JPH0512946B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a continuous hypertonic salt treatment device for blood, and more specifically, to continuous hypertonic salt treatment of the blood of a cancer-bearing individual to treat blood of the same species as the cancer-bearing individual. This device relates to a new device that can transform plasma into plasma that selectively exhibits a pronounced anticancer effect on cancer cells, and can be used as a treatment device for cancer patients and as an anticancer plasma (or serum)
It can be used as a manufacturing device.

[Prior art and technical issues to be solved]

Plasma (serum) of cancer-bearing individuals was collected using the Staphylococcus aureus Cowans strain.
I) and its bacterial cell membrane component protein A
Bansal has already reported that when protein A is perfused and then returned to the individual, its expression immediately induces a highly specific antitumor effect (tumor necrosis) selectively against the tumor. .
SC, Terman DS, RayP.K, Holohan TV,
There have been thorough studies by researchers such as, and they have been reported in detail.

Therefore, when examining the cause of tumor necrosis phenomenon and the mechanism of action of plasma perfusion in the above research report, we found that the amount of protein A required for tumor necrosis is too small and that passive injection is effective. Therefore, it is difficult to say that the mechanism of action is the removal of immunosuppressive substances, as originally thought by Dr. Bansal, and protein A may be used in ways that are negative to the leakage of bound substances, such as covalent bonds. Since tumor necrosis occurred even when a fixed column was used, it is difficult to say that leakage of bacterial substances is an essential requirement as claimed by Dr. Terman, and in the end, in light of the research results of Dr. Holohan, The plasma (serum) of a tumor-bearing individual is necessary for the expression of tumor necrosis, and the result of the reaction between this tumor-bearing individual's plasma and staphylococcus or protein A plays an important factor. We should think that there is. However, this theory of Holohan et al.
At present, this remains only a guess, and much remains to be done in future research to elucidate the true mechanism of action that causes tumor necrosis.

By the way, in actual cancer treatment, plasma exchange of cancer patients is often attempted in hopes of removing immunosuppressive substances or having some kind of anticancer effect. There have been very few reports of such dramatic tumor necrosis, and on the contrary, the very recognition of the phenomenon of strong selective necrotic effects on rapidly developing tumors has been called into question. Because this is not fully understood, staphylococcal substances are being directly administered blindly, exposing patients to extremely dangerous situations, and it is humanely problematic to leave them as they are. be.

Under these circumstances, elucidating the mechanism of the strong antitumor effect mentioned above and establishing a safe method and system for cancer control are urgent tasks that can be called the common aspirations of all humankind.

Therefore, the present inventor conducted theoretical and experimental research through repeated trial and error on the correlation between the antitumor effect and the plasma of cancer-bearing individuals, as well as the mechanism of action when serum causes tumor necrosis. It is caused by the denaturation and dissociation of immune complexes that occur as a result of being in a tumor-bearing state as a substance that specifically exists in the plasma of cancer-bearing individuals, and tumor-related antibodies (anti-tumor antibodies) exist as the active substance. I have come to believe that this is the case.

However, regarding the method of immune complex dissociation,
Although various proposals have been made in the past, the present inventor proposed that hypertonic salts (for example: 0.5 mol of potassium chloride,
We obtained new knowledge that treating the plasma of a tumor-bearing individual with 1.5 moles of sodium chloride can dissociate immune complexes with less denaturation.Based on this knowledge, we conducted further tests.
When autologous plasma of a cancer-bearing individual treated with the hypertonic salt at room temperature (21°C) to 37°C for about 30 minutes or allogeneic plasma of an individual with the same type of tumor is injected intravenously,
We have discovered that this method causes acute tumor necrosis that is extremely similar to that seen when using biologics such as staphylococcus or protein A.

Needless to say, the salt used in the above-mentioned hypertonic salt treatment is an extremely physiological substance, and its safety is far superior to, and incomparable to, the case of using the previously well-known biological preparations mentioned above. However, the salt concentration adopted is extremely non-physiological and requires desalting or dilution operations before administration to living organisms. In addition, generally speaking, not only is the amount of plasma (serum) in living organisms limited, but also the plasma (serum) of cancer-bearing individuals with their own or similar tumors is extremely valuable. There is a need for technology that can efficiently process the data without imposing an unreasonable burden on people.

An object of the present invention is to provide a new device that can safely, continuously, and efficiently perform hypertonic salt treatment of plasma (serum), which can exhibit outstanding antitumor effects as described above.

[Technical means adopted to solve the problem]

The present inventor has completed a "continuous hypertonic salt treatment device for blood" by skillfully and systematically linking the technical means listed in A to E below, and has succeeded in solving the above technical problem. It is.

That is, the present invention provides: A. An anticoagulant adder for adding an anticoagulant to blood collected from a cancer-bearing individual and flowing through a conduit; B. An anticoagulant is added and delivered at a predetermined hydraulic pressure. A plasma separator that separates and extracts plasma from blood; C A salt adder that adjusts the plasma separated and extracted by this separator to a predetermined salt concentration by mixing hypertonic salt; D. A delay reactor that allows the plasma to flow slowly to cause a contact reaction between the plasma and hypertonic salts; The subject matter is a continuous hypertonic salt anti-cancer treatment device for blood, which includes technical means such as: a salt concentration reducer;

Therefore, I would like to add a comment regarding the above technical means constituting the present invention.

First, in the above technical means A, "cancer-bearing individual"
means a cancer patient or an animal that has developed cancer naturally or has been caused to develop cancer by transplantation of cancer cells or administration of carcinogens. An "additive" that mixes anticoagulant into the blood collected from cancer-bearing individuals.
As such, well-known instruments commonly used in conventional blood transfusion methods are appropriately adopted. Further, as the "anticoagulant", sodium citrate that removes calcium ion of a coagulation factor, heparin that antagonizes thrombin, coumarin derivatives and indandione derivatives that reduce prothrombin, etc. are used.

Next, as a plasma separator, red blood cells, white blood cells,
It has an excellent separation function that does not allow formed components such as platelets to pass through, yet allows proteins with molecular weights of several million units (the most important "immune complexes") to pass through effectively. When adopting a return configuration, the blood and plasma volumes should be kept as small as possible (preferably 30 ml or less) in order to reduce the burden on patients who are in a physically weakened state.
It is necessary to stop it. Therefore, an ultrafilter such as a hollow fiber dialyzer having holes of about 0.2 μm may be suitable as the plasma separator of the present invention.

Next, as a salt adder, use a well-known dropper filled with hypertonic salt solution, a forced salt solution infusion device equipped with a pump or other means of pumping, or a membrane-type hemodialyzer that does not filter albumin. be able to. When using a hypertonic saline dropper or syringe, connect it to the plasma conduit to increase the salt concentration of the plasma separated and extracted by the plasma separator to a hypertonic state (using sodium chloride). When using potassium chloride, the plasma salt concentration is 0.75 to 2.0 mol, and when using potassium chloride, the plasma salt concentration is 0.25 to 1.0 mol). Also,
When a membrane-type hemodialyzer that does not permeate albumin is used as the salt adder 3, a hypertonic salt solution is used as the dialysate, and the plasma separated and extracted from the plasma separator 2 is filtered through the hemodialyzer. Accordingly, the salt concentration shall be adjusted as described above.

Next, as a delay reactor, diameter 0.3
Although it is possible to use a winding conduit constructed by winding a ~1.0 cm plastic tube in a coiled or zigzag shape, or to use a well-known model hemodialyzer that does not permeate albumin, either Even when using a type of day-time reactor, its internal volume is 10 to 100
ml is ideal. This is because at room temperature (21°C) to 37°C, it is necessary to ensure a contact reaction time of at least 30 minutes between the plasma components and the hypertonic salt. It is convenient to arrange this delay reactor in such a way that it can be replaced so that the flow rate of the processed plasma can be changed depending on the use, and in this sense, various types of delay reactors configured in a cartridge type can be prepared as attachments. It is preferable to keep it.

