JP3110931B2 - Argatroban preparation with smooth muscle cell growth inhibitory action - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel use of argatroban for inhibiting smooth muscle cell proliferation. More specifically, the present invention relates to the prevention of vascular hypertrophy or stenosis after percutaneous angioplasty, vascular transplant surgery, internal arteriotomy, and organ transplant surgery.

[0002]

2. Description of the Related Art Blood vessels have a layered structure of an intima composed of vascular endothelial cells, a media composed of vascular smooth muscle cells, fibroblasts and the like, and an adventitia. Normally, in healthy adults, vascular smooth muscle cells maintain blood pressure by their contractile and relaxing functions,
It supplies blood to all organs such as the brain, heart, and digestive organs, and regulates blood volume. Recently, a pathological condition in the vascular wall has been shown to excessively proliferate vascular smooth muscle cells in response to vascular damage (Ross R, N Engl).
J Med, 314, 488-500, 1986).
This overgrowth narrows the vascular lumen, in some cases blocks the blood vessels, and interferes with the distribution of blood to the area under control.

[0003] The proliferation of these cells may be based on internal damage or external damage. In the case of internal damage, for example, atherosclerosis, renal hypertension, pulmonary hypertension, etc. Disease, vasculitis, and diabetic retinopathy. The case due to external injury is due to a wound or surgery, and examples of the surgery include percutaneous angioplasty using a balloon or laser, percutaneous angioplasty using a stent, atherectomy, rotaplator, etc. Percutaneous angioplasty using a technique called New Device, vascular transplantation surgery including vascular bypass surgery and artificial vascular graft surgery, invasive diagnostic methods involving internal incision of blood vessels such as arterial catheterization, kidney, liver, lung and heart And other organ transplant operations.

According to various reports, restenosis occurs in patients with coronary artery stenosis after about 3 to 6 months after percutaneous coronary angioplasty. 40% (Nobuyosi M et al,
J Am Coll Cardiol, 12, 616-
623), 40% by laser (BittlJA)
et al, Am J Cardiol, 70, 15
33-1539, 1992 and Haase KK e
tal, J International Car
diol, 5, 15-23, 1992), 20-30% when using a stent (Ellis SG et a).
1, Circulation, 86, 1836-184
4,1992), 20-30 in the case of atherectomy
% (Holmes DR Jr et al, Inte
rnational J Cardiol, 35, 14
3-146, 1992 and Kuntz RE et a
1, J Am Coll Cardiol, 21, 15
-25, 1993) and case 3 by rotaputer
7% (Junji Takatani and Hiroshi Yamaguchi, Hyundai Medical, 25, 2733-2737, 1993). 15 ~ for coronary artery transplantation
20% (Cataldo S et al, Circ
ulation, 88, 93-98, 1993).

[0005] In these operations, heparin is used to prevent stenosis or occlusion of thrombotic blood vessels during and after the operation (Heras M et al.).
al, Circulation, 78, 654-66.
0, 1988). It has been reported that heparin and heparan sulfate (hereinafter referred to as "heparins"), which is a heparin-like substance in vivo, have a smooth muscle cell growth inhibitory effect.
The inhibitory effect of heparins on smooth muscle cell proliferation is not directly related to the anticoagulant activity (Japanese Patent Laid-Open Publication No. 5-97
884). Heparin, on the other hand, suppresses the proliferation of vascular smooth muscle cells in normal subjects, but has no effect on the proliferation of vascular smooth muscle cells in patients with restenosis (Philip Chane).
tal, Lancet, 341, 341-342, 1
993). In fact, even with the administration of heparin, the proliferation of vascular smooth muscle cells clinically diagnosed as restenosis cannot be prevented (Ellis SG et al, Am Heart).
J, 117, 777-782, 1989). Therefore, a drug that can simultaneously prevent not only the proliferation of vascular smooth muscle in the acute phase but also the proliferation of smooth muscle cells in the chronic phase has been desired.

