CA2133754A1 - Compositions of platelet activating factor antagonists and methods of treating interleukin-2 induced lung injury therewith - Google Patents
Compositions of platelet activating factor antagonists and methods of treating interleukin-2 induced lung injury therewithInfo
- Publication number
- CA2133754A1 CA2133754A1 CA002133754A CA2133754A CA2133754A1 CA 2133754 A1 CA2133754 A1 CA 2133754A1 CA 002133754 A CA002133754 A CA 002133754A CA 2133754 A CA2133754 A CA 2133754A CA 2133754 A1 CA2133754 A1 CA 2133754A1
- Authority
- CA
- Canada
- Prior art keywords
- platelet
- activating factor
- factor antagonist
- composition according
- use according
- 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.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Abstract
Invented is a method of treating Interleukin-2 induced lung injury in a mammal, including human, which comprises administering to such mammal an effective amount of a platelet-activating factor antagonist.
Description
i~093~2~ 75a~ Pcr/usg3/o3347 "Compositions of Pl~telet Activating Factor Antagoni~ts and Methods of Tr~a~ng Interleukin-2 Induccd Lung Injury Therewith"
:' This invention rela~es to . a method of treating interleukin-2 induc:d lung injury in a mammal, including a human, in need thereof which comprises ~dminist~ring to .`
such mammal an effective amouin~ of a pla~elet-activating ~`
~a~tor antagonist .
Human recombinant ~nterleukin-2 l IL-2 ) has beer showrl t~ me~iat~ tumor regressio~ ~ n animals (Ettinghausen, ~S.~E;. et al. ~n~ 2784-27g2 ~19B7)~) and Humans (Rosenberg, ~ S~A. et al. ~,_~,~
~ 14135 ~ (~1985) ) ~ and is currently under investigation as a n w treatment modality: for patients ~' with advanced metastatic cancer (Rosenberg,~ S.A. et al.:
E~ k~ 8~9 tl~87)~
The systemic use of IL-2 has, however, also been associated with disorders such as, microvascu~ar injury and pulmonary adema (Clausnerj F.L. et al.
Phy.s;.nl. ~:1030-1037 ~1988) and Rosenstein, M~
Imm~n~l~ 1735 1742 (1986)) (hereinafter "lung 35 in~ury")~ The acute pulmonary toxicity associa~ed with IL-2 infusion has been proposed t~ result from Lymphocyt~ ac~ivation (Anderson, T.D. et al. h~k~
InY~ 598-612 (l9~B), Damle, N.K. et al. J.
W093/~0822 2133~ S 4 PCT/~S93/~3347 mm~nQl~ 142:2660-2669 (1989) and Damle, N.K. et al.
Imm~nQl_ 138:1779-1785 (1987)), the production of inflammatory mediators such as interleukin-1 (IL-1) Numerof, R.P. et al. ~ I m~ 4250-4257 (1988)) or .:
5 tumor Necrosis Factor-~ (Helsopt H.E. et al. ~1QQ~ :
1~:1374-1380 (1989) and Nedwin, G.~. et al. .I Immunvl~
2492-2496 (1985) and from the IL-2 induced activation of Humoral systems such as the comple~ent cascade (Thijs, L.G. J. Imm~noL~ 2419-2424 (1990)).
10 The actual mechanism(s) of IL-2-induced lung injury is ":~
presently unknown.
.. .
PAE (platelet activating factor) is phospholipid acetyl-glyceryl-ether-phosphoryl-choline ~AGEPC) which is known as a potent lipid mediator releas2d by animal and human proinflammatory cells. These cells include mainly basophilic and neutrophi.lic granulocytes, macrophages lfrom blood and tissue) and thrombocytes which are involved in inflammatory reactions.
Compounds which inhibit PAF are reported to be of `~:-potential value in the treatment. of a va~iety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritisr rhi.nitis, bronchitis and urticaria, the treatment of circulatory shockr gastric, ulceration, psoriasis and cardiovascular conditions, including angina, thrombosis and stroke, (W0 91/17162 published November 14, 199l).
Presently, PAF inhi~itors are not known as having utility in treating IL-2-induced lung injuries.
W093/20822 2 1 3 3 7 5 ~ P~T/~S93/03347 summ~ry ~f the Invention This invention relates to a method of treating interleukin-2 induced lung injury in a mammal, including 5 . a human, in nePd thereof which compris~s administering to such mammal an.effective amount of a platelet activating factor antagonist.
'.
Illustrative of compounds that have PAF activity are the following comopunds O ':".' N N
N
:
which is 5 [~2-Chlorophenyl)-3,4-dihydro-10 methyl- ~:
3-~(4~morpholinyl)carbonyl~-2H,7H~
~ cyclopenta[4,5]thieno[3,2-f]~1,2,4~triazolo[4,3-: a3[1,4]diazepine. This compound is disclosed and 20 claimed in European Application No. 254245~A published :
January 27, 1988, as ha~ring platelet-activating factor antagonist activity.
:~ B) 3~N
o N-C(CH2~2~ )~
~CI ~
W093/208~ PC~/US93J03347 213375~
which is 3 ~4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a]~1,4]-diazepin-2-yl]-1-(4-morpholinyl)-l~propanon and which is disclosed .. :-in U.S. Patent No. 4968794 as having platelet~activating ~--factor antagonist activity. ~ ' ,~, ~'.' C ) ~. ~
CH30 ~3--S-CH2-C~ 1 N)\\N
t::H~, 1 0 ' ~ "' which is ~etrahydro-4,7,8ylO methyl-(chlor~- -2phenyl)-Ç[(dimethoxy~3,4pheny.~thio]methylthiocarbonyl-: ~ 9 pyrido[4',3'-4,5]~hieno[3,2-f]tr~iazolo-1,2,4[4j3~
a]diazepine-1~4 :~hereinafter compound C) and which is :~: ;15 disclosed in U.S. Patent No. 5r049~559 as a~specific platelet-acti-ating:factor antagonist.
: D3 ~; ; : C~6-H5 CONH ~
: <~N ~S ~ ~ .
:
;~
'~
WOg3/~0X22 PCT~US93/~3347 213375~ ~
. 5 which is (+) N-(3-benzoylphenyl)3-(3 pyridyl~-lH, 3H pyrrolo [1,2-c] thiazole-7 carboxamide and which is disclosed and claimed in U.S. Patent 4,783,472 as having plat~let-activating factor a~tagonist activity.
By the term "treating" as used herein is meant ~:
pxophylactic or therapeutic therapy. :-By the term "U" as used herein is meant a unit o~
IL 2 activity as specified by the manufacturer (i.e.
v Hoffman-La Rocke, Nutley, NJ).
It has now been disco~ered that compounds which are antagonists ~f platelet-actlva~ing factor are useful in treating interleukin-2 (IL-2) induced lung injury.
Compound C was tested for its ln ~lYQ potency in treating IL-2 induced lung injury. To perform the experiments recombinant human IL-2 ~obtained from Hoffman-La Roche, Nutley, NJ) was reconstituted before use with 1 ml o~ 0.9% NaCl per 106U IL-2. A ~05 U ~ose of IL-2 was prepared by diluting the above 106 U dose 10 ~:
times. Compound C was solubilized in 64% DMSO, in 0.9%
20 NaCl to reach a concentration of 5 mg/ml. Male Sprague- :~
Dawley Rats (obtained from Charles River, Wilmington, MA) were housed in groups of three in s~andard cages, ;~
and kept with ~ood and water ad libitum in a temperature controlled ~oom ~22C) on a 12 hour ~;
dark/light cycle, until surgery.
Following anesthesia with pe~toba~bital (30 mg/kg, i.p.) the animals were randomly asso~rted into three groups.
Group I. IL-2 at 105 U/kg (n=14) ~as used hèrein the term "n" means the number of rats), 106 U/kg (n-18) or vehicle (n=12) was infused intravenously for on~ hour (syringe infusion pump 22, Harvard :~
apparatus, South Natick, MA).
