JPS6327430A - Activity enhancing substance inducer for blood stem cell colony-stimulating factor - Google Patents

Abstract

PURPOSE:The titled substance containing an adrenochrome derivative or salt thereof as an active ingredient. CONSTITUTION:An activity enhancing substance inducer for blood stem cell colony-stimulating factor (CSF) obtained by containing a compound expressed by the formula (A is NH, O or S) or salt thereof, e.g. 1-methyl-5- guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole, etc., as an active ingredient. Oral agents, e.g. tablet, capsule, granule, powder, liquid formulation, etc., parenteral agent, e.g. subcutaneous, intramuscular, intravenous injection, etc., may be cited as the dosage form thereof. The compound expressed by the formula will not individually enhance the activity of the CSF, but is capable of inducing a substance for enhancing the activity of the CSF. A CSF inducer, e.g. a lithium compound, etc., is preferably administered to living bodies as a method for providing the CSF therein. The dose thereof is 150-450mg/adult/ day for oral administration and 10-100mg/adult/day for injection.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is directed to the use of blood stem cell colony-stimulating factor when white blood cells decrease due to radiation irradiation, drug administration, disease, etc.
r.

A C3F activity enhancer inducer that restores a decreased number of leukocytes by inducing a substance that enhances the activity of C3F (hereinafter abbreviated as C3F as necessary) and promoting the differentiation and proliferation of blood stem cells into leukocytes. It is related to.

Conventional technology Originally, white blood cells do not have the ability to self-proliferate, and their lifespan is said to be only a few days.The homeostasis of the number of white blood cells in peripheral blood is maintained by differentiation and proliferation of blood stem cells such as bone marrow. There is. Colony stimulating factor (C5F) is known as a factor that stimulates the differentiation and proliferation of blood stem cells into white blood cells (neutrophils, macrophages, etc.).

For bone marrow disorders such as bone marrow disorders during radiation therapy, bone marrow disorders during chemotherapy with antibiotics, etc., and bone marrow disorders caused by diseases such as rheumatoid arthritis and Felty syndrome,
The patient's white blood cell count is markedly reduced.

When the number of peripheral white blood cells (neutrophils) is less than approximately 1,500 cells/mm3, treatment is often restricted due to bone marrow damage that easily invites bacterial infection.

Even when the number of white blood cells decreases, the body's homeostatic function works, so colony-stimulating factor (C5F) is naturally produced within the body, and the number of white blood cells gradually recovers. If the period is long, the patient's life will be at risk from bacterial infection during that period, so it is necessary to quickly restore the decreased white blood cell count to a normal level.

Currently, an effective drug that restores white blood cells once they have decreased has not yet been found, but as an alternative measure, in order to keep the decrease in white blood cells to a minimum during radiation therapy, it is possible to Various attempts have been made to administer radioprotective agents. The prior administration of radioprotective agents is aimed at scavenging radicals generated by radiation irradiation and preventing DNA damage.

Such radioprotective agents include cysteine, sodium cyanide, glutathione, cystyamine, cystamine, 2-
7minoethylisothiourea, 2-mercaptopropionylglycine, inosine, etc. have been proposed. Among these, cystiamine and 2-7minoethylisothiourea are representative, and glutathione and inosine are also said to be effective as radioprotective agents.

Recently, 1-methyl-5-guanylhydrazone-
Adrenochrome derivatives such as methanesulfonate of 6-oxo-2,3,5,6-tetrahydroindole (i.e., adrenochrome guanylhydrazone) and carbazochrome sodium sulfonate are commercially available as radioprotective agents.

Problems to be solved by the invention However, cystiamin as a radioprotective agent, 2
-7 Minoethyl isothiourea exhibits a strong radioprotective effect, but its toxicity is also very strong.
2-7minoethylisothiourea 657 mg/kg
(intraperitoneal administration), therefore the effective dose and LD,
Judging from the relationship with , it is difficult to say that cystiamin and 2-aminoethylisothiourea are safe drugs.

Glutathione and inosine are radioprotective agents with relatively low toxicity, but have the problem that their effective dosages are considerably large.

1-Methyl-5-guanylhydrazone-6-oxo-2
, 3,5,6-tetrahydroindole methanesulfonate, and carbazochromosodium sulfonate, the former has a slightly better radioprotective effect, but in both cases, the leukopenia suppressive effect due to its radioprotective effect is further enhanced. There was a desire to improve.

All of the above-mentioned radioprotective agents are administered before radiation irradiation to keep the decrease in white blood cells to a minimum, and are not intended to restore the once decreased white blood cell count.

Furthermore, according to the research of the present inventors, even if these protective agents are administered after radiation irradiation (or drug administration such as anticancer drugs)
Even after administration, no recovery effect or only a slight effect on white blood cell counts was observed.

However, since the degree of white blood cell reduction during radiotherapy or drug therapy such as anticancer drugs differs depending on the patient, administering a protective agent in advance is not necessarily an effective means, and as mentioned above, even the administration of a protective agent can reduce the number of white blood cells. In some cases, the decrease cannot be suppressed sufficiently.

In view of this situation, the present inventors have been conducting intensive research on drugs that can restore white blood cells that have decreased due to radiotherapy and drug therapy, and have developed a drug that induces a substance that enhances the activity of colony-stimulating factor (C3F). succeeded in finding a drug.

Means for Solving the Problems The present invention provides a blood stem cell colony stimulating method containing an adrenochrome derivative represented by formula 1 (wherein A is NH, O or S) or a pharmacologically acceptable salt thereof as an active ingredient. ``Factor activity enhancer inducer''.

The present invention will be explained in detail below.

Adrenochrome derivatives represented by the formula (wherein A is NHlo or S) include: (1) When A in the formula is NH, that is, 1-methyl-5-guanylhydrazone-6-oxo-2,3,5 ，
6-tetrahydroindole (i.e., adrenochrome guanyl hydrazone) or a pharmacologically acceptable salt thereof; ■ When A in the formula is 0, that is, adrenochrome semicarbazone or a pharmacologically acceptable salt thereof; (2) When A in the formula is S, that is, adrenochrome thiosemicarbazone or a pharmacologically acceptable salt thereof.

These adrenochrome derivatives may be free, but are preferably in the form of pharmacologically acceptable salts so as to impart water solubility. Examples of pharmacologically acceptable salts include methane. Salts of various organic or inorganic acids include sulfonates (mesylate type), ascorbates, oxalates, citrates, tartrates, lactates, acetates, hydrochlorides, and sulfates.

Among the above ①, ②, and ②, 1-methyl-5-guanylhydrazone-6-oxo-2,3゜5.6-tetrahydroindole of ② has a large inducing effect on the C5F activity enhancer, and is particularly effective in inducing C5F activity enhancers. Methanesulfonate is important.

The adrenochrome derivative or its salt does not itself enhance C5F activity, but rather induces a substance (polymeric substance) that enhances C3F activity.

Therefore, the above adrenochrome derivative or its salt is rC
It only performs its function in the presence of the 3Fs.

As one method for making C3F exist, a method of administering a C3FJ guide agent such as a lithium compound to a living body is suitably adopted. Here, examples of the lithium compound include lithium chloride and lithium carbonate.

Another way to make C3F exist is to introduce C3F into living organisms.
One example is a method of directly administering 3F.

Still another method of making C3F exist is to wait for the production of C5F by the natural recovery power of the living body.

Of these, the first method is currently the most effective. Furthermore, as CSF itself is expected to be approved as a drug, it is thought that the second method will also be effective in the near future. The third method can also be adopted depending on the patient's symptom status.

C5F stands for neutrophil-macrophage stem cell colony-stimulating factor (granulocyte-macropha).
geocolony-stimulating fact
or: GM-CSF), macrophage-based stem cell colony stimulating factor (macraphag
e colony-stimulating fact
or: M-C5F), neutrophil stem cell colony-stimulating factor (granulocyte colony-st
Imulating factor: G-C5F
), megakaryocytic stem cell colony stimulating factor (megakar
7ocyte colony-stimulatin
g factor: MK-C3F), multifunctional stem cell colony stimulating factor (multicolon7-s
Timulating factor: mult
iC5F).

The inducer of the present invention is administered orally as a tablet, capsule, granule, powder, liquid preparation, etc., and parenterally as a subcutaneous, intramuscular or intravenous injection solution.

If the inducing agent is water-insoluble, it is usually administered orally.

