Note: Descriptions are shown in the official language in which they were submitted.
CA 02251949 1998-10-16
_ WO 97/49396 j PCT/GB97/01713
USE OF LOFEX1DINE 1N THE MANUFACTURE OF A MEDICAMENT FOR TREATING ATTEN-
TION DEFICIT HYPERACTtVE DTSORDER
This invention relates to the treatment of an Attention Deficit Hyperactivity
Disorder (hereinafter ADHD) and to pharmaceutical compositions useful in the
treatment of such conditions.
ADHD is a condition affecting a significant proportion of children and which
is
manifest by learning difficulties, restlessness, inability to settle to any
task,
argumentativeness, low fi-ustration tolerance and aggressive conduct. In the
past, a
traditional method of treating such children was by administration of psycho
stimulant
such as methyl phenidate. While psycho stimulants are useful in increasing
attention
spans, they have major side-effects, including loss of appetite and insomnia
and do not
deal with the problems of hyperactivity.
More recently, clonidine has been tested as a drug for treating ADHD (see
Hunt et al, Journal of the American Academy of Child Adolescent Psychiatry -
24, 1
January 1995). Although clonidine has been shown to be effective, it does,
unfortunately, involve side-effects, the most serious of which is causing
hypotension
and a high level of sedation. While a measure of sedation can be useful in the
treatment of hyperactive children, it does not assist in increasing attention
span.
The present invention is based on the discovery that Lofexidine has usefulness
in the treatment of ADHD without incurring the same level of side-effects as
clonidine.
According to the present invention there is provided the use of Lofexidine or
a
non-toxic pharmaceutical acceptable salt thereof, in the preparation of a
medicament
for the treatment of ADHD.
Lofexidine, 2-[a-(2,6-dichlorophenoxy)ethyl]-OZ-imidazole, has been used
clinically for opiate detoxification (see Gold et al - Drug & Alcohol
Dependency -
1981, 8, 307-315). Lofexidine is believed to work in opiate detoxification by
reducing brain noradrenergic activity, thereby suppressing the withdrawal
symptoms.
The neurological reasons for ADHD are not, at present, known but it is
possible that
SUBSTITUTE SHEET (RULE 26)
CA 02251949 1998-10-16
_ WO 97/49396 PCT/GB97/01713
2
clonidine and lofexidine may alleviate the symptoms by acting on alpha 2
receptors in
the brain, to affect the rate of release of noradrenaline and that activity
may contribute
to their usefulness in treating ADHD. However, because of the different
activities
noted in the case of clonidine and lofexidine, it is apparent that they act
either in a
different way on the same receptors, or perhaps on associated receptors.
Investigations with monkeys have shown that dose rates of the order of 0.005
mg to 0.02 mg per kilogram show an improvement in cognitive function with
little
sedation or blood pressure problems. This translates into a daily dose rate
for adults
of up to about 3 mg, e.g. about 0.5 to about 2.~ mg per day, typically about 1
to 2 mg
per day. In the case of children, the daily dose rate is expected to be
correspondingly
smaller. The dose administered would, to a large extent, depend upon the
method of
administration.
The drugs can be administered in traditional form for oral administration,
e.g.
as tablets, lozenges, dragees and capsules. However, for the administration of
the
drug to children, which is likely to be its major use, it may be preferred to
formulate
the composition as a suppository, skin patch or oral liquid preparation such
as a syrup.
The drugs can also be administered parentalty, e.g. by intramuscular or
subcutaneous
injection, using formulations in which the drug is employed in a saline or
other
pharmaceutically acceptable, injectable composition.
An advantage of lofexidine for these purposes is that it is water-soluble,
especially at a slightly acid pH.
Preparations for suitable for paediatric use include aqueous syrups, which are
preferably formulated with an acid constituent such as citric or ascorbic
acid.
Sweetners and flavourings are also desirable ingredients. In the case of
liquid
preparations, a typical concentration would be about 0.0> to ? mg, e.g. 0.1 to
1 mg,
per > ml of aqueous liquid. For example, if the daily dose is. say, about 1 mg
per day,
CA 02251949 1998-10-16
WO 97/49396 ~ PCT/GB97/01713
then an oral liquid formulation may contain 0.2 mg per S ml and five 5 ml
spoonfuls
would be administered throughout the day.
Another good method of administering the compositions of the invention is in
the form of skin patches. A typical structure suitable for use as a skin patch
is as
follows.
Occlusive backing
Hydroph-lic gFl +
c~ ug
i
;, ,
.. . , . . , ... . ~, ... ..-
Adhesive
Rate controlling Release liner
hydrophobic membrane
The concentration of the lofe~idine in the hydrophilic gel layer is preferably
calculated so as to deliver a dosage of about 0.05 to 2 mg per day.
Controlled release compositions may also be useful in the practice of this
invention. The controlled release composition may be designed to give an
initial high
dose of the active material and then a steady dose over an e.~tended period of
time, or
a slow build up to the desired dose rate, or variations of these procedures.
Vasal spray compositions are also a useful way of administering the
pharmaceutical preparations of this invention to patients such as children for
whom
compliance is difficult. such formulations are generally aqueous and are
packaged in a
nasal spray applicator ~.viiicu delivers v ~.,ne spray of the composition ;o
the nasal
passages.
SUBSTITUTE SHEET (RULE 26)
CA 02251949 1998-10-16
WO 97149396 PCTIGB97I01713
4
Suppositories are also a traditionally good way of administering drugs to
children and can be used for the purposes of this invention. Typical bases for
formulating suppositories include water-soluble diluents such as polyalkylene
glycols
and fats, e.g, cocoa oil and polyglycol ester or mixtures of such materials.
In the treatment of ADHD patients in accordance with the invention, lofexidine
can be used alone or together with other active materials. For example,
lofexidine can
be used in conjunction with clonidine andlor with a related alpha 2 adrenergic
agonist
such as guanfacine. This can be beneficial because clonidine produces a quick
but
short acting benefit in improving the condition of a ADHD patients, while
lofexidine
with or without guanfacine or clonidine gives a prolongation of the effect. It
is also
believed that lofexidine may also be useful in conjunction with guanfacine on
its own
for extending the affect of the treatment over an extended period.
In the case of clonidine, this drug can be used to provide a quick effect,
while
lofexidine administered simultaneously or subsequently provides a longer-
lasting
control of ADHD. Dosage rates for clonidine in this embodiment are relatively
low,
e.g. 0.005 to 0.01 mg/kg, and may be administered by a skin patch to establish
a low
level of clonidine in the patient's blood. Lofexidine is also preferably
administered at a
low dosage level, preferably from about 0.008 to 0.015 mg/kg, e.g. about 0.01
mg/kg.
Because lofexidine may, in some patients, cause a small degree of sedation, a
stimulant
may be incorporated in the medication or administered separately in
conjunction with
the lofexidine. Suitable stimulants include methyl phenidate, dexamphetamine
or
pemoline
Although the invention has been described primarily as a therapy for children,
it
can also be used for adults, although dosage rates may be different in the
case of
adults.
CA 02251949 1998-10-16
WO 97/49396 PCT/GB97/017I3
S
The following Examples show the effect of lofexidine alone administered to
monkeys. In these tests, the monkeys used were aged specimens and were tested
for
attention span by repetitively carrying out a set task with and without
treatment with
lofexidine, administered parentally at the rate of 0.01 mg and 0.05 mg per kg
per day.
The tabulated results below show an improvement in attention span of up to
about
60% with no apparent sedation and with little effect on blood pressure.
Example 1
Monkey
Number Task Correct % Appearance after
vehicle alone medicament improvementdrug administration
1 9 out of 30 26 out of 56.6 calm, not pale
30
2 23 out of 30 28 out of 17 alert
30
vehicle alone medicament
at 0.~ m~
1 7 out of 1 ~. ~ 26 out of ~ 63.27 sleepy
30 ~
Although the result for monkey 1 in the above test showed a slightly greater
percentage improvement after administering five times the dosage in the first
test, the
subject was noticeably sleepy. This suggests that a dosage level of about 0.01
mg/kg
is likely to be the optimum.
Example 2
Two young monkeys who had become agitated because of a move to new
quarters and developed 'ADHD like' behaviour were examined to determine the
effect
CA 02251949 1998-10-16
WO 97149396 PCT/GB97/01713
6
of lofexidine on this behaviour. Again, the monkeys were tested by giving them
a
repetitive task and noting the number of times when the task was carried out
correctly.
The monkeys were tested after injection of a saline solution of lofexidine at
the rate of
0.01 mg/kg and after injection of the saline vehicle alone. The results are as
follows:-
Monkey Task correct
Number
vehicle alonemedicament at 0.01 improvement
mg
3 14 out of 21 out of 30 23
30
4 11 out of 17 out of 30 20
30
In both cases. the monkeys appeared alert and non-sedated after administration
of the.medicament.
