CA1322522C - Traumatic and ischemic brain injury treatment with opiate-receptor antagonists - Google Patents
Traumatic and ischemic brain injury treatment with opiate-receptor antagonistsInfo
- Publication number
- CA1322522C CA1322522C CA000568593A CA568593A CA1322522C CA 1322522 C CA1322522 C CA 1322522C CA 000568593 A CA000568593 A CA 000568593A CA 568593 A CA568593 A CA 568593A CA 1322522 C CA1322522 C CA 1322522C
- Authority
- CA
- Canada
- Prior art keywords
- opiate
- receptor
- patient
- receptor antagonist
- brain injury
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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
- A61K31/435—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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention involves composition and use thereof for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity.
The present invention involves composition and use thereof for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity.
Description
1322~22 TRAUMATIC AND ISCHEMIC BRAIN INJURY TREATMENT ~TH OPIATE-RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
Endogenous opioids may be released following traumatic or ischemic injury of the cen~ral nervous system. These opioids may serve as secohdary pathophysiologic factors contributing to the neurological disorder which stems from the injury to the central nervous system. Opiate receptor antagonists, such as naloxone, has been used to treat brain or spinal cord injury at dosages in the range of 1 to 10 mg/kg of body weight of the patient.
However, naloxone is not completely selective nor a pure opiate antagonist in all situations. At low dosages, naloxone has considerable selectivity for the mu-opiate receptor. At higher dosages, naloxone acts on o~her opiate receptors, including the delta and kappa receptors.
Further at higher dosages, naloxone may have effects that are not mediated by opiate receptors.
In order to simplify and enhance the safety of central nervous system protocols, opiate receptor antagonists which - e~hibit a high degree of specificity for or enhanced activity at a specific opiate receptor are being sought.
Also, oplate receptor anta~onists which act exclusively as such without producing any undesirable side reactions within the body are preferred.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition and use thereof for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity in a patient.
AS an opiate-receptor antagonist of the present invention there is contemplated any pharmaceutically acceptable ,,,~~
~2~
compound or salt thereof having enhanced activity at the kappa-opiate receptor capable of inducing opiate receptor antagonistic activity.
As an effective amount of the opiate-receptor antagonist of the present invention there is contemplated an amount of antagonist which is sufficient to induce opiate receptor antagonistic activity. An effective amount of the opiate receptor antagonist of the present invention is from about 0.01 to about 10 mg/kg body weight of the patient daily. A
preferred embodiment of the present invention involves an effective amount of the opiate receptor antagonist from about 0.1 to 1 mg/kg body weight of the patient daily.
The opiate receptor antagonist of the present invention may be administered to the patient in any dosage form convenient under the patient's specific circumstances.
U~ually, 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 an opiate receptor antagonist having enhanced activity at or specificity for the kappa opiate receptor 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 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 the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein the opiate receptor antagonist administered to the patient is 3-(2-alpha,6-alpha,llS*)-(~
cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate.
A further preferred embodiment of the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.04 to about 4 mg/kg 3-4 times daily. A more preferred embodiment of the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.1 to about 1 mg/kg 3-4 times daily.
The following illustrate the invention.
3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 5 mg/cc.
3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 1 mg/cc.
Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injury is accomplished through injection of 0.1 mg/kg of the pharmaceutical preparation of Example 1 4 times daily for 1 day.
Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injury is accomplished through injection of 0.5 of the pharmaceutical preparaticn of Example 2 3 times daily for 1 day.
,.' ~:
BACKGROUND OF THE INVENTION
Endogenous opioids may be released following traumatic or ischemic injury of the cen~ral nervous system. These opioids may serve as secohdary pathophysiologic factors contributing to the neurological disorder which stems from the injury to the central nervous system. Opiate receptor antagonists, such as naloxone, has been used to treat brain or spinal cord injury at dosages in the range of 1 to 10 mg/kg of body weight of the patient.
However, naloxone is not completely selective nor a pure opiate antagonist in all situations. At low dosages, naloxone has considerable selectivity for the mu-opiate receptor. At higher dosages, naloxone acts on o~her opiate receptors, including the delta and kappa receptors.
Further at higher dosages, naloxone may have effects that are not mediated by opiate receptors.
In order to simplify and enhance the safety of central nervous system protocols, opiate receptor antagonists which - e~hibit a high degree of specificity for or enhanced activity at a specific opiate receptor are being sought.
Also, oplate receptor anta~onists which act exclusively as such without producing any undesirable side reactions within the body are preferred.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition and use thereof for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity in a patient.
AS an opiate-receptor antagonist of the present invention there is contemplated any pharmaceutically acceptable ,,,~~
~2~
compound or salt thereof having enhanced activity at the kappa-opiate receptor capable of inducing opiate receptor antagonistic activity.
As an effective amount of the opiate-receptor antagonist of the present invention there is contemplated an amount of antagonist which is sufficient to induce opiate receptor antagonistic activity. An effective amount of the opiate receptor antagonist of the present invention is from about 0.01 to about 10 mg/kg body weight of the patient daily. A
preferred embodiment of the present invention involves an effective amount of the opiate receptor antagonist from about 0.1 to 1 mg/kg body weight of the patient daily.
The opiate receptor antagonist of the present invention may be administered to the patient in any dosage form convenient under the patient's specific circumstances.
U~ually, 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 an opiate receptor antagonist having enhanced activity at or specificity for the kappa opiate receptor 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 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 the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein the opiate receptor antagonist administered to the patient is 3-(2-alpha,6-alpha,llS*)-(~
cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate.
A further preferred embodiment of the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.04 to about 4 mg/kg 3-4 times daily. A more preferred embodiment of the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.1 to about 1 mg/kg 3-4 times daily.
The following illustrate the invention.
3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 5 mg/cc.
3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 1 mg/cc.
Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injury is accomplished through injection of 0.1 mg/kg of the pharmaceutical preparation of Example 1 4 times daily for 1 day.
Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injury is accomplished through injection of 0.5 of the pharmaceutical preparaticn of Example 2 3 times daily for 1 day.
,.' ~:
Claims (8)
1. A composition for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity in the patient.
2. The composition of claim 1, wherein said opiate-receptor antagonist is 3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate.
3. The composition of claim 1, wherein said opiate-receptor antagonist is in a dosage form of from about 0.04 mg/kg to about 4 mg/kg body weight of the patient for administration 3 - 4 times daily.
4. The composition of claim 1, wherein said opiate-receptor antagonist is in a dosage form of from about 0.1 mg/kg to about 1 mg/kg body weight of the patient for administration 3 - 4 times daily.
5. The use of an effective amount of an opiate-receptor antagonist for inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury, said antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity in such patient.
6. The use according to claim 5, wherein said opiate-receptor antagonist is 3-(2-alpha,6-alpha,llS*)-(-)-l-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6-methano-3-benzazocin-11-yl)-3-pentanone methane sulfonate.
7. The use according to claim 5, wherein said opiate-receptor antagonist is adapted to be administered in a dosage of from about 0.04 mg/kg to about 4 mg/kg of body weight of the patient 3 - 4 times daily.
8. The use according to claim 5, wherein said opiate-receptor antagonist is adapted to be administered in a dosage of from about 0.1 mg/kg to about 1 mg/kg of body weight of the patient 3 - 4 times daily.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5833787A | 1987-06-05 | 1987-06-05 | |
| US058,337 | 1987-06-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1322522C true CA1322522C (en) | 1993-09-28 |
Family
ID=22016198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000568593A Expired - Fee Related CA1322522C (en) | 1987-06-05 | 1988-06-03 | Traumatic and ischemic brain injury treatment with opiate-receptor antagonists |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0348440A1 (en) |
| JP (1) | JPH02500439A (en) |
| CA (1) | CA1322522C (en) |
| WO (1) | WO1988009605A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5354758A (en) * | 1992-12-16 | 1994-10-11 | Japan Tobacco Inc. | Benzomorphans useful as NMDA receptor antagonists |
-
1988
- 1988-06-03 CA CA000568593A patent/CA1322522C/en not_active Expired - Fee Related
- 1988-06-06 EP EP88905524A patent/EP0348440A1/en not_active Withdrawn
- 1988-06-06 JP JP63505179A patent/JPH02500439A/en active Pending
- 1988-06-06 WO PCT/US1988/001839 patent/WO1988009605A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1988009605A2 (en) | 1988-12-15 |
| JPH02500439A (en) | 1990-02-15 |
| EP0348440A1 (en) | 1990-01-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |