CN1061893C

CN1061893C - Acoustical contrast agent

Info

Publication number: CN1061893C
Application number: CN93110606A
Authority: CN
Inventors: 柯铭清
Original assignee: Individual
Current assignee: Individual
Priority date: 1993-03-08
Filing date: 1993-03-08
Publication date: 2001-02-14
Anticipated expiration: 2013-03-08
Also published as: CN1091980A

Abstract

The present invention relates to an acoustic contrast which belongs to a diagnostic drug for cardiovascular diseases. Urea oxygen CH4N2O. H2 O2 is used as the acoustic contrast agent, a clathration reaction is carried out on urea and hydrogen peroxide according to a proportion of (1 to 4M) to 1M, and then, the urea and the hydrogen peroxide are filtered, crystallized and dried. During visualization, physiological saline or dextrose is used for preparing 4 to 6% of a urea oxygen solution so as to carry out vein push injection, and each push injection quantity is 0.1 to 0.5 ml. A plurality of clinical tests indicate that the urea oxygen is used for the acoustic contrast of angiocarpy. The present invention has the advantages of good development effect, result coinciding with the acoustic contrast after operation diagnosis, convenient use, safety, few side effects and low expense, and is an ideal acoustic contrast. The present invention is worthy of popularization and application.

Description

Acoustic contrast

Acoustic contrast belongs to the diagnostic agent of cardiovascular disease.

Sixties Cramiak at first uses the blue green liquor of indigo cyanogen injecting contrast in cardiac catheter entad, and this law technology difficulty is big, the expense height, and have certain risk; The hydrogen peroxide shadowgraph technique that the seventies China king new house professor proposes, method is easy, and development effect is good, but hydrogen peroxide is a medicine for external use, can not make injecting drug use, so the birth of injection hydrogen peroxide preparation is thirsted for by the world of medicine.The contrast agent of using in the world has sodium bicarbonate/ascorbic acid, sodium bicarbonate/ammonium chloride, pure CO at present ₂, glucose solution, self-blood and bicarbonate sodium ester acid mixed liquor etc., its shortcoming is the CO that is produced ₂The quality and quantity heterogeneity of bubble or air bubble, bubble is not of uniform size, operates waywardly, influences development effect.External make glycerite with urea oxygen and be for external application, do oral cavity cleaning, sterilization and otology elimination and earwax, see that never urea oxygen makes the report of acoustics contrast agent.

The present invention is intended to develop a kind of acoustic contrast, and is not only simple and easy to use, expense is low, safety but also radiography effect satisfied.

The technical scheme that realizes task of the present invention is: with urea oxygen CH ₄N ₂OH ₂O ₂Make the acoustics contrast agent, urea and 14% above hydrogen peroxide are being carried out inclusion reaction with the ratio of 1～4M: 1M below 75 ℃, after filtration, filtrate is being lower than crystallization under 20 ℃ the temperature conditions, aseptic subpackaged after decompress filter drying or the lyophilization, content of hydrogen peroxide is 25～36%.When using urea oxygen radiography, be mixed with 4～6% urea oxygen solution row vein with normal saline or 5% glucose injection and inject, inject 0.1～0.5ml at every turn, inject in 10 seconds and finish, can repeat to inject 3～4 times, be no less than 4～5 minutes each blanking time.

Be described in further detail the present invention below.

Urea oxygen Urea Peroxide molecular formula CH ₄N ₂OH ₂O ₂, this product is white crystals or lyophilized powder block, and odorless decomposes in air gradually, and chance light is perishable, soluble in water, and is unstable in ether, ethanol.After this product is injected and is entered blood circulation in the body, decomposite hydrogen peroxide rapidly, under the catalase effect in blood, discharge oxygen again, part combines with hemoglobin, and part is free state and forms the micro-bubble disperse in blood, and enters heart with blood flow, intensive cloud echo can appear on ultrasoundcardiogram, thus form clear can correlated image.

The preparation of urea oxygen preparation is that the hydrogen peroxide more than urea and 14% is being carried out inclusion reaction below 75 ℃, Filter the back and be lower than crystallization under 20 ℃ the temperature conditions, aseptic subpackaged after decompress filter drying or the lyophilization, content of hydrogen peroxide is 25～36% in the preparation.

The a series of animal experiment proof of urea oxygen is safe and feasible with urea oxygen do intravenous injection.

1, acute toxicity test.

Method: selecting body weight is 40 of the healthy mices of 16～20g, is divided into two groups.One group of intravenous injection urea oxygen, another group intravenous injection hydrogen peroxide compares the toxicity of two kinds of medicines to animal.

