JPH01249062A - Outside body circulation circuit - Google Patents

Abstract

PURPOSE:To provide a system for the remedy of the malignant tumor by installing a blood circulating flow passage which separates a portion of the blood plasma composition in the blood taken out from a living body by a blood plasma separator and treats said component by salts or acids and returns the blood plasma treated in an adjusting device and the residual blood component into a living body. CONSTITUTION:The blood taken out from an artery A is introduced into a blood plasma separator 4 by a pump 2, and a portion of the blood plasma component is separated by the blood plasma separator 4, and the residual blood component is returned into a vein V1. While, the blood plasma separated by the blood plasma separator 4 is introduced into a treating agent accommodation container 9 in which a treating agent consisting of acids is previously accommodated, by a pump 8. At this time, if a constant quantity of the blood plasma is sent into the container 9. The blood flow from the artery A is suspended. Then, after the blood plasma and the treating agent are mixed for a certain time in the container 9, the salt concentration and pH of the blood plasma are adjusted according to the environment in a living body by an adjusting device 14, and the blood is returned into the vein V2 by a pump 17.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) Tumor The present invention relates to an extracorporeal WI ring circuit used for the treatment of malignant tumors and the like.

(Conventional technology) Autoimmune diseases including malignant tumors J! L% liver failure, DIC,
"Double filtration plasma separation and exchange method" as a treatment method for intractable diseases such as hyperlipidemia (edited by Tetsuo Agishi, Igakushoin, 1984)
) has been proposed.

In this method, blood is continuously drawn from the patient, separated into plasma and blood cells using a separation membrane, and the large molecular weight fraction is removed from the obtained plasma using another separation membrane (albumin fraction). The blood is returned to the patient along with the blood cell components. The above-mentioned large molecular weight components contained in plasma are thought to be various specific and non-specific immunosuppressive substances present in the blood of cancer-bearing patients, for example. Immunosuppressive substances that belong to the large molecule TH class, for example, form large matrices in which various substances such as antigens, antibodies, and complement bind to antibodies produced by the surface of malignant tumor cells as specific antigens. It is believed that these are immune complexes formed. In patients with malignant tumors.

These immunosuppressive substances cause a decline in immune function, and as a result of the complex interplay of these substances and other factors, tumor cells deviate from the normal immune surveillance mechanism and grow and metastasize. It is said that then. Therefore, malignant tumors can be improved by selectively removing large molecular weight fractions as in the above method. However, such methods of removing immunosuppressive substances do not have the effect of actively attacking malignant tumor cells and causing necrosis. Furthermore, when removing large molecular weight fractions using a separation membrane, there is a risk that a portion of plasma proteins necessary for living organisms may also be removed.

Examples of improvement in malignant tumors by treating blood include:
In addition, there is a report by Takeshi Shiraki titled "Acute tumor necrosis resulting from intravenous administration of serum from tumor-bearing rabbits treated with hypertonic saline."
(Clinical Immunology, June 1986 issue, pages 544-547). According to this report, serum obtained from a tumor-bearing rabbit is mixed with a concentrated sodium chloride aqueous solution, and the sodium chloride concentration is reduced by dilution or dialysis.
Blood is again returned to the treated area by intravenous injection. It has been confirmed that cancer shrinkage is caused by such treatment. However, according to Shiraki's method, there is a risk that contaminants may be mixed in during each step such as blood collection, serum (or plasma) separation, treatment with aqueous sodium chloride solution, and intravenous injection, and these must be done aseptically. This requires a very complicated operation.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and its purpose is to provide a system that can effectively treat malignant tumors and the like. Another object of the invention is to
It is an object of the present invention to provide the above-mentioned system which can treat malignant tumors easily and safely by processing body fluids from a living body, particularly blood, and without limiting the reaction time depending on the length of the flow path or the like.

(Means and effects for solving problem a) The extracorporeal circulation circuit of the present invention (a) introduces the 111 fluid collected from the living body into a plasma separator to separate a part of the plasma components, and a blood circulation channel for returning blood components to the living body, and a plasma channel for introducing the plasma components separated by the plasma separator into a processing agent storage container containing a processing agent made of salt or acid; , (c) the container in which the plasma component and the treatment agent are mixed; (d) the plasma treated in the container is transferred to the in-vivo environment 1.
An extracorporeal circulation circuit comprising: a flow path leading to an adjustment device for adjusting ζ; (e) the adjustment device; and (f) a flow path for returning plasma processed by the adjustment device to the living body. This circuit 1 achieves the above object.

An example of the extracorporeal circulation circuit of the present invention is shown in FIG.

Before flowing blood into the circuit, add physiological saline (α15MNa) in advance.
In C1), all the circuits except the processing agent storage container 9 are pre-primed. Blood collected from artery A is
The plasma is then introduced into a plasma separator 4 by a pump 2. A part of the plasma components is separated by the plasma separator 4, and the remaining blood components are returned to the vein V via the tube 5.

This flow path constitutes a blood circulation flow path. Note that the pressures at the inlet and outlet sides of the plasma separator 4 are detected by pressure detectors 3 and 6, respectively.

On the other hand, the plasma separated by the M separator 4 is
Thereafter, the pump 8 introduces a processing agent made of salt or acid into a processing agent storage container 9 in which a processing agent is stored in advance. tube 7
and pump 8 constitute a plasma flow path. At this time, the connecting portion 10 of the container 9 with the further downstream side is closed, and when a certain amount of plasma is sent to the container, the blood flow from the blood flow ff1A is stopped.

After processing the plasma and the processing agent by mixing them in the container 9 for a certain period of time, the connection part 10 is opened, and the processed plasma is passed through the Chague 11 and flowed into the regulating device 141 by the pump 12 into the cell. .

The salt concentration and pH of the plasma treated with the treatment agent are adjusted to the in-vivo environment by the D adjustment device [14]. Next, the adjusted plasma passes through the pipe 15, passes through the pipe 18 by the pump 17, and is returned to the vein V. The inlet and outlet pressures of the regulating device 14 are detected by pressure sensors 13.16. At this time, by connecting the Chaeg 18 to the tube 5, the adjusted plasma may be combined with the blood components in the chineap 5 and returned to the living body through the vein v1.

As the processing agent containing salt or acid contained in the container 9, it is preferable to use a hypertonic inorganic salt solution or an organic salt solution as the salt, and an acidic solution as the acid. Inorganic salts used include sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate, sodium phosphate,
These include potassium phosphate, ammonium phosphate, ammonium sulfate, sodium phosphate, and potassium borate. Organic salts include, for example, sodium citrate, potassium citrate, sodium acetate, potassium acetate, sodium birophosphate, potassium birophosphate, sodium phthalate, 7
Potassium chlorate, sodium heptalate, potassium hexamalate, sodium tartrate, potassium tartrate, sodium succinate, potassium succinate, sodium formate, potassium lactate, sodium lactate, and potassium lactate. moreover"
q PIPE, known as a component of Good's buffer solution
S-sodium, PI PE5-caritum, MOPS
-Sodium, MOPS-Calitum, HEPES-Sodium, HEPES-Calicum, Tris-hydrochloride, Glycine-hydrochloride, Tricine hydrochloride, TAP S-
sodium, TAPS-caritum, CAPS-sodium, CAPS-caritum, TES-sodium,'
Examples include rES-Calicum and Bicine hydrochloride. The above-mentioned inorganic salts and organic salts can be prepared by pi('4:a
Provide a buffering effect in the range of O to aO, or use an appropriate l! It is preferable to adjust the pH to a range of aO to aO using an equilibrating liquid. These inorganic salts or organic salts are used in an aqueous solution (hypertonic salt) of 0.5 M or more, preferably about 1 to 4 M, at a rate of α1 to 100 ml per 1 ml of plasma. Of these, hypertonic aqueous sodium chloride solutions are particularly suitable.

As the acidic solution, a common aqueous inorganic or organic acid solution such as hydrochloric acid, phosphoric acid, acetic acid, or citric acid can be used, and various acidic buffers are preferably used. Examples of acidic buffers include glycine-hydrochloric acid buffer, citrate buffer, acetate buffer, phosphate buffer, borate buffer, and potassium phthalate-hydrochloric acid buffer. The pH of the acidic aqueous solution when mixed with plasma is below &0, preferably below 15 (usually
10" mole or more).

For some reason, treatment with a treatment agent consisting of a salt or an acid is thought to induce a factor that acts aggressively against malignant canker sores. Become.

The volume ratio of plasma to the processing agent is not particularly limited. For example, if the treatment liquid is a 3M sodium chloride aqueous solution for 100 d of plasma, it is desirable that the treatment time be 10 d to 200 d. When using a sodium chloride aqueous solution with an even lower concentration, a larger amount of processing agent is required.

