WO1988009675A1 - Inhibition of arachidonic acid metabolism - Google Patents

Inhibition of arachidonic acid metabolism Download PDF

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Publication number
WO1988009675A1
WO1988009675A1 PCT/US1988/001838 US8801838W WO8809675A1 WO 1988009675 A1 WO1988009675 A1 WO 1988009675A1 US 8801838 W US8801838 W US 8801838W WO 8809675 A1 WO8809675 A1 WO 8809675A1
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Prior art keywords
inhibitor
patient
arachidonic acid
effective amount
receptor blocker
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PCT/US1988/001838
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French (fr)
Inventor
Alan I. Faden
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Medicis Corporation
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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Free fatty acids are the products of hydrolysis of phosphoglycerides. This hydrolysis reaction can proceed by several pathways as follows:
  • the concentration of metabolites of arachidonic acid in central nervous system tissue also increases following traumatic or ischemic central nervous system injury. Since the metabolites are potent vasoconstrictors and promoters of platelet aggregation, they were investigated as possible causes of permanent secondary injury stemming from traumatic and ischemic central nervous system injury including injuries to the brain or spinal cord. DETAILED DESCRIPTION OF THE INVENTION It has been discovered that the inhibition of arachidonic acid metabolism limits secondary injury stemming from traumatic or ischemic central nervous system injury. Pharmaceutical preparations capable of such inhibition have been developed.
  • the first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury which comprises administering to a patient suffering from said traumatic or ischemic central nervous system injury an effective amount of a pharmaceutically acceptable composition capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism such that the metabolism of said arachidonic acids is inhibited.
  • compositions containing one or more active ingredients in admixture with pharmaceutically acceptable excipients capable of inhibition of arachidonic acid metabolism by blocking or substantially blocking the cyclooxygenase and lipoxygenase metabolic pathways or receptors for their metabolic products. That is, the invention contemplates a dual functioning active ingredient which inhibits both pathways and a combination active ingredient which two or more ingredients in admixture inhibit metabolism of the free fatty acid.
  • pharmaceutically acceptable composition there is contemplated a composition which performs the desired function within acceptable toxicity limits.
  • an effective amount of the pharmaceutically acceptable composition of the present invention there is contemplated an amount of said composition sufficient to inhibit metabolism of arachidonic acid or to block the effects of metabolites on their receptors.
  • a preferred embodiment of the first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a cyclooxygenase inhibitor, an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
  • cyclooxygenase inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting cyclooxygenase.
  • a lipoxygenase inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting lipoxygenase.
  • the pharmaceutically acceptable composition comprises one or more active ingredients capable of inhibiting the cyclooxygenase and lipoxygenase enzymes which are responsible for the metabolism of arachidonic acid. Inhibition of the enzymes governing both metabolic pathways results in the inhibition of the metabolism of the free fatty acid.
  • the pharmaceutically acceptable inert ingredient is a function of the dosage form through which the active ingredient is administered.
  • the arachidonic acid inhibitory composition of the present invention may be administered to the patient in any dosage form convenient under the patient's specific circumstances. Usually, parenteral administration is preferred.
  • a parenteral dosage form there is contemplated a dosage unit suitable for intravenous administration which comprises (i) an effective amount of a pharmaceutically acceptable composition capable of inhibiting arachidonic acid metabolism and (ii) a pharmaceutically acceptable solution.
  • a pharmaceutically acceptable solution there is contemplated any solution which is safe for injection and which is biologically inert and hence does not interfere with the active ingredient.
  • a pharmaceutically acceptable solution may include an isotonic solution suitable for injection into a patient.
  • the isotonic solution may contain water, salt and conventional ingredients such as glucose.
  • the active ingredient responsible for inhibition of cyclooxygenase and lipoxygenase may be the same compound.
  • exemplary of such compounds is [3-amino-l- (M- trifluoro ethyl) phenyl]-2-pyrazidine which may be obtained through Burroughs-Welcome.
  • an effective amount of such a dual functioning active ingredient there is contemplated an amount of said active ingredient sufficient to inhibit metabolism of arachidonic acid.
  • An effective amount of a dual functioning active ingredient is from about 1 to about 40 g/kg body weight of the patient 2-4 times daily.
  • a more preferred effective amount of a dual functioning active ingredient is from about 5 to about 10 mg/kg body weight of the patient 2-4 times daily.
  • a more preferred embodiment of this aspect provides a method of inhibiting arachidonic acid metabolism, wherein [3-amino-l-(M-trifluoromethyl) phenyl]-2-pyrazidine is administered at a dose of about 5 to about 15 mg/kg body weight of the patient every 4 hours.
  • the pharmaceutically acceptable composition of this embodiment may contain one active ingredient for the inhibition of cyclooxygenase and one active ingredient for the inhibition " of lipoxygenase.
  • Such a combination of active ingredients will also serve to inhibit arachidonic acid metabolism.
  • a combination active ingredient there is contemplated administration of a cyclooxygenase inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient and a lipoxygenase inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient daily.
  • a preferred dosage of a cyclooxygenase inhibitor is from about 0.5 to about 5.0 mg/kg body weight of the patient and a lipoxygenase inhibitor from about 0.5 to about 5.0 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
  • Another more preferred embodiment of the first aspect of the present invention provides a method for inhibition of arachidonic acid metabolism, wherein said lipoxygenase inhibitor is administered at a dose of from about 0.5 mg/kg to about 5.0 mg/kg body weight of the patient every 4 hours.
  • a still more preferred embodiment of the invention involves a method for arachidonic acid metabolism inhibition, wherein said lipoxygenase inhibitor is 3- methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one. 3- methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one can be obtained through Bayer.
  • Another more preferred embodiment provides a method for inhibition of arachidonic acid metabolism, wherein said cyclooxygenase inhibitor is selected from the group comprising l-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH- indole-3-acetic acid, al.pha-methyl-4- (2- methylpropyl)benzene acetic acid and 2-(acetyloxy)benzoic acid.
  • cyclooxygenase inhibitor is selected from the group comprising l-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH- indole-3-acetic acid, al.pha-methyl-4- (2- methylpropyl)benzene acetic acid and 2-(acetyloxy)benzoic acid.
  • 1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3- acetic acid can be obtained in accordance with the procedure disclosed in U.S. Patent No
  • Alpha- methyl-4-(2-methylpropyl)benzene acetic acid can be obtained in accordance with the procedures disclosed in U.S. Patent Nos. 3,228,831 and 3,385,886.
  • 2- (Acetyloxy)benzoic acid can be obtained in accordance with the procedures disclosed in U.S. Patent Nos. 2,890,240 and 3,235,583.
  • Another preferred embodiment of the first aspect of the present invention provides a method for decreasing the action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
  • a leukotriene receptor blocker there is contemplated any pharmaceutically acceptable active ingredient capable of blocking the leukotriene receptor.
  • the leukotriene receptor blocker of the present invention may be either a leukotriene C 4 receptor blocker or a peptidyl-leukotriene receptor blocker.
  • a thromboxane receptor blocker there is contemplated any pharmaceutically acceptable active ingredient capable of blocking the thromboxane receptor.
  • the pharmaceutically acceptable composition comprises one or more active ingredients capable of blocking the leukotriene and thromboxane receptors which are essential in the metabolism of arachidonic acid to form thromboxane and leukotriene metabolites. Blocking receptors in both metabolic pathways results in the inhibition of the metabolism of the free fatty acid.
  • the pharmaceutically acceptable composition of thisf embodiment may contain one active ingredient for blocking • the leukotriene receptor and one active ingredient for blocking the thromboxane receptor.
  • active ingredients will also serve to inhibit arachidonic acid metabolism.
  • a combination active ingredient there is contemplated administration of a leukotriene receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient and a thromboxane receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient daily.
  • a more preferred dosage of a leukotriene receptor blocker is from about 1 to about 10 mg/kg body weight of the patient and a thromboxane receptor blocker from about 1 to about 10 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
  • a more preferred embodiment of this aspect involves a method for inhibiting the formation or action of arachidonic acid metabolites, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 mg/kg to 10.0 mg/kg body weight of the patient bolus followed by 1.0 mg/kg to 10.0 mg/kg body weight of the patient every 3-6 hours.
  • a still more preferred embodiment provides an inhibition method, wherein said leukotriene receptor blocker is (1-[2-hydroxy-3-propyl-4-[4-(lH ⁇ - tetrazol-5-yl)-butoxy]-phenyl ethanone. (l-[2 ⁇ hydroxy-3- propyl-4-[4-(lH-tetrazol-5-yl)-butoxy]-phenyl ethanone can be obtained through Eli Lilly.
  • the third embodiment of the first aspect of the present invention provides a method for decreasing the action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a .thromboxane synthetase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
  • a thromboxane synthetase inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting thromboxane synthetase.
  • the pharmaceutically acceptable composition comprises one or more active ingredients capable of blocking the leukotriene receptor which prevents the actions of peptidyl-leukotrienes in mediating secondary injury, and inhibiting thromboxane synthetase enzyme which is responsible for the synthesis of thromboxane metabolites. Blocking the receptor of one pathway and inhibiting a major enzyme in the other results in the inhibition of the detrimental actions of the free fatty acid.
  • the pharmaceutically acceptable composition of this embodiment may contain one active ingredient for blocking the leukotriene receptor and one active ingredient for inhibiting thromboxane synthetase.
  • active ingredients will also serve to inhibit arachidonic acid metabolism.
  • a combination active ingredient there is contemplated administration of a leukotriene receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient and a thromboxane synthetase inhibitor at a dosage of from about 1 to about 100 mg/kg body weight of the patient daily.
  • a more preferred dosage of a leukotriene receptor blocker is from about 1 to about 10 mg/kg body weight of the patient and a thromboxane synthetase inhibitor from about 10 to about 20 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
  • a ' more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 mg/kg to 10.0 mg/kg body weight of the patient bolus followed by 1.0 mg/kg to 10.0 mg/kg body weight of the patient every 3-6 hours.
  • a still more preferred embodiment provides an inhibition method, wherein said leukotriene receptor blocker is (l-[2- hydroxy-3-propyl-4-[4-(lH-tetrazol-5-yl) -butoxy]-phenyl ethanone.
  • a more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said thromboxane synthetase inhibitor is administered at a dose of about 1.0 to about 5.0 mg/kg body weight of the patient every 6 hours.
