JP7813018B2 - Zinc supplementation after bypass surgery - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act was applied. Announced on April 26, 2019, in the online version of the electronic abstract app "MICEnavi" (https://www.micenavi.jp/jsvs47/) at the 47th Annual Meeting of the Japanese Society for Vascular Surgery.

Patent Law Article 30, Paragraph 2 applied. Presented at the 47th Annual Meeting of the Japanese Society for Vascular Surgery on May 24, 2019.

The present invention relates to zinc supplementation therapy after bypass surgery, particularly after lower limb bypass surgery. More specifically, the present invention relates to a protective agent for peripheral circulatory disorders after bypass surgery, characterized by administering zinc at a specific dosage to a subject exhibiting hypozincemia after bypass surgery, as well as an agent for improving the healing of wounds, ulcers, or gangrene caused by peripheral circulatory disorders after bypass surgery.

In recent years, coupled with the aging population and the rise in lifestyle-related diseases, the incidence of peripheral diseases of the lower limbs, such as critical limb ischemia caused by arteriosclerosis obliterans, has been increasing. In particular, critical limb ischemia can lead to the development of ulcers and gangrene in the feet as the condition progresses, and in severe cases may require amputation, significantly affecting patients' quality of life.

Treatments for ischemic diseases such as critical limb ischemia include drug therapy using antiplatelet agents and peripheral vasodilators, endovascular treatment using stents or balloon catheters in the affected area, and, in severe cases, bypass surgery. Bypass surgery is a surgical procedure that bypasses the affected area, connecting the central artery and peripheral artery using artificial blood vessels or the patient's own blood vessels, to deliver blood to tissues distal to the occluded lesion. Because bypass surgery delivers blood to the periphery, bypassing the affected area, it is said to have the advantage of longer-term patency compared to endovascular treatment (Non-Patent Document 1).

Azuma, Nobuyoshi, Heart, vol. 45, No. 1, p. 16 (2013)

However, even among patients who undergo bypass surgery, there are some who experience poor prognosis, such as restenosis after surgery. Poor prognosis following bypass surgery not only necessitates further treatment, such as reoperation, but in severe cases may lead to ulcers, gangrene, and various other complications, necessitating amputation. For this reason, there has been a demand for the development of technology to improve the prognosis following bypass surgery.

The present invention has been made in view of the above circumstances, and has as its object to provide a drug for improving the prognosis of lower limb bypass surgery.

After conducting studies using numerous cases, the inventors confirmed that serum zinc concentration influences the prognosis of bypass surgery. Specifically, they found that patients who are deficient in serum zinc after bypass surgery have a relatively lower graft patency rate compared to patients with sufficient serum zinc. Further intensive research led to the discovery that administering a certain amount of zinc to patients who are deficient in serum zinc after bypass surgery can improve the prognosis of bypass surgery, leading to the completion of the present invention.

That is, the present invention is a protective agent for peripheral circulatory disorders after bypass surgery, which contains zinc acetate as an active ingredient and is orally administered twice daily after meals at a dose of 50 mg of zinc to subjects with hypozincemia after bypass surgery.

The present invention also provides an agent for improving the healing of wounds, ulcers, or gangrene caused by peripheral circulatory disorders after bypass surgery, which contains zinc acetate as an active ingredient and is orally administered twice daily after meals at a dose of 50 mg of zinc to a subject with hypozincemia after bypass surgery.

The present invention makes it possible to provide a therapeutic agent for peripheral circulatory disorders caused by hypozincemia after bypass surgery, or an agent for improving the healing of wounds, ulcers, or gangrene caused by hypozincemia after bypass surgery.

1A and 1B are photographs of the affected area in cases where ulcers that developed after bypass surgery were cured by administration of the peripheral circulatory disorder protective agent according to the present invention (A: 2 weeks after the start of administration, B: 1 month after the start of administration, C: 2 months after the start of administration).

The present invention is described in detail below.

The present invention relates to an agent for protecting against peripheral circulatory disorders and for improving healing after bypass surgery, which contains zinc acetate as an active ingredient and is characterized by being orally administered twice daily after meals at a dose of 50 mg of zinc to subjects who exhibit hypozincemia after bypass surgery, particularly after lower limb bypass surgery.

Here, a peripheral circulatory disorder protective agent refers to a drug that heals and improves the condition of affected areas, such as wounds, ulcers, or gangrene, caused by peripheral circulatory disorder, and protects the subject (patient) from damage. Because it heals and improves the condition of the patient's affected area, it can also be defined as a wound, ulcer, or gangrene healing and improvement agent.

The peripheral circulatory disorder protective agent and healing improvement agent of the present invention are defined by the active ingredient, dosage, and method of use.

The peripheral circulatory disorder protective agent of the present invention can be provided in various oral dosage forms containing zinc oxide as an active ingredient. Preferred forms include tablets, orally disintegrating tablets, capsules, and granules containing zinc acetate as an active ingredient. It is desirable that all forms have a certain level of dissolution rate or higher. Specifically, a formulation with a 15-minute dissolution value of 85% or higher according to Method 2 of the Japanese Pharmacopoeia Dissolution Test (paddle method, water, test solution volume 900 mL, 50 rpm) is preferably used. Using a formulation that meets these conditions makes it possible to effectively increase serum zinc concentrations.