The flow rate at which plasma is sent to the processing agent storage container 9 is not particularly limited, but must be at a level that does not cause clogging of the blood separator.

The processing agent storage container 9 is made of commercially available vinyl chloride 200 d
b> 400 ml (Dm liquid/<7g, 500ml
nebh et al. 1000 me infusion bag or 100
Although it is convenient to use a me blood transfusion chamber, the type thereof is not limited.

It is desirable that the processing time for plasma and the processing agent in the processing agent storage container 9 be 10 minutes or more.

There are many types of plasma separators 4 commercially available, but the types are not limited. Most of the commercially available products are of the hollow fiber type, and there are various materials such as cellulose acetate, polyvinyl alcohol, polypropylene, and polyethylene, all of which are suitable.

The adjustment device 14 has a function of adjusting the plasma treated with the treatment agent to the in-vivo environment. For example, it is a device that performs desalination and neutralization, and has the function of adjusting plasma, which has a high salt concentration or low pH due to the above processing, to the original in-vivo environment. Desalination equipment includes dialysis equipment,
An ion exchanger, a gel filtration device, an ultrafiltration device, etc. are used, and a dialysis device, an ion exchanger, etc. are used as the neutralization device.

For example, a hollow fiber type dialyzer is suitable as the dialyzer. Moreover, the dialysis method under supply pressure is particularly suitable because desalination and dehydration can be performed simultaneously. In addition, ion exchange f
# To remove NaCl, for example, using fat, N
The anion exchange resin columns except for "a" and the anion exchange resin columns except for CI- are arranged in sequence. The Glu filtration device includes a liquid feeding path for removing salts that are eluted later than plasma components out of the circuit. In addition, if a hollow fiber type ultrafiltration device is used and the pressure on the outside of the hollow fiber is made positive,
Low-molecular compounds such as salts inside the hollow fibers come out of the hollow fibers together with water and are removed, while high-molecular compounds are not removed.
This is advantageous because the total volume of plasma treated as described above can be reduced by dehydration and the concentration of effective macromolecular compounds can be increased.

In addition, if plasma that has been desalted or neutralized using a dialysis device, ion exchanger, gel filtration device, etc. is further treated with such an ultrafiltration device, it will be dehydrated and concentrated, so this embodiment is also applicable. suitable.

Pumps and pressure detectors are installed at appropriate locations in the circuit.There are many commercially available products for these, and any of them can be used. Examples include type pressure detectors.

In another embodiment of this circuit, it is also possible to remove the mixture of plasma and salt or acid treatment agent introduced into the treatment agent container 9 and store it for a certain period of time. The circuit is then used as follows. 2nd circuit
As shown in the figure, a certain amount of plasma is sent to the container 9 and treated by mixing for a certain period of time.
Separate and store at low temperature. Thereafter, when in use, the circuit is used as shown in FIG. 3, the tip 11 is attached, and the pump 12 causes the flow to flow into the regulating device [14].

The adjusted plasma is transferred to the chain 1 by the pump 17.
8, blood was returned to Shizu aRvt.

(Example) Example 1 Tumor cells Vx2 were subcutaneously transplanted into the backs of 10 domestic rabbits.

Twenty days after the transplantation, the circuit of the present invention shown in FIG. 1, in which the treatment agent storage container 9 had been removed (the entire circuit had been brimmed), was connected to the artery A of five of these birds with heparin-containing physiological saline. Henohydrin supply 1a to the blood coming out from artery A
From 19 to/(Phosphorus was supplied as an anticoagulant.

This blood is introduced into a plasma separator 4 (manufactured by Asahi Medical Co., Ltd., trade name: Nigekuzumaf 0-AP-03H0), one part of the plasma component is separated, and the remaining blood component is passed through a tube 5 and sent from a protamine supply device 20. Procumin was added to neutralize the hebalin and then blood was returned to the vein vl.

30 ml of the separated plasma component was flowed into the blood bag 9 containing 30 me of 3M sodium chloride aqueous solution at a flow rate of z5i over 12 minutes. Clean the blood bag (
After shaking, it was left to stand for 10 minutes. Thereafter, the connection part 10 was opened, and the sodium chloride-treated plasma was transferred at a flow rate of 5°0 me/us to a conditioning device (manufactured by Asahi Medical Co., Ltd., product name: AM-03°) 14 consisting of a hollow fiber dialysis column. It was sent to desalinate. Desalted plasma has a sodium chloride concentration Ql
After passing through the cheese 18 and adding protamine from the protamine supply device 20, it was injected into the vein V. The time required for implementation was approximately 40 minutes. The remaining five birds were prepared as a control group without treatment. As a result of blood processing using the circuit of the present invention, the average diameter of tumors in the control group 10 days after treatment was 20.
- while the treated group was 15d. Also,
The survival rate in the control group was 40% at 40 days after transplantation (20 days after transplantation), but it was 80% in the treated group.

Example 2 Tumor cells Vx2 were transplanted into the thighs of 10 domestic rabbits. Twenty days after transplantation, five of the birds were connected to the circuit of the present invention as shown in FIG. All of the circuits, except for the processing agent storage container 9, had been previously brimmed with a physiological saline solution containing phosphorus. Heparin was supplied to the blood discharged from the artery A from the He/4 phosphorus supply device 19 as a blood coagulation inhibitor. This blood is introduced into a plasma separator 4 (manufactured by Asahi Medical Co., Ltd., product name: Plasma Flow AP-03Ho),
After separating a part of the plasma components and passing the substitute blood components through the chain 5 and adding protamine from the protamine supply device 20, the blood was returned to the static M Vl.
The photoseparated plasma component 30-
3M sodium chloride aqueous solution ff30wn at a flow rate of ml
/ was stored and allowed to flow into the blood bag 9. The blood bag filled with plasma was separated from the circuit and incubated at -20"C for 3
After storing for a day, it was thawed. The thawed blood bag 9 was connected to the circuit as shown in FIG. 3 so that the plasma treated from the same individual could flow into it. In addition, prior to connection, the circuit was pre-brimmed with physiological saline. next,
The mixture in the blood bag 9 was sent at a flow rate of 5.0 ml/un to a conditioning device 14 consisting of a hollow fiber dialysis column (manufactured by Shio Medical Co., Ltd., local product name: AM-03) for desalination. Plasma whose sodium chloride concentration had been reduced to 0.15 M by desalting was passed through Chague 18, and after addition of protamine, it was injected into vein V. Ten days after the treatment, the average thigh muscle width of the five birds in the control group was on the 4.0 side, whereas it was on the &2 side in the treated group. The average survival time after transplantation was 48 days in the treated group compared to 35 days in the control group.

(Effects of the Invention) As described above, malignant tumors and the like can be effectively treated using the circuit of the present invention. The basic operation is to process the patient's blood and return it, so it does not put a burden on the patient's body like a surgical operation, there is almost no loss of plasma proteins during processing, and there is no external Because the circuit is isolated from the environment, there is no contamination by N bacteria and it is safe.

In addition, by using a container containing a processing agent made of salt or acid as a processing container for processing the processing agent and plasma components, the processing time can be limited by the length of the flow path, etc. The device can be made smaller because it can be changed freely.

Furthermore, by using a container, the circuit can be separated at once, thereby shortening the administration time, making it possible to administer the treated plasma at an appropriate time, and further reducing the burden on the patient.

As described above, the present circuit can be used to effectively treat, for example, patients for whom surgery is difficult or patients with malignant lesions for whom anticancer drug administration is inappropriate.

[Brief explanation of the drawing]

FIGS. 1, 2, and 3 are explanatory diagrams in which the circuit of the present invention is applied to Kusai, etc., and the blood thereof is processed to treat malignant M tumors. It should be noted that FIGS. 2 and 3 are diagrams for separate implementation. A artery 11 tube v1. VL static IF 12 Honfu l tube 13 Pressure detector 2 Pump 14
Adjustment device 3 Pressure detector 15 Tube 4 Plasma separator 16 Pressure detector 5 Tube
17 Pump 6 Pressure detector 18 Tube 7 19 Henokirin supply device 8 Pump 20 Procumin supply device 9 Processing agent storage container 10 Connection part and above

Claims (1)

[Claims] 1. (a) A blood circulation channel for introducing blood collected from a living body into a plasma separator to separate a part of the plasma components and returning the remaining blood components to the living body; (b) a plasma flow path for introducing the plasma component separated by the plasma separator into a processing agent storage container containing a processing agent consisting of a salt or an acid; , the container in which the plasma is mixed; (d) a flow path leading the plasma processed in the container to a conditioning device for conditioning it to an in-vivo environment; (e) the conditioning device; f) an extracorporeal circulation circuit comprising: a flow path for returning the plasma processed by the conditioning device to the living body;