Note: Descriptions are shown in the official language in which they were submitted.
~28~
The use of human growth hormone for the treatment of
intoxicated individuals
________________________________________________________
The invention relates to the use of human growth hormone
for the treatment of individuals who are intoxicated
with poisonous substances of the type which is degraded
in the liver by microsomal enzymes.
Furthermore the invention rlelates to a preparation for
treating such intoxicated individuals. Medicine intoxi-
cated patients, such as individuals who have taken over-
doses oF soporifics, f.ex. barbiturates, have previously
been treated with pumping outs and respiration.
So far, however, there has been no actual antidote against
toxic substances, f.ex. barbiturates, which are absorbed
in the organism and accumulate in the liver where they
are slowly degraded enzymatically.
The present invention is based on the observation that
the presence of hGH reduces the time in which toxic
substances of the type indicated are active. It is thus
assumed that the the breaking down of toxic substances,
f.ex. barbiturates, in the liver may be accelerated
through the administration of human growth hormone,
hGH. The reason For this effect is not known, but it
is assumed that hGH either activates the degradable
enzymes or causes increased production of such enzymes.
In accordance herewith the effect of hGH is one which
functions in connection with all toxic substances of
the type which is mainly absorbed and broken down in
the liver.
Apart from barbiturates such toxic substances comprise
- ~286Z24
alcohol. In co,nsequence hGH is suitable for treating
alcoholic poisoning.
Any in itself known preparation containing a pharmacolo-
gically active dose of hGH may be used for treating
intoxicated individuals. The method of administration
is not important to the effect achieved, if only it
is ensured that the quantity of hGH preparation admi-
nistered has a certain magnitude, normally corresponding
to a maximum of 100 IU/kg body weight.
The hGH preparation applied may appropriately be admini-
stered in injectable doses of 0.1-10 IU/kg body weight,
administered at intervals up to 10 times.
Instead the hGH preparation may be administered in the
form of an infusion preparation where the hGH prepara-
tion is continuously being administered to the patient
in amounts of appropriately up to 100 IU/kg body weight.
This amount should be administered over not more than
1 day, but in certain instances, and if required, the
treatment may be continued over a longer period of time.
One method of administration is the use of nasal prepara-
tions, f.ex. in spray form, where the hGH preparation
contains substances which facilitate the penetration
of mucous membranes.
Depending on the method of administration the prepara-
tion may contain any suitable vehicles or subsidiary
materials of the usual kinds and which may be selected
by a person skilled in the art.
In the folLowing the invention will be illustrated by
means of some working examples.
i286224
EXAMPLE 1
Biosynthetic human growth hormone, pituitary human growth
- hormone (Nanormon and pituitary 22K, all manufactured
5 by Nordisk Eentofte A/S, were tested for their effect
on the duration of hexabarbital narcosis in mice. The
three growth hormone preparations were administered
subcutaneously to mice in dosages of 0.25, 2.5 and 25
IU/kg body weight. Nanormon ~ buffer was used as placebo.
The freeze-dried materials were dissolved in 3 ml distilled
water to obtain isotonic solutions. Further dilutions
were made with Nanormon ~ buffer. The stock solutions
contained 1.4 mg protein/ml (B-hGH), 1.1-1.5 mg/ml (P22K)
and 1-6 mg/ml protein (Nanormon ~ ), and the biological
potencies as determined by a preliminary tibia test
were 2.0 IU/mg, 1.9 IU/mg and 2.6 IU/mg, respectively.
25 IU/kg, 2.5 IU/kg and 0.25 IU/kg body weight was ad-
2û minstered in volumes of 0.2 ml/mouse, i.e. 10 ml/kg
body weight subcutaneously in the neck. The same volumes
of Nanormon ~ buffer was used as placebo.
A 0.4O solution of hexobarbital in distilled water added
approximately 10/ul 5 N NaOH per ml was prepared. NaOH
was from the Chemical Control Department. The mice were
dosed with 0.5 ml (100 mg/kg) intraperitoneally.
Male and female NMRI mice from Gl. 80mholtgaard, Ry,
were acclimatized for 4-7 days before use at 20 + 1C,
60 + 5O relative humidity, air change 16 per hour and
light from 7.30 a.m. till 7.30 p.m~ The animals had
free access to Altromin diet and drinking water and
were kept in rectangular polypropylene or Macrolon ~
cages with Spanvall beech bedding. When the mice were
used, they were 20+2 9 and 26-31 days old (male mice),
Z24
28-33 days old (female mice).
Each dosage of growth hormone was administered to four
groups of 10 mice, the two groups having growth hormone
s.c. 1/2 hour before hexobarbital i.p. and the other
two groups having growth hormone 2 hours before hexobar-
bital dosing. The treatments were randomly assigned
to the groups and a placebo group was included each
experimental day. During thle narcosis the mice were
placed on a heated operation table (37C) (from Hugo
Sachs Elektronik), and the time from disappearance till
reappearance of the righting reflex was registered as
the sleeping time.
Results
In table lA and lB the results are known for male and
female mice respectively, when the growth hormone prepa-
rations were administered 1/2 h before hexobarbital
dosing. All three growth hormone preparations caused
a significant shortening of the hexobarbital sleeping
time (for significance levels see the tables). Effects
were observed even after 0.25 iu/kg - nearly therapeutic
doses. There were no differences between male and female
mice. In all groups the onset of narcosis was within
a few minutes after hexobarbital i.p., and it was not
changed by the previous dosing of growth hormones. Tables
2A and 2B show the corresponding results for male and
female mice when the growth hormones were dosed 2 h
prior to hexobarbital. Apparently the eFfects of growth
hormone are practically absent. This means that the
effect is of rather short duration. The mechanism of
action is not known, and the effect has not been reported
in the literature. As the other pharmacological results
do not support in any way a central stimulating action
of growth hormone, other explanations may be that growth
~L~8622~
hormone promotes redistribution of hexobarbital from
the brain to other tissues or perhaps causes an induction
of the microsomal enzymes in the liver responsible for
the oxidative metabolism of barbiturates.
Conclusion
Biosynthetic human growth hormone, Nanormon ~ and pituitary
22K human growth hormone, all decrease the duration
of hexobarbital narcosis in mice significantly. Effects
are seen even after û.25 IU~'kg body weight (approximately
human theraoeutic doses). The effect is of rather short
duration, less than 2-2 1/2 hours.
~ 1~86:224
Dllratioll of hexr)barbital narcosis in micc.
Ihc dosrs of (Irowth llormone were injected subcutaneously
30 min~ltes before intraperitoneal administration of
hexobarl)ital, 100 mg/kg.
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Duration of hexobarbital narcosis in mice.
Ihe doses of growth hormonc ~ere injected subcutaneously
3û minutes before intraperitoneal administration of
hexobarbital, 100 mg/kg.
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Duration nf hexobarbital narcosis in mice.
The doses of growtll hormone were injecte(~ sui)cutaneously
120 minutes before intraperitoneal administration of
hexobarbital, 100 mg/kg.
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12~6224
Duration of hrxobarbital narcosis in mice.
The doses of growth hormolle were injrcted subcutaneously
120 minutes before intraperitoneal administration Or
hexobarbital, 100 mg/kg.
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-
EXAMPLE 2
Eksperiments were carried out as mentioned in example
1, substituting pentabarbital for hexobarbital.
A similar effect was found, except that it was more
pronounced on female mice than on male mice.
