JP2914454B2 - Vascular diagnostic aid - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a blood vessel diagnostic aid used for diagnosing vascular function related to vascular disease.

BACKGROUND OF THE INVENTION Conventionally, invasive or non-invasive diagnostic methods have been used to diagnose patients with or suspected of having coronary artery disease. Non-noxious methods include electrocardiography, radionuclide angiography (eg, using technetium-99m labeled red blood cells, injecting them first, and then checking the equilibrium), perfusiocardiography (perfusio
n) The flash coefficient method (diagnosis using radiopharmaceuticals that emit positrons such as technetium 201, rubidium 82, and nitrogen 13), and ultrasonic cardiac diagnosis (M mode and two-dimensional). The indication of coronary artery disease depends on myocardial oxygen supply and the balance of supply. These non-infringing methods can be performed on stationary subjects, but the difference between supply and demand is not enough to detect anomalies in stationary subjects. Therefore, a method of applying a stimulus (strain) is often performed in order to improve the reproducibility of such a diagnostic method. The most widely used stimulation or tonic methods utilize standard exercise. When the subject is exercising, the myocardial oxygen demand exceeds the oxygen supply. This type of stimulation is commonly used in electrocardiography, radionuclide vascular diagnostics, myocardial perfusion flash index, ultrasonic cardiac diagnostics,
And used in connection with a ventricular angiography diagnostic method.

More recently, methods for increasing myocardial oxygen supply using pharmaceutical techniques have been developed. Specifically, coronary vasodilators (eg, nitrate, papaverine, dipyridamole, etc.) are used for this purpose. Although the mechanism of action is not clear, these drugs greatly dilate normal vessels compared to diseased vessels, causing shunts or "myocardial steal" (natural blood flow). Stimulation with drugs is particularly useful for patients who cannot exercise, and even for patients who can exercise, it is as effective or more effective than the stimulation method. In addition, exercise can increase oxygen demand, and coronary vasodilators increase oxygen supply, so that their use in conjunction with one another can produce the greatest diagnostic effect.

Coronary resection is currently the standard invasive method of diagnosing coronary artery disease. However, this method only confirms the anatomical extent of the disease and provides little information about the functional significance of the visible lesion. In addition, microvascular disease exceeds the resolution limit of currently available devices. Recently, in an attempt to explore the functional significance of coronary artery disorders, coronary dilators are injected into the coronary arteries or veins, and then coronary artery blood flow is measured in several ways, for example:
It has been proposed to measure by Doppler catheterization, video densitometry, coronary artery thermal dilatation, radionuclide clearance of inert gas, and the like. These techniques have come to be widely used to measure coronary flow reserve volume, which provides information on the functional significance of stenotic vessels. Known coronary vasodilators (eg, nitrate, papaverine, dipyridamole, etc.) have been used for this purpose but have not been publicly approved for this purpose. Vasodilator adenosine, adenosine receptor agonists, metabolic precursors or by-products of adenosine,
And phosphorylated derivatives of adenosine have never been used in the above diagnostic methods.

[Object of the Invention] An object of the present invention is to provide a diagnostic aid used for diagnosing the degree of heart disease.

Another object of the present invention is to reduce the washout time of a radiolabel used in unstimulated radiography compared to the radiolabel washout obtained with currently used stimulating or kinetic radiography. To provide a diagnostic aid that can

SUMMARY OF THE INVENTION The present invention is a diagnostic aid characterized by adenosine and its precursor adenosine triphosphate, which is effective in dilatation of blood vessels, with intravenous infusion at a dose of about 20-200 mcg / kg / mi.
n or intracoronary infusion is a liquid diagnostic aid used in the diagnostic imaging of myocardial dysfunction with a dose of about 2 to 20 mcg, and has a predetermined effect when used in the method of diagnosing myocardial dysfunction Demonstrate.

DETAILED DESCRIPTION OF THE INVENTION Adenosine is chemically 9-β-D-ribosranosyl-9H-purine-6-amine, 6-amino-9-β-D.
-Ribofuranosyl-9H-purine, 9-β-D-ribosranosidoadenine, or adenine riboside.

Adenosine is a widely distributed nucleoside in nature and is artificially produced from yeast nucleic acids. Adenosine is alcohol insoluble. Crystallized from water, melting point 234-1
35 ° C, [α] ¹¹ = 61.7 degrees (c = 0.706 in water), [α] ⁹
= -58.2 degrees (c = 658 in water), uv _max = 260nm (15100),
_{C 10 H 13 N 5 O 4} ( empirical formula), a molecular weight 267.24.

 The structural formula is as follows.

The present invention is a diagnostic aid which imparts irritation or tension to this adenosine and the adenosines defined above when applying any non-invasive diagnostic method. For example, when performing myocardial perfusion imaging of thallium 201 to diagnose a myocardial disorder or disease, adenosine is injected intravenously.
Here thallium 201 is any other radiopharmaceutical such as rubidium 82, technetium 99m, technetium derivative,
It may be replaced with one of nitrogen 13 and iodine 123. Similarly, adenosine may be administered as a pharmaceutical stimulant or tonic when performing radionuclide angiography to diagnose myocardial damage. In this case, the radionuclide angiography is first flowed to the right and / or left ventricle and then equilibrated. Similarly, adenosine may be used as a stimulant in ultrasound cardiac diagnostics for diagnosing local wall motion abnormalities. Similarly, adenosine can be used as a drug stimulant in connection with invasive measures of coronary artery flow, such as intracardiac catheterization to diagnose the functional significance of stenotic coronary vessels.

The diagnostic aid of the present invention has an effective amount for dilating the coronary artery of about 50 to
It can be administered intravenously at 200 mcg / kg / min. The adenosine diagnostic aid of the present invention is usually mixed with a pharmaceutically suitable carrier, for example, physiological water, dextrose, water, or other carriers.
This mixed solution contains a wide range of active ingredients, for example from about 1 to 12 mg / ml.

This amount of diagnostic aid reduces the coronary artery blood flow by a factor of about 4-5. This amount of papaverine often causes transmission during the GT period, resulting in electrocardiographic or systemic blood flow abnormalities, whereas the adenosines of the present invention are excellent vasodilators suitable for this purpose.

The diagnostic aid of the present invention can be used in a diagnostic method using a radiopharmaceutical and various other diagnostic methods described above.

What can be used in the present invention as well as adenosine is its precursor adenosine triphosphate. This is because, immediately after administration, this substance is metabolically decomposed and almost completely converted to adenosine via adenosine diphosphate and adenosine monophosphate.

Diagnosis of human coronary artery disease using the diagnostic aid of the present invention, ie, a diagnostic aid selected from adenosine, adenosine receptor agonists, metabolic precursors of adenosine, by-products of adenosine, and phosphorylated derivatives of adenosine That is, a diagnostic method that is effective for the existence or evaluation is myocardial perfusion (pe
rfusion) imaging, including radiopharmaceutical myocardial perfusion imaging, planar (conventional) flash counting, single photon emission computed tomography (SPECT), positron emission flash tomography (PE
T), nuclear magnetic resonance imaging (NMR), injection contrast-enhanced ultrasound, digital subtraction angiography (DSA), ultrafast X-ray computed tomography (CINECT), and the like.

The diagnostic aid of the present invention, i.e., selected from adenosine, adenosine receptor agonists, metabolic precursors of adenosine, by-products of adenosine, and phosphorylated derivatives of adenosine, is used in place of exercise to replace the human ventricle. Ultrasound ventricular imaging, ventricular angiography, radionuclide angiography, and the like are effective diagnostic methods for diagnosing, ie, presenting or evaluating local anemia disorders.

The diagnostic aid of the present invention, that is, a diagnostic aid selected from adenosine and adenosine triphosphate is used as a coronary artery hyperemia or dilator, and the method for measuring the vasodilation reserve volume (margin volume) of the human coronary artery is coronary. This is a method of measuring the blood flow velocity of an artery.

 Examples will be described below.

Description of Examples Example 1 This example demonstrates the effect of intravenous infusion of adenosine as a pharmacological stimulant in relation to thallium-201 flash counting. In the first experiment, 20 healthy people were given a flat (conventional) thallium 201
A cross-test was performed using flash counting to compare the effects of exercise and adenosine. In the second study, a cross-over study was performed using 12 planar (conventional) thallium 201 flash counts in 12 healthy subjects and 14 patients with coronary artery disease found by vascular examination to demonstrate the effect of dipyridamole and adenosine. Were compared. In a third study, a cross-over study was performed using thallium-201 single-photon emission silicate tomography (SPECT) on 18 healthy subjects and 15 patients with coronary artery disease known to have vascular examination. The effect of adenosine was compared.

In the first experiment, 20 healthy people (19-39 years old) were subjected to two times a flat (conventional) thallium 201 flash counting method. In one test, maximal exercise (stepping exercise) (Bruce method) was performed as a stimulation method, while adenosine was injected intravenously instead of exercise. The stimulation test with adenosine was performed according to a standard procedure. Started with a steady infusion of 20 mcg / kg / min. At intervals, the injection volume was sequentially multiplied to a maximum of 140 mcg / kg / min. The maximum tolerated dose was administered for at least 5 minutes prior to the administration of a single bolus thallium 210 (about 2.0 mci). Initial (stimulated) imaging was performed 5-10 minutes after administration of thallium 201, and delayed (redistribution) imaging was performed 3-4 hours after administration. Adenosine injection was performed until the end of the initial imaging procedure. Three sets of images were obtained for each of the early and delayed imaging methods (left artery oblique, anterior, and left lateral projection). Images were obtained and reconstructed according to standard methods. Adenosine infusion was tolerated in all subjects. Motor and adenosine stimulated images were interpreted as normal (ie, no perfusion defects were detected).
This experiment shows that adenosine can be compared to the exercise method for diagnosing normality by planar thallium-201 flash counting.

In a second experiment, a random crossover test was performed using 12 stimulated and redistributed planar (conventional) thallium 201 flash counts on 12 healthy subjects and 14 patients with coronary artery disease known to have coronary artery disease. The effects of dipyridamole and adenosine were compared. In one test, dipyridamole 300 mg was orally administered as a method of stimulation, and in another test, adenosine was administered intravenously as a method of stimulation. Dipyridamole stimulated imaging was performed by standard methods, and adenosine stimulated imaging was performed according to the method described above. Again, adenosine infusion was tolerated by all subjects.

Adenosine and dipyridamole sensitivity, specificity, and overall predictive accuracy of 88.8 each for detecting coronary artery disease
%, 87.5% and 88.0%, and 77.7%, 82.6% and 80.5
%Met. Positive expected values for adenosine and dipyridamole images were 84.2% and 77.7%, respectively.
This experiment demonstrates that adenosine imaging is safe and superior to dipyridamole in detecting significant coronary vascular disease by vascular imaging.

In a third study, vascular examinations showed no coronary artery disease (n = 8) and healthy subjects (n = 10)
A total of 18 patients and 15 patients with coronary artery disease found to have coronary artery disease were cross-tested using thallium 201 single photon emission silicate tomography (SPECT) to compare the effects of adenosine. Start adenosine only at 50 mcg / kg / min for all subjects, 25 mcg / kg / min at 1 minute intervals
The maximum was increased to 140 mcg / kg / min. The maximum tolerated dose is at least 1 before administration of one thallium 201 (about 3.0 mci).
Minutes and later for about 3 minutes. Initial (stimulation) imaging was performed 5-10 minutes after thallium administration, followed by delayed (redistribution) imaging 3-4 hours after thallium administration.
SPECT images were obtained and reconstructed according to standard methods. Adenosine infusion was tolerated in all subjects. Okita was usually weak in 76% of subjects with side effects, did not require any treatment, and disappeared shortly after discontinuing the adenosine infusion. Back pain occurred in 53% of subjects, headaches in 34%, and skin rash in 15%. The dose-dependent decrease was due to blood pressure due to cardiac contraction (hypotension), and a reflexive increase in the number of hearts was common. Perfusion defects were detected during adenosine-stimulated imaging in all 15 patients, and these vessels were reversible in 9 (sensitivity = 100%).
Adenosine-stimulated images were interpreted as normal by 16 out of 18 healthy subjects (89% sensitivity). This study showed that adenosine-induced coronary vasodilation was safe for diagnosing patients with coronary artery disease using SPECT thallium flash counting.
Indicates a convenient and promising auxiliary.

Example 2 In this example, the effect of adenosine administered intravenously as a pharmacological stimulant in ultrasound imaging is evaluated.