  • a still more preferred embodiment involves the inhibition method, wherein said thromboxane synthetase inhibitor is (3 ⁇ (1H- imidazole-1-yl-methyl)-2-methyl-lH-indole-l-propanoic acid. (3- (lH-imidazole-1-yl-methyl) -2-methyl-lH-indole-1- propanoic acid can be obtained through Pfizer of England.
  • a fourth embodiment of the first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a phospholipase A inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredient.
  • a phospholipase A 2 inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting phospholipase A 2 .
  • the pharmaceutically acceptable composition comprises one or more active ingredients capable of inhibiting the enzyme phospholipase A 2 which is essential in the metabolism of arachidonic acid.
  • Inhibition of the enzyme phospholipase A 2 enzyme which is involved in arachidonic acid metabolism upstream of both the cyclooxygenase and lipoxygenase pathways results in the inhibition of the metabolism of the free fatty acid. That is, arachidonic acid metabolism is inhibited through inhibition of the metabolic route prior to the split into the cyclooxygenase and lipoxygenase alternative pathways.
  • a phospholipase A 2 inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient.
  • a more preferred dosage of a phospholipase A 2 inhibitor is from about 1 to about 10 mg/kg body weight of the patient. Dosages of the active ingredient may be administered in divided dosages.
  • a more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said phospholipase A inhibitor is administered at a dose of about 50 to about 200 micrograms/kg body weight of the patient every 2 hours.
  • a still more preferred embodiment involves an inhibition method, wherein said phospholipase A 2 inhibitor is N 4 -(6- chloro-2-methoxy-9-acridinyl) -N 1 , N 1 -diethyl-l, 4- pentanediamine. N 4 -(6-chloro-2-methoxy-9-acridinyl)-N 1 ,
  • N 1 -diethyl-l,4-pentanediamine can be obtained in accordance with the procedure disclosed in U.S. Patent No. 2,113,357.
  • a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a cyclooxygenase inhibitor and an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient, wherein, said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
  • a preferred embodiment of this aspect provides a pharmaceutical composition, wherein said cyclooxygenase inhibitor and said lipoxygenase inhibitor is [3-amino-l-(M- trifluoromethyl) phenyl]-2-pyrazidine.
  • Another preferred embodiment of this aspect provides a pharmaceutical composition, wherein said cyclooxygenase inhibitor is selected from the group comprising l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid, alpha-methyl-4-(2-methylpropyl)benzene acetic acid or 2- (acetyloxy)benzoic acid.
  • said cyclooxygenase inhibitor is selected from the group comprising l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid, alpha-methyl-4-(2-methylpropyl)benzene acetic acid or 2- (acetyloxy)benzoic acid.
  • a further preferred embodiment of the second aspect provides a pharmaceutical composition, wherein said lipoxygenase inhibitor is 3-methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one.
  • the third aspect of the present invention provides a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C receptor blocker as a peptidyl-leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
  • a preferred embodiment of this aspect involves a pharmaceutical composition, wherein said leukotriene receptor blocker is (1-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
  • a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C receptor blocker, an effective amount of a thromboxane synthetase inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
  • a preferred embodiment of the fourth aspect provides a pharmaceutical composition, wherein said leukotriene receptor blocker is (l-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
  • Another preferred embodiment of the fourth aspect of the present invention provides a pharmaceutical composition, wherein said thromboxane synthetase inhibitor is (3-(lH- imidazole-1-yl-methyl)-2-methyl-lH-indole-1-propanoic acid.
  • a further aspect of the present invention provides a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a phospholipase A 2 inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredient.
  • a preferred embodiment of this aspect involves a pharmaceutical composition, wherein said phospholipase A 2 inhibitor is N 4 -(6-chloro-2-methoxy-9-acridinyl)-N 1 , N 1 - diethyl-1,4-pentanediamine.
  • EXAMPLE 1 [3-amino-l-(M-trifluoromethyl) phenyl]-2-pyrazidine is admixed with an isotonic solution to give a final concentration of [3-amino-l-(M-trifluoromethyl) phenyl]-2- pyrazidine in solution of 100 mg/cc.
  • EXAMPLE 2 3-methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one and l-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH-indole-3- aceti ⁇ acid are admixed with an isotonic solution to give a final concentration of 3-methyl-l-[2-(2-napthyloxy) ethyl]- 2-pyrazolin-5-one and 1-(4-chlorobenzoyl)-5-metho ⁇ y-2- methyl-lH-indole-3-acetic acid in solution of 20 and 50 mg/cc, respectively.
  • EXAMPLE 3 (1-[2-hydroxy-3-propy1-4-[4-(lH-tetrazol-5-yl)-butoxy]- phenyl ethanone and a thromboxane receptor blocker are admixed with an isotonic solution to give a final concentration of (l-[2-hydroxy-3-propyl-4-[4-(lH-tetrazol- 5-yl)-butoxy]-phenyl ethanone and thromboxane receptor blocker in solution of 50 and 100 mg/cc, respectively.
  • EXAMPLE 4 (1-[2-hydroxy-3-propy1-4-[4-(lH-tetrazol-5-yl)-butoxy]- phenyl ethanone and a thromboxane receptor blocker are admixed with an isotonic solution to give a final concentration of (l-[2-hydroxy-3-propyl-4-[4-(lH-tetrazol- 5-yl)-butoxy]-
  • N 4 -(6-chloro-2-methoxy-9-acridinyl)-N 1 , N 1 -diethyl-l,4- pentanediamine is admixed with an isotonic solution to give a final concentration of N 4 -(6-chloro-2-methoxy-9- acridinylJ-N 1 , N 1 -diethyl-l,4-pentanediamine in solution of 100 mg/cc.
  • Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 1 into the patient such that 10 mg/kg body weight of the patient of the active ingredient is administered every 4 hours.
  • EXAMPLE 7 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 2 into the patient such that 2 mg/kg body weight of the patient of the lipoxygenase inhibitor ingredient and 5 mg/kg body weight of the patient of the cyclooxygenase inhibitor is administered every 4 hours.
  • Treatment of a patient suffering from a traumatic or ischemic central" nervous system injury is accomplished through injection of the preparation of Example 3 into the patient such that 4 mg/kg body weight of the patient of the leukotriene receptor blocker ingredient is administered bolus and 4 mg/kg body weight of the patient of the leukotriene receptor blocker is administered every 4 hours thereafter, and 5 mg/kg body weight of the patient of the thromboxane receptor ingredient is administered every 4 hours.
  • EXAMPLE 9 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 4 into the patient such that 4 mg/kg body weight of the patient of the leukotriene receptor blocker ingredient is administered bolus and 4 mg/kg body weight of the patient of the leukotriene receptor blocker is administered every 4 hours thereafter, and 3 mg/kg body weight of the p ⁇ itient of the thromboxane synthetase inhibitor ingredient is administered every 6 hours.
  • EXAMPLE 10 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 5 into the patient such that 100 micrograms/kg body weight of the patient of the active ingredient is administered every 2 hours.

Abstract

The present invention provides methods for decreasing the formation of arachidonic acid metabolites following traumatic or ischemic central nervous system injury by administering to a patient suffering from said traumatic or ischemic central nervous system injury an effective amount of a pharmaceutically acceptable composition capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism such that the metabolism of said arachidonic acids is inhibited. Compositions useful in the practice of such methods are also contemplated.

Description

INHIBITION OF ARACHIDONIC ACID METABOLISM BACKGROUND OF THE INVENTION In normal central nervous system tissue, the concentration of free fatty acids such as arachidonic acid, oleic acid, linoleic acid and docosahexanoiσ acid is low. However, the concentration of the free fatty acids increases in response to traumatic or ischemic central nervous system injury. See, for example, Bazan et al., Adv. Neurol.. v. 28, pp. 197-205 (1980) and Faden et al. L. Neuroche . (in press) .
Free fatty acids are the products of hydrolysis of phosphoglycerides. This hydrolysis reaction can proceed by several pathways as follows:
(1) through the action of phospholipase A2; (2) through the action of phospholipase A and lysopholpholipase; and
(3) through the sequential action of phospholipase C, diacylglycerol lipase and monoacylglycerol lipase. Arachidonic acid obtained from these hydrolysis reactions can be metabolized to form eicosanoids through two major pathways:
(1) the cyclooxygenase pathway which produces prostaglandins and thromboxanes; and
(2) the lipoxygenase pathway which produces hydroperoxy and hydroxy compounds and leukotrienes.
See Wolfe, J. Neurochem.. v. 38, pp. 1-14 (1982) .
The concentration of metabolites of arachidonic acid in central nervous system tissue also increases following traumatic or ischemic central nervous system injury. Since the metabolites are potent vasoconstrictors and promoters of platelet aggregation, they were investigated as possible causes of permanent secondary injury stemming from traumatic and ischemic central nervous system injury including injuries to the brain or spinal cord. DETAILED DESCRIPTION OF THE INVENTION It has been discovered that the inhibition of arachidonic acid metabolism limits secondary injury stemming from traumatic or ischemic central nervous system injury. Pharmaceutical preparations capable of such inhibition have been developed.
The first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury which comprises administering to a patient suffering from said traumatic or ischemic central nervous system injury an effective amount of a pharmaceutically acceptable composition capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism such that the metabolism of said arachidonic acids is inhibited.
As a pharmaceutically acceptable composition of the present invention, there is contemplated a composition containing one or more active ingredients in admixture with pharmaceutically acceptable excipients capable of inhibition of arachidonic acid metabolism by blocking or substantially blocking the cyclooxygenase and lipoxygenase metabolic pathways or receptors for their metabolic products. That is, the invention contemplates a dual functioning active ingredient which inhibits both pathways and a combination active ingredient which two or more ingredients in admixture inhibit metabolism of the free fatty acid. By pharmaceutically acceptable composition, there is contemplated a composition which performs the desired function within acceptable toxicity limits. As an effective amount of the pharmaceutically acceptable composition of the present invention, there is contemplated an amount of said composition sufficient to inhibit metabolism of arachidonic acid or to block the effects of metabolites on their receptors. A preferred embodiment of the first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a cyclooxygenase inhibitor, an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
By a cyclooxygenase inhibitor, there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting cyclooxygenase. By a lipoxygenase inhibitor, there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting lipoxygenase.
In this embodiment, the pharmaceutically acceptable composition comprises one or more active ingredients capable of inhibiting the cyclooxygenase and lipoxygenase enzymes which are responsible for the metabolism of arachidonic acid. Inhibition of the enzymes governing both metabolic pathways results in the inhibition of the metabolism of the free fatty acid.
The pharmaceutically acceptable inert ingredient is a function of the dosage form through which the active ingredient is administered. The arachidonic acid inhibitory composition of the present invention may be administered to the patient in any dosage form convenient under the patient's specific circumstances. Usually, parenteral administration is preferred. As a parenteral dosage form there is contemplated a dosage unit suitable for intravenous administration which comprises (i) an effective amount of a pharmaceutically acceptable composition capable of inhibiting arachidonic acid metabolism and (ii) a pharmaceutically acceptable solution. As a pharmaceutically acceptable solution there is contemplated any solution which is safe for injection and which is biologically inert and hence does not interfere with the active ingredient. As such a pharmaceutically acceptable solution may include an isotonic solution suitable for injection into a patient. The isotonic solution may contain water, salt and conventional ingredients such as glucose.
The active ingredient responsible for inhibition of cyclooxygenase and lipoxygenase may be the same compound. Exemplary of such compounds is [3-amino-l- (M- trifluoro ethyl) phenyl]-2-pyrazidine which may be obtained through Burroughs-Welcome.
As an effective amount of such a dual functioning active ingredient, there is contemplated an amount of said active ingredient sufficient to inhibit metabolism of arachidonic acid. An effective amount of a dual functioning active ingredient is from about 1 to about 40 g/kg body weight of the patient 2-4 times daily. A more preferred effective amount of a dual functioning active ingredient is from about 5 to about 10 mg/kg body weight of the patient 2-4 times daily.
A more preferred embodiment of this aspect provides a method of inhibiting arachidonic acid metabolism, wherein [3-amino-l-(M-trifluoromethyl) phenyl]-2-pyrazidine is administered at a dose of about 5 to about 15 mg/kg body weight of the patient every 4 hours.
The pharmaceutically acceptable composition of this embodiment may contain one active ingredient for the inhibition of cyclooxygenase and one active ingredient for the inhibition " of lipoxygenase. Such a combination of active ingredients will also serve to inhibit arachidonic acid metabolism. In a combination active ingredient, there is contemplated administration of a cyclooxygenase inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient and a lipoxygenase inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient daily. A preferred dosage of a cyclooxygenase inhibitor is from about 0.5 to about 5.0 mg/kg body weight of the patient and a lipoxygenase inhibitor from about 0.5 to about 5.0 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
Another more preferred embodiment of the first aspect of the present invention provides a method for inhibition of arachidonic acid metabolism, wherein said lipoxygenase inhibitor is administered at a dose of from about 0.5 mg/kg to about 5.0 mg/kg body weight of the patient every 4 hours. A still more preferred embodiment of the invention involves a method for arachidonic acid metabolism inhibition, wherein said lipoxygenase inhibitor is 3- methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one. 3- methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one can be obtained through Bayer.
Another more preferred embodiment provides a method for inhibition of arachidonic acid metabolism, wherein said cyclooxygenase inhibitor is selected from the group comprising l-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH- indole-3-acetic acid, al.pha-methyl-4- (2- methylpropyl)benzene acetic acid and 2-(acetyloxy)benzoic acid. 1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3- acetic acid can be obtained in accordance with the procedure disclosed in U.S. Patent No. 3,161,654. Alpha- methyl-4-(2-methylpropyl)benzene acetic acid can be obtained in accordance with the procedures disclosed in U.S. Patent Nos. 3,228,831 and 3,385,886. 2- (Acetyloxy)benzoic acid can be obtained in accordance with the procedures disclosed in U.S. Patent Nos. 2,890,240 and 3,235,583.
Another preferred embodiment of the first aspect of the present invention provides a method for decreasing the action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
By a leukotriene receptor blocker, there is contemplated any pharmaceutically acceptable active ingredient capable of blocking the leukotriene receptor. The leukotriene receptor blocker of the present invention may be either a leukotriene C4 receptor blocker or a peptidyl-leukotriene receptor blocker. By a thromboxane receptor blocker, there is contemplated any pharmaceutically acceptable active ingredient capable of blocking the thromboxane receptor.
In this embodiment, the pharmaceutically acceptable composition comprises one or more active ingredients capable of blocking the leukotriene and thromboxane receptors which are essential in the metabolism of arachidonic acid to form thromboxane and leukotriene metabolites. Blocking receptors in both metabolic pathways results in the inhibition of the metabolism of the free fatty acid.
The pharmaceutically acceptable composition of thisf embodiment may contain one active ingredient for blocking • the leukotriene receptor and one active ingredient for blocking the thromboxane receptor. Such a combination of active ingredients will also serve to inhibit arachidonic acid metabolism. In a combination active ingredient, there is contemplated administration of a leukotriene receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient and a thromboxane receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient daily. A more preferred dosage of a leukotriene receptor blocker is from about 1 to about 10 mg/kg body weight of the patient and a thromboxane receptor blocker from about 1 to about 10 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
A more preferred embodiment of this aspect involves a method for inhibiting the formation or action of arachidonic acid metabolites, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 mg/kg to 10.0 mg/kg body weight of the patient bolus followed by 1.0 mg/kg to 10.0 mg/kg body weight of the patient every 3-6 hours. A still more preferred embodiment provides an inhibition method, wherein said leukotriene receptor blocker is (1-[2-hydroxy-3-propyl-4-[4-(lH~- tetrazol-5-yl)-butoxy]-phenyl ethanone. (l-[2~hydroxy-3- propyl-4-[4-(lH-tetrazol-5-yl)-butoxy]-phenyl ethanone can be obtained through Eli Lilly.
The third embodiment of the first aspect of the present invention provides a method for decreasing the action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a .thromboxane synthetase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients. By a thromboxane synthetase inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting thromboxane synthetase. In this embodiment, the pharmaceutically acceptable composition comprises one or more active ingredients capable of blocking the leukotriene receptor which prevents the actions of peptidyl-leukotrienes in mediating secondary injury, and inhibiting thromboxane synthetase enzyme which is responsible for the synthesis of thromboxane metabolites. Blocking the receptor of one pathway and inhibiting a major enzyme in the other results in the inhibition of the detrimental actions of the free fatty acid.
The pharmaceutically acceptable composition of this embodiment may contain one active ingredient for blocking the leukotriene receptor and one active ingredient for inhibiting thromboxane synthetase. Such a combination of active ingredients will also serve to inhibit arachidonic acid metabolism. In a combination active ingredient, there is contemplated administration of a leukotriene receptor blocker at a dosage of from about 0.5 to about 50 mg/kg body weight of the patient and a thromboxane synthetase inhibitor at a dosage of from about 1 to about 100 mg/kg body weight of the patient daily. A more preferred dosage of a leukotriene receptor blocker is from about 1 to about 10 mg/kg body weight of the patient and a thromboxane synthetase inhibitor from about 10 to about 20 mg/kg daily. Dosages of the combination active ingredient may be administered in divided dosages.
A' more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 mg/kg to 10.0 mg/kg body weight of the patient bolus followed by 1.0 mg/kg to 10.0 mg/kg body weight of the patient every 3-6 hours. A still more preferred embodiment provides an inhibition method, wherein said leukotriene receptor blocker is (l-[2- hydroxy-3-propyl-4-[4-(lH-tetrazol-5-yl) -butoxy]-phenyl ethanone.
A more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said thromboxane synthetase inhibitor is administered at a dose of about 1.0 to about 5.0 mg/kg body weight of the patient every 6 hours. A still more preferred embodiment involves the inhibition method, wherein said thromboxane synthetase inhibitor is (3~(1H- imidazole-1-yl-methyl)-2-methyl-lH-indole-l-propanoic acid. (3- (lH-imidazole-1-yl-methyl) -2-methyl-lH-indole-1- propanoic acid can be obtained through Pfizer of England. A fourth embodiment of the first aspect of the present invention provides a method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury, wherein said pharmaceutically acceptable composition comprises an effective amount of a phospholipase A inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredient.
By a phospholipase A2 inhibitor there is contemplated any pharmaceutically acceptable active ingredient capable of inhibiting phospholipase A2.
In this embodiment, the pharmaceutically acceptable composition comprises one or more active ingredients capable of inhibiting the enzyme phospholipase A2 which is essential in the metabolism of arachidonic acid. Inhibition of the enzyme phospholipase A2 enzyme which is involved in arachidonic acid metabolism upstream of both the cyclooxygenase and lipoxygenase pathways results in the inhibition of the metabolism of the free fatty acid. That is, arachidonic acid metabolism is inhibited through inhibition of the metabolic route prior to the split into the cyclooxygenase and lipoxygenase alternative pathways.
In this embodiment, there is contemplated administration of a phospholipase A2 inhibitor at a dosage of from about 0.1 to about 20 mg/kg body weight of the patient. A more preferred dosage of a phospholipase A2 inhibitor is from about 1 to about 10 mg/kg body weight of the patient. Dosages of the active ingredient may be administered in divided dosages.
A more preferred embodiment of this aspect involves a method for inhibiting the formation of arachidonic acid metabolites, wherein said phospholipase A inhibitor is administered at a dose of about 50 to about 200 micrograms/kg body weight of the patient every 2 hours. A still more preferred embodiment involves an inhibition method, wherein said phospholipase A2 inhibitor is N4-(6- chloro-2-methoxy-9-acridinyl) -N1, N1-diethyl-l, 4- pentanediamine. N4-(6-chloro-2-methoxy-9-acridinyl)-N1,
N1-diethyl-l,4-pentanediamine can be obtained in accordance with the procedure disclosed in U.S. Patent No. 2,113,357.
In a second aspect of the present invention, there is provided a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a cyclooxygenase inhibitor and an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient, wherein, said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
A preferred embodiment of this aspect provides a pharmaceutical composition, wherein said cyclooxygenase inhibitor and said lipoxygenase inhibitor is [3-amino-l-(M- trifluoromethyl) phenyl]-2-pyrazidine.
Another preferred embodiment of this aspect provides a pharmaceutical composition, wherein said cyclooxygenase inhibitor is selected from the group comprising l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid, alpha-methyl-4-(2-methylpropyl)benzene acetic acid or 2- (acetyloxy)benzoic acid.
A further preferred embodiment of the second aspect provides a pharmaceutical composition, wherein said lipoxygenase inhibitor is 3-methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one.
The third aspect of the present invention provides a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C receptor blocker as a peptidyl-leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
A preferred embodiment of this aspect involves a pharmaceutical composition, wherein said leukotriene receptor blocker is (1-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C receptor blocker, an effective amount of a thromboxane synthetase inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
A preferred embodiment of the fourth aspect provides a pharmaceutical composition, wherein said leukotriene receptor blocker is (l-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
Another preferred embodiment of the fourth aspect of the present invention provides a pharmaceutical composition, wherein said thromboxane synthetase inhibitor is (3-(lH- imidazole-1-yl-methyl)-2-methyl-lH-indole-1-propanoic acid.
A further aspect of the present invention provides a pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a phospholipase A2 inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredient.
A preferred embodiment of this aspect involves a pharmaceutical composition, wherein said phospholipase A2 inhibitor is N4-(6-chloro-2-methoxy-9-acridinyl)-N1, N1- diethyl-1,4-pentanediamine.
The following are illustrative of the present invention
EXAMPLE 1 [3-amino-l-(M-trifluoromethyl) phenyl]-2-pyrazidine is admixed with an isotonic solution to give a final concentration of [3-amino-l-(M-trifluoromethyl) phenyl]-2- pyrazidine in solution of 100 mg/cc.
EXAMPLE 2 3-methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one and l-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH-indole-3- acetiσ acid are admixed with an isotonic solution to give a final concentration of 3-methyl-l-[2-(2-napthyloxy) ethyl]- 2-pyrazolin-5-one and 1-(4-chlorobenzoyl)-5-methoαy-2- methyl-lH-indole-3-acetic acid in solution of 20 and 50 mg/cc, respectively.
EXAMPLE 3 (1-[2-hydroxy-3-propy1-4-[4-(lH-tetrazol-5-yl)-butoxy]- phenyl ethanone and a thromboxane receptor blocker are admixed with an isotonic solution to give a final concentration of (l-[2-hydroxy-3-propyl-4-[4-(lH-tetrazol- 5-yl)-butoxy]-phenyl ethanone and thromboxane receptor blocker in solution of 50 and 100 mg/cc, respectively. EXAMPLE 4
(1-[2-hydroxy-3-propy1-4-[4-(lH-tetrazol-5-yl)-butoxy]- phenyl ethanone and (3-(lH-imidazole-l-yl-methyl)-2-methyl- lH-indole-1-propanoic acid are admixed with an isotonic solution to give a final concentration of (l-[2-hydroxy-3- propyl-4-[4-(lH-tetrazol-5-yl)-butoxy]-phenyl ethanone and (3- (lH-imidazole-1-yl-methyl) -2-methyl-lH-indole-l- propanoic acid in solution of" 10 and 50 mg/cc, respectively.
EXAMPLE 5 N4-(6-chloro-2-methoxy-9-acridinyl)-N1, N1-diethyl-l,4- pentanediamine is admixed with an isotonic solution to give a final concentration of N4-(6-chloro-2-methoxy-9- acridinylJ-N1, N1-diethyl-l,4-pentanediamine in solution of 100 mg/cc. EXAMPLE 6
Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 1 into the patient such that 10 mg/kg body weight of the patient of the active ingredient is administered every 4 hours.
EXAMPLE 7 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 2 into the patient such that 2 mg/kg body weight of the patient of the lipoxygenase inhibitor ingredient and 5 mg/kg body weight of the patient of the cyclooxygenase inhibitor is administered every 4 hours. _, - EXAMPLE 8
Treatment of a patient suffering from a traumatic or ischemic central" nervous system injury is accomplished through injection of the preparation of Example 3 into the patient such that 4 mg/kg body weight of the patient of the leukotriene receptor blocker ingredient is administered bolus and 4 mg/kg body weight of the patient of the leukotriene receptor blocker is administered every 4 hours thereafter, and 5 mg/kg body weight of the patient of the thromboxane receptor ingredient is administered every 4 hours.
EXAMPLE 9 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 4 into the patient such that 4 mg/kg body weight of the patient of the leukotriene receptor blocker ingredient is administered bolus and 4 mg/kg body weight of the patient of the leukotriene receptor blocker is administered every 4 hours thereafter, and 3 mg/kg body weight of the pεitient of the thromboxane synthetase inhibitor ingredient is administered every 6 hours.
EXAMPLE 10 Treatment of a patient suffering from a traumatic or ischemic central nervous system injury is accomplished through injection of the preparation of Example 5 into the patient such that 100 micrograms/kg body weight of the patient of the active ingredient is administered every 2 hours.

Claims

WHAT IS CLAIMED IS:
1. A method for decreasing the formation or action of arachidonic acid metabolites following traumatic or ischemic central nervous system injury which comprises administering to a patient suffering from said traumatic or ischemic central nervous system injury an effective amount of a pharmaceutically acceptable composition capable of blocking both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism such that the metabolism of said arachidonic acids is inhibited.
2. A method of claim 1, wherein said pharmaceutically acceptable composition comprises an effective amount of a cyclooxygenase inhibitor, an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
3. A method of claim 2, wherein [3-amino-l-(M- trifluoromethyl) phenyl]-2-pyrazidine is administered at a dose of about 5 to about 15 mg/kg body weight of the patient every 4 hours.
4. A method of claim 2, wherein said lipoxygenase inhibitor is administered at a dose of about 0=5 mg/kg to about 5.0 mg/kg body weight of the patient every 4 hours.
5. A method of claim 2, wherein said lipoxygenase inhibitor is 3-methyl-l-[2-(2-napthyloxy) ethyl] -2- pyrazolin-5-one.
6. A method of claim 2, wherein said cyclooxygenase inhibitor is selected from the group comprising l-(4- chlorobenzoyl)-5-methαxy-2-methyl-lH-indole-3-aσ<=vtiσ acid, alpha-methyl-4-(2-methylpropyl)benzene acetic acid and 2- (acetyloxy)benzoic acid.
7. A method of claim 1, wherein sai pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredients.
8. A method of claim 7, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 to about 10.0 mg/kg body weight of the patient bolus followed by 1.0 to about 10.0 mg/kg body weight of the patient/hr.
9. A method of claim 8, wherein said leukotriene receptor blocker is (l-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
10. A method of claim 1, wherein said pharmaceutically acceptable composition comprises an effective amount of a leukotriene receptor blocker, an effective amount of a thromboxane synthetase inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of th ' active ingredients.
11. A method of claim 10, wherein said leukotriene receptor blocker is administered at a dose of about 1.0 to about 10.0 mg/kg body weight of the patient bolus followed by 1.0 to about 10.0 mg/kg body weight of the patient/hr.
12. A method of claim 10, wherein said leukotriene receptor blocker is (1-[2-hydroxy-3-propyl-4-[4-(lH- tetrazol-5-yl)-butoxy]-phenyl ethanone.
13. A method of claim 10, wherein said thromboxane synthetase inhibitor is administered at a dose of about 1.0 to about 5.0 mg/kg body weight of the patient every 6 hours.
14. A method of claim 10, wherein said thromboxane synthetase inhibitor is (3-(lH-imidazole-l-yl-methyl)-2- methyl-lH-indole-1-propanoic acid.
15. A method of claim 1, wherein said pharmaceutically acceptable composition comprises an effective amount of a phospholipase A2 inhibitor and a pharmaceutically inert ingredient which does not interfere with the arachidonic acid metabolism inhibitory function of the active ingredient.
16. A method of claim 15, wherein said phospholipase A2 inhibitor is administered at a dose of about 50 to about 200 micrograms/kg body weight of the patient every 2 hours.
17. A method of claim 15, wherein said phospholipase A inhibitor is N -(6-chloro-2-methoxy-9-acridinyl)-N1, N1- diethyl-1,4-pentanediamine.
18. A pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a cyclooxygenase inhibitor and an effective amount of a lipoxygenase inhibitor and a pharmaceutically inert ingredient, wherein said "inert—j_ngred±ent does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
19. A pharmaceutical composition of claim 18, wherein said cyclooxygenase inhibitor and said lipoxygenase inhibitor is [3-amino-l-(M-trifluoromethyl) phenyl]-2- pyrazidine.
20. A pharmaceutical composition of claim 18, wherein said cyclooxygenase inhibitor is selected from the group comprising 1-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH- indole-3-acetic acid, alp a-methyl-4- (2- methylpropyl)benzene acetic acid or 2-(acetyloxy)benzoic acid.
21. A pharmaceutical composition of claim 18, wherein said lipoxygenase inhibitor is 3-methyl-l-[2-(2-napthyloxy) ethyl]-2-pyrazolin-5-one.
22. A pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C4 receptor blocker or a peptidyl-leukotriene receptor blocker, an effective amount of a thromboxane receptor blocker and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
23. A pharmaceutical composition of claim 22, wherein said leukotriene receptor blocker is (l-[2-hydroxy-3- propyl-4-[4-(lH-tetrazol-5-yl)-butoxy]-phenyl ethanone.
24. A pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a leukotriene C receptor blocker or a peptidyl-leukotriene receptor blocker, an effective amount of a thromboxane synthetase inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredients.
25. A pharmaceutical composition of claim 24, wherein said leukotriene receptor blocker is (l-[2-hydroxy-3- propy1-4-[4-(lH-tetrazol-5-yl)-butoxy]-phenyl ethanone.
26. A pharmaceutical composition of claim 24, wherein said thromboxane synthetase inhibitor is (3-(lH-imidazole- 1-yl-methyl)-2-methyl-lH-indole-l-propanoic acid.
27. A pharmaceutical composition capable of inhibition of arachidonic acid metabolism suitable for administration to a patient which comprises an effective amount of a phospholipase A2 inhibitor and a pharmaceutically inert ingredient, wherein said inert ingredient does not interfere with the arachidonic acid metabolism inhibitory properties of the active ingredient.
28. A pharmaceutical composition of claim 27, wherein said phospholipase A2 inhibitor is N4-(6-chloro-2-methoxy- 9-acridinyl)-N1, N1-diethyl-l,4-pentanediamine.
PCT/US1988/001838 1987-06-05 1988-06-06 Inhibition of arachidonic acid metabolism WO1988009675A1 (en)

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