JP2002249433A - Inhibitor of blood vessel calcificaion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inhibitor of blood vessel calcification and a preventive and/or a curative for blood vessel calcification disorder. SOLUTION: The inhibitor of blood vessel calcification and the preventive and/or the curative for blood vessel calcification disorder include, as an active ingredient, ethidronic acid, clodronic acid or their pharmacologically acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a vascular calcification inhibitor. More specifically, the present invention relates to an inhibitor effective against vascular calcification in an artificial dialysis patient and a preventive and / or therapeutic agent effective against vascular calcification disorder.

[0002]

2. Description of the Related Art Artificial dialysis is performed on patients with reduced renal function. When dialysis is continued for a long time, vascular calcification disorder is remarkably observed in the blood vessels of patients,
Ectopic calcification disease may be induced. At present, no effective treatment has been established for such vascular calcification disorders and ectopic calcification diseases. Salts of etidronic acid and clodronic acid belong to bisphosphonate compounds and are called by the names etidronate and clodronate, respectively. These compounds have an effect of promoting bone mass increase by inhibiting bone resorption, and are widely used as therapeutic agents for osteoporosis. At high concentrations, these compounds may tend to inhibit bone formation (calcification of bone). Further, it is known that these compounds have various actions such as an analgesic action in addition to a bone resorption suppressing action. However, it is completely unknown whether etidronic acid, clodronic acid or their pharmacologically acceptable salts inhibit calcification in blood vessels, which are organs other than bones, especially whether they are effective for hemodialysis patients. I didn't.

[0003]

An object of the present invention is to provide an agent for inhibiting vascular calcification and an agent for preventing and / or treating vascular calcification disorders.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a vascular calcification inhibitor comprising [1] etidronic acid, clodronic acid or a pharmaceutically acceptable salt thereof as an active ingredient,
[2] the inhibitor of [1], wherein the vascular calcification is ectopic calcification in a hemodialysis patient; [3] an abnormality caused by vascular calcification in an dialysis patient receiving a vitamin D derivative; The inhibitor according to [1], which is ectopic calcification, [4] ethidronic acid, clodronic acid or a pharmaceutically acceptable salt thereof as an active ingredient, and contains at least about 200 mg of the active ingredient per day [ The inhibitor according to any one of 1) to [3], and [5] an active ingredient in an amount of about 200 per day.
The inhibitor according to any one of [1] to [4], wherein the inhibitor according to any one of [1] to [4], wherein the vascular calcification is calcification of an arterial blood vessel. And [7] a prophylactic and / or therapeutic agent for vascular calcification disorders, comprising the vascular calcification inhibitor of any of [1] to [6].

[0005]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of etidronic acid, clodronic acid or a pharmacologically acceptable salt thereof in a rat renal failure model, which is a model of vascular calcification, particularly ectopic calcification in dialysis patients [ After partial nephrectomy, high dose (0.004
(mg / g rat body weight) of a rat administered with calcitriol], based on the surprising finding of the present inventors that they show a strong inhibitory ability against vascular calcification. By the vascular calcification inhibitor of the present invention, vascular calcification, particularly vascular calcification in dialysis patients, vascular calcification in long-term dialysis patients, and blood vessels induced in dialysis patients receiving administration of vitamin D derivatives Calcification can be suppressed.

[0006] The pharmacologically acceptable salts of etidronic acid or clodronic acid include alkali metal salts such as sodium salt, potassium salt and lithium salt. As the active ingredient of the present invention, etidronic acid or a pharmacologically acceptable salt thereof is suitable, and more preferred examples include etidronic acid sodium salt, and particularly preferred is etidronic acid disodium salt. Vascular calcification refers to a phenomenon in which insoluble calcium salts and the like are deposited in blood vessels, such as calcification in arterial blood vessels. Examples of the vascular calcification include ectopic calcification of an dialysis patient (vascular calcification), particularly ectopic calcification (vascular calcification) induced in an dialysis patient receiving administration of a vitamin D derivative. . As the vitamin D derivative, vitamin D (calciferol), vitamin D ₃ (cholecalciferol), calcitriol (1,25-dihydroxycholecalciferol), alfacalcidol (1.alpha.-hydroxy cholecalciferol Fellow Le), Farekarushi Triols (26, 26, 26, 27, 27, 27
-Hexafluoro-1,25-dihydroxycholecalciferol) and the like.

[0007] The agent for preventing and / or treating vascular calcification of the present invention reduces or suppresses symptoms by suppressing vascular calcification.
It can provide an excellent effect for application to diseases that can be prevented or treated, that is, vascular calcification disorders. Vascular calcification disorders include thickening of the intima of the arteries and calcification of the inner elastic plate, media and media elastic fibers.For example, vascular calcification disorders that are remarkably observed in long-term hemodialysis patients or vitamins Ectopic calcification diseases in hemodialysis patients induced by D derivatives.

The usage of the active ingredient in the vascular calcification inhibitor and the preventive and / or therapeutic agent for vascular calcification disorders of the present invention, such as the dose and frequency of administration, varies depending on the disease to be treated, the age and weight of the patient, etc. Then, it is preferable to adjust as appropriate. For example, for an adult (50 kg), about 200 to about 1000 mg
Can be cited as a preferred dose. In terms of body weight, a daily dose of 4 to 20 mg / kg body weight can be mentioned as a preferred dose. The administration frequency may be any of daily administration or intermittent administration depending on the condition of the patient and the like, and can be appropriately adjusted.

[0009] The administration form of the vascular calcification inhibitor and the preventive and / or therapeutic agent for vascular calcification disorders of the present invention is determined depending on the form of the preparation, the age, sex and other conditions of the patient, the degree of the disease, and the like. , Oral administration and parenteral administration. Oral administration is preferred from the viewpoint of convenience in patients. For oral administration, for example, powders, granules,
It can be used as a unit dosage form of tablets, pills, capsules, solutions and syrups. Tablets or capsules for oral administration include, for example, auxiliary agents such as binders, fillers, diluents, tableting tablets, lubricants, disintegrants, coloring agents, flavoring agents, wetting agents and the like. Can be added. Tablets can be coated, for example, with conventional coating agents, for example, fillers such as cellulose, mannitol, lactose; disintegrants such as starch derivatives, polyvinylpolypyrrolidone;
It can be produced by mixing, filling, or tableting using a lubricant such as magnesium stearate; a wetting agent such as sodium lauryl sulfate; When used as a liquid preparation for oral administration, for example, aqueous or oily suspensions, solutions, emulsions, syrups and the like, or a dry form that can be redissolved with water (sterilized / distilled water) or an appropriate medium before administration. Provided as a formulation. Such solutions include the usual additives such as sorbitol, syrup,
Precipitating inhibitors such as methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose and aluminum stearate gel; emulsifiers such as lecithin, sorbitan monooleate and gum arabic; oily or non-aqueous media such as olive oil and ethyl alcohol;
Preservatives such as methyl, ethyl or propyl esters of hydroxybenzoic acid, sorbic acid;
Coloring agents; flavoring agents and the like may be added. In addition, the formulations may contain pharmaceutically acceptable auxiliaries. Examples of the adjuvant include an excipient, a buffer, a tonicity adjusting agent, a wetting agent, a binder, a filler, a stabilizer, a flavoring agent, and the like. More specifically, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride,
Examples include calcium chloride, sorbitan monolaurate, triethanolamine oleate, simple syrup, gelatin, sodium carboxymethylcellulose, gum arabic, sodium alginate, glycerin, D-mannitol and the like.

[0010] For parenteral administration, it can be used as a unit dosage form such as injections and suppositories. The injection may be administered intravenously, alone or as a mixture with usual adjuvants such as glucose and amino acids, and may be administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. Suppositories may be administered rectally. For subcutaneous injection, intramuscular injection, local injection, or intraperitoneal administration, the prophylactic and / or therapeutic agent of the present invention may be treated with an aqueous carrier (such as conventional water for injection) or a non-aqueous carrier (such as a conventional oily solvent or hydrophilic solvent). Etc.) in the form of a solution or suspension. For intravenous administration, it can be used, for example, in the form of a solution or suspension in a pharmacologically acceptable carrier, preferably an aqueous carrier. As the aqueous carrier, for example, water, buffered water, 0.4% by weight of physiological saline, and the like can be used. The aqueous solution thus prepared can be packaged as it is or lyophilized, and the lyophilized preparation may be used by dissolving it in a sterile aqueous solution before administration. In the vascular calcification inhibitor and the vascular calcification disorder preventive and / or therapeutic agent of the present invention, a drug delivery material that enables local administration such as a blood vessel may be appropriately used. Furthermore, the agent for inhibiting vascular calcification and the agent for preventing and / or treating vascular calcification disorders can be administered as a sustained-release preparation using a biocompatible material such as collagen.

[0011] The pharmacological effects of the vascular calcification inhibitor and the prophylactic and / or therapeutic agent for vascular calcification disorders of the present invention are described in, for example, the rat renal failure model in which calcification is induced, as described in Examples below. Can be used to evaluate the frequency of calcification onset by soft X-ray photography, pathological examination by von Kossa staining, and the like. Specifically, the evaluation of the frequency of calcification onset by soft radiography can be performed by comparing a photograph of a normal blood vessel and a calcification image (white) of an artery taken by soft radiography. .
In the pathological examination, a von Kossa stained specimen of a blood vessel is prepared, the inner circumference of the entire blood vessel and the inner circumference of the blood vessel corresponding to the calcified portion are measured, and then the inner circumference of the blood vessel / the inner circumference of the entire blood vessel ( %), The calcification rate of the individual, and calculating the average calcification rate of each group. In addition, pharmacological effects in patients, for example, ultrasound,
It can be evaluated by diagnosis using CT, X-ray photography, or the like.

[0012]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Inhibition test of etidronate on arterial calcification in a rat renal failure (partial nephrectomy) model (1) Preparation and grouping of rat renal failure model Rats (strain: Wis
tar, male, 6 weeks old). As a feed, a vitamin D deficient solid feed (manufactured by CLEA Japan) was used in order to keep the intake of vitamin D (including precursors and active forms) constant.
Tap water was available ad libitum. That is, a rat is subjected to a sham-operation using a body weight as an index to perform a sham operation.
ol group (group 1 in Table 1) and an NX group performing nephrectomy (groups 2 to 4 in Table 1). / 3 were removed and removed. Two weeks later, at the age of 8 weeks, the entire right kidney was similarly removed.
A rat renal failure model was obtained. Table 1 shows the experimental groups and the number of cases in each group.

[0014]

[Table 1]

(2) Induction of calcification In the rat renal failure model obtained in the above (1), calcitriol (manufactured by Wako Pure Chemical Industries) 4
μg / kg was orally administered twice a week to induce ectopic calcification in the abdominal aorta and heart. Calcitriol was dissolved in ethanol for hormone quantification and then diluted with medium-chain triglyceride to give the concentrations shown in Table 1, respectively.

(3) Preparation of Etidronate Solution and Setting of Dose Etidronate disodium salt (Dydronel) was used as etidronate. Weigh etidronate disodium salt, dissolve in distilled water for injection, and p with 1N NaOH.
It was adjusted to H7.4 to obtain an etidronate solution.

(4) Administration Method From the day after the right nephrectomy, etidronate was subcutaneously administered to a rat renal failure model in which calcification was induced in the above (2) using a disposable syringe and a 26G injection needle 5 times a week for 8 weeks. . The dose volume was 5 ml / kg, and was
The dose was calculated from the weight measured twice. Distilled water for injection was administered to the ethidronate non-administered calcitriol administration group (the second group in Table 1).

(5) Blood biochemical test The day after the final administration, blood was collected from the abdominal aorta under ether anesthesia, and the serum was collected by centrifugation. The creatinine value was measured using an ultra-trace multipurpose automatic biochemical analyzer CHEM1 (manufactured by Bayer). Table 2 shows the results.

(6) Soft X-ray photography A soft X-ray photograph was taken of the aorta (10 cm from the origin of the heart) extracted at the time of sacrifice, and the frequency of calcification was determined for each group. Soft X-ray photography is performed by the imaging device S
Using OFRON TypeSRO-M50, imaging was performed under soft X-ray irradiation conditions of 27 kv, 3 mA, and 2 minutes.

(7) Pathological Examination As a result of soft X-ray photograph observation, calcification was frequently observed in the rats in each group in the calcitriol-administered group without etidronate (the second group in Table 1). A von Kossa-stained specimen of the origin of the artery from the left heart was prepared. The inner perimeter of the entire blood vessel and the inner perimeter of the blood vessel corresponding to the calcified portion are determined by the bone morphometry system Ver. 3.0, measured using the MGA-4300 program (manufactured by System Supply).
Then, the inner perimeter of the blood vessel / the inner perimeter (%) of the entire blood vessel is obtained,
The average calcification rate of each group was calculated as the calcification rate of the individual.

(8) Evaluation Results The obtained data (blood biochemical examination, pathological examination, bone mineral density) was analyzed using a SAS system. Sham
For the groups excluding the Control group (the first group in Table 1), the equal variance of each group was tested by Bartlett's equal variance test. If the variances are equal, Tukey
-Kramer's multiple comparison test, when the variances are not equal, a non-parametric Steel-Dass test is used to calculate Nx-Contro for each dose of calcitriol.
Group 1 (second group in Table 1) and etidronate administration group (Table 1
(Medium, third group and fourth group). Risk factor 5
% Or less was judged to be significant.

Blood Biochemical Examination The day after the final administration of etidronate, blood was collected from the abdominal aorta of the rat, and the obtained serum was subjected to an ultra-trace multipurpose automatic biochemical analyzer CHEM1 (manufactured by Bayer).
, The creatinine value was measured. Table 2 shows the results.

[0023]

[Table 2]

[0024] Since the creatinine value of the partially nephrectomized group (the second to fourth groups in Table 2) is 0.97 mg / dl or more, renal function is reduced, and it is considered to be effective as a renal failure model. Was.

Soft X-ray photography Soft X-ray photography was performed on the excised abdominal aorta. As a result, the Sham-Control group (first in Table 3)
In group (1), calcification in the abdominal aorta was observed in 1/9 cases. In the ethidronate non-administered calcitriol administration group (second group in Table 3), calcification was observed in 10/10 cases. In the calcitriol + etidronate 2 mg / kg administration group (the third group in Table 3), no calcification was observed. In the calcitriol + etidronate 10 mg / kg administration group (the fourth group in Table 3),
A calcification image was observed in 1/9 cases.

Pathological Examination A specimen was prepared at the origin of the artery of the heart, and the inner circumference of the blood vessel corresponding to the calcified portion / the inner circumference of the entire blood vessel (%) was determined. Table 3 shows the results.

[0027]

[Table 3]

As shown in Table 3, calcification was observed mainly in the media of the arterial wall at both sites. In addition, Sham-C
Compared with the calcification frequency of the ontrol group (the first group in Table 3), the calcification frequency of the etidronate-nonadministered calcitriol-administered group (the second group in Table 3) was increased. On the other hand, calcitriol + etidronate 2 mg /
The calcification rate of the kg administration group (the third group in Table 3) was 2.2%.
This indicates that the calcification rate was significantly lower than that of the calcitriol-administered group without etidronate (the second group in Table 1). In addition, the calcification rate of the calcitriol + etidronate 10 mg / kg administration group (the fourth group in Table 3) was 21.3%, and the lime of the calcitriol non-administration calcitriol administration group (the second group in Table 3). Although no significant difference was observed in comparison with the calcification rate, it can be seen that the calcification suppression tendency was observed. These facts indicate that etidronate has an action of suppressing vascular calcification induced by calcitriol. In addition, it can be seen that etidronate exhibits a calcification inhibitory action and is useful as a therapeutic agent for vascular calcification in dialysis patients.

Example 2 Twenty weeks of chronic maintenance dialysis patients suffering from ischemic heart disease (including patients after coronary artery bypass surgery) and having evident vascular calcification lesions were treated with etidronate 800 mg for 12 weeks. Once daily between meals. Evaluation of the improvement of vascular calcification was performed using quantitative CT scans before and after the administration of etidronate.
The evaluation is made by the determination method. As a result, it can be seen that the calcification in each of the three proximate coronary arteries and the thoracic aorta is reduced and improved after the administration compared to before the administration.

[0030]

The vascular calcification inhibitor of the present invention can suppress vascular calcification in an artificial dialysis patient. In addition, the agent for preventing and / or treating vascular calcification disorders of the present invention reduces, suppresses, prevents or treats symptoms by suppressing vascular calcification. In particular, vascular calcification disorders in hemodialysis patients can be prevented and / or treated.

Claims (7)

[Claims] 1. A vascular calcification inhibitor comprising etidronic acid, clodronic acid or a pharmacologically acceptable salt thereof as an active ingredient. 2. The inhibitor according to claim 1, wherein the vascular calcification is ectopic calcification in a hemodialysis patient. 3. The inhibitor according to claim 1, wherein the vascular calcification is ectopic calcification induced in a hemodialysis patient receiving a vitamin D derivative. 4. The inhibitor according to claim 1, wherein etidronic acid, clodronic acid or a pharmaceutically acceptable salt thereof is used as an active ingredient, and the active ingredient is at least about 200 mg per day. 5. The inhibitor according to claim 1, which contains the active ingredient in an amount of about 200 mg to about 1000 mg per day. 6. The inhibitor according to claim 1, wherein the vascular calcification is calcification of arterial blood vessels. 7. A preventive and / or therapeutic agent for vascular calcification disorders, comprising the vascular calcification inhibitor according to any one of claims 1 to 6.