In the case of tablets, capsules, etc., binders (gelatin,
gum arabic, tragacanth, polyvinylpyrrolidone, etc.)
, excipients (lactose, corn starch, calcium phosphate, etc.), lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.), disintegrants (potato starch, etc.), lubricants (sodium lauryl sulfate, etc.) It can contain conventional excipients, such as suspending agents, emulsifying agents, non-aqueous vehicles, in the case of liquid preparations and injections,
Preservatives, stabilizers, etc. can be included.

For example, when C3F is induced by administration of a lithium compound, the timing of administration is 3 days after administration of the lithium compound.
It is desirable to administer the inducing agent of the present invention after about 4 days have elapsed.

This is because the lithium compound (LiC1・Hz
O) This is because colony stimulating activity appears several days after administration of the lithium compound, as shown in the pattern of appearance of colony stimulating activity induced in serum when 60 mg/kg was administered to 057B mice.

By selecting the timing of administration in this way, the white blood cell count can be recovered most efficiently. However, the optimal timing of administration varies depending on individual patient differences, symptoms, radiation dose, drug type and dosage, etc. Further, depending on the case, the inducing agent of the present invention may be administered in two or more doses, or may be administered simultaneously with the administration of the lithium compound.

The dose of the inducer of the present invention is often, for example, 150 to 45011 g per adult per day in the case of oral administration, and 10 to 100 g per day in the case of injection.

The toxicity of the inducer of the present invention is as follows in the case of methanesulfonate of 1-methyl-5-guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole.

Table 1 (L Dyo) mg/k
g Rats were given the above inducer at 800 mg/kg, 1600 m
As a result of continuous administration for one month of 3200 g/kg of intestines, no abnormal changes were observed in blood and urine biochemical tests, organ weights, pathological anatomical findings, and histological findings.

- 100g/kg of the above inducer to arrogant 11 rats, 400+*
As a result of continuous administration of 1600 mg/kg and 1600 mg/kg for 6 months, weight gain was suppressed in the high dose group. Biochemical tests of blood and urine revealed no abnormal changes. Histopathological findings showed that renal collecting ducts were enlarged to 1600 m
It was partially observed in the mg/kg administration group.

Next summer 1: 20mg, 200mg, lo for mice and rats
As a result of continuous oral administration of oOsg for 7 days from the 8th to the 14th day of pregnancy, no effects were observed on the mother, fetus, or newborn.

Target diseases to which the inducing agent of the present invention can be applied include bone marrow disorders during radiotherapy, bone marrow disorders during chemotherapy such as anticancer drugs,
Examples include diseases such as rheumatoid arthritis and Felty syndrome.

Effect The C5F activity enhancer inducer of the present invention has a mechanism of action that is fundamentally different from that of conventional radioprotective agents that are administered before radiation irradiation.

For example, when L-929 cell culture supernatant is added to C57BL mouse bone marrow cells and cultured, colonies are formed. This colony is a bone marrow stem cell that has been stimulated by colony stimulating factor (C3F) contained in the L-929 cell culture supernatant to differentiate and proliferate. An example of the inducing agent of the present invention for this colony forming culture. 1-Methyl-5-guanylhydrazone-6-oxo-2 as
, 3,5,6-tetrahydroindole methanesulfonate, the number of colonies formed actually decreases. In other words, the inducer of the present invention itself has the effect of suppressing colony formation.

However, when serum before or after administration of the inducer of the present invention is added to this culture, the number of colonies formed is greater when the serum after administration is added than when the serum is added before administration. To increase.

However, as mentioned above, when the inducing agent of the present invention itself is added to the colony-forming culture, colony formation is suppressed. It is reasonable to assume that this is because a substance that enhances C3F activity is induced.

When the serum after administration of the inducer of the present invention is treated at 56° C. for 30 minutes, the colony stimulation enhancing activity is lost. Moreover, even if the serum after administration of the inducing agent of the present invention is dialyzed to remove low molecules, the colony stimulation enhancing activity is not lost. This indicates that the C3F activity induced by the administration of the inducing agent of the present invention This indicates that the enhancing substance is a polymeric substance.

Induction of the C5F activity enhancer by administering the inducer of the present invention is observed in rabbits, mice, and humans. Moreover, this induction is observed both by intravenous administration and oral administration.

In order to examine whether the in vitro activity can be observed in vitro, mitomycin C was administered to C57BL mice to reduce the white blood cell count, and then the present invention was administered to C57BL mice. No effect was observed with the administration of the inducer of the present invention alone, but when the lithium compound was administered before the administration of mitomycin C, administration of the inducer of the present invention after the administration of mitomycin C showed no effect. , a promoting effect on the recovery of peripheral white blood cell counts was observed.

This result means that in the absence of C5F, even the administration of the inducer of the present invention does not promote the recovery of the number of white blood cells, but in the presence of C3F, the number of white blood cells quickly recovers.

Example Next, the present invention will be further explained with reference to Examples.

In the following, powder A is 1-methyl-5-guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole methanesulfonate, and powder B is adrenochrome semicarbamate. Adrenochrome thiosemicarbazone is labeled as "Zone" and "Water Solution C", and carbazochrome sodium sulfonate is labeled as "comparative agent".

(In Vitra Bone Marrow Colony Formation Method) Example 1 i1 Direct Plate Mutual 1j After killing C57BL mice by cervical dislocation, the femoral canal was removed aseptically. Subsequent operations were also performed aseptically. Both ends of the femoral canal After excising it with scissors, RPM11640 culture solution was injected from one end using a syringe with a 21G needle, the bone marrow cells were poured out, and a bone marrow cell suspension was obtained.

RPMI 1640 culture medium was used as the culture medium, and the cell number was adjusted to 1.5X 10 cells/mu.
Culture was performed under the following conditions.

However, since agarose solidifies at low temperatures, after autoclaving the agarose solution adjusted to 4 times the concentration in advance, before cooling it, place it in a 37°C water bath to warm it.
Furthermore, a 2-fold concentrated RPM11640 culture solution (37°C) was added to prepare a 0.9% agarose-RPMI culture solution at 37°C and used.

The above medium L-929 cell culture supernatant was prepared using colony stimulating factor (
CSF).

7 in the above-mentioned medium under CO2, 5%, 37°C, high humidity conditions.
Culture was carried out for one day, and the number of formed colonies was counted using an inverted microscope.

Blood W Nodo The following serum samples were used.

100 mg/kg of solution A was intravenously injected into five C57BL mice, and blood was collected 20 minutes after administration. As a control, the same amount of physiological saline was administered to five C57BL mice, and the mice were harvested in the same manner.

After the blood was left at room temperature for 40 minutes, it was centrifuged at 2000 rpm for 10 minutes to obtain serum.

pattern The results are shown in Table 2.

Table 2 (Note) Does the number of colonies indicate bone marrow cells? , 5X 10+ colonies per individual.

In addition, when a culture medium lacking L-929 cell culture soil as C3F was used, the number of colonies was O in both the control and post-administration serum cases.

Example 2 11 gang thoughts 1j Same as Example 1.

and 6-method C3F, PHA was used instead of L-929 cell culture supernatant.
The same as in Example 1 except that 15% of the stimulated human lymphocyte culture supernatant (the supernatant obtained by culturing human lymphocytes for 2 days with the addition of PHA (red kidney bean lectin)) was used.

serum sample The following serum samples were used.

New Sealant - 5 powder powder for 3 white rabbits
mg/kg was administered intravenously, and blood was collected before and 20 minutes after administration. After leaving this blood at room temperature for 40 minutes, 2000 rp
Serum was obtained by centrifugation at m for io minutes.

Red l The results are shown in Table 3.

Table 3 Reference Example 1 An experiment was conducted in the same manner as in Example 2, except that powder A was used in varying quantities in place of the serum sample. The results are shown in Figure 2.

Reference Example 2 Experiment was conducted in the same manner as in Example 2, except that 15% L-929 cell culture supernatant was used instead of PHA-stimulated human lymphocyte culture supernatant as C3F, and powder A was used in varying amounts instead of the serum sample. I did it. The results are shown in Figure 3.

From Figures 2 and 3, when powder A itself was added to the bone marrow colony forming culture, even in the presence of C5F,
It can be seen that the number of colonies tends to decrease.

Example 3 11 Indigo Mutual 1j Same as Example 1.

Cultivation and cultivation Same as Example 1.

Blood: Same as Example 2. However, the serum samples obtained by collecting blood before and after administration in Example 2 were used as they were, or after being heat-treated at 56° C. for 30 minutes.

Class! The results are shown in Table 4.

Table 4 Example 4 11 Rat Garden Star 1j Same as Example 1.

Call ・ Same as Example 1.

Blood 1''77' zl Same as Example 2, except that serum obtained by collecting blood before and after administration in Example 2 was added to 500 mJL of RPMI164.
Each sample was dialyzed twice with 0 culture solution and used.

■ The results are shown in Table 5.

Table 5 Example 5 11 summer plate mutual 1j Same as Example 1.

and culture Same as Example 1.

blood mnonoi The following serum samples were used.

Liquid medicine A was orally administered at 5 mg/kg to three humans, and blood was collected before and 20 minutes after administration. 40 minutes at room temperature.
After standing for 1 minute, centrifugation was performed at 2000 rpm for 10 minutes to obtain serum.

class j The results are shown in Table 6.

Table 6 Note that when a culture medium lacking L-929 cell culture supernatant as C5F was used, the number of colonies was O for both pre-administration serum and post-administration serum.

Example 6 11 dishes 1j each Same as Example 1.

door and d Same as Example 1.

Blood 1 and 2" The following serum samples were used.

New sealant Φ Water agent A for 3 white rabbits,
Liquid formulation B and liquid formulation C1 comparative agents were orally administered at 50 g/kg each, and blood was collected before and 20 minutes after administration. The blood was left at room temperature for 40 minutes and then centrifuged at 2000 rpm for 10 minutes to obtain serum.

Class! The results are shown in Table 7.

Table 7 Example 7 Liquid medicine A was orally administered to 3 New Sealant white rabbits at a dose of 501 g/kg as a serum sample, and administered for 20 minutes, 1 hour, 2 hours, and 4 hours before administration, and 20 minutes, 1 hour, 2 hours, and 4 hours after administration. After that, the experiment was conducted in the same manner as in Example 6 except that blood was collected 8 hours later. The results are shown in Figure 4.

From FIG. 4, it can be seen that in oral administration, an increase in activity was observed immediately after administration, and activity was observed even 8 hours later. However, after 24 hours, no activity is observed.

(Recovery of in vitro 0 peripheral leukocytes) Example 8 Using 5 C57BL mice each (4 mice in (b) below),
Administration was performed according to the following procedure. Note that in this Example 8 and the following Example 9, "sampling" means "sampling of one tail's arterial blood."

(a) Control■ Intraperitoneal administration of mitomycin C at 10 mg/kg■
Sampling 5 days after administration of mitomycin C ■ Sampling 9 days after administration of mitomycin C (b) Administer only solution A ■ Intraperitoneal administration of mitomycin CI Omg/kg ■
3 days after administration of mitomycin C: 50 mg/kg of this drug A
Intraperitoneal administration ■ Sampling 5 days after mitomycin C administration ■ Sampling 9 days after mitomycin C administration (c) Li administration, administration ■ Intraperitoneal administration of 60 mg/kg of lithium chloride water salt 1 day before mitomycin C administration ■ Mitomycin 010 mg/kg Intraperitoneal administration■
Sampling 5 days after administration of mitomycin C ■ Sampling 9 days after administration of mitomycin C (d) Li, powder A
Concomitant administration ■ Lithium chloride aqueous salt 60 mg/kg administered intraperitoneally 1 day before mitomycin C administration ■ Mitomycin 010 mg/kg administered intraperitoneally ■
3 days after administration of mitomycin C, dose of this drug A was increased to 50 mg/day,
Intraperitoneal administration■ Sampling 5 days after mitomycin C administration■ Sampling results 9 days after mitomycin C administration are shown in Table 8.The values in Table 0 are based on the average peripheral leukocyte count of each group before mitomycin C administration, which is 100%. It is expressed as a ratio to

Table 8 Note 1, p<0.005 (Studen
t t ) Note 2. Cloud p < 0.001 From Table 8, compared to the control, there was no difference in the liquid drug A administration group, and no significant difference in the Li administration group, but L
It can be seen that in the group in which i and powder A were used in combination, the number of peripheral white blood cells was significantly recovered.

Example 9 Using 5 C57BL mice each (4 mice in (b) below),
Administration was performed according to the following procedure.

(a) Control ■ Whole body irradiation with 500 rad/mouse ■ Sampling 14, 21, and 28 days after radiation irradiation (b) Administration of powder A only ■ Whole body irradiation with 500 rad/mouse ■ 9 and 16 days after radiation irradiation This drug Intraperitoneal administration of A at 50 mg/kg each ■ 14, 21, and 28 days after radiation irradiation Sampling (c) LL administration ■ Whole body irradiation with 500 rad/mouse ■ Radiation 5. After 12 days, 60 each of lithium chloride water salt ■ Intraperitoneal administration of 500 rad/kg of radiation ■ Sampling 14, 21, and 28 days after radiation irradiation (d) Combined administration of Li and solution A ■ Whole body irradiation of 500 rad/mouse (multiple) Salt 60 B/kg each
Intraperitoneal administration of this drug 9.16 days after radiation 50 mg/kg of each drug was administered intraperitoneally ■ 14.21 and 28 days after radiation irradiation The sampling results are shown in Table 9.0 The values in Table 0 are the values before radiation The average number of peripheral leukocytes in each group is taken as 100%, and the figures are expressed as a percentage of that.

Table 9 Effects of the Invention The inducing agent of the present invention contains blood stem cell colony stimulating factor (CS
F) Inducing a polymeric substance that enhances the activity of the factor in its presence.

That is, for leukopenia caused by radiation irradiation, administration of drugs such as anticancer drugs, certain diseases, etc., CSF is induced by appropriate means (such as administration of a lithium compound) before the induction of the present invention. When the agent is administered, (i) the inducing agent induces a C5F activity enhancer in the body, (ii) the activity enhancer enhances the C3F activity,
(iii) As a result of a series of actions in which C3F with enhanced activity promotes the differentiation and proliferation of blood stem cells into white blood cells, the decreased number of white blood cells is quickly restored to the normal number.

Conventional radioprotective agents are administered before radiation irradiation to capture radicals generated by radiation and reduce DN.
The inducer of the present invention aims to prevent A damage and suppress the decrease in leukocytes as much as possible, but the inducer of the present invention attempts to restore already decreased leukocytes through the actions of (i), (ii), and (iii) above. It has an excellent therapeutic effect even on symptoms for which conventional radioprotective agents are insufficiently effective or cannot be treated.

Furthermore, the inducer of the present invention has been conventionally used as a pharmaceutical agent such as a hemostatic agent and a radioprotective agent, and is therefore highly safe.

Therefore, the inducer of the present invention is extremely useful as a therapeutic agent for leukopenia.

[Brief explanation of drawings]

FIG. 1 is a graph showing the appearance pattern of colony stimulating activity induced in serum when a lithium compound was administered to C57B mice. FIG. 2 is a graph showing the relationship between the number of colonies and the concentration of liquid medicine A in Reference Example 1. FIG. 3 is a graph showing the relationship between the number of colonies and the As degree of the liquid medicine in Reference Example 2. FIG. 4 is a graph showing the relationship between the 4-colony stimulation enhancing activity and the blood collection time after administration in Example 7. Figure 1: Number of days after administration of 01 2345G7 (days) Figure 2: Powder strength (Pg mQ) Figure 3: Main rules A m K (Pg/rJ) Figure 4: Time (minutes)

Claims (6)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Blood stem cell colony stimulation using an adrenochrome derivative or a pharmacologically acceptable salt thereof as an active ingredient (in the formula, A is NH, O, or S) Factor activity enhancer inducer. (2) The derivative according to claim 1, which contains 1-methyl-5-guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole or a pharmacologically acceptable salt thereof as an active ingredient. agent. (3) The inducer according to claim 2, which contains a methanesulfonate of 1-methyl-5-guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole as an active ingredient. (4) The inducer according to claim 1, which contains adrenochrome semicarbazone or a pharmacologically acceptable salt thereof as an active ingredient. (5) The inducer according to claim 1, which contains adrenochrome thiosemicarbazone or a pharmacologically acceptable salt thereof as an active ingredient. (6) The inducer according to claim 1, which is an activity enhancer inducer of neutrophil/macrophage stem cell colony stimulating factor.