Next, as the salt concentration reducer, a model hemodialyzer that does not permeate albumin or a diluent injector can be used. If the former type of dialyzer is used, desalination should be performed by osmotic pressure using a hypotonic solution such as 0-5% glucose solution, 0-1% saline, or a well-known hemodialysis solution. I can do it. In addition, if the latter diluent injector is adopted, the diluent should be 0 to 5
% glucose solution, 0 to 1% saline solution, or distilled water is used, and the hypertonic salt-treated plasma is mixed with this to an extent that the concentration is isotonic.

In addition, when using the present invention as a cancer treatment device, an infusion adder is attached to the injection tube to dilute or add a thickener to adjust the viscosity of the liquid, or to add therapeutic drugs such as vasopressors and antibiotics. Intervene or
It is free to install a neutralizer adder for adding a neutralizer to eliminate the effect of the anticoagulant.

The basic means constituting the present invention are as described above. However, when actually producing the present invention as a device, it is necessary to intervene with a blood pump or constant pressure device that pumps blood at a required speed, add a self-control mechanism using a salt concentration sensor, or add a self-control mechanism using a salt concentration sensor. A storage pack is inserted to store the above-mentioned treated plasma that has reduced the amount of plasma, and furthermore, the remaining tangible components such as red blood cells, white blood cells, and platelets from which the plasma component has been separated in a plasma separator are sent to a collection tube. However, the present invention naturally contemplates adding a mechanism for combining the hypertonic salt-treated plasma flowing from the salt concentration reducer or reservoir and supplying it to the syringe.

As has become clear from the above explanation, the device of the present invention can be used as a cancer treatment device when connected to the blood vessels of cancer patients, and can also be used to produce antitumor plasma by collecting the treated plasma supplied from the salt concentration reducer. It becomes a device. Of course,
It goes without saying that when the device of the present invention is used as an anti-tumor plasma production device, cancer-bearing individuals are target organisms other than humans.

As a precaution, please use the plasma separator, salt adder,
The preferred performance items for the delay reactor are summarized and listed as follows.

(a) Plasma separator: Allow proteins with molecular weights in the millions to leak freely, but do not allow red blood cells, white blood cells, and platelets to pass through.

A plasma flow rate of 25 to 200 ml/h is obtained, and
Dead space should be as small as possible.

(b) Saltizer: If a hollow fiber dialyzer is used, it must not allow albumin to pass through.

Whether using a dropper, syringe, or dialyzer, the plasma is
If the flow rate is 200 milliliters/hour, the plasma salt concentration can be adjusted to 0.75 to 2.0 mol for sodium chloride treatment and 0.25 to 1.0 mol for potassium chloride treatment.

(c) Delay reactor The internal volume must be 10 to 150 ml.

〔Example〕

Hereinafter, the present invention will be described in more detail based on embodiments shown in the accompanying drawings.

The apparatus disclosed in FIG. 1 is generally depicted as forming an extracorporeal circulation circuit for a cancer-bearing individual.

In the same drawing, the reference numeral 1 is an Irligator-type anticoagulant adder, which has the function of adding an anticoagulant to blood that is continuously collected from a cancer-bearing individual using a blood sampler _I1 and sent through a conduit S. has.
Incidentally, as the additive 1, it is of course possible to use a syringe equipped with forced pressure feeding means using a pump.
The blood to which the anticoagulant has been added by the adder 1 is pumped by a roller pump P ₁ with a pressure gauge,
The plasma is sent to a plasma separator 2.

What is designated by numeral 2 is a plasma separator. Plasma separator 2 adopted by this example device
is a membrane-type plasma separator (manufactured by Toray Industries, Inc., product name: PLASMAX PS-
02''), and the formed components such as red blood cells, white blood cells, and platelets are guided directly into the injection tube T and into the syringe I ₂
This is then injected into a cancer-bearing individual (patient) together with hypertonic salt-treated plasma, which will be described later.

The one designated by numeral 3 is a dropper type salter, which directly adds sodium chloride or potassium chloride solution. This salt solution dropper directly adds and mixes a sodium chloride solution with a concentration of 1.5 to 3.0 mol or more, or a potassium chloride solution with a concentration of 0.50 to 1.25 mol or more to blood plasma, and the salt concentration of the plasma is reduced to chloride. 0.75 for sodium
~2.0mol, for potassium chloride, adjust to 0.25~1mol. The plasma thus equilibrated with hypertonic salts or adjusted to a hypertonic salt solution is transferred to the plasma pump P ₂
and then led to a delay reactor.

The one designated by numeral 4 is a winding pipe type delay reactor constructed by winding a plastic tube with an inner diameter of 0.6 cm into a coil shape to have an inner volume of 60 ml, and is designed to have a temperature of 21 to 37°C. It has a built-in constant temperature mechanism to maintain the temperature. Plasma that has been contacted with hypertonic salts passes through the conduit for approximately 30 minutes, during which time it produces anti-tumor antibodies. The hypertonic salt-treated serum that has thus produced anti-tumor antibodies is sent to the salt concentration reducer 5.

What is designated by the code 5 is a salt concentration reducer, specifically a dialyzer (manufactured by Asahi Medical Co., Ltd.) that can be equipped with a large number of polyacrylonitrile hollow fibers that have a partition molecular weight of 55,000 and do not allow albumin (molecular weight 60,000) to escape. Product name:
"AHFUN") has been adopted. In this salt concentration reducer 5, 0-1% saline, 0-5% glucose solution, or the like is used as a dialysate to reduce the hypertonic salt-treated plasma to about an isotonic solution.

The plasma, whose salt concentration has been reduced in this way, is sent to a pack-type reservoir 6 via a constant pressure regulator 7 and stored therein, and further guided to an injection tube T to be inserted into a syringe I ₂
As a result, it is injected into a cancer-bearing individual (patient) together with the aforementioned formed components such as red blood cells, white blood cells, and platelets.

In addition, what is designated by the reference numeral 8 in the figure is a replenishment fluid adder 8, which is used to remove albumin when the concentration of blood cell components separately fed from the plasma separator 2 increases and the concentration becomes too high. Addition of viscosity-adjusting liquids such as containing liquids or electrolyte solutions, or administration of vasopressors, antibiotics, anticancer drugs, etc., when necessary to maintain control of the condition of an individual (patient) or amplify anticancer effects. It is used to replenish and add the required liquid agent at the appropriate time. Also, what is indicated by the reference numeral 9 is a neutralizing agent adder 9, which is used to add an antagonist corresponding to the previously used anticoagulant in order to eliminate the effect of the anticoagulant added in the above-mentioned adder 1. Or a neutralizing agent is added.

Although the device of this embodiment is generally constructed as described above, the present invention is by no means limited to the above-mentioned embodiments, and it should be noted that various modifications can be made within the scope of the claims. Needless to say, the present invention does not include, for example, replacing the plasma separator 2, salt adder 3, delay reactor 4, and salt concentration reducer 5 in the present invention with equivalent means or conventional means other than those shown in the Examples. There is no question that it falls within the technical scope of

〔Effect of the invention〕

As explained above with the examples, according to the device of the present invention, the blood of a cancer-bearing individual can be continuously treated with hypertonic salts, so that the blood can be treated with a marked effect selectively against cancer cells of the same type as the cancer-bearing individual. Plasma that exhibits cancerous effects can be easily obtained, exhibiting revolutionary efficacy as a cancer treatment device, and greatly advancing cancer immunotherapy.

As described above, the present invention greatly advances the control of cancer, which is a long-cherished desire of humankind, and its usefulness is worthy of international attention.

[Brief explanation of drawings]

FIG. 1 is a system explanatory diagram systematically representing the apparatus of the present invention. 1...Anticoagulant adder, 2...Plasma separator, 3
... Salter, 4 ... Delay reactor, 5 ... Salt concentration reducer, 6 ... Reservoir, G ... Conduit, 7 ... Constant pressure device, 8 ... Replenishment infusion adder, 9 ... Neutralization Agent additive, I ₁ ... blood sampler, I ₂ ... syringe, R ... collection tube, T ... injection tube.

Claims (1)

[Scope of Claims] 1 Addition device 1 for adding an anticoagulant to blood collected from a cancer-bearing individual and flowing through conduit G
and; a plasma separator 2 that separates and extracts plasma from blood to which an anticoagulant is added and which is fed under a predetermined hydraulic pressure.
and a salt adder 3 that adjusts to a predetermined salt concentration by mixing hypertonic salt into the plasma separated and extracted by this separator 2; and by slowly flowing the plasma mixed with this hypertonic salt. A delay reactor 4 for causing a contact reaction between the plasma and hypertonic salts; and a salt concentration reducing device 5 for reducing the plasma salt concentration flowing out from the delay reactor 4 to an isotonic level and flowing it to the collection pipe R. An apparatus for continuous hypertonic salt treatment of blood, characterized in that: 2. The continuous hypertonic salt treatment apparatus for blood according to claim 1, wherein a hollow fiber dialyzer with a pore size of about 0.2 μm is used as the plasma separator 2. 3 A dropper is used as the salt adder 3, and the dropper mixes a hypertonic salt solution into the plasma separated and extracted from the plasma separator 2 to reduce the plasma salt concentration to 0.3.
3. The method according to claim 1 or 2, wherein the amount is adjusted to 2.0 mol/.
Continuous hypertonic salt treatment device for blood. 4. A membrane-type hemodialyzer that does not permeate albumin is used as the salt adder 3, while a hypertonic salt solution is used as the dialysate, and the plasma separated and extracted from the plasma separator 2 is filtered through the hemodialyzer. The continuous hypertonic salt treatment device for blood according to claim 1 or 2, wherein the salt concentration is adjusted to 0.3 to 2.0 mol/. 5. Continuous hypertonic salting of blood according to any one of claims 1 to 4, wherein the delay reactor 4 is a meandering conduit constructed by winding a plastic tube with a diameter of 0.3 to 1.0 cm into a coiled shape. Processing equipment. 6. A claim in which a membrane-type hemodialyzer that does not permeate albumin is used as the salt concentration reducer 5, and a hypotonic solution is used as the dialysate to reduce the plasma flowing from the reactor 4 to an isotonic concentration. 6. The continuous hypertonic salt treatment device for blood according to any one of 1 to 5. 7 Using a syringe as the salt concentration reducer 5, add 0.5-5% glucose solution, 0-1% saline, distilled water, and other solutions for injection to the plasma flowing from the reactor 4. Claim 1-
5. The continuous hypertonic salt treatment device for blood according to any one of 5. 8. Continuous hypertonicity of blood according to any one of claims 1 to 7, wherein the hypertonic salt-treated plasma whose salt concentration has been reduced to an isotonic level via the salt concentration reducer 5 is stored in the reservoir 6. Salt treatment equipment. 9 Claim comprising a replenishment transfusion blood adder 8 for adding a conditioning solution such as an albumin-containing solution or a sugar/electrolyte solution, or a therapeutic agent such as an antibiotic or a vasopressor to the hypertonic salt-treated plasma flowing from the reservoir 6. 1~
8. The continuous hypertonic salt treatment device for blood according to any one of 8. 10 The remaining formed components such as red blood cells, white blood cells, and platelets from which the plasma components have been separated in the plasma separator 2 are sent to the collection tube R, and are collected from the salt concentration reducer 5 or reservoir 6, or from these 5 or 6. The blood is combined with the hypertonic salt-treated plasma flowing from the replenishment fluid adder 8 interposed between the two, and a neutralizing agent that eliminates the effect of the anticoagulant is added to the blood in the neutralizing agent adder 9, and then transferred to the syringe _I2 . The continuous hypertonic salt treatment device for blood according to any one of claims 1 to 9, comprising a supplying mechanism.