WO1988009605A2 - Traumatic and ischemic brain injury treatment with opiate-receptor antagonists - Google Patents
Traumatic and ischemic brain injury treatment with opiate-receptor antagonists Download PDFInfo
- Publication number
- WO1988009605A2 WO1988009605A2 PCT/US1988/001839 US8801839W WO8809605A2 WO 1988009605 A2 WO1988009605 A2 WO 1988009605A2 US 8801839 W US8801839 W US 8801839W WO 8809605 A2 WO8809605 A2 WO 8809605A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- opiate
- receptor
- traumatic
- brain injury
- receptor antagonist
- 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.)
- Ceased
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
Definitions
- Endogenous opioids may be released following traumatic or ischemic injury of the central nervous system. These opioids may serve as secondary pathophy ⁇ iologic factors contributing to the neurological disorder which stems fro"m 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 g/kg of body weight of the patient.
- 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 other opiate receptors, including the delta and kappa receptors. Further at higher dosages, naloxone may have effects that are not mediated by opiate receptors.
- opiate receptor antagonists v/hich exhibit a high degree of specificity for or enhanced activity at a specific opiate receptor are being sought. Also, opiate receptor antagonists which act exclusively as such without producing any undesirable side reactions within the body are preferred.
- the present invention provides a method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises 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.
- an opiate-receptor antagonist of the present invention there is contemplated any pharmaceutically acceptable compound or salt thereof having enhanced activity at the kappa-opiate receptor capable of inducing opiate receptor antagonistic activity.
- 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. Usually, parenteral administration is preferred.
- 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.
- 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 pharmaceuti ally acceptable solution may be mentioned an i ⁇ otonic 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 , US*) - (-) -1- cyclopentyl-5-(l,2,3,4,5, 6-hexahydro-8-hydroxy-3 ,6,11- trimethyl-2 , 6-methano-3-benzazocin-ll-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.
- EXAMPLE 3 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.
- EXAMPLE 4 Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injuiy is accomplished through injection of 0.5 of the pharmaceutical preparation of Example 2 3 times daily for 1 day.
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)
- Other In-Based Heterocyclic Compounds (AREA)
Description
1
TRAUMATIC AND ISCHEMIC BRAIN INJURY TREATMENT WITH OPIATE- RECEPTOR ANTAGONISTS BACKGROUND OF THE INVENTION Endogenous opioids may be released following traumatic or ischemic injury of the central nervous system. These opioids may serve as secondary pathophyεiologic factors contributing to the neurological disorder which stems fro"m 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 g/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 other 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 v/hich exhibit a high degree of specificity for or enhanced activity at a specific opiate receptor are being sought. Also, opiate receptor antagonists 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 method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises 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.
As an opiate-receptor antagonist of the present invention there is contemplated any pharmaceutically acceptable
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. 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 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 pharmaceuti ally acceptable solution may be mentioned an iεotonic 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 , US*) - (-) -1- cyclopentyl-5-(l,2,3,4,5, 6-hexahydro-8-hydroxy-3 ,6,11- trimethyl-2 , 6-methano-3-benzazocin-ll-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.
EXAMPLE 1
3- (2-alpha , 6-alpha, IIS*) - (-) - -cyclopentyl-5-
(1,2,3,4,5, 6-hexahydro-8-hydroxy-3 , 6 , ll-trimethyl-2 , 6- methano-3-benzazocin-ll-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.
EXAMPLE 2 3- (2-alpha, 6-alpha, US*) -(-) -l-cyclopentyl-5-
(1,2,3,4,5, 6-hexahydro-8-hydroxy-3 ,6,1 l-trimethy1-2 , 6- methano-3-benzazocin-ll-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.
EXAMPLE 3 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.
EXAMPLE 4 Induction of opiate receptor antagonistic activity in a patient suffering from traumatic or ischemic brain injuiy is accomplished through injection of 0.5 of the pharmaceutical preparation of Example 2 3 times daily for 1 day.
Claims
1. A method of inducing opiate-receptor antagonistic activity in a patient suffering from ischemic or traumatic brain injury which comprises administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor sxitable to permit the induction of opiate-receptor antagonistic activity.
2. A method of claim 1, wherein said opiate-receptor antagonist is 3-(2-alpha, 6-alpha,IIS*)-(-)-l-cyclopentyl-5- (1,2,3,4,5, 6-hexahydro-8-hydroxy-3, 6, ll-trimethyl-2, 6- methano-3-benzazocin-ll-yl)-3-pentanone methane sulfonate.
3. A method of claim 1, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.01 mg/kg to about 4 mg/kg 3-4 times daily.
4. A method of claim 1, wherein said opiate-receptor antagonist is administered in a dosage of from about 0.1 mg/kg to about 1 mg/kg 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 |
|---|---|
| WO1988009605A2 true WO1988009605A2 (en) | 1988-12-15 |
Family
ID=22016198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1988/001839 Ceased WO1988009605A2 (en) | 1987-06-05 | 1988-06-06 | 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) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013641A1 (en) * | 1992-12-16 | 1994-06-23 | Japan Tobacco Inc. | Benzomorphan useful as nmda receptor antagonist |
-
1988
- 1988-06-03 CA CA000568593A patent/CA1322522C/en not_active Expired - Fee Related
- 1988-06-06 WO PCT/US1988/001839 patent/WO1988009605A2/en not_active Ceased
- 1988-06-06 JP JP63505179A patent/JPH02500439A/en active Pending
- 1988-06-06 EP EP88905524A patent/EP0348440A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013641A1 (en) * | 1992-12-16 | 1994-06-23 | Japan Tobacco Inc. | Benzomorphan useful as nmda receptor antagonist |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02500439A (en) | 1990-02-15 |
| EP0348440A1 (en) | 1990-01-03 |
| CA1322522C (en) | 1993-09-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3966940A (en) | Analgetic compositions | |
| EP0319243B1 (en) | Pharmaceutical compositions | |
| KR19990067527A (en) | Use of efinastin for the treatment of pain | |
| US5426120A (en) | Pharmaceutical composition containing γ-hydroxybutyric acid or its lactone in the treatment of drug dependence and nutritional disorders | |
| CA2137916A1 (en) | Des-tyr dynorphin analogues | |
| US4379789A (en) | Analgesic composition | |
| US4906637A (en) | Traumatic and ischemic brain injury treatment with opiate-receptor antagonists | |
| Kojima et al. | Comparison of Sedative Effects of Medetomidine‐Midazolam,. Acepromazine‐Butorphanol and Midazolam‐Butorphanol in Dogs | |
| EP0295836B1 (en) | Use of dioxopiperidine derivatives for the manufacture of topical medicaments as analgesics | |
| US5025018A (en) | Central nervous system injury treatment with opiate-receptor antagonist | |
| IE60121B1 (en) | Anxiolytic composition | |
| EP0315681B1 (en) | Use of nalmefene for the manufacture of a pharmaceutical composition for central nervous system injury treatment | |
| CA1322522C (en) | Traumatic and ischemic brain injury treatment with opiate-receptor antagonists | |
| EP0213676B1 (en) | Pharmaceutical compositions containing acth (1-24) for the therapy of shock conditions and of respiratory and cardiocirculatory insufficiencies | |
| Young et al. | Antagonism of the effect of delta sleep-inducing peptide by naloxone in the rat | |
| US6114370A (en) | Amnesic sedation composition and method of administering same | |
| US5807827A (en) | Des-Tyr dynorphin analogues | |
| JPH0518811B2 (en) | ||
| EP0357663A1 (en) | Treatment of traumatic injury with nmda receptor blockers | |
| JPS61189222A (en) | Drug combined with central analgesic and adenine as active components | |
| JP2579187B2 (en) | Combination of central analgesic and forskolin as active ingredients | |
| US3764679A (en) | Iodinin as an anti-hypertensive agent | |
| US3517103A (en) | Methods and compositions of reserpine alkaloids with antidepressants for treating hypertension | |
| GB2317110A (en) | Anti-diarrhoeal compositions comprising loperamide | |
| WO1995017189A1 (en) | NEW USE OF δ-OPIOID RECEPTOR ANTAGONISTS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): JP |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE FR GB IT LU NL SE |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1988905524 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 1988905524 Country of ref document: EP |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1988905524 Country of ref document: EP |