Result: urea oxygen group LD ₅₀＞300mg/kg

Hydrogen peroxide group LD ₅₀150mg/kg

The toxicity that injection urea oxygen is described is starkly lower than hydrogen peroxide (P＜0.001)

2, urea oxygen is to white mice normal pressure hypoxia endurance test.

Method: choose 23 of healthy mices, be divided into two groups at random.

Urea oxygen group: the urea oxygen 0.8ml of implantation concentration 1.5%, annotate 1 fen kind of speed.

Matched group: inject sodium chloride solution, dosage notes speed and urea oxygen group are together.

Put in promptly moving into after the two treated animal administrations and absorb CO ₂75 milliliters of volumetrical port grinding bottles of sodica calx in, and jump a queue immediately, timing, observe white mice and cease breathing the time, experiment is carried out under 22 ℃ of room temperatures.

The result: the group calling of urea oxygen is inhaled dwell time at 9 minutes 11 seconds to 20 minutes, average out to 11 minutes and 32 seconds.

The matched group white mice respiratory arrest time is at 6 minutes 15 seconds to 9 minutes and 20 seconds, average out to 7 minutes and 30 seconds.

Two groups of significant differences (P＜0.001)

Test shows that injection urea oxygen has the laboratory animal of raising hypoxia-bearing capability.

3, urea oxygen is to the therapeutical effect of anoxia animal

Method: select 32 of healthy rabbits, female 15, male 17, body weight is made urea oxygen group for 1.57～3.88 kilograms, and other gets 11 of healthy rabbits, and female 6, male 5, body weight 1.85～3.52kg compares group.Fixedly rabbit exposes a side femoral artery, and after the oxygen determination dividing potential drop of drawing blood, the control air inflow of masking is per hour measured partial pressure of oxygen by the femoral artery blood drawing then to form anaerobic condition, when controlling air inflow after 2～3 hours, PaO ₂Reduce to 〉=10mmHg person, be considered to anaerobic condition, promptly begin to handle.

Urea oxygen group: quiet contains urea oxygen 1% glucose 30ml, drips off in 60 fens kinds.Divide immediately, 0.5,1,2,3,4 hour 6 times from 1 milliliter of femoral artery blood drawing, the oxygen determination dividing potential drop is also observed respiratory change.

Matched group: quiet 10% glucose 30ml, all the other methods are with urea oxygen group.

The result:

Quiet urea oxygen of urea oxygen group PaO after 0.5,1,2,3 hour ₂Than obviously raising before the administration, significant difference (P＜0.001) reached the peak 10.44mmHg that on average raises in 2 hours, and curative effect can be kept 4 hours, partial pressure of oxygen difference this moment still significantly (P＜0.05)

Matched group: in the time of 30 minutes, partial pressure of oxygen obviously raises (P＜0.05) at quiet 10% glucose, and all the other there is no rising in 1～4 hour.

Experiment shows that urea oxygen is effective to the anoxia treatment of animals.

4, safety test

With 5 of the healthy mices of body weight 17～20 gram, respectively by the urea oxygen solution 0.24ml of tail vein injection 1%, annotate speed and be no less than 1 minute, observe and have or not death and active situation; 10 of white mice if any death should be got body weight 18～19 gram in addition continue test according to last method.Observe death and the active situation of white mice in 48 hours.

Through test, white mice does not have death in the vein urea oxygen 48 hours, and is therefore safe in utilization.

The clinical research result of urea oxygen is as follows:

1, influence the development effect factor:

Clinical research shows that the development effect of urea oxygen and its working concentration and injection speed have substantial connection.1% low concentration be use amount greatly to 20ml, development effect is also not ideal enough, also can obtain ideal development effect (seeing the following form) and 5% concentration is use amount below 1ml.

The relation of urea oxygen concentration and development effect

Concentration	Consumption	Visualization ratio (person-time)	Apparent rate (person-time)
1％	10	25％ (6/24)	75％ (18/24)
1％	20	34％ (21/25)	16％ (4/25)
5％	0.5	100％ (182/182)	0 (0/182)

Urea oxygen development effect is except that outside the Pass having with working concentration, and is also closely related with injection speed.

It is good with the interior development effect than the speed of injecting more than 10～20 seconds or 20 seconds at 10 seconds to inject speed controlling, and the former visualization ratio reaches 97.989 (195/199 person-times), and the consequence visualization ratio is 44.1% (14/29 person-time), void in whole then more than 20 seconds.

2, image occurs and holds time:

A large amount of clinical cases are observed, and image occurs in 4～21 seconds after injecting urea oxygen, and image holds time and may persist to 1 minute, illustrates that urea oxygen has the fast and persistent characteristics of time of developing, for diagnose, observation analysis image and film making provide time enough.

3, adverse reaction rate and dose relationship:

The presentation of results urea oxygen adverse reaction rate and the dosage of clinical observation 589 examples have substantial connection.In doing " interior oxygen supply " treatment, using dosage lg, adverse reaction rate are 28%; When acoustic contrast, 49 examples of 0.1～0.2g dosage group, adverse reaction rate is 128 examples of 4%, 0.025 dosage group, adverse reaction rate is 2%.This shows that adverse reaction rate descends along with the minimizing of dosage.The dosage that acoustic contrast uses is little, and untoward reaction is few and light, and is therefore safe in utilization.

4, clinical practice:

The attached First Academy of Hunan medical university makes contrast medium with urea oxygen and 127 routine clinical plans are examined the cardiac carries out acoustic contrast, obtains promising result, and method and result are as follows:

Method

(1) object of observation: 127 routine clinical plans are examined among the cardiac, male 73 examples, women 54 examples, minimal ages 57 days, maximum 70 years old age, 11 people below 10 years old, 4 people more than 50 years old.

(2) drug dose and use:

Contain urea oxygen 1 gram of hydrogen peroxidase 10 .3 gram, the injection normal saline solution with 0.9% is mixed with 5% urea oxygen solution for standby.

Selecting the shallow table vein at hand, forearm or other positions with 1-2ml syringe and scalp intravenous needle is that point of puncture is injected urea oxygen, once inject 0.4～0.5ml, 0.3ml below 10 years old, not one year old person 0.2ml, can repeat to inject, per injection blanking time is 4～5 minutes, or treats that last time image was injected after disappearing again.Cyanosis type cardiac consumption cuts down according to the circumstance.

3, result:

127 examples are all succeedd through 182 person-times of quiet notes urea oxygen solution acoustic contrasts.Positive findings 49 people wherein, acoustic contrast meets the congenital heart disease room and lacks person 25 people, and the chamber lacks person 16 people, endocardial cushion defect 2 people, Le Shi tetra logy 2 people, coronary sinus vein is expanded 1 people, and all the other 3 people still need do further inspection.The room lacks 4 people and the chamber lacks the capable defect repairing art of 5 people, and post operative diagnosis conforms to the acoustic contrast diagnosis.Have 3 examples carrying out occurring the property a crossed minor response in the acoustic contrast process with urea oxygen: 1 example cough, 1 example is uncomfortable in chest, the dizzy headache of another example, this may be owing to due to part pulmonary capillary one property crossed oxygen bolt, must not handle especially.

Clinical practice shows urea oxygen as the cardiac acoustic contrast agent, and easy to use, expense is low, and the cloud echo that the injection back occurs is even, contrast is big in the blood, and development effect is good, and the effect of paying is little, be ideal acoustic contrast, and this medicine is solid dosage forms, is easy to carry about with one and deposits.

The clinical observation result of example is also consistent with the attached First Academy surplus the Annex II hospital 4340 of Hunan medical university, none example death among the routine radiography patient surplus in the of 4340, non-cyanosis type patient is except that having of short duration slight dry cough, headache, extremity or facial slight numbness individually, there is not other untoward reaction, at the congenital heart disease of cyanosis type or have among the patient of pulmonary hypertension and once had 1 example that severe headache is arranged, continue three hours, after last oxygen, rest, alleviate no sequel; Other perspires after the scarce patient infusion in the big chamber of two examples is arranged, fidgety, bradycardia, and promptly recover half an hour after last oxygen, medication in time, also do not have sequela, and safety is good.

For avoiding child and cyanosis type congenital heart disease patient's untoward reaction, need the working concentration of urea oxygen, dosage and blanking time strict control.

Therefore to make acoustics contrast agent developed image clear, stable for urea oxygen, and positive check result and surgical outcome all meet, and are better than at present other acoustic contrast of employing both at home and abroad, and safety, the effect of paying is little, easy to use, expense is low, especially is fit to third world countries' needs.

Claims

1, a kind of acoustic contrast of diagnosis of cardiovascular diseases is characterized in that this contrast agent is urea oxygen CH ₄N ₂OH ₂O ₂Urea and 14% above hydrogen peroxide are being carried out inclusion reaction with the ratio of 1～4M: 1M below 75 ℃, after filtration, filtrate is being lower than crystallization under 20 ℃ the temperature conditions, aseptic subpackaged after decompress filter drying or the lyophilization, content of hydrogen peroxide is 25～36%.