Fifteen patients were selected for a motor (stimulation) SPECT thallium 201 tomographic experiment. Perfusion defects on tomographic images were fixed (irreversible) in 6 patients and reversible in 9 patients. These patients were subsequently performed at rest (baseline) and with intravenous infusion of adenosine as described above (see Example 3, third experiment). Ultrasound imaging was performed 1 minute (baseline) before adenosine infusion, maximum adenosine infusion period (140 mcg / kg / min), and 3 minutes after discontinuation of adenosine infusion. All experiments included images along the sternum (mitral valve, papillary muscle, and long axis and single axis at apical height) and apical views (4 chambers, 2 chambers, and apical long axis). All ultrasound cardiac images were interpreted by standard quantitative and qualitative techniques. Ultrasound cardiac images obtained at rest were interpreted as normal in all subjects. However, left ventricular wall dyskinesia was obtained in all six patients with fixed thallium perfusion defects during the period of diagnosis using adenosine (stimulation).
However, left ventricular wall motion was considered normal in all patients with reversible perfusion defects during the diagnosis period using adenosine (stimulation). This experiment indicates that adenosine is useful as a pharmacological stimulant in echocardiography of localized anemia ventricular injury.

Example 3 This example demonstrates that intravenous and intraarterial adenosine is used in connection with coronary artery blood flow reserve measurement (CBFR), particularly in connection with arterial imaging using a Doppler flow catheter. Shows its effect as a pharmacological stimulant.

Patients with angiographically normal left coronary arteries were examined by coronary angiography. A 3F Doppler catheter was positioned in the left coronary artery, arterial flow velocity (CBFV) was measured, and mean arterial pressure, stroke volume, and ECG were recorded simultaneously. Repeated measurements of baseline CBFV were followed by a cross-over, incremental administration of intracoronary papaverine (8-12 mg bolus), intracoronary adenosine administration (4-14 mcg, bolus), and intravenous adenosine administration (70-140 mcg). / kg / min). Each drug was administered until a maximal coronary hyperemia response occurred. ECG intervals were unchanged during adenosine administration, but papaverine steadily prolonged the QT interval (mean 96 ± 18 m
Seconds). A maximal coronary hyperemia response (4-5 fold increase in CBFV) was obtained with 14 mcg intra-arterial adenosine bolus and 140 mcg / kg / min intravenous adenosine compared to papaverine. Compared to papaverine, the coronary hyperemia responded faster to adenosine (10 seconds to 20 seconds), and adenosine degraded faster (37 seconds to 118 seconds), consistent with its very short half-life. This experiment shows that maximal coronary coronary hyperemia can be achieved by intravenous or intraarterial adenosine, and that adenosine is useful for measuring the vasodilation reserve volume (margin volume) of stenotic coronary vessels. .

[Effects] Adenosine or a similar substance as described above as a pharmacological stimulant of the present invention is used in patients who cannot exercise or do not want exercise at a load suitable for non-invasive diagnosis of coronary artery disease in patients. It is better than using exercise as a stimulant. The adenosine of the present invention or the above-mentioned similar substance is nitrate,
It is superior to conventional products such as papaverine and sipyridamole. Adenosine has a very short half-life (less than 20 seconds). As a result, the onset of action and loss from the human body is rapid, and the time to perform the diagnostic method is reduced. Moreover, even if side effects occur, they can be suppressed promptly by reducing the infusion rate, and there is no need to interrupt the infusion or perform diuretic treatment with theophylline. Furthermore, since adenosine is a substance that is self-generated in the body, it does not cause an allergic reaction.

Continuation of the front page (72) Inventor Daniel E. Hilleman, South One Hundred and Thirteenth Street, 1424, Omaha, Nebraska, United States of America Am. Coll. Cardio, Vol. 9 No. 1 (1987) pp. 59-67 Am. J. Cordiol. Vol. 39 No. 3 (1977) p. 403-406 Bulletin of Kobe University School of Medicine Vol. 45, No. 4, p. 563-570

Claims (1)

(57) [Claims] An active ingredient selected from adenosine and adenosine triphosphate is carried on a liquid medium at a concentration of 1 to 12 mg / ml, and the intravenous infusion is performed at a dose of 50 to 200 mcg.
A liquid diagnostic aid for use in diagnostic imaging of myocardial dysfunction performed at / kg / min for at least 5 minutes.