COMPOSITION ANALOGUE A L'HORMONE LIBERANT LA THYROTROPINE ET UTILISATION DE LADITE COMPOSTION

THYROTROPIN-RELEASING HORMONE ANALOG COMPOSITION AND USE THEREOF

Abrégé anglais

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.

Revendications

The embodiments of the invention in which an exclusive property
or privilege is claimed are defined as follows:
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.
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.

Description

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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
.

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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

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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.
EXAMPLE 1
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.
EXAMPLE 2
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.
EXAMPLE 3
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.
EXAMPLE 4
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.