~roup II. IL-2 at 106 U/kg was administered by bolus injection followed by IL-2 at 10~ :
W093/20822 2~337~4 P~T/U~93~03347 U~kg intravenous injecti.on for one hour (n=6), vehicle treated animals served as controls (n=6). .
Group III. IL-2 at 106 U/kg was administered by intravenous injection for 1 hour, 30 minutes after pretreatme ~ 'wlth compound C (~0 mg/kg, I.P.) ~n=6~"or compound C
vehicle (n=6). ~-At the end of the experimental pe~iod the le~t lung was removed and immediately frozen on dry ice until assayed. When defrosted the luny was weighed to determine wet weight. Dry weight was determined a~ter -`
the lung was dried at 80C for 36; hours,~and the .
pulmonary w~ter content was calculated by subtracting lS the lung dry wei~ht from the wet lung weight .
The wet:~485 ~4 mg), dry (92 ~4 mg)~ and:wet-dxy (pulmonary water content, 393 *~ mg) lung weight did not ~differ among the control (veh'Lcle tre:ated)~ gro~ps~IL-2 increased wet (P< O.OS), dry and wet-dry (~P<O.O~) Iung `.- 20 :welght~ in~a~dos:e-dependent manner. The wet-dry/dr~
ratio howeve~r remained unchanged.~ Pretreatment:with compound C prevented the respon~ses` (P<0~.05~
T~e r~esults of ~he above experiment5~clearly demonstrates~the therapeutic utility~of~platelet~
25~ activating:f;act~or antagonist on treating:IL-2 induced:
lun~ injury.
: ~ This invention discloses platelet-activating~factor antagonist ~nd pharmaceutically acceptab~le salts or hydrates or solvates thereof as being useful for 30 treating IL-2 induced lung injury in mammals, i~cluding humans.
A platelet-activating factor antagonist~or a pharmaceutically acceptable salt or hydrate or solvate thereof ~an be administered to a :subject in a 35 con~rentional dosage form prepared b~7 combining a ~ platelet-activating factor antagonist or a . W093/20822 ~1337~ PCT/US93/03347 pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmac2utically acceptable carrier or diluent according to known techniques~
It will be recognized by one of skill in the ar~
that the foxm and character of the phar~aceutically asceptable carrier or diluent is dictated by the amount of acti~e ingredient with which it is to be combined, the route of administration and vther well-}cnown variables. A platelet activating factor antagonist or a 10 pharmaceutically acceptable salt or hydrate or solva~e ~:
thereof is administered to a mammal, including a human, in an amoun~ sufficient to prevent or alleviate I~2 induced lung injury.
The route of administration of the platelet~
activating factor antagonist :is ~ot critlcal but is usually oral or parenteral, perferably:oral.
The ~erm parenteral as used herein includes intravenous, intramuscularr subcutaneous, intranasal, intxarectal, tran3dermal, intravayinal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 20 mg/kg of total body weight, most preferably, from about 0.1 mg/kg to about 5 mg/kg. Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 150 mg.
The platelet activating factor antagonist which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution o~ the compound or -~5 pharmaceutically acceptable salt in a suitable liquid carrier~s) for example, ethanol, glycerine, non-aqueous W~93/2~822 PCT/~S93/03347 2133~ ~ 4 - 8 - :
solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservati~e, flavoring or coloring agent.
A composition in the form of a tablet:can be ~.
prepared using any suitable pharmaceuti~al carrier ~s) routinely us~d for preparing solid for ~ ations. ~:
Examples of such carriers include magn.eslum stearate, ~-~
starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be 10 prepared using routine encapsulation procedures. For :-example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternativel.y, a dispersion or ~-suspension can be prepared using any suitable pharmac~utical carrier (s), for example aqueous gums, :
celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
The daily oral dosage regimen will preferably be : from about 0.01 mg/kg to about 20 mg/kg of total body ~0 weight. Pre~erably each oral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 150 mg.
: While it is possible for an activate ingredient to be administered alone, it is preferable to present it as ~-
:' This invention rela~es to . a method of treating interleukin-2 induc:d lung injury in a mammal, including a human, in need thereof which comprises ~dminist~ring to .`
such mammal an effective amouin~ of a pla~elet-activating ~`
~a~tor antagonist .
Human recombinant ~nterleukin-2 l IL-2 ) has beer showrl t~ me~iat~ tumor regressio~ ~ n animals (Ettinghausen, ~S.~E;. et al. ~n~ 2784-27g2 ~19B7)~) and Humans (Rosenberg, ~ S~A. et al. ~,_~,~
~ 14135 ~ (~1985) ) ~ and is currently under investigation as a n w treatment modality: for patients ~' with advanced metastatic cancer (Rosenberg,~ S.A. et al.:
E~ k~ 8~9 tl~87)~
The systemic use of IL-2 has, however, also been associated with disorders such as, microvascu~ar injury and pulmonary adema (Clausnerj F.L. et al.
Phy.s;.nl. ~:1030-1037 ~1988) and Rosenstein, M~
Imm~n~l~ 1735 1742 (1986)) (hereinafter "lung 35 in~ury")~ The acute pulmonary toxicity associa~ed with IL-2 infusion has been proposed t~ result from Lymphocyt~ ac~ivation (Anderson, T.D. et al. h~k~
InY~ 598-612 (l9~B), Damle, N.K. et al. J.
W093/~0822 2133~ S 4 PCT/~S93/~3347 mm~nQl~ 142:2660-2669 (1989) and Damle, N.K. et al.
Imm~nQl_ 138:1779-1785 (1987)), the production of inflammatory mediators such as interleukin-1 (IL-1) Numerof, R.P. et al. ~ I m~ 4250-4257 (1988)) or .:
5 tumor Necrosis Factor-~ (Helsopt H.E. et al. ~1QQ~ :
1~:1374-1380 (1989) and Nedwin, G.~. et al. .I Immunvl~
2492-2496 (1985) and from the IL-2 induced activation of Humoral systems such as the comple~ent cascade (Thijs, L.G. J. Imm~noL~ 2419-2424 (1990)).
10 The actual mechanism(s) of IL-2-induced lung injury is ":~
presently unknown.
.. .
PAE (platelet activating factor) is phospholipid acetyl-glyceryl-ether-phosphoryl-choline ~AGEPC) which is known as a potent lipid mediator releas2d by animal and human proinflammatory cells. These cells include mainly basophilic and neutrophi.lic granulocytes, macrophages lfrom blood and tissue) and thrombocytes which are involved in inflammatory reactions.
Compounds which inhibit PAF are reported to be of `~:-potential value in the treatment. of a va~iety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritisr rhi.nitis, bronchitis and urticaria, the treatment of circulatory shockr gastric, ulceration, psoriasis and cardiovascular conditions, including angina, thrombosis and stroke, (W0 91/17162 published November 14, 199l).
Presently, PAF inhi~itors are not known as having utility in treating IL-2-induced lung injuries.
W093/20822 2 1 3 3 7 5 ~ P~T/~S93/03347 summ~ry ~f the Invention This invention relates to a method of treating interleukin-2 induced lung injury in a mammal, including 5 . a human, in nePd thereof which compris~s administering to such mammal an.effective amount of a platelet activating factor antagonist.
'.
Illustrative of compounds that have PAF activity are the following comopunds O ':".' N N
N
:
which is 5 [~2-Chlorophenyl)-3,4-dihydro-10 methyl- ~:
3-~(4~morpholinyl)carbonyl~-2H,7H~
~ cyclopenta[4,5]thieno[3,2-f]~1,2,4~triazolo[4,3-: a3[1,4]diazepine. This compound is disclosed and 20 claimed in European Application No. 254245~A published :
January 27, 1988, as ha~ring platelet-activating factor antagonist activity.
:~ B) 3~N
o N-C(CH2~2~ )~
~CI ~
W093/208~ PC~/US93J03347 213375~
which is 3 ~4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a]~1,4]-diazepin-2-yl]-1-(4-morpholinyl)-l~propanon and which is disclosed .. :-in U.S. Patent No. 4968794 as having platelet~activating ~--factor antagonist activity. ~ ' ,~, ~'.' C ) ~. ~
CH30 ~3--S-CH2-C~ 1 N)\\N
t::H~, 1 0 ' ~ "' which is ~etrahydro-4,7,8ylO methyl-(chlor~- -2phenyl)-Ç[(dimethoxy~3,4pheny.~thio]methylthiocarbonyl-: ~ 9 pyrido[4',3'-4,5]~hieno[3,2-f]tr~iazolo-1,2,4[4j3~
a]diazepine-1~4 :~hereinafter compound C) and which is :~: ;15 disclosed in U.S. Patent No. 5r049~559 as a~specific platelet-acti-ating:factor antagonist.
: D3 ~; ; : C~6-H5 CONH ~
: <~N ~S ~ ~ .
:
;~
'~
WOg3/~0X22 PCT~US93/~3347 213375~ ~
. 5 which is (+) N-(3-benzoylphenyl)3-(3 pyridyl~-lH, 3H pyrrolo [1,2-c] thiazole-7 carboxamide and which is disclosed and claimed in U.S. Patent 4,783,472 as having plat~let-activating factor a~tagonist activity.
By the term "treating" as used herein is meant ~:
pxophylactic or therapeutic therapy. :-By the term "U" as used herein is meant a unit o~
IL 2 activity as specified by the manufacturer (i.e.
v Hoffman-La Rocke, Nutley, NJ).
It has now been disco~ered that compounds which are antagonists ~f platelet-actlva~ing factor are useful in treating interleukin-2 (IL-2) induced lung injury.
Compound C was tested for its ln ~lYQ potency in treating IL-2 induced lung injury. To perform the experiments recombinant human IL-2 ~obtained from Hoffman-La Roche, Nutley, NJ) was reconstituted before use with 1 ml o~ 0.9% NaCl per 106U IL-2. A ~05 U ~ose of IL-2 was prepared by diluting the above 106 U dose 10 ~:
times. Compound C was solubilized in 64% DMSO, in 0.9%
20 NaCl to reach a concentration of 5 mg/ml. Male Sprague- :~
Dawley Rats (obtained from Charles River, Wilmington, MA) were housed in groups of three in s~andard cages, ;~
and kept with ~ood and water ad libitum in a temperature controlled ~oom ~22C) on a 12 hour ~;
dark/light cycle, until surgery.
Following anesthesia with pe~toba~bital (30 mg/kg, i.p.) the animals were randomly asso~rted into three groups.
Group I. IL-2 at 105 U/kg (n=14) ~as used hèrein the term "n" means the number of rats), 106 U/kg (n-18) or vehicle (n=12) was infused intravenously for on~ hour (syringe infusion pump 22, Harvard :~
apparatus, South Natick, MA).
~roup II. IL-2 at 106 U/kg was administered by bolus injection followed by IL-2 at 10~ :
W093/20822 2~337~4 P~T/U~93~03347 U~kg intravenous injecti.on for one hour (n=6), vehicle treated animals served as controls (n=6). .
Group III. IL-2 at 106 U/kg was administered by intravenous injection for 1 hour, 30 minutes after pretreatme ~ 'wlth compound C (~0 mg/kg, I.P.) ~n=6~"or compound C
vehicle (n=6). ~-At the end of the experimental pe~iod the le~t lung was removed and immediately frozen on dry ice until assayed. When defrosted the luny was weighed to determine wet weight. Dry weight was determined a~ter -`
the lung was dried at 80C for 36; hours,~and the .
pulmonary w~ter content was calculated by subtracting lS the lung dry wei~ht from the wet lung weight .
The wet:~485 ~4 mg), dry (92 ~4 mg)~ and:wet-dxy (pulmonary water content, 393 *~ mg) lung weight did not ~differ among the control (veh'Lcle tre:ated)~ gro~ps~IL-2 increased wet (P< O.OS), dry and wet-dry (~P<O.O~) Iung `.- 20 :welght~ in~a~dos:e-dependent manner. The wet-dry/dr~
ratio howeve~r remained unchanged.~ Pretreatment:with compound C prevented the respon~ses` (P<0~.05~
T~e r~esults of ~he above experiment5~clearly demonstrates~the therapeutic utility~of~platelet~
25~ activating:f;act~or antagonist on treating:IL-2 induced:
lun~ injury.
: ~ This invention discloses platelet-activating~factor antagonist ~nd pharmaceutically acceptab~le salts or hydrates or solvates thereof as being useful for 30 treating IL-2 induced lung injury in mammals, i~cluding humans.
A platelet-activating factor antagonist~or a pharmaceutically acceptable salt or hydrate or solvate thereof ~an be administered to a :subject in a 35 con~rentional dosage form prepared b~7 combining a ~ platelet-activating factor antagonist or a . W093/20822 ~1337~ PCT/US93/03347 pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmac2utically acceptable carrier or diluent according to known techniques~
It will be recognized by one of skill in the ar~
that the foxm and character of the phar~aceutically asceptable carrier or diluent is dictated by the amount of acti~e ingredient with which it is to be combined, the route of administration and vther well-}cnown variables. A platelet activating factor antagonist or a 10 pharmaceutically acceptable salt or hydrate or solva~e ~:
thereof is administered to a mammal, including a human, in an amoun~ sufficient to prevent or alleviate I~2 induced lung injury.
The route of administration of the platelet~
activating factor antagonist :is ~ot critlcal but is usually oral or parenteral, perferably:oral.
The ~erm parenteral as used herein includes intravenous, intramuscularr subcutaneous, intranasal, intxarectal, tran3dermal, intravayinal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 20 mg/kg of total body weight, most preferably, from about 0.1 mg/kg to about 5 mg/kg. Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 150 mg.
The platelet activating factor antagonist which are active when given orally can be formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution o~ the compound or -~5 pharmaceutically acceptable salt in a suitable liquid carrier~s) for example, ethanol, glycerine, non-aqueous W~93/2~822 PCT/~S93/03347 2133~ ~ 4 - 8 - :
solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservati~e, flavoring or coloring agent.
A composition in the form of a tablet:can be ~.
prepared using any suitable pharmaceuti~al carrier ~s) routinely us~d for preparing solid for ~ ations. ~:
Examples of such carriers include magn.eslum stearate, ~-~
starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be 10 prepared using routine encapsulation procedures. For :-example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternativel.y, a dispersion or ~-suspension can be prepared using any suitable pharmac~utical carrier (s), for example aqueous gums, :
celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
The daily oral dosage regimen will preferably be : from about 0.01 mg/kg to about 20 mg/kg of total body ~0 weight. Pre~erably each oral dosage unit will contain the active ingredient in an amount of from about 2 mg to about 150 mg.
: While it is possible for an activate ingredient to be administered alone, it is preferable to present it as ~-
2~ a pharmaceutical formulation.
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a plateletwactivatiny factor antagonist or a pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the exact condition heing treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of s}cill in the art that the optimal course of :~
treatment, i.w., the number of doses of a platelet-WV93~20822 2 1 3 3 7 S 4 PCT/US93/03~7 . . .
_ g _ activating factor antagonist or a phaxmaceutically acceptable salt or hydrate or ~olvate thereof given per day and duration of therapy, can be ascertained hy those skilled in the art using conventional course of .
S treatment determination tests.
Without further elaboration, it is believed that one skilled in the art can~ using the preceding ::
description, utilize the present invention to its fullest extent. The following examples are, there~ore, to be construed as merely illustrati.~e and nst a limitation of the scope of the pr~sent invention in any way.
A oxal dosage form for administering a pla~el~t-activating factor antagonist is produced by filing a standard two piece hard gelatin c~psule with the ingredients in the proportions shown in Table I, below.
: ~ Compound C 25 mg Lactose 5S mg Talc 16 mg Magnesium Stearate 4 mg ,:
An injectable form for administering a platelet~
activating factor antagonist is produced by stirring ~:
1.5% by weight of Compound C in 10% by volume propylene glycol in water.
',~
The sucrose, calcium sulfate dihydrate and a platelet-activating factor anta~onist shown in Table II
below, are mixecl and granulated in the proportions shown ~V093/~0~22 21337S~ PCr/US93/033~7 with a 10% gelatin so1ution. Th~ wet granules are screened, dried, mixed with the starch~ talc and stearic ~-acid, screened and compxessed into a tablet.
Compound C 2 0 mg calcium sul:Eate dihydrate30 mg ::
sucrose 4 mg starch 2 mg -~
talc 1 mg ~
stearic acld 0 . 5 mg ;~;
While the above descriptions ~n~ examples fully describe the invention and the prefexred embodiments ~0 thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming -within the scope of the following claims.
~ '''";
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a plateletwactivatiny factor antagonist or a pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the exact condition heing treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of s}cill in the art that the optimal course of :~
treatment, i.w., the number of doses of a platelet-WV93~20822 2 1 3 3 7 S 4 PCT/US93/03~7 . . .
_ g _ activating factor antagonist or a phaxmaceutically acceptable salt or hydrate or ~olvate thereof given per day and duration of therapy, can be ascertained hy those skilled in the art using conventional course of .
S treatment determination tests.
Without further elaboration, it is believed that one skilled in the art can~ using the preceding ::
description, utilize the present invention to its fullest extent. The following examples are, there~ore, to be construed as merely illustrati.~e and nst a limitation of the scope of the pr~sent invention in any way.
A oxal dosage form for administering a pla~el~t-activating factor antagonist is produced by filing a standard two piece hard gelatin c~psule with the ingredients in the proportions shown in Table I, below.
: ~ Compound C 25 mg Lactose 5S mg Talc 16 mg Magnesium Stearate 4 mg ,:
An injectable form for administering a platelet~
activating factor antagonist is produced by stirring ~:
1.5% by weight of Compound C in 10% by volume propylene glycol in water.
',~
The sucrose, calcium sulfate dihydrate and a platelet-activating factor anta~onist shown in Table II
below, are mixecl and granulated in the proportions shown ~V093/~0~22 21337S~ PCr/US93/033~7 with a 10% gelatin so1ution. Th~ wet granules are screened, dried, mixed with the starch~ talc and stearic ~-acid, screened and compxessed into a tablet.
Compound C 2 0 mg calcium sul:Eate dihydrate30 mg ::
sucrose 4 mg starch 2 mg -~
talc 1 mg ~
stearic acld 0 . 5 mg ;~;
While the above descriptions ~n~ examples fully describe the invention and the prefexred embodiments ~0 thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming -within the scope of the following claims.
~ '''";
Claims (20)
1. Use of a platelet-activating factor antagonist in the manufacture of a medicament for use in treating interleukin-2 induced lung injury in a mammal.
2. A use according to claim 1 wherein the mammal is a human.
3. A use according to claim 2 wherein the platelet-activating factor antagonist is 5-[(2-Chorophenyl)-3,4-dihydro-10-methyl-3-[(4-morpholinyl)carbonyl]-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3 a][1,4]diazepine.
4. A use according to claim 2 wherein the platelet-activating factor antagonist is 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]-diazepin-2-yl]-1-(4-morpholinyl)-1-propanon.
5. A use according to claim 2 wherein the platelet-activating factor antagonist is tetrahydro-4,7,8,10 methyl-(chloro-2phenyl)-6[(dimethoxy-3,4phenyl)thio]methylthiocarbonyl-9-pyrido[4',3'-4,5]thieno[3,2-f]triazolo-1,2,4[4,3-a]diazepine-1,4.
6. A use according to claim 2 where the platelet-activating factor antagonist is (+)N-(3-benzoylphenyl)3-(3 pyridyl)-1H,3H pyrrolo [1,2-c]thiazole-7 carboxamide.
7. A use according to claim 2 wherein the platelet-activating factor antagonist is administered orally.
8. A use according to claim 7 wherein from about 0.01 mg/kg to about 20 mg/kg of the platelet-activating factor antagonist is administered per day.
9. A use according to claim 2 wherein the platelet-activating factor antagonist is administered parenterally.
WO 93/20822 PCT/US93/0334?
WO 93/20822 PCT/US93/0334?
10. A use according to claim 9 wherein from about 0.01 mg to about 20 mg/kg of the platelet-activating factor antagonist is administered per day.
11. A pharmaceutical composition for use in the treatment of interleukin-2 induced lung injury in a mammal comprising a platelet-activating factor antagonist, and a pharmaceutically acceptable carrier.
12. A composition according to claim 11 wherein the mammal is a human.
13. A composition according to claim 12 wherein the platelet-activating factor antagonist is 5-[(2-Chlorophenyl)-3,4-dihydro-10-methyl-3-[(4-morpholinyl)carbonyl]-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
14. A composition according to claim 12 wherein the platelet-activating factor antagonist is 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]-diazepin-2-yl]-1-(4-morpholinyl)-1-propanon.
15. A composition according to claim 12 wherein the platelet-activating factor antagonist is tetrahydro-4,7,8,10 methyl-(chloro-2phenyl)-6[(dimethoxy-3,4phenyl)thio]methylthiocarbonyl-9 pyrido[4',3'-4,5]thieno[3,2-f]triazolo-1,2,4[4,3-a]diazepine-1,4.
16. A composition according to claim 12 wherein the platelet-activating factor antagonist is (+)N-(3-benzoylphenyl)3-(3 pyridyl)-1H, 3H
pyrrolo [1,2-c] thiazole-7 carboxamide.
pyrrolo [1,2-c] thiazole-7 carboxamide.
17. A composition according to claim 12 wherein the platelet-activating factor antagonist is administered orally.
18. A composition according to claim 17 wherein from about 0.01 mg/kg to about 20 mg/kg of the platelet-activating factor antagonist is administered per day.
19. A composition according to claim 12 wherein the platelet-activating factor antagonist is administered parenterally.
20. A composition according to claim 19 wherein from about 0.01 mg to about 20 mg/kg of the platelet-activating factor antagonist is administered per day.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929207645A GB9207645D0 (en) | 1992-04-08 | 1992-04-08 | Methods |
| GB9207645.4 | 1992-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2133754A1 true CA2133754A1 (en) | 1993-10-28 |
Family
ID=10713637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002133754A Abandoned CA2133754A1 (en) | 1992-04-08 | 1993-04-08 | Compositions of platelet activating factor antagonists and methods of treating interleukin-2 induced lung injury therewith |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0634933A1 (en) |
| JP (1) | JPH07505885A (en) |
| KR (1) | KR950700740A (en) |
| AU (1) | AU4281993A (en) |
| CA (1) | CA2133754A1 (en) |
| GB (1) | GB9207645D0 (en) |
| WO (1) | WO1993020822A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3502392A1 (en) * | 1985-01-25 | 1986-07-31 | Boehringer Ingelheim KG, 6507 Ingelheim | NEW THIENO-TRIAZOLO-1,4-DIAZEPINO-2-CARBONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS |
| FR2601015B1 (en) * | 1986-07-04 | 1988-08-05 | Rhone Poulenc Sante | NOVEL 1H, 3H-PYRROLO (1,2-C) THIAZOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| GB8911030D0 (en) * | 1989-05-13 | 1989-06-28 | Scras | Hetrazepine derivatives |
-
1992
- 1992-04-08 GB GB929207645A patent/GB9207645D0/en active Pending
-
1993
- 1993-04-08 JP JP5518492A patent/JPH07505885A/en active Pending
- 1993-04-08 WO PCT/US1993/003347 patent/WO1993020822A1/en not_active Application Discontinuation
- 1993-04-08 EP EP93912168A patent/EP0634933A1/en not_active Withdrawn
- 1993-04-08 CA CA002133754A patent/CA2133754A1/en not_active Abandoned
- 1993-04-08 AU AU42819/93A patent/AU4281993A/en not_active Abandoned
-
1994
- 1994-10-07 KR KR1019940703602A patent/KR950700740A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR950700740A (en) | 1995-02-20 |
| EP0634933A1 (en) | 1995-01-25 |
| AU4281993A (en) | 1993-11-18 |
| GB9207645D0 (en) | 1992-05-27 |
| WO1993020822A1 (en) | 1993-10-28 |
| JPH07505885A (en) | 1995-06-29 |
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