Patients to whom the peripheral circulatory disorder protective agent and healing improving agent of the present invention are administered are those who have hypozincemia after bypass surgery. Here, hypozincemia refers to a state in which serum zinc levels are reduced and the body is deficient in zinc.

The standard range for serum zinc is 80-130 μg/dL. According to the 2018 Guidelines for the Treatment of Zinc Deficiency, a serum zinc concentration between 60 μg/dL and 80 μg/dL is considered latent zinc deficiency, and a serum zinc concentration below 60 μg/dL is considered zinc deficiency.

The peripheral circulatory disorder protective agent of the present invention is particularly suitable for use in patients with zinc deficiency. Specifically, it is orally administered to patients confirmed to have a serum zinc concentration of less than 60 μg/dL after bypass surgery. However, even if a patient is classified as having potential zinc deficiency based on the above criteria (serum zinc concentration of 60 μg/dL or greater but less than 80 μg/dL), if the patient's condition worsens and, for example, the ankle brachial pressure index (ABI) value shows signs of restenosis, the agent may be administered at a similar dose.

The peripheral circulatory disorder protective agent and healing improving agent of the present invention is orally administered at a dose of 50 mg of zinc twice a day, morning and evening, after meals. Administration is then continued while monitoring the patient's condition, and if the serum zinc concentration reaches 100 μg/dL or higher, administration is discontinued. If the serum zinc concentration decreases after discontinuation and falls below 60 μg/dL, administration is resumed at the same dosage.

The present invention will be described below with reference to specific embodiments, but it will be understood that the present invention is not limited to these embodiments, and that various changes and modifications thereto may be made by those skilled in the art without departing from the scope or spirit of the present invention as defined in the appended claims.

Reference Example: Forty-four patients who underwent infrainguinal bypass surgery for severe lower limb ischemia were divided into a zinc-deficient group (serum zinc concentration less than 60 μg/dL, 23 patients with 24 limbs, age 74±8 years) and a zinc-sufficient group (serum zinc concentration 60 μg/dL or more, 21 patients with 21 limbs, age 70±7 years), and the graft patency rate and limb salvage rate 12 months after bypass surgery were compared.

The results showed that the one-year primary and secondary graft patency rates were 18±10% and 36±12%, respectively, in the zinc-deficient group and 53±12% and 53±12% in the zinc-sufficient group, with the zinc-sufficient group showing significantly higher values. Furthermore, the one-year limb salvage rate was 47±12% in the zinc-deficient group and 95±5% in the zinc-sufficient group, again significantly higher in the zinc-sufficient group. The one-year wound healing rate was also examined, with the zinc-deficient group showing a significantly higher rate of 48±12% and 86±9%, respectively, in the zinc-sufficient group.

Example 1
This is a case in which a patient underwent bypass surgery (proximal anastomosis: popliteal artery above the knee, peripheral anastomosis: dorsalis pedis artery) due to severe lower limb ischemia in the left leg artery, and limb salvage was achieved through postoperative zinc supplementation. This patient's initial progress after bypass surgery was uneventful, but two months later, intimal hyperplasia along the entire length of the graft caused graft occlusion and an ulcer developed in the heel. Revascularization and local negative pressure wound therapy were performed, but the condition did not improve. When serum zinc levels were measured, they were found to have fallen to 49 μg/dL.

A zinc acetate preparation (Nobelzin® Tablets 50 mg, manufactured by Nobelpharma Co., Ltd., 50 mg zinc per tablet) was then orally administered, one tablet each morning and evening. As a result, the ulcer site gradually improved after the start of administration, and was healed two months later (Figure 1). These results demonstrate that the use of the peripheral circulatory disorder protective agent of the present invention can improve the condition of patients with hypozincemia after bypass surgery.

According to the present invention, it is possible to provide an agent for protecting peripheral circulatory disorders caused by hypozincemia after bypass surgery, or an agent for improving the healing of wounds, ulcers, or gangrene caused by hypozincemia after bypass surgery.

Claims (3)

A protective agent for peripheral circulatory disorders after bypass surgery, which contains zinc acetate as an active ingredient and is characterized by being orally administered 50 mg of zinc twice a day after meals to subjects with hypozincemia after lower limb bypass surgery. An agent for improving the healing of wounds, ulcers, or gangrene caused by peripheral circulatory disorders after bypass surgery, which contains zinc acetate as an active ingredient and is orally administered after meals at a dose of 50 mg twice a day to subjects with hypozincemia after lower limb bypass surgery. The peripheral circulatory disorder therapeutic agent according to claim 1, or the healing improving agent according to claim 2, wherein the subject is a subject confirmed to have a serum zinc concentration of less than 60 μg/dL after lower limb bypass surgery.