Argatroban is represented by the formula (1):

Embedded image (2R, 4R) -4-methyl- [N2-
((RS) -3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2
-A general name given to piperidine carboxylic acid hydrate, and this compound belongs to N2-arylsulfonyl-L-argininamides.

[0007] Argatroban is disclosed in JP-B-61-4882.
As described in No. 9, it is a compound having a selective antithrombin action having a completely new mechanism of action not found in conventional drugs. That is, argatroban specifically and reversibly inhibits thrombin by sterically binding to the active site of thrombin. As a result, argatroban strongly potentiates the three main effects of thrombin: (1) fibrin generation, (2) fibrin stabilization by activation of factor XIII, and (3) platelet aggregation. Inhibit.

[0008] Argatroban has an antithrombotic effect like heparins, but the antithrombin III polypeptide is required for the inhibitory action of heparins, whereas argatroban is as described above. Does not require other in vivo factors for its inhibitory action (Kumada T. and Ab)
iko Y. , Thrombosis Research
h, 24, 285-298, 1981). In addition, the anticoagulant activity of argatroban has less difference between individuals and is easier to use than heparin (Katsuyuki Fukutake, et al., Cardiology, 2
9, 190-196, 1991). As a result, it is known that argatroban can be clinically applied to limb ulcers, resting pain, and cold sensation in chronic arterial occlusion.

[0009]

Means for Solving the Problems The inventor of the present invention has intensively studied whether or not the problem of intimal hyperplasia occurring in the chronic phase as well as the problem of the acute phase can be simultaneously solved. As a result, argatroban cannot be prevented by heparins. The present inventors have found that they also have an inhibitory effect on smooth muscle cell proliferation, and have completed the present invention. That is, the gist of the present invention is represented by the following formula (1)

Embedded image And a smooth muscle cell growth inhibitor comprising argatroban as an essential component. Another gist of the present invention is that the above formula
Acute containing argatroban shown in (1) as an essential component
Prevents Smooth Muscle Cell Proliferation in the Early and Chronic Phases
It is a possible smooth muscle cell proliferation inhibitor.
Argatroban represented by the formula (1) as an essential component
Percutaneous angioplasty, vascular graft surgery, internal arteriotomy and
It is a prophylactic agent for vascular hypertrophy or stenosis after organ transplant surgery.

[0010] The smooth muscle cell proliferation inhibitor of the present invention is administered to mammals including humans alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the dosage regime and the route of administration. For example, when argatroban is administered parenterally by intravenous injection, intraarterial injection, subcutaneous injection, or intramuscular injection, it is used as a solution to which a solute such as salt or glucose is added to make the solution isotonic. You. Argatroban is orally administered in the form of tablets, capsules or granules containing suitable excipients such as starch, lactose, sucrose and the like. In addition, argatroban is added with sugar, corn syrup, flavor, pigment, etc., dehydrated and solidified, and used as a lozenge or lozenge. For oral administration as a solution, add coloring and flavoring. The optimal dose of the therapeutic agent of the present invention for humans is determined by a physician depending on the administration method and patient condition. The optimal dose for an animal is determined by the veterinarian, depending on the animal species, the mode of administration, and the condition of the animal. In order to obtain an effect equivalent to that of intravascular administration by oral administration, a large amount of administration is required.

[0011]

EXAMPLES The present invention will be described specifically with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist. Example 1 [Experimental Materials and Experimental Method] White rabbits reared on an artificial diet (trade name: Oriental diet) containing 2% by weight of cholesterol for 2 weeks were subjected to the test. The femoral artery was exposed under pentobarbital anesthesia. A portion of the artery was incised and a catheter sheath (5F) was inserted retrograde. Next, a balloon catheter for transluminal angioplasty (balloon diameter 3.5 mm) was inserted through the sheath, the tip was advanced into the common iliac artery, and the blood vessel lumen was injured by balloon dilation (3 minutes). The obstacle is deep inju reaching the media
was ry. The operation was performed bilaterally, with one side serving as a control side not receiving drug treatment and the other side serving as a drug administration side receiving local administration of the drug. The test drug was injected into the angioplasty site via the catheter sheath.

After removing the balloon catheter and the catheter sheath, the operation site was sutured. After the operation, the animals were kept on the above-mentioned artificial diet containing cholesterol, and angiography was performed 4 weeks later. That is, under pentobarbital anesthesia,
The abdomen was opened and the aorta was exposed. Catheter sheath (5F)
Was inserted antegrade, an angiographic catheter (3F) was inserted through the sheath, and the tip was placed in the aorta. 5 ml of a contrast agent (iopamidol) was injected through the angiographic catheter described above, and a blood vessel was imaged in the common iliac artery region under X-ray fluoroscopy [manufactured by Toshiba Corporation; X-ray cineangio apparatus], and an X-ray film And recorded.

The degree of obstruction of the inner diameter of the blood vessel by angiography was calculated by the following equation (A). Vascular inner diameter occlusion degree (%) = [lumen diameter (m
m) / Outer diameter of angioplasty site (mm)] x 100
(A) The lumen diameter of the angioplasty performing section and the outer diameter of the angioplasty performing section in the above formula (A) are shown in FIG. 1 below, and are the values of the angiogram recorded on the X-ray film. The relevant sentence was measured. After completion of the angiography, the rabbit was sacrificed and the common iliac artery was removed. After embedding and fixing, thin sections were prepared, and hematoxylin and eosin and anti-human platelet-derived growth factor (PD
GF), and a pathological specimen was prepared.

Experimental Results 1 Argatroban was dissolved in a 20% sorbitol solution,
A dose of 0.05 mg / kg was administered to 6 rabbits. The blood vessel inner diameter occlusion was 72 ± 26% (mean ±
Standard deviation, number of cases = 6), 15 ± 19% on drug administration side
(Mean value ± standard deviation, number of cases = 6), and statistically significantly (t-test, P <0.001) prevented the development of stenosis of the vascular lumen.

Experimental Results 2 Histopathological findings by hematoxylin and eosin staining revealed proliferation of vascular smooth muscle cells consistent with the arterial stenosis. That is, it was found that the narrowing of the blood vessel lumen observed by angiography was caused by the proliferation of smooth muscle cells. In the staining using the anti-PDGF serum, the positively stained portion is shown as the expression (or presence) of the PDGF protein. On the control side, a large amount of PDGF protein expression was observed in all vascular tissues (17 cases / 17 cases), whereas on the argatroban-administered side, only a part of blood vessels (4 cases / 17 cases)
Example) PDGF protein expression was observed. (Chi-square test, P <0.05). PDGF is known to promote smooth muscle cell proliferation (Raine E).
et al, J Biol Chem, 257, 515.
4-5180, 1982), the inhibitory effect of argatroban on smooth muscle cell proliferation, in whole or in part,
It has been shown to be in avoiding the expression of PDGF.

[0016]

Industrial Applicability The smooth muscle cell proliferation inhibitor of the present invention can prevent not only the proliferation of vascular smooth muscle cells in the acute phase but also the proliferation of smooth muscle cells in the chronic phase. The formulation of the present application is effective for preventing hypertrophy or stenosis of blood vessels after percutaneous angioplasty, vascular transplantation, internal artery incision and organ transplantation.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram showing a lumen diameter of an angioplasty performing section and an outer diameter of an angioplasty performing section in an angiogram.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61K 31/4709 A61P 9/00 A61P 43/00 C07D 401/12 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The formula (1): A smooth muscle cell growth inhibitor comprising argatroban as an essential component. 2. Smooth muscle cells occurring in the acute and chronic phases
2. The smooth muscle cell proliferation according to claim 1, wherein the proliferation of the smooth muscle cells can be simultaneously prevented.
Growth inhibitor. (3) Formula (1) : Percutaneous blood vessels containing argatroban as an essential component
Plastic surgery, vascular transplant surgery, internal arteriotomy and organ transplantation
Preventive agent for postoperative vascular hypertrophy or stenosis.