WO1993023066A1 - Platelet growth promoter - Google Patents

Abstract

A platelet growth promoter containing FK566, a substance represented by formula (I), or a pharmaceutically acceptable salt thereof as the active ingredient.

Description

 Platelet count enhancer Technical field

 The present invention relates to a platelet number enhancer (platelet number increasing agent) containing FK 565 represented by the following formula or a pharmaceutically acceptable salt thereof as an active ingredient, and is used in the field of medicine. Background art

 FK565 has an immunopotentiating effect and is known to be useful as an anticancer agent, an anti-AIDS agent, an antiviral agent, etc. (Japanese Patent Application Laid-Open Nos. 56-45449, 60-104019) And JP-A-64-38030).

 However, it was not known at all that FK565 had a platelet count increasing activity. Disclosure of the invention

 The invention is based on the formula

Contain

FΚ565 or a pharmaceutically acceptable salt thereof is useful as a platelet count reduction inhibitor, a decreased platelet count increase agent, a prophylactic or therapeutic agent for thrombocytopenia, a prophylactic or therapeutic agent for purpura, etc. is there. FΚ565 or a pharmaceutically acceptable salt thereof is, for example, Since it antagonizes side effects such as thrombocytopenia due to administration of anti-cancer drugs without impairing the efficacy of anti-cancer drugs such as ittomycin C and cis-bratin, it is also useful as an anti-cancer drug side effect reducer is there.

 Pharmaceutically acceptable salts of FK565 include, for example, organic or inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, and severe acids. Organic or inorganic acids such as salt, trifluorophosphate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, hydrochloride, sulfate, ganate, phosphate, etc. And acid addition salts of

The FK565 of the present invention can be used in the form of a solid, semisolid or liquid preparation containing a mixture with an organic or inorganic carrier or excipient suitable for oral or parenteral administration. . The FK565 of the present invention is used in, for example, tablet pellets, capsules, suppositories, solutions, emulsions, suspensions, and usually mixed with non-toxic and pharmaceutically acceptable carriers to form appropriate dosage forms. . The carriers used here are water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium sulfate, talc, methylcellulose, polyethylene glycol, corn starch, keratin, colloidal silica, and potato starch. , Urea and other carriers used in the manufacture of solid, semi-solid or liquid preparations, as well as auxiliaries, stabilizers, thickeners and colorings and fragrances You may do it.

When FK565 is applied to humans or animals, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection or oral administration. The dose of FK565 of the present invention varies depending on conditions such as the age of each individual patient to be treated and the degree of the disease, but generally, the daily dose of the active ingredient for humans or animals is high. 0.01-1 Omg / kg is administered for prophylaxis or treatment. The platelet count increasing activity of FK565 will be described below.

The effect of increasing platelet count in normal quizzes

 Test method

A single intravenous dose of FK565 (0.1 mg / kg or 0.1 mg / kg) is given to three normal cynomolgus monkeys, blood is collected daily, and the platelet count is measured by SysmexE—4000 (automatic blood cells). The number was automatically measured using a counting device (Toa Medical Electronics Co., Ltd.). As a control, blood was collected from the same individual the day before administration. Separately, a saline was administered to the control group.

The platelet count in each group was calculated by setting the platelet count on the day before the administration as 100% for the platelet count in each dose.

Table 1 shows the test results.

table 1

Platelets on the day before administration Platelets on the day before administration Platelets on the day before administration Platelets on the day before administration Nine administrations on five administrations on nine administrations Compounds on seven administrations

 (mg / kg) Day blood / h plate number day blood / j ヽ plate number day blood / 1 day plate number

5 Ratio (%) Ratio (%) Ratio (%)

Notes — Sole U lUb 丄 1 b i 丄 n

 JCxVOOO U, U 丄

FK565 0.1 166.4 161.1 158.2

Fifteen

After a single intravenous administration of? 1 ^ 565 at 0.1111 ₂ , 1 ^ and 0.01 mg / kg, a dose-dependent increase in platelet count was observed from day 5, with a maximum increase of about 66% ( 0. lmgZkg administration group).

20 Exam 2

 Effect of increasing platelet count in normal mice

 Test method

 FK565 (0.01 mg / kg. O.lmgZkg or l.OmgZkg) was administered to normal mice (five ddY female mice (7 weeks old) purchased from Nippon S.L.C.) in a single intravenous dose of 25 mg / day. Blood samples were collected and the platelet count was automatically measured using Sysmex E-4000. Separately, a saline was administered to the control group.

 The platelet count in each dose was calculated with the platelet count in the control group taken as 100%.

Table 2 shows the test results. Test results

 m

When FK565 was administered once intravenously at a dose of 0.01, 0.1, and l.Omg, the maximum increase was about 30% (O.lmg / kg administration group) on the fifth day after administration. Exam 3

 Effect of increasing platelet count in normal mice

 Test method

Normal mice (ddY female mice (7 weeks old) purchased from Japan SLC, Inc.) FK565 (0.01 mg / kg. O.lmgZkg or l.Omg / kg) once a day for 3 days, and blood is collected daily, and the platelet count is measured using Sysmex E-4000. And automatic measurement. Separately, saline was administered to the control group.

 The platelet count in each dose was calculated with the platelet count in the control group taken as 100%.

 Table 3 shows the test results.

FK565 administered 0.01, 0.1 and l.OmgZkg once a day for 3 days On the seventh day, a dose-dependent increase in platelet count was observed (p <0.001), and the maximum increase was as high as about 92%, especially in the l.Omg / kg group.

Exam 4

Effect of increasing platelet count in normal mice

Test method

A single intravenous or subcutaneous administration of FK565 (O.lmgZkg or l.OmgZkg) to normal mice (five ddY female mice (7-week-old) purchased from Nippon S.L.C.) was collected daily. Then, the platelet count was automatically measured using Sysmex E-4000.

 With the platelet count of the FK565 O.lmg / kg iv (iv) administration group taken as 100%, the change in platelet count in each administration group was calculated.

Table 4 shows the test results.

gt¾ conclusion: ^

Table 4

試験 5

Exam 5

 Effect of increasing platelet count in normal mice

 Test method - ; .

A group of normal mice (ddY female mice (7 weeks old) purchased from S.L.C.) FK565 (0.01 mg / kg, O.lmg / Zkg or l.Omg / kg) was administered once intravenously or orally to 5 of them, and blood was collected daily and the platelet count was measured using Sysmex E-4000. Was measured automatically. A saline was administered to the control group.

Assuming the platelet count in the control group as 100%, the change in platelet count at each dose is calculated as u.

Table 5 shows the test results.

Test results

Table 5

試験 4及び 5での投与経路の比較検討結果より、静脈内投与、皮下投与及び経口投 与のいずれにおいても血小板数の増加が観察された。

Based on the results of comparative study of administration routes in Studies 4 and 5, intravenous, subcutaneous and oral An increase in the number of platelets was observed in any of the treatments.

 5 Test D

Effect of platelet count on platelet count decreased by mitomycin C (MMC) Test method

MMC (manufactured by Kyowa Hakko Co., Ltd.) 5.6 mg Zkg was intravenously administered to ddY female 'mice (7 weeks old) (5 animals per group) (this administration day is hereafter referred to as dayO. The day is called day2.) FK565 0.1 mg / kg was intravenously administered once a day from dayO to 2 for 3 days, blood was collected on day9, and the platelet count was measured automatically using Sysmex E-4000. A group to which MMC was administered but not to FK565 was used as a control. The change in platelet count in each group was calculated with the platelet count in the group (saline-administered group) not receiving MMC as 100%.

Table 6 shows the test results.

 ¾ ^

Table 6

In the MMC alone group, the platelet count reached a nadir at day 9 (down to 33.9% of that in the saline group). In the FK565 combination group, the decrease in blood size caused by MMC administration was significantly suppressed (FK565 O.lmgZkg only reduced by 55%, with a significant difference of P <0.05). Effect of increasing platelet count on platelet count reduced by mitomycin C (MMC)

 MMC (manufactured by Kyowa Hakko Co., Ltd.) 3.2 mg / kg once daily intravenously on dayO and day 3 to ddY female mice (7 weeks old) (5 animals per group), and FK565 O.lmgZkg once daily The dose was intravenously administered for four days from day O to 3, and blood was collected on day 8 and day 10 and the platelet count was automatically measured using Sysmex E-4000. A group to which MMC was administered but not to FK565 was used as a control. The change in platelet count in each group was calculated, with the platelet count in the group not receiving MMC (saline-administered group) as 100%.

 Table 7 shows the test results.

 Test results

 Table 7

 In the MMC-only group, the platelet count gradually decreased and reached a nadir at day 10 (down to 32.6% of the saline-administered control group), and then recovered slowly. In the FK565 administration group, the decrease in platelet count due to MMC administration was significantly suppressed at daylO.

 #Blood collection method

 ① Blood sampling from mice,

15% EDTA4Na (pH 8.0) 10 ^ 1 was added to whole blood collected from a mouse, and the mixture was stirred and mixed at room temperature. It was stored under ice cooling between platelet count measurements. Daily platelet count In some cases, blood was collected using another animal.

② Blood sampling from monkeys

Blood was collected from the brachial vein of the monkey using a 2.5 ml syringe (pre-filled with 15% EDTA4Na (pH 8.0) 20 / z1 as an anticoagulant). It was stored under ice cooling until the platelet count was measured.

As is clear from the above test results, FK565 is useful for the treatment and prevention of thrombocytopenia caused by anticancer drugs and the like.

Example

Hereinafter, the present invention will be described with reference to examples.

Example

 FK565 200mg

Mannitol 400mg

Magnesium stearate 10mg

Starch 50mg The above components are formulated into tablets by a conventional method.

Claims

The scope of the claims  Formula:

A platelet count increasing agent comprising, as an active ingredient, the FK565 substance or a pharmaceutically acceptable salt thereof represented by the following formula: