Note: Descriptions are shown in the official language in which they were submitted.
CA 02251255 1998-10-20
TITLE OF THE INVENTION
The use of dopaminergic agents in the management of sexual dysfunction.
FIELD OF THE INVENTION
The invention relates to the use of dopaminergic agents, namely pramipexol,
for
improving or obtaining sexual function, particularly in males.
BACKGROUND OF THE INVENTION
The effects of dopamine agonists on sexual function are known to the
practitioners.
In most cases, a decrease of the libido is reported when dopamine agonists are
administered alone, although some mild and inconsistent enhancement of sexual
function has been noted during the treatment of Parkinson's disease with
agonists
such as amantadine, parlodel, bromocriptine and bupropion. Paradoxically, it
is also
known that dopaminergic agents enhance libido when co-administered with
antidepressives, which themselves decrease libido.
Amantadine, parlodel, bromocriptine and bupropion are examples of dopaminergic
agents having a weak activity with severe side effects. Pramipexol (1 to 5 mg
/ daily
dose divided in 3 doses) and ropirinol ( 3 to 24 mg / daily dose in 2 or 3
subdivided
doses) are two promising agonists for the treatment of Parkinson's disease,
these
drugs having much less undesirable side effects than other dopaminergic
agents.
Ropirinol is a selective DZ agonist while pramipexol is a selective D3 agonist
with
a DZ presynaptic activity.
A rare incidence of decreased libido or impotence is reported for pramipexol
and
ropirinol when administered to Parkinson's patients not concomitantly treated
with
levodopa. To the inventors' surprise, patients treated with pramipexol has
noticed,
on the contrary, an increase of the libido and penile rigidity (that should
not be
confused with priapism which is an undesirable, uncontrollable and painful
penile
CA 02251255 1998-10-20
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rigidity). It was further observed that penile rigidity can be enhanced by the
ad hoc
administration of seldanofil which further improved capacity for full and
sustained
penetration during sexual intercourse.
STATEMENT OF THE INVENTION
These observations open a new avenue for potential uses of pramipexol and
pharmacologically equivalent drugs, namely ropirinol, alone or in combination
with
vasodilating drugs maintaining a high nitric oxide level, such as sildenofil.
It is worthwhile noting that about 35% of the patients do not respond to
sildenofil.
Those patients may respond to a combination of sildenofil and pramipexol.
DESCRIPTION OF THE INVENTION
Without being bound to any theory, the inventors have made a comprehensive
review of the mechanisms involved in sexual function and tried to draw a
rationale
for the effect of pramipexol on sexual function.
For practical reasons, the discussion is directed to male sexual function.
Measurable parameters and visual observations can be more objectively obtained
in male subjects for obvious reasons. It is however not excluded that women
may
benefit from the present invention.
PHYSIOLOGICAL AND PHARMACOLOGICAL BACKGROUND OF THE MALE
~EXUALREFLEXES
There are 4 principal male sexual reflexes: libido, erection, ejaculation and
orgasm.
The anatomical substrate, the neural pathways and the neurochemical
transmitter
profile for each of these reflexes are understood to a variable degree.
The libido, or sexual drive is primarily determined by male hormones via their
action
on central nervous system structures in the hypothalamus and limbic system.
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The erection reflex has a segmental and suprasegmental component. The
segmental or spinal reflex is influenced by both sympathetic and
parasympathetic
nerves. The sympathetic nerves originate from the T11-L2 cord levels and reach
the
target tissues via the hypogastric nerves, pelvic plexus, cavernous nerves and
pudendal nerves as postganglionic fibers. The parasympathetic innervation
originates from the S2-4 spinal segments and reach the target tissue as nervi
erigentes and the pelvic plexus mixed with sympathetic nerves. Descending
suprasegmental tracts both facilitate and inhibit the erection reflex. These
pathways
originate in the hypothalamus and limbic system, the hypothalamic medial
preoptic
area being the principal integrating center. The tracts descend through the
median
forebrain bundle, ventrolateral pons and medulla and the lateral columns of
the
spinal cord. The neurochemical transmitters for the sympathetic nerves is
norepinephrine while acetylcholine is for the parasympathetic nerves. The
facilitatory central pathways are dopaminergic. The erection reflex is
facilitated
at the segmental level by parasympathetic fibers and inhibited by sympathic
nerves.
The erection reflex can be initiated by mechanical stimulation of the
peripheral
erogenic zones which sets up a primary spinal reflex or by psychogenic stimuli
which, through the central facilitatory pathways, sets up a secondary spinal
reflex.
Synergistic action of both systems are the most efficient. The facilitatory
neural
impulses for the erection reflex causes massive vasodilation of the penile
arteries,
maximum filling of the expandable caverns of the corpora vavernosa, and
passive
compression of the effluent veins. As a result, a marked increase of the
penile
tumescence occurs. The marked penile arterial vasodilation, which is the
ultimate
final effector mechanism bringing about erection, is predicated upon
relaxation of the
arterial smooth muscle. This, in turn, is activated by the rapid synthesis of
NO and
possibly other vasoactive peptides. NO synthesis is facilitated by cyclic GMP
which
is degraded by a specific phosphodiasterase. Therefore, the erection reflex
can be
' stimulated by inhibiting this enzyme which would maintain a high NO level.
Sildenofil
(Viagra) is such a compound.
In summary on the basis of the above facts, the erection reflex can be
stimulated at
the level of penile smooth muscle (dilation), or stimulation of the
parasympathic
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nerves and/or inhibiting the sympathetic nerves, or by stimulating the central
dopaminergic system or perhaps a judicial combination of more than one
factors.
The neural pathways that mediate the ejaculation reflex is similar to those of
the
erection reflex but the trigger signal is mainly a sympathomimetic one. This
indicates the fine tuning of the plasticity and the dynamic equilibrium that
must
operate to ensure effective sexual function. The ejaculation reflex activates
smooth
muscles in the seminal vesicles and prostate and mediated by fibers in the
pudendal
nerve. This action expels the semen and usually is associated with orgasm.
While
the ejaculation reflex usually occurs while the erection is still in full
force, ejaculation
and orgasm may still occur without significant erection.
Orgasm is a complex sensory experience mainly localized to the erogenic zones
and
require the integrity of somatic sensory afferent fibers in the pudendal
nerve.
Orgasm is also associated with complex autonomic phenomena (breathing, pulse,
blood pressure, etc.) and psychological experience all of which require the
integrity
of still undefined peripheral and central neural pathways.
RATIONALE FOR USING DOPAMINERGIC AGENTS FOR IMPROVING MALE
SEXUAL FUNCTIONS
From the foregoing discussions it becomes clear that abnormal or defective
sexual
reflexes may arise from pathological alterations of the nerves and neuronal
centers
that mediate and control these reflexes. Abnormalities of the relevant
sympathetic
or parasympathetic or somatosensory afferent nerves at the periphery can be
involved in a great variety of diseases such as peripheral neuropathies (i.e.
diabetes)
or myelopathies (i.e. trauma, multiple sclerosis, etc.). Another common cause
of
erectile disfunction is vascular insufficiency with impaired blood flow to the
penile
arteries or defective smooth muscle dilatation in response to the
parasympathetic
nerve signal. These peripheral causes of erectile dysfunction can be treated
by
vasodilatory agents or drugs that increase NO level of arterial smooth muscles
(i.e.
Sildanofil). However in a substantial number of cases impaired sexual reflexes
and
erectile dysfunction can be caused mainly by a defect in the facilitatory
central
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pathways for the segmental reflexes. These pathways are dopaminergic.
Hypoactive suprasegmental facilitation of the sexual reflexes may occur in
psychiatric diseases (i.e. depression) or simply because of anxiety and stress
or due
to undetermined causes. The administration of vasodilatory treatment
modalities for
such cases will only be partially useful. However, dopaminergic drugs can be
expected to restore the facilitation of the various sexual reflexes,
particularly
those subserving erection. Such an approach may also be effective to
supplement peripheral vasodilatory treatment when the main dysfunction is
peripheral. Some mild and inconsistent enhancement of sexual function has,
indeed, been noted during the administration of dopamine agonists such as
amantadine, parlodel, bromocriptine and bupropion. However these were
relatively
weak dopaminergic agents with severe side effects. Wth the advent of
pramipexol,
the situation has dramatically changed.
PRELIMINARY CLINICAL OBSERVATIONS
In 1997, pramipexol hydrochloride or PH (Mirapex) has been introduced into the
treatment of Parkinson's disease either to boost the action of levodopa or as
a first-
line medication. As noted later PH is a potent ligand for all classes of
striatal
dopamine receptors and produces strong dopaminergic stimulation without
significant major side effects. This has been a big improvement over
previously
available direct dopaminergic agents. In our practice we have encountered 5
idiopathic Parkinson's patients in stages 1-2 of the disease, who were taking
therapeutic doses (about 1 mg tid) of Mirapex. These patients noted marked
improvement of their bradycardia and rigidity of limbs, but in addition they
noted 2
additional features that could not by any means be attributed to the motor
effects of
Mirapex. This included a conspicuous sustained increase of the caliber and
length
of the penile shaft as well as a sustained increase of tumescence. However,
this did
not reach the state of priapism and there was no penile discomfort at all. In
addition,
the 5 male patients observed that upon normal natural stimulation of the penis
during
sexual encounters, a much firmer and more sustained erection could be attained
and
there was a facilitation of the ejaculation and the intensity of orgasm. In 2
patients,
the additional use of Viagra further improved these functions and there were
no
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harmful interactions between PH and Viagra. From these observations and from
the
above discussed central neurotransmitter pharmacology, there is a real
potential of
using PH to correct or improve erectile dysfunction not only in patients with
central
and/or peripheral erectile dysfunction, but also in patients who suffer penile
atrophy
(affecting the corpora cavernosa) after prostatectomy.
DESCRIPTION OF SALIENT FEATURES OF PRAMIPEXOL HYDROCHLORIDE
Pramipexol is an agonist of all classes of central and peripheral dopamine
receptors.
It is excreted in the urine. The drug is indicated to treat early and late
Parkinson's
disease alone or in combination with Levodopa. The average daily dose of 1 mg
tid
po must be built up gradually over a period of weeks. Side effects, usually
with full
dose, include orthostatic hypotension, hallucination, dyskinesisas, headache,
constipation and somnolence. Side effects are mild and rare. Serious drug
interaction may occur with agents that tend to cause hypotension. Therefore,
its
combined use with Sildanofil hydrochloride should be envisaged cautiously.
OBJECTS OF THE PRESENT INVENTION
Based on the above observations, the present invention provide a therapeutic
usefulness of pramipexol for male sexual dysfunction in the following
situations:
a) A single-time use for obtaining or improving erection otherwise not
possible, without or with Sildanofil, in patients with central or
peripheral neurogenic erectile dysfunction;
b) A chronic use of a dose for the purpose of obtaining or improving
erection; and
c) A chronic use to prevent or minimize penile atrophy after
prostatectomy.
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REFERENCES
1. Stewart, J., Autonomic Regulation of Sexual Function In Clinical Autonomic
Disorders, 2"d Ed., PA Low, Lipincott-Raven Publ., Philadelphia, 1997,
pp129-134.
2. Zvara, P., Brock, GB., Determining the source of im,notence, Can., J.Diag.,
4;49-55, 1994.
3. Pollack, MH., Smoller, JW., Management of antide~~ressant-induced side
ff~ ects, The Guilford Press Publ., NY, NY, 1996, pp 451-489.
