EP0357663A1

EP0357663A1 - Treatment of traumatic injury with nmda receptor blockers

Info

Publication number: EP0357663A1
Application number: EP19880904031
Authority: EP
Inventors: Alan I. Faden
Original assignee: INNOVATIVE THERAPEUTICS Corp
Current assignee: INNOVATIVE THERAPEUTICS Corp
Priority date: 1987-04-06
Filing date: 1988-04-05
Publication date: 1990-03-14
Also published as: WO1988007811A2

Description

TREATMENT OF TRAUMATIC INJURY WITH NMDA RECEPTOR BLOCKERS

BACKGROUND OF THE INVENTION It has been suspected that excitatory amino acids may serve as a final common pathway for toxins and pathogens, and, as a result, cause cell death. Further, it has been postulated that the blockade of N-methyl-D-aspartate (NMDA) receptors may be effective in the treatment of epilepsy and stroke.

It has been discovered that secondary ischemia is a pathophysiological factor in secondary injury caused by brain or spinal traumatic injuries. It has further been discovered that the blockade of NMDA receptors is effective in the treatment of secondary ischemia. However, NMDA receptor compounds are not typically centrally active. That is, the penetration of these compounds into the central nervous system is limited.

Liposome entrapment has been proposed as a possible route to increase the biological halflives of certain pharmaceuticals and enhance transport into various cells and across the blood-brain barrier. Liposome entrapment of NMDA receptor compounds may permit the compounds to penetrate into the central nervous system in pharmaceutically effective amounts.

An alternative to liposome entrapment involves the development or discovery of new NMDA receptor blocking compounds which have the capability to penetrate into the central nervous system in pharmaceutically effective amounts. Thus, centrally active NMDA receptor blocking compounds were investigated. (+) -5-methy1-10,ll-dihydro-5H-debenzo[a,d]cyclohepten-

5,10-imine aleate is known as a potent anticonvulsant.

Studies investigating the mechanism in which (+)-5-methy1-

10,ll-dihydro-5H-debenzo[a,d]cyclohepten-5,10-imine maleate functions as an anti-convulsant have revealed that (+)-5- methyl-10, ll-dihydro-5H-debenzo[a,d]cyclohepten-5,10-imine maleate binding sites are associated with NMDA receptors. Al s o , ( + ) - 5 -methyl - 10 , l l-dihydro-5H- debenzo [a,d] cyclohepten-5, 10-imine maleate exhibits excellent central nervous system penetration. .sin this invention there is .provided a method, of treating a patient suffering acute or subacute from traumatic injury to the brain or spinal column which comprises administration to said patient an effective amount of a centrally active N-methyl-D-aspartate receptor blocking compound.

-As a NMDA _^receptor blocking compound of the present invention there is contemplated any centrally active compound which exhibits NMDA blocking activity such as (+)- 5-methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine maleate.

A preferred embodiment of the invention provides a method of treating a patient suffering from traumatic injury wherein said aspartate receptor blocking compound is (+)-5- methyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maieate.

(+) -5-ιrtethyl-10,ll-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine maleate can be prepared through the following procedure. (+)-5-methyl-10,ll-dihydro-5H- debenzo[a,d]cyclohepten-5,10-imine maleate is a known compound which can, for example, be obtained from Merck, Sharp and Don e.

Another preferred embodiment of the invention provides a method of treating a patient suffering from traumatic injury wherein said administration is received by said patient once daily for at least one day. Still another pre erred embodiment provides^■ a treatment protocol wherein said administration is received by said patient once daily for at least two days. Another preferred embodiment of the invention provides a method of treating a patient suffering from traumatic injury wherein said centrally active N-methyl-D-aspartate receptor blocking compound is administered in a dosage unit suitable for intravenous administration which comprises (i) an effective amount of a centrally active N-methyl-D- aspartate receptor blocking compound 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 pharmaceutically acceptable solutions may be mentioned an isotonic solution suitable for injection into a patient. The isotonic solution may contain water, salt and conventional ingredients such as glucose.

A preferred embodiment of this aspect provides a dosage unit wherein said effective amount of the active ingredient is from about 0.1 to about 100 mg/Kg body weight of the patient. A still more preferred embodiment of this aspect provides a dosage unit wherein said effective amount of the active ingredient is from about 1.0 to about 50 mg/Kg body weight of the patient. In addition to the intravenous dosage form discussed above, the active ingredient of the present invention is capable of being administered in any manner which will allow the NMDA receptor blocking compound to enter the blood stream without substantial degradation. Thus, other administration routes such as intramuscular, subcutaneous or oral are also contemplated by the present invention.

The following Examples illustrate the invention:

EXAMPLE 1 (+) -5-methyl-10, ll-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine maleate is admixed with an isotonic solution to obtain a final concentration of active ingredient in the solution of 10 mg/cc.

EXAMPLE 2

Treatment of a patient suffering from a traumatic injury is accomplished- through injection into the patient of the pharmaceutical preparation of Εxample 1 such that 1 mg/kg body weight of the patient of the active ingredient is administered three times daily for two days.

EXAMPLE 3 Treatment of a patient suffering from a traumatic injury -.is .accomplished through injection into the patient of the pharmaceutical preparation of Εxample 1 such that 10 mg/kg body weight of the patient of the active ingredient is administered three times daily for two days. EXAMPLE 4

Treatment of a patient suffering from a traumatic injury is accomplished through injection into the patient of the pharmaceutical preparation of Example 1 such that 100 mg/kg body weight of the patient of the active ingredient is administered.three times daily for two days.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a patient suffering from acute or subacute traumatic injury to the brain or spinal column which comprises administration to said patient an effective amount of a centrally active N-methyl-D-aspartate receptor blocking compound.

2. A method of claim 1 wherein said aspartate receptor blocking compound is (+) -5-methyl-10, ll-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine maleate.

3. A method of claim 2 wherein said administration is received by said patient one to three times daily for at least one day.

4. A method of claim 2 wherein said administration is received by said patient one to three times daily for at least two days.

5. A method of claim 1 wherein said centrally active N- methyl-D-aspartate receptor blocking compound is administered in a dosage unit suitable for intravenous administration which comprises (i) an effective amount of a centrally active N-methyl-D-aspartate receptor blocking compound and (ii) a pharmaceutically acceptable solution.

6. A method of claim 5 wherein said dosage unit comprises an amount of the active ingredient from about 0.1 to about 100 mg/Kg body weight of the patient.

7. A method of claim 5 wherein said dosage unit comprises an amount of the active ingredient from about 1.0 to about 50 mg/Kg body weight of the patient.