JPH09202736A - Hemostatic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a hemostatic agent capable of quickly and surely stopping the bleeding without necessitating an extensive surgical operation. SOLUTION: This hemostatic agent contains an ultrasonic sensitive agent such as porphyrin, chlorin, water-soluble chlorophyll derivative, acridine derivative, xanthene derivative, tetracycline, surfactant or mitomycin. The chlorin is phenophorbide or acrine derivative such as methylene blue, furosein, acrine orange or neutral red. The xanthene derivative is e.g. rhodamine, rose bengal or erythrocin. Tween 80 can be used as the surfactant. The ultrasonic sensitive agent is activated to coagulate the blood in a short time by introducing the ultrasonic sensitive agent to the bleeding site by intravenous injection and applying ultrasonic radiation to the bleeding site. Bleeding can easily and quickly be stopped by this process.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hemostatic agent capable of quickly stopping bleeding.

[0002]

2. Description of the Related Art The most common cause of death due to traffic accidents, gastric ulcers, and rupture of esophageal varices is heavy bleeding, and it is important to stop bleeding in critical care. To improve patient survival, hemostasis should be performed as soon as possible.

Bleeding from traffic accidents is often caused by rupture of internal organs due to abdominal blow. In the case of visceral hemorrhage such as rupture of the internal organs or hemorrhage in the liver where a catheter or endoscope cannot be used for treatment, it is difficult to stop the bleeding by means other than surgery. Therefore, for example, effective hemostasis cannot be performed at an accident occurrence site or during transportation to a hospital.

[0004] There are several endoscopic hemostasis methods for bleeding due to gastric ulcer and esophageal varices, but it is difficult to ensure hemostasis. As a hemostatic method currently adopted, a method of burning out a bleeding source with a laser or high frequency is known, but the success rate is not so high, and
There is a problem that it may damage other than the bleeding site.

There is also a method of activating the coagulation system by spraying a drug called thrombin, which is a drug that causes a chemical reaction to solidify blood, at the bleeding site, but the sufficient effect has not been obtained.

[0006]

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a hemostatic agent that can stop bleeding quickly and reliably without the need for major surgery.

[0007]

The present invention is a hemostatic agent using an ultrasonically sensitive drug. As the ultrasonic-sensitive drug, porphyrin, chlorin, water-soluble chlorophyll derivative, acridine derivative, xanthene derivative, tetracycline, surfactant, or mitomycin can be used.

The above chlorins include methylene blue,
Phenophorbide, such as furosein, acrine orange, and neutral red, and aculin derivatives can be used.

Rhodamine, rose bengal, or erythrosine can be used as the xanthene derivative.

Tween 80 can be used as the above surfactant.

After the ultrasonic sensitive drug is intravenously injected and sent to the bleeding site, ultrasonic waves are applied to the bleeding site to activate the ultrasonic sensitive drug and coagulate blood in a short time. Thereby, hemostasis can be performed easily and quickly.

The substances mentioned above are examples of ultrasonically sensitive drugs. In addition to these substances, many photosensitizers such as photofrin are known to be sensitive to ultrasonic waves. Chemical changes that release singlet oxygen are considered to be one effect of ultrasonic treatment, and another effect is to lower the threshold of cavitation caused by ultrasonic waves. Cavitation is a phenomenon in which a gas dissolved in an aqueous solution becomes bubbles under a certain acoustic vibration, or bubbles that have already existed vibrate or repeatedly expand and contract.

A decrease in the threshold value of cavitation in the presence of the substance of the present invention means that less energy is required to generate cavitation at the target site. This requires more energy to generate the same amount of cavitation in the absence of this material.

There are several possible conditions that cause cavitation. One is how much gas is dissolved in the aqueous solution. The other is the intensity of ultrasonic waves. Furthermore, the state changes with the frequency of the ultrasonic waves. Generally at lower frequencies the cavitation threshold is lower. For example, 20-40 kilohertz is used in ultrasonic cleaners and the like. On the other hand, in order to generate cavitation in the body at 1 megahertz, since the cavitation threshold value is high, ultrasonic waves of considerable intensity are required. With an ultrasonic treatment apparatus having a frequency of 1 megahertz or higher, the only way to cause cavitation at a specific site is to increase the ultrasonic intensity or lower the cavitation threshold value.

Cavitation has various effects when it is generated in the human body. That is, cavitation causes drug activation and kinetic changes. For example, ultrasonic waves generate minute bubbles of 0.01 to 100 micrometers in the body fluid, but some bubbles disappear instantly. Some of them vibrate at the same size and frequency as ultrasonic waves. There are some that gradually expand. Where there are bubbles to destroy, a high temperature region may be recognized and electromagnetic waves may be generated. This is called sonoluminescence. In such a situation, it activates nearby drugs and substances, releases single-effect oxygen to exert an antitumor effect, and induces coagulation reaction. As another factor, cavitation is a bubble in blood, urine, bile, and intercellular fluid and causes a mixing action called microstreaming. This agitation can distribute or transport the molecule or drug into the tissue of interest.
For example, thrombolytic drugs can be efficiently permeated into the thrombus by cavitation or microstreaming to dissolve the thrombus. As another example, cavitation can temporarily create a bypass on the skin to allow transdermal drug delivery without a needle. As another example, cavitation can be applied to therapy by changing the form of a drug that is not toxic into the form that is toxic by the effect of free radicals. It is also possible to administer a drug that accumulates in a tumor and subsequently irradiate it with ultrasonic waves to cause cavitation in the tumor, induce toxicity of the drug, and destroy the tumor. As another use example, blood can be extracted outside the body, where a non-toxic drug exhibits an antitumor effect by ultrasonic irradiation, and can be applied to the treatment of specific diseases, particularly leukemia.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION

[Bleeding due to rupture of internal organs, bleeding within the liver]
It is explanatory drawing which shows the form of treatment at the time of stopping the bleeding from the internal organs which is difficult to use a catheter or an endoscope.

First, an ultrasonic sensitive drug is intravenously injected into a patient, and a diagnostic ultrasonic wave is applied to the patient's body A by an ultrasonic diagnostic apparatus (not shown), and a diagnostic ultrasonic echo image of the internal organ B is displayed. While confirming the bleeding site C, the therapeutic ultrasonic energy from the therapeutic ultrasonic generator 1 is concentrated on the bleeding site C, and blood is coagulated in the target broken blood vessel to stop the bleeding.

As a drug administration method, in addition to vascular injection, percutaneous injection, poultice, or catheter can be used.

The therapeutic ultrasound element may or may not be compatible with the patient's skin. An example of a non-compliant therapeutic ultrasound element is a rigid ultrasound transducer commonly used in ultrasound diagnosis of internal organs. The therapeutic ultrasonic element can be used for diagnosis by converging ultrasonic waves and can be modified so that it can also be used for therapy.

FIG. 2 shows an adaptive therapeutic ultrasonic generator 1.
Is a schematic cross-sectional view showing an example of the configuration of FIG. 1, in which a plurality of ultrasonic vibration elements 1b are attached to the inner peripheral surface of a base body 1a made of a flexible synthetic resin. Ultrasonic transducer 1
In b, for example, electrodes are attached to both surfaces of a plate-shaped piezoelectric element, and ultrasonic energy is radiated in the arrow direction by applying an electric signal of ultrasonic frequency between the electrodes.

Since the therapeutic ultrasonic wave 1 can be curved according to the shape of the body A of the patient, the ultrasonic energy can be concentrated on the bleeding site C.

[In case of gastric ulcer, bleeding from esophageal varices]
FIG. 3 is an explanatory diagram showing a mode of treatment for stopping bleeding from internal organs in which a catheter or an endoscope can be used. FIG. 4 is a schematic cross-sectional view showing a configuration example of the tip of the endoscope.

First, an ultrasonic sensitive drug is previously intravenously injected into a patient. After that, the bleeding site C of the internal organ B (stomach in the example of FIG. 3) is confirmed with the esophagus or the gastroscope 2, and ultrasonic waves are locally or extensively attached to the distal end of the sheath 2a of the endoscope 2. An ultrasonic wave is radiated by the ultrasonic vibrating element 2c provided to stop the blood. Ultrasonic waves activate the drug present in the blood and instantly solidify it, so that the hemostatic effect is higher than in the conventional method.

The ultrasonic vibration element 2c is a cylindrical piezoelectric element having an optical fiber 2b at its center and electrodes attached to the inner and outer peripheral surfaces thereof, and an electric signal of ultrasonic frequency is applied between the electrodes. As a result, ultrasonic energy is emitted in the direction of the arrow. When the ultrasonic vibration element 2c has a cylindrical shape, ultrasonic energy is uniformly radiated in the radial direction with respect to the axis of the endoscope 2. However, the ultrasonic vibrating element is not limited. For example, the sheath 2a of the endoscope 2
A disk-shaped ultrasonic vibrating element, through which the optical fiber 2b passes through the center, may be attached to the tip of the ultrasonic wave. In this case, ultrasonic energy is radiated in a concentrated manner in the axial direction of the endoscope 2.

As the ultrasonic sensitive drug, hematoporphyrin derivative, rose bengal and the like can be used. The ultrasonic energy is 0.1 to 10
It can be used in a range of 00 watts / square centimeter.

The ultrasonically sensitive drug or enhancer is
(A) hematoporphyrin, porphyrin which is protoporphyrin, (b) chlorin, (c) water-soluble chlorophyll derivative, (d) acridine derivative, (e) rhodamine, erythrosine, xanthene derivative such as rose bengal, (f) tetracycline, (G) a surfactant such as Tween 80, or (h) mitomycin may be used.

In addition, as a medical application method, an ultrasonic sensitive drug may be administered on the skin for the purpose of percutaneous absorption of the drug, or an ultrasonic sensitive substance may be administered to an artery or a vein to cause thrombolysis. More drug can be taken up in the thrombus. It is also possible to promote a drug such as photofrin in blood circulating in the body with an ultrasonic sensitive drug. The ultrasound-sensitive drug may be systemically administered and taken into the tumor, or may be directly injected into the tumor. Administration by an endoscope or an ultrasonic sensitive drug by a catheter may be used.

[0028]

EFFECTS OF THE INVENTION According to the present invention, bleeding from internal organs can be quickly and reliably stopped by a simple procedure of injecting an ultrasonic sensitive drug into a patient and irradiating ultrasonic waves. In particular, since bleeding can be stopped early by treatment immediately after bleeding, for example, during transportation in an ambulance, the mortality rate due to a large amount of bleeding can be reduced. If the bleeding can be stopped even temporarily, full-scale treatment can be performed after arrival at the hospital, so it can be expected to significantly reduce the mortality rate.

Further, by applying the present invention to a bleeding site where the hemostatic effect due to surgery cannot be expected so much,
More severe bleeding can be treated.

Since ultrasonic waves can be applied to a wide area, a plurality of bleeding sources can be treated at the same time.

Further, since bleeding can be stopped by irradiating ultrasonic waves from outside the body, bleeding of organs such as the liver in the deep part of the body and the abdominal aorta can be treated without surgery.

Further, since ultrasonic waves are used, there is little risk of damaging the organs, and hemostasis can be performed more safely than with a laser or high frequency.

[Brief description of drawings]

FIG. 1 is an explanatory diagram showing a form of treatment for stopping bleeding from internal organs where it is difficult to use a catheter or an endoscope.

FIG. 2 is a schematic cross-sectional view showing a configuration example of a therapeutic ultrasonic wave generation device.

FIG. 3 is an explanatory diagram showing a form of treatment for stopping bleeding from internal organs in which a catheter or an endoscope can be used.

FIG. 4 is a schematic cross-sectional view showing a configuration example of a tip of an endoscope.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 ... Ultrasonic generator for treatment, 1a ... Base | substrate, 1b ... Ultrasonic vibrating element, 2 ... Endoscope, 2a ... Sheath, 2b ... Optical fiber, 2c ... Ultrasonic vibrating element

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/65 A61K 31/65 35/78 35/78 H // C07D 487/22 C07D 487/22

Claims (6)

[Claims] 1. A hemostatic agent using an ultrasonic wave promoting substance. 2. The ultrasonic wave accelerator is any one of porphyrin, chlorin, water-soluble chlorophyll derivative, acridine derivative, xanthene derivative, tetracycline, surfactant, and mitomycin.
The described hemostatic agent. 3. The hemostatic agent according to claim 2, wherein the porphyrin is hematoporphyrin or protoporphyrin. 4. The hemostatic agent according to claim 2, wherein the chlorin is phenophorbide such as methylene blue, flosein, acrine orange, and neutral red, and an acrine derivative. 5. The xanthene derivative is rhodamine,
Rose bengal or erythrosine.
The described hemostatic agent. 6. The hemostatic agent according to claim 1, wherein the surfactant is Tween 80.