CA1316830C - Agent for treating or preventing thrombocytopenia - Google Patents
Agent for treating or preventing thrombocytopeniaInfo
- Publication number
- CA1316830C CA1316830C CA000579395A CA579395A CA1316830C CA 1316830 C CA1316830 C CA 1316830C CA 000579395 A CA000579395 A CA 000579395A CA 579395 A CA579395 A CA 579395A CA 1316830 C CA1316830 C CA 1316830C
- Authority
- CA
- Canada
- Prior art keywords
- group
- agent
- treating
- compound
- thrombocytopenia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
An agent for treating or preventing thrombocytopenia is disclosed. The agent comprises, as an active ingredient, a compound of the formula (I):
(I) wherein X represents an amino acid residue selected from the group consisting of l-alanine, L-serine and L-valine, Y represents a group represented by the following formula
An agent for treating or preventing thrombocytopenia is disclosed. The agent comprises, as an active ingredient, a compound of the formula (I):
(I) wherein X represents an amino acid residue selected from the group consisting of l-alanine, L-serine and L-valine, Y represents a group represented by the following formula
Description
FIELD OF THE INVENTION
This invention relates to an agent for treating or preventing thrombocytopenia which comprises, as an active ingredient, a compound of the formula (I):
CH20H .
~0 ~ ~ H~OH (I) HAcyl CONH2 CH3CHCO -X -NHcHcH2cH2co-y .
wherein X represents an amino acid residue selected from the group consisting of L-alanine, L-serine and L-valine, Y represents a group represented by-the following formula `
COOH
-NHCH(CH2~n~NHc-A
wherein n represents an integer of 1 to 6, A represents a ~saturated straight or branched chain aliphatic hydro-carbon group having 7 to 29 carbon atoms, and Acyl repre-~ :sents an acyl group having 2 to 6 carbon atoms.
:
~ -: . . . . ~ ~
.
131683(~
Multipotential stem cells, which can differen-tiate to granulocytes, monocytes ~macrophages), red blood cells, platelets, lymphocytes, exist in the bone marrow of higher animals. The stem cells differentiate to precursory cells and the cells differentiate to the above blood cells. On the differentiation, several specific growth factors function to each blood cell's differentia-tion. For example, Interleukin~3 functions to the multipotential stem cells to induce the differentiation thereof to precursory granulocytes, and granulocyte growth factors such as granulocyte-colony stimulating factor function to the precursory cells to induce the differentiation thereof to granulocytes.
On the other hand, precursory cells such as megakaryocytes are supposed to require thrombopoietin in the diffe~entiation thereof to platelets. However, the detail of the differentiation has not been clarified.
Platelets have a significant role to maintain the health independently or in cooperation with the other blood cells. Therefore, when the differentiation to platelets is inhibited, some diseases caused by reduction of platelets number appear.
Example of the diseases includes symptomatic 25 ~ thrombocytopenia, idiophatic thrombocytopenia and the :: :
- : .
l like caused by anticancer agent, radiation, blood disease, etc., and symptoms thereof include bleeding, coagulation defect and the like.
As the treating method for thrombocytopenia, only platelets transfusion, which is complicated and expensive, was used. However, this is not the fundamental treatment of the disease.
The compound of the formula (I) is disclosed in U.S. Patent 4,317,771, and has an excellent adjuvant activity and treating or preventing effect on infection of microorganisms. However, it has been unknown that the compound of the formula (I) is effective for treatment or prevention of thrombocytopenia.
SUMMARY OF l'HE INVENTION
This invention relates to an agent for treating or preventing thrombocytopenia which comprises a compound of the formula (I) as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutical preparations containing the compound of the formula (I) include tablets, capsules, powders, granules, injections, suppositories, sprays, dermal preparations and the like. These preparations can be prepared by known pharmaceutical techniques using appropriate additives such as excipients, e.g., corn tarch, lactose, mannitol, etc., binders, e.g., , `:
: ... . .: .
