CA1322521C - Thyrotropin-releasing hormone analog composition and use thereof - Google Patents
Thyrotropin-releasing hormone analog composition and use thereofInfo
- Publication number
- CA1322521C CA1322521C CA000568592A CA568592A CA1322521C CA 1322521 C CA1322521 C CA 1322521C CA 000568592 A CA000568592 A CA 000568592A CA 568592 A CA568592 A CA 568592A CA 1322521 C CA1322521 C CA 1322521C
- Authority
- CA
- Canada
- Prior art keywords
- thyrotropin
- releasing hormone
- hormone analog
- patient
- prolineamide
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/066—TRH, thyroliberin, thyrotropin releasing hormone
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention involves methods, compositions and use thereof for treating traumatic brain injury in a patient suffering from traumatic brain injury by administering to said patient an effective amount of a thyrotropin-releasing hormone analog having the carboxy-terminal prolineamide. The TRH analog is orotyl-L-histidyl-L-prolineamide or a derivative thereof.
The present invention involves methods, compositions and use thereof for treating traumatic brain injury in a patient suffering from traumatic brain injury by administering to said patient an effective amount of a thyrotropin-releasing hormone analog having the carboxy-terminal prolineamide. The TRH analog is orotyl-L-histidyl-L-prolineamide or a derivative thereof.
Description
~322~21 T~YROTROPIN-RELEASING HORMONE ANALOG COMPOSITION AND USE
T~IEREOF
BACKGROUND OF THE INVENTION
Thyrotropin-releasing hormone (TRH) has been foulnd in the spinal cord and has been found to have a variety Qf effects on the central nervous system. For example, TRH has potent excitatory effects in the spinal cord, thereby increasing neuronal activity and enhancing monosynaptic and polysynaptic reflexes.
TRH improves long-term neurologic outcome following experimental spinal trauma. Consequent]y, I-pyxo-2-aminoadipyl-histidyl-thiazolidine-4-carbo~amide and orotyl-L-histidyl-L-prolineamide, synthetic ana~ogs ther?of, were studied for such activity in Faden et al., Neurolo~y, vol.
35, pp. 1331-1334 (1985).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition and use thereof for traumatic brain injury in a patient suffering from brain trauma which comprises an effective amount of a thyrotropin-releasing hormone analog having preservation of the carboxy-terminal prolineamide moiety, wherein said thyrotropin-releasing hormolle analog is orotyl-L~histidyl-l,-prolineamide or a Aerivative thereof. Orotyl-L-histidyl-L-prolineamide may be obtained through Chemie Grunenthal.
As an effective amount of the thyrotropin-releasins hormone analog of the present invention ihere is contemplated an amount of analog which is substantially higher than that required to induce thyrotropin-releasing hormone activity. An effective amount of the thyrotrop-n-releasing hormone analog of the present invention is from about 0.2 to about 2 mg/kg body weight of the patient administered 2-4 times dur:ing the first ~,~ hol~rs aftcr trauma, 1-2 times daily thereafter. A preferred embodiment of the present invention involves an effective amount of .
~ 3 ~
the hormone analog from about 0.2 to 1 mg/kg body weight of the patient administered within 24 hours of trauma as 2-4 intravenous or intramuscular injections over 24 hours.
The thyrotropin-releasing hormone analog 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 thyrotropin-releasing hormone analog having an unmodified carboxy terminus 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.
Such a pharmaceutically acceptable ~olution may contain purified water admixed with preservatives, flavors, colorants, flavor enhancing agents and other excipients.
Exemplary of such additives are sodium benzoate, methyl paraben, propylene glycol, glycerin, sorbitol, alcohol, sucrose, saccharin, menthol and citric acid.
An additional embodiment of the present invention provides a method of treating traumatic or ischemic brain injury in a patient suffering from ischemic or traumatic brain injury, wherein a thyrotropin-releasing hormone analog is administered in a dosage of from about 0.2 to about 2 mg/kg 2-4 times daily. A more preferred embodiment involves a method, wherein a thyrotropin-releasing hormone ~2~2~
analog is administered in a dosage of from about 0.5 to about 1 mg/kg 2-4 times daily.
The following illustrate the invention.
Orotyl-L-histidyl-L-prolineamide is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 10 mg/cc.
Orotyl-L-histidyl-L-prolineamide is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 50 mg/cc.
Induction of tissue protection activity in a patient suffering from traumatic brain injury is accomplished through injection of 0.2 mg/kg of the pharmaceutical preparation of Example 1 2 times daily for 1 day.
Induction of tissue protective activity in a patient suffering from traumatic brain injury is accomplished through injection of 1.0 mg/kg of the pharmaceutical preparation of Example 2 4 times daily for 1 day.
T~IEREOF
BACKGROUND OF THE INVENTION
Thyrotropin-releasing hormone (TRH) has been foulnd in the spinal cord and has been found to have a variety Qf effects on the central nervous system. For example, TRH has potent excitatory effects in the spinal cord, thereby increasing neuronal activity and enhancing monosynaptic and polysynaptic reflexes.
TRH improves long-term neurologic outcome following experimental spinal trauma. Consequent]y, I-pyxo-2-aminoadipyl-histidyl-thiazolidine-4-carbo~amide and orotyl-L-histidyl-L-prolineamide, synthetic ana~ogs ther?of, were studied for such activity in Faden et al., Neurolo~y, vol.
35, pp. 1331-1334 (1985).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition and use thereof for traumatic brain injury in a patient suffering from brain trauma which comprises an effective amount of a thyrotropin-releasing hormone analog having preservation of the carboxy-terminal prolineamide moiety, wherein said thyrotropin-releasing hormolle analog is orotyl-L~histidyl-l,-prolineamide or a Aerivative thereof. Orotyl-L-histidyl-L-prolineamide may be obtained through Chemie Grunenthal.
As an effective amount of the thyrotropin-releasins hormone analog of the present invention ihere is contemplated an amount of analog which is substantially higher than that required to induce thyrotropin-releasing hormone activity. An effective amount of the thyrotrop-n-releasing hormone analog of the present invention is from about 0.2 to about 2 mg/kg body weight of the patient administered 2-4 times dur:ing the first ~,~ hol~rs aftcr trauma, 1-2 times daily thereafter. A preferred embodiment of the present invention involves an effective amount of .
~ 3 ~
the hormone analog from about 0.2 to 1 mg/kg body weight of the patient administered within 24 hours of trauma as 2-4 intravenous or intramuscular injections over 24 hours.
The thyrotropin-releasing hormone analog 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 thyrotropin-releasing hormone analog having an unmodified carboxy terminus 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.
Such a pharmaceutically acceptable ~olution may contain purified water admixed with preservatives, flavors, colorants, flavor enhancing agents and other excipients.
Exemplary of such additives are sodium benzoate, methyl paraben, propylene glycol, glycerin, sorbitol, alcohol, sucrose, saccharin, menthol and citric acid.
An additional embodiment of the present invention provides a method of treating traumatic or ischemic brain injury in a patient suffering from ischemic or traumatic brain injury, wherein a thyrotropin-releasing hormone analog is administered in a dosage of from about 0.2 to about 2 mg/kg 2-4 times daily. A more preferred embodiment involves a method, wherein a thyrotropin-releasing hormone ~2~2~
analog is administered in a dosage of from about 0.5 to about 1 mg/kg 2-4 times daily.
The following illustrate the invention.
Orotyl-L-histidyl-L-prolineamide is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 10 mg/cc.
Orotyl-L-histidyl-L-prolineamide is admixed with 10 cc isotonic solution to obtain a final concentration of active ingredient in the solution of 50 mg/cc.
Induction of tissue protection activity in a patient suffering from traumatic brain injury is accomplished through injection of 0.2 mg/kg of the pharmaceutical preparation of Example 1 2 times daily for 1 day.
Induction of tissue protective activity in a patient suffering from traumatic brain injury is accomplished through injection of 1.0 mg/kg of the pharmaceutical preparation of Example 2 4 times daily for 1 day.
Claims (6)
1. A composition for treating traumatic brain injury in a patient suffering from traumatic brain injury which comprises an effective amount of a thyrotropin-releasing hormone analog having preservation of the carboxy-terminal prolineamide moiety in a pharmaceutically acceptable solution, said thyrotropin-releasing hormone analog being orotyl-L-histidyl-L-prolineamide or a derivative thereof.
2. The composition of claim 1, wherein said thyrotropin-releasing hormone analog is in a dosage form of from about 0.2 to about 2 mg/kg body weight of the patient for administration 2 - 4 times daily.
3. The composition of claim 1, wherein said thyrotropin-releasing hormone analog is in a dosage form of from about 0.2 to about 1.0 mg/kg body weight of the patient for administration 2 -
4 times daily.
4. The use of an effective amount of a thyrotropin-releasing hormone analog having preservation of the carboxy-terminal prolineamide moiety for treating traumatic brain injury in a patient suffering from traumatic brain injury, said thyrotropin-releasing hormone analog being orotyl-L-histidyl-L-prolineamide or a derivative thereof.
4. The use of an effective amount of a thyrotropin-releasing hormone analog having preservation of the carboxy-terminal prolineamide moiety for treating traumatic brain injury in a patient suffering from traumatic brain injury, said thyrotropin-releasing hormone analog being orotyl-L-histidyl-L-prolineamide or a derivative thereof.
5. The use according to claim 4, wherein said thyrotropin-releasing hormone analog is adapted to be administered in a dosage of from about 0.2 to about 2 mg/kg body weight of the patient 2 - 4 times daily.
6. The use according to claim 4, wherein said thyrotropin-releasing hormone analog is adapted to be administered in a dosage of from about 0.2 to about 1.0 mg/kg body weight of the patient 2 - 4 times daily.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5838087A | 1987-06-05 | 1987-06-05 | |
| US058,380 | 1987-06-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1322521C true CA1322521C (en) | 1993-09-28 |
Family
ID=22016452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000568592A Expired - Fee Related CA1322521C (en) | 1987-06-05 | 1988-06-03 | Thyrotropin-releasing hormone analog composition and use thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0317613A1 (en) |
| JP (1) | JPH01503465A (en) |
| CA (1) | CA1322521C (en) |
| WO (1) | WO1988009606A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5458822A (en) * | 1993-06-21 | 1995-10-17 | Owens-Corning Fiberglas Technology, Inc. | Method for manufacturing a mineral fiber product |
-
1988
- 1988-06-03 CA CA000568592A patent/CA1322521C/en not_active Expired - Fee Related
- 1988-06-06 EP EP88905331A patent/EP0317613A1/en not_active Withdrawn
- 1988-06-06 JP JP63504973A patent/JPH01503465A/en active Pending
- 1988-06-06 WO PCT/US1988/001840 patent/WO1988009606A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1988009606A2 (en) | 1988-12-15 |
| EP0317613A1 (en) | 1989-05-31 |
| JPH01503465A (en) | 1989-11-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |