline and pressure loading. Administration of topiroxostat maintained Ea / Ees in OLETF and LETO rats at around 1.

In addition, hearts were collected from some rats (8 animals / group each) in each group under a pressure load of 200 mmHg by continuous intravenous administration of phenylephrine, and the left ventricular myocardium was collected using the ATPColorimetric / Fluorometric Assay Kit (BioVision). The ATP content in it was measured. The results are shown in FIG. The amount of myocardial ATP under pressure was significantly lower in OLETF rats than in LETO rats, but significant recovery was observed with administration of topiroxostat.

From the above results, it was shown that the administration of topiroxostat improved the diabetic heart failure observed by OLETF and manifested by the pressure load of phenylephrine administration.

Claims (3)

A pharmaceutical composition containing a xanthine oxidase inhibitor as an active ingredient for the prevention and / or treatment of heart failure associated with diabetes. The pharmaceutical composition according to claim 1, wherein the heart failure associated with diabetes is heart failure in which the left ventricular contractility is maintained. The pharmaceutical composition according to claim 1 or 2, wherein the xanthine oxidase inhibitor is topiroxostat.

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