~ 31 6830 1 hydroxypropyl cellulose, polyvinyl pyrrolidone, etc., disintegrators, e.g., low substituted hydroxypropyl cellulose, crystalline cellulose, etc., and lubricants, e.g., talc, magnesium stearate, etc. If desired, the preparations of the present invention can be a slow release (sustained-release) preparation which can be prepared using known pharmaceutical techniques.
The agent according to the present invention can be administered orally or parenter~lly. The dose level usually ranges from about 100 to about 400 ~g/day in case of subcutaneous administration or from about 2 to about 20 mg/day in case of oral administration for adult human (about 50 to 60 kg body weight). The therapeutic effect of the agent according to the present invention is expected to be further enhanced by combining with whole blood transfusion or platelets transfusion which is a typical therapeutic method for thrombocytopenia.
The compounds of the foxmula (I) is of low toxicity~ For example, LD50 of Compound A described in Example 1 which is a typical compound of the formula (I) was found to be 600 to 1,000 mg/kg in rats by subcutaneous injection.
The compound of the formula (I) has an excellent effect on prevention or treatment of ehrombooytopenia as illustrated in E~amples hereinafter , `
l described and, therefore, the compound is useful as an excellent agent for preventing or treating thrombocytopenia.
The present invention is hereinafter illustrated in greater detail with reference to Examples, however, it should be understood that these examples are not to be construed as limiting the present invention.
EXAMPLE
(1) A vial containing:
Compound A 0.2 mg D-Mannitol 45.0 mg Potassium dihydrogen phosphate 1.95 mg Sodium hydrogen phosphate 8.31 mg (2) An additive solution in ampule containing:
Distilled water for injection l ml According to the above formulation, a lyophili~ed injection containing 200 ~g of Compound A was prepared using known pharmaceutical techniques. In using this preparation, the additive solution in the ampule is injected into the vial just before the use to instantly prepare an injectable solution containing Compound A.
ComPound A: N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N -stearoyl-L-lysine (an anomeric mixture) 1 31 ~830 Compound A (200 ~g) was administered subcuta-neously to 20 patients with mulignant lymphoma in a single daily dose for 10 consecutive days from 3 to 5 day after the starting day of chemotherapy for the above disease (administered group). Blood test was carried out on the 7, 10, 14, 17, 21 and 24th days from the starting day of the chemotherapy. A cross over method was used to determine the effect of Compound A; that is, the same patients as above were used as the control group without administering with Compound A, and the number of platelets in the administered group was compared to that in the control group. The result was shown in Table 1 below as mean + standard error.
- - -- - ~ -: , , - , - . .: .
. : . .:
: ~ , .
. ~
~: :
131~830 TABLE I
Platelets Nunber ) at the Starting Day of P1ate!ets_Number ) (,differe ce from the before) Chemotherapy 7th Day 10th Da~ 14th Da,v17th Day 21st Day 24th DaY
Administered Group -4.3+1.7 -7.Z~1.6 -4.4~2.33.8+1.8 5,9+?,0 0.7t2.1525,7 t 1.9 Control Group -8,9+?,4 -10.7+?.7 -8.~!:2.8-2.3+?,6 3,5+?,4 -3.S~3.3 28.6 + 2.5 a): x 104/mm3 *: ~he difference was significant at the level of 5% or less by paired t-test.
**: The difference was significant at the level o 1% or less by paired t-test.
As is apparent from the results in Table 1 above, the increase of platelets number was observed in the administered group, and a tendency to suppress the decrease thereof caused by the chemotherapy and to restore the platelets number was observed.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
. , - :-. .
-- .
. ' .~' ; ~ ' ' ': ' -:- -,
This invention relates to an agent for treating or preventing thrombocytopenia which comprises, as an active ingredient, a compound of the formula (I):
CH20H .
~0 ~ ~ H~OH (I) HAcyl CONH2 CH3CHCO -X -NHcHcH2cH2co-y .
wherein X represents an amino acid residue selected from the group consisting of L-alanine, L-serine and L-valine, Y represents a group represented by-the following formula `
COOH
-NHCH(CH2~n~NHc-A
wherein n represents an integer of 1 to 6, A represents a ~saturated straight or branched chain aliphatic hydro-carbon group having 7 to 29 carbon atoms, and Acyl repre-~ :sents an acyl group having 2 to 6 carbon atoms.
:
~ -: . . . . ~ ~
.
131683(~
Multipotential stem cells, which can differen-tiate to granulocytes, monocytes ~macrophages), red blood cells, platelets, lymphocytes, exist in the bone marrow of higher animals. The stem cells differentiate to precursory cells and the cells differentiate to the above blood cells. On the differentiation, several specific growth factors function to each blood cell's differentia-tion. For example, Interleukin~3 functions to the multipotential stem cells to induce the differentiation thereof to precursory granulocytes, and granulocyte growth factors such as granulocyte-colony stimulating factor function to the precursory cells to induce the differentiation thereof to granulocytes.
On the other hand, precursory cells such as megakaryocytes are supposed to require thrombopoietin in the diffe~entiation thereof to platelets. However, the detail of the differentiation has not been clarified.
Platelets have a significant role to maintain the health independently or in cooperation with the other blood cells. Therefore, when the differentiation to platelets is inhibited, some diseases caused by reduction of platelets number appear.
Example of the diseases includes symptomatic 25 ~ thrombocytopenia, idiophatic thrombocytopenia and the :: :
- : .
l like caused by anticancer agent, radiation, blood disease, etc., and symptoms thereof include bleeding, coagulation defect and the like.
As the treating method for thrombocytopenia, only platelets transfusion, which is complicated and expensive, was used. However, this is not the fundamental treatment of the disease.
The compound of the formula (I) is disclosed in U.S. Patent 4,317,771, and has an excellent adjuvant activity and treating or preventing effect on infection of microorganisms. However, it has been unknown that the compound of the formula (I) is effective for treatment or prevention of thrombocytopenia.
SUMMARY OF l'HE INVENTION
This invention relates to an agent for treating or preventing thrombocytopenia which comprises a compound of the formula (I) as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
Pharmaceutical preparations containing the compound of the formula (I) include tablets, capsules, powders, granules, injections, suppositories, sprays, dermal preparations and the like. These preparations can be prepared by known pharmaceutical techniques using appropriate additives such as excipients, e.g., corn tarch, lactose, mannitol, etc., binders, e.g., , `:
: ... . .: .
~ 31 6830 1 hydroxypropyl cellulose, polyvinyl pyrrolidone, etc., disintegrators, e.g., low substituted hydroxypropyl cellulose, crystalline cellulose, etc., and lubricants, e.g., talc, magnesium stearate, etc. If desired, the preparations of the present invention can be a slow release (sustained-release) preparation which can be prepared using known pharmaceutical techniques.
The agent according to the present invention can be administered orally or parenter~lly. The dose level usually ranges from about 100 to about 400 ~g/day in case of subcutaneous administration or from about 2 to about 20 mg/day in case of oral administration for adult human (about 50 to 60 kg body weight). The therapeutic effect of the agent according to the present invention is expected to be further enhanced by combining with whole blood transfusion or platelets transfusion which is a typical therapeutic method for thrombocytopenia.
The compounds of the foxmula (I) is of low toxicity~ For example, LD50 of Compound A described in Example 1 which is a typical compound of the formula (I) was found to be 600 to 1,000 mg/kg in rats by subcutaneous injection.
The compound of the formula (I) has an excellent effect on prevention or treatment of ehrombooytopenia as illustrated in E~amples hereinafter , `
l described and, therefore, the compound is useful as an excellent agent for preventing or treating thrombocytopenia.
The present invention is hereinafter illustrated in greater detail with reference to Examples, however, it should be understood that these examples are not to be construed as limiting the present invention.
EXAMPLE
(1) A vial containing:
Compound A 0.2 mg D-Mannitol 45.0 mg Potassium dihydrogen phosphate 1.95 mg Sodium hydrogen phosphate 8.31 mg (2) An additive solution in ampule containing:
Distilled water for injection l ml According to the above formulation, a lyophili~ed injection containing 200 ~g of Compound A was prepared using known pharmaceutical techniques. In using this preparation, the additive solution in the ampule is injected into the vial just before the use to instantly prepare an injectable solution containing Compound A.
ComPound A: N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N -stearoyl-L-lysine (an anomeric mixture) 1 31 ~830 Compound A (200 ~g) was administered subcuta-neously to 20 patients with mulignant lymphoma in a single daily dose for 10 consecutive days from 3 to 5 day after the starting day of chemotherapy for the above disease (administered group). Blood test was carried out on the 7, 10, 14, 17, 21 and 24th days from the starting day of the chemotherapy. A cross over method was used to determine the effect of Compound A; that is, the same patients as above were used as the control group without administering with Compound A, and the number of platelets in the administered group was compared to that in the control group. The result was shown in Table 1 below as mean + standard error.
- - -- - ~ -: , , - , - . .: .
. : . .:
: ~ , .
. ~
~: :
131~830 TABLE I
Platelets Nunber ) at the Starting Day of P1ate!ets_Number ) (,differe ce from the before) Chemotherapy 7th Day 10th Da~ 14th Da,v17th Day 21st Day 24th DaY
Administered Group -4.3+1.7 -7.Z~1.6 -4.4~2.33.8+1.8 5,9+?,0 0.7t2.1525,7 t 1.9 Control Group -8,9+?,4 -10.7+?.7 -8.~!:2.8-2.3+?,6 3,5+?,4 -3.S~3.3 28.6 + 2.5 a): x 104/mm3 *: ~he difference was significant at the level of 5% or less by paired t-test.
**: The difference was significant at the level o 1% or less by paired t-test.
As is apparent from the results in Table 1 above, the increase of platelets number was observed in the administered group, and a tendency to suppress the decrease thereof caused by the chemotherapy and to restore the platelets number was observed.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
. , - :-. .
-- .
. ' .~' ; ~ ' ' ': ' -:- -,
Claims (2)
1. An agent for treating or preventing thrombocytopenia which comprises, as an active ingredient, a compound of the formula (I):
(I) wherein X represents an amino acid residue selected from the group consisting of L-alanine, L-serine and L-valine, Y represents a group represented by the following formula wherein n represents an integer of 1 to 6, A represents a saturated straight or branched chain aliphatic hydro-carbon group having 7 to 29 carbon atoms, and Acyl repre-sents an acyl group having 2 to 5 carbon atoms.
(I) wherein X represents an amino acid residue selected from the group consisting of L-alanine, L-serine and L-valine, Y represents a group represented by the following formula wherein n represents an integer of 1 to 6, A represents a saturated straight or branched chain aliphatic hydro-carbon group having 7 to 29 carbon atoms, and Acyl repre-sents an acyl group having 2 to 5 carbon atoms.
2. An agent for treating or preventing thrombocytopenia as claimed in claim 1, wherein the active ingredient is N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000579395A CA1316830C (en) | 1988-10-05 | 1988-10-05 | Agent for treating or preventing thrombocytopenia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000579395A CA1316830C (en) | 1988-10-05 | 1988-10-05 | Agent for treating or preventing thrombocytopenia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1316830C true CA1316830C (en) | 1993-04-27 |
Family
ID=4138860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000579395A Expired - Fee Related CA1316830C (en) | 1988-10-05 | 1988-10-05 | Agent for treating or preventing thrombocytopenia |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1316830C (en) |
-
1988
- 1988-10-05 CA CA000579395A patent/CA1316830C/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |