Note: Descriptions are shown in the official language in which they were submitted.
CA 02325930 2000-11-14
1488-2
1
A medicament for prevention and treatment of
sexual dysfunction
FIELD OF THE INVENTION
The present invention relates to a medicament for prevention and
treatment of sexual dysfunction, and particularly, to a medicament for
prevention
and treatment of sexual dysfunction comprising potassium channel openers
and/or
papaverin.
DESCRIPTION OF THE PRIOR ART
Studies regarding female sexual function are very few compared with
studies regarding male sexual function due to social and cultural prejudices
in
which female sexual expression was traditionally considered as a taboo or
disgrace. However, sexual dysfunction exists in women as well as men. In
sexual dysfunction of normal couples, erectile dysfunction and dysspermia
(i.e.,
ejaculation disorder) comprise 40°/o of male sexual dysfunction, and
excitement
and orgasmic disorders comprise 63% of female sexual dysfunction. (Refer to
Frank E, Anderson C, Rubinstein D. Frequency of sexual dysfunction in 'normal'
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2
couples. New Engl J Med 1978: 299: 111- 115). Female sexual response is
classified into following phases: sexual desire, sexual arousal, excitement,
plateau,
orgasm, and resolution. Female sexual dysfunction is classified into following
disorders according to female sexual response phases: hypoactive sexual desire
disorder, excitement disorder, orgasmic disorder, dyspareunia and vaginismus.
(Refer to Leiblum SR. Definition and classification of female sexual disorder.
Int
J Impot Res 1998: 10: 104-6).
Blood flow into clitoris and vagina increases and a secretion from vagina
increases in sexual desire, and blood engorgement in vagina and enlargement of
clitoris to sexual stimuli like male penis erection occur in sexual arousal or
excitement, although it is difficult to separate clitoris from vagina in
female sexual
response phase. (Refer to Geer JH. Direct measurement of genital responding.
Am Psychol 1975: 30: 415-418). These series of responses in women are very
similar to penis erection responses in men. In case of vagina, the relaxation
of
vascular smooth muscle and increase of blood flow are also important responses
in sexual arousal. The blood engorgement in vagina according to the above
responses results in increase of length and inner diameter of vagina, and the
increase of secreting fluid from vagina makes insertion of the penis into
vagina
easy. (Refer to Park k, Goldstein I, Andry C, Siroky MB, Krane RJ, Azadzoi KM.
Vasculogenic female sexual dysfunction : the hemodynamic basis for vaginal
engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res
1997: 9: 27-37).
In the past, most of studies regarding causes of female sexual dysfunction
were focused on sexual disinclination in terms of psychiatry or temperamental
CA 02325930 2000-11-14
3
causes due to female hormone deficiency in post-menopause. Morbidity of
female sexual dysfunction increases with age in women like men, and the
increase
of morbidity of female sexual dysfunction is associated with menopause or the
increase of vascular system risk factors. In reality, women with vascular
system
risk factors or post-menopausal women complained dysfunction of vagina or
clitoris more frequently than the control group. (Refer to Sadeghi-Nejad H,
Moreland R, Traish A, Azadzoi K, Nehra A, Abobakr RA. et al. Impotence is a
couple's disease: studies in female sexual dysfunction. J. Urol 1996: 155:
677A).
Since decrease of female hormone in climacterium or post-menopause
results in changes of vascular system, the decrease of female hormone and
vasculogenic female sexual dysfunction interact in complex. Practically, the
decrease of female hormone in menopause decreases the amount of vaginal
secretion by decreasing blood flow into the pelvic region. However, female
hormone supplementation therapy restores the blood flow. In addition, while co-
administration of progesterone and female hormone inhibits blood improvement
effect of estrogen compared with administration of female hormone alone, co-
administration of male and female hormones increases sexual drive of women
compared with administration of female hormone alone. (Refer to Simon JA.
Double-blind comparision of two doses of estrogen and estrogen-androgen in
naturally post-menopausal women: neuroendocrine, psychological and
psychosomatic effects. Fertil Steril 1996: 66: 871-875). Recently, it was
found
that this is because the decrease of female hormone acts as vascular system
risk
factors, and vaginal nitric oxide synthase(NOS) and necrosis of cells such as
smooth muscle of vaginal wall, vascular endothelium, nerve, vaginal epithelial
cell
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4
or the like are controlled by female hormone.
Hemodynamic studies regarding male erectile dysfunction were developed
very well, and attempts to apply the above studies to concepts and studies of
vasculogenic sexual dysfunction of female external genitalia which have
embryological and anatomical similarity with male external genitalia were
tried.
As a result of study regarding smooth muscles of clitoris and vagina, it was
found
that the vaginal engorgement and enlargement of clitoris in sexual arousal
resulted
from increase of blood flow according to smooth muscle relaxation by
neurotransmitters such as nitric oxide(NO) or vasoactive intestinal
peptide(VIP)
rather than hormones which have systemic and complex actions in case of women
like men. Therefore, decrease of blood flow due to various causes in addition
to
the decrease of female hormone in menopause, or inappropriate response of
smooth muscle to neurotransmitters in clitoris or vagina may cause
vasculogenic
female sexual dysfunction.
To develop a laboratory animal model for study of vasculogenic female
sexual dysfunction, arteriosclerosis was induced in the internal organ bone
artery
of a female rabbit and then blood flow of clitoris and vaginal wall were
determined
by stimulating pelvic nerves. As a result, blood flow of arteriosclerosis
group
decreases significantly compared to that of normal control group. This result
is
associated with decrease in internal pressure of vaginal wall and of corpus
cavernosum of clitoris and length of vagina. Therefore, it was suggested that
arteriosclerosis acts as an important factor in female sexual dysfunction such
as
vaginal engorgement insufficiency and clitoral erectile insufficiency. (Refer
to
Park k, Goldstein I, Andry C, Siroky MB, Krane RJ, Azadzoi KM. Vasculogenic
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female sexual dysfunction: the hemodynamic basis for vaginal engorgement
insufficiency and clitoral erectile insufficiency. Int J Impot Res 1997: 9: 27-
37).
The reason why a concrete approach of vasculogenic female sexual dysfunction
is
proposed, although decrease of blood flow in clitoris or vagina may occur
5 secondarily by decrease of female hormone as described above, is that
vaginal
blood flow increased in sexual desire or sexual arousal causes secreting fluid
in
vagina to increase, thereby reducing pain in sexual intercourse and increasing
orgasm and sexual drive according to elevation of sense of clitoris.
Therefore,
like treatment of male erectile dysfunction, treatment efficiency of a method
of
directly relaxing smooth muscle in clitoris or vaginal wall which is a target
organ
may be much higher than that of female hormone therapy which exhibits indirect
and secondary effects.
In female sexual arousal, responses of female external genitalia may be
separated into response of clitoris and vagina. Among them, clitoris has a
pair of
erectile tissues similar to corpus cavernosum penis. Acetylcholine by
cholinergic
nerve and nitric oxide by non-adrenergic, non-cholinergic nerve system act as
neurotransmitters in sexual arousal, and relaxation of smooth muscle and
increase
of blood flow due to the neurotransmitters cause enlargement of clitoris.
(Refer to
Semmens JP, Semmens EC. Sexual function and the menopause. Clin Obstet
Gynecol1984:27:717-723).
Azadzoi et al reported that unlike neurotransmitters in clitoris, primary
neurotransmitter involved in relaxation of vaginal smooth muscle is VIP,
rather than
nitric oxide (NO). (Refer to Azadzoi KM, Tarcan T, Siroky MB, Krane RJ,
Goldstein
I., Characterization of elitoral cavernosal and vaginal smooth muscle
contractility in
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6
the rabbit. Int J Impot Res 1998: 10 Suppl 2: S58). However, Hoyle et al
reported that all nerves utilizing NO(nitric oxide), NPY(neuropeptide Y), VIP,
CGRP(calcitonin gene related peptide) and substance P as neurotransmitters can
control blood flow of human vaginal wall and permeability of blood capillary
as a
result of study regarding neurotransmitters which control blood vessels of
human
vaginal wall. (Refer to Hoyle CHV, Stones RW, Robson T, Whitley K, Burnstock
G.
Innervation of vasculature and microvasculature of the human vagina by NOS and
neuropeptide-containing nerves. J Anal 1996: 188: 633-644). That is, it is
assumed that various neurotransmitters act in complex according to the kind
and
location of nerve, tissue managed by nerve or the like.
Ion channels of cell membrane are involved in contraction and relaxation
of smooth muscle of all organs, and opening and shutting of these ion channels
respond diversely according to membrane voltage and ion concentration in
cells,
etc. Generally, if cell membrane voltage is depolarized by nerve stimulation,
membrane voltage-dependent calcium channel opens and increased calcium
concentration due to intracellular Ca influx contracts smooth muscle. If
potassium channel opens by membrane voltage or increased intracellular calcium
concentration, intracellular potassium which maintains higher concentration
than
outside the cell efflux into outside the cell, and cell membrane voltage
becomes re-
polarized and membrane voltage-dependent calcium channel becomes closed.
These cause intracellular calcium concentration to decrease and smooth muscle
to be relaxed.
There are various kinds of potassium channels in cell membrane.
Membrane voltage-dependent potassium channels(Kv) which open by membrane
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7
voltage are inhibited by 4-aminopyridine. Also, calcium-dependent potassium
channels(Kca) which open and shut by intracellular calcium concentration
exist.
Most of the calcium-dependent potassium channels are maxi-K channels having
large conductance which are inhibited by TEA(tetraethylammonium) or kaliotoxin
and charybdotoxin. And the calcium-dependent potassium channels having small
conductance are inhibited by apamin. Further, ATP-dependent potassium
channels(KATP) which open by decrease of intracellular ATP concentration in
metabolic inhibition or severe hypoxia can be inhibited by tolbutamide or
glibenclamide and TEA. However, ATP-dependent potassium channels are rarely
open in normal condition. Therefore, there are much different opinions
regarding
physiological mechanism thereof. (Refer to Leiblum SR. Definition and
classification of female sexual disorder. Int J Impot Res 1998: 10: 104-6).
Among various potassium channels, KATP and maxi-K channels are
considered as being physiologically most appropriate in smooth muscle of
corpus
cavernosum. Maxi-K channels are most common subtype of potassium channels
which exist in smooth muscle of corpus cavernosum penis. Maxi-K channels
comprise approximately 90% of outward K current in smooth muscle cell of human
corpus cavernosum penis which was cultivated in vitro. Also, maxi-K channels
control membrane voltage.
Relaxation mechanisms of smooth muscle through opening of potassium
channels may be classified into three mechanisms. The first mechanism
comprises increase of cGMP production by NO or the like, and accordingly,
activation of protein kinase G (PKG). Activated PKG is involved in opening of
maxi-K channels and acts on calcium channel to make smooth muscle relaxed by
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8
inhibiting calcium transfer of channel. Although activated PKG is considered
as
being involved in opening of KATP channels, there are contradictory opinions
regarding the above theory. The second mechanism comprises increase of
cAMP by PGE~ or the like, and accordingly, activation of protein kinase A
(PKA).
Activated PKA also causes opening of maxi-K channels and closing of calcium
channels, thereby inducing relaxation of smooth muscle. Most neurotransmitters
causing relaxation of smooth muscle induce relaxation of smooth muscle
directly
or indirectly by means of these two mechanisms(i.e., the first and second
mechanisms). Therefore, that acetylcholine, L-arginine and PGE~ make slices
relaxed in proportion to concentration may be explained in two aspects of
calcium
channels and potassium channels. That is, it is presumed that cGMP is
accumulated via pathway of NO, and then PKG is activated and activity of maxi-
K
channels increases, and accordingly, calcium channels are inhibited and
transfer
of calcium ions is inhibited, and then amount of intracellular calcium ions
decreases, and the above phenomina make smooth muscle relaxed.
The last mechanism utilizes potassium channel openers such as pinacidil
which act directly on potassium channel to make smooth muscle relaxed. Such
method may provide excellent relaxation effect and decrease systemic side
effects
because it acts directly on potassium channel without complex processes using
neurotransmitters. Further, such method has clinical value because it may
provide complementary effect to relaxation effect of other medicaments.
Therefore, study regarding roles of potassium channels in relaxation of
vaginal
smooth muscle makes direct approach possible and is much simpler than study
regarding various neurotransmitters.
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9
Papaverin was first discovered by Meck in 1948, and is an alkaloid
extracted from a poppy similar to opium. Papaverin is a direct smooth muscle
relaxant. Firstly, papaverin increases concentrations of cAMP and cGMP by
inhibiting actions of cyclic mononucleotide phosphodiesterase. Secondly,
papaverin controls myosin light chain and inhibits contraction by blocking
calcium
channels and inhibiting calcium influx. When papaverin was injected to penis
of
the erectile dysfunction patient, it is difficult to find out what mechanism
it mainly
works through. However, papaverin relaxes all elements of penis erection
tissue,
that is, artery of penis, smooth muscle of corpus cavernosum and vein of
penis.
Therefore, papaverin is a potent smooth muscle relaxant and it is known that a
complication of continued penis erection developed very often when papaverin
was administered to the male erectile dysfunction patient.
Considering the direction of study regarding female sexual dysfunction
hitherto, there is a tendency that for diagnosis of vasculogenic female sexual
dysfunction, determination of blood flow of clitoris or vagina using color
Doppler
ultrasonography waves is mainly carried out and then patients with lowered
blood
flow are treated with administration of smooth muscle relaxants. As
therapeutic
agents of female sexual dysfunction which have been developed by many
pharmaceutical companies, oral administration of viagra, apomorphine, topical
application of PGE~ cream and the like are known. Also, as effective
therapeutic
agents of erectile dysfunction, injection therapy of erection inducers into
corpus
cavernosum is known. Although injection formulations are more effective in
erection inducing effect than oral drugs such as viagra, injection
formulations have
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defects such as pain, a fear to injection, continued penis erection, etc.
SUMMARY OF THE INVENTION
s
The inventors of the present invention have conducted intensive
researches and experiments to develop medicaments which can effectively
prevent and treat sexual dysfunction. The present inventors have developed
medicaments of the present invention by confirming that when a medicament
10 comprising a potassium channel opener(e.g., nicorandil, cromakalim,
pinacidil and
minoxidil) and/or papaverin was used, it has an excellent effect of relaxing
smooth
muscles of corpus cavernosum penis and smooth muscles of vaginal wall through
various animal experiments, and finding that the medicament can increase blood
flow in penis and clitoris, during researches and experiments.
is An object of the present invention is to provide a medicament for
preventionand treatment of female dysfunctioncomprising one
sexual kind of
potassiumchannel opener selected the groupconsisting of nicorandil,
from
pinacidil and cromakalim, and/or papaverin.
Another object of the present invention is to provide a medicament for
prevention and treatment of male sexual dysfunction comprising one kind of
potassium channel opener selected from the group consisting of nicorandil and
cromakalim, and optional papaverin.
In accordance with the present invention, there are provided a
medicament for prevention and treatment of female sexual dysfunction
comprising
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~.1
one kind of KATP channel opener selected from the group consisting of
nicorandil,
pinacidil and cromakalim, and/or papaverin.
Also, there are provided a medicament for prevention and treatment of
male sexual dysfunction comprising one kind of KArP channel opener selected
from
the group consisting of nicorandil and cromakalim, and optional papaverin.
The present invention has many advantages, including providing a
medicament for prevention and treatment of sexual dysfunction which can treat
sexual dysfunction, and providing a medicament for prevention and treatment of
sexual dysfunction which has excellent treatment effects of sexual dysfunction
and
no side effect. These and other features, aspects, and advantages of the
present
invention will become better understood with reference to the following
description
and appended claims.
is BRIEF DESCRIPTION OF THE DRAWING
Figure 1 a is a graph showing the relaxation of precontracted clitoral strips
to the administration of minoxidil, nicorandil, papaverin and PGE~. Each drug
induced a dose-dependent increase of relaxation.
Figure 1 b is a graph showing the relaxation of precontracted vaginal strips
to the administration of minoxidil, nicorandil, papaverin and PGE~. Each drug
induced a dose-dependent increase of relaxation.
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12
Figure 2a is a graph showing the relaxation of precontracted clitoral strips
to the administration of papaverin and PGE~ after pretreatment of minoxidil or
nicorandil. Each drug mixture induced a dose-dependent increase of relaxation.
Pretreatment of minoxidil or nicorandil significantly enhanced relaxation
induced
by papaverin or PGE~, alone, respectively.
M: minoxidil ; N: nicorandil ; PA: papaverin ; and PG : prostaglandin E~.
Figure 2b is a graph showing the relaxation of precontracted vaginal strips
to the administration of papaverin and PGE~ after pretreatment of minoxidil or
nicorandil. Each drug mixture induced a dose-dependent increase of relaxation.
Pretreatment of minoxidil or nicorandil significantly enhanced relaxation
induced
by papaverin or PGE~, alone, respectively.
M: minoxidil ; N: nicorandil ; PA: papaverin ; and PG : prostaglandin E~.
DETAILED DESCRIPTION
The present invention provides a medicament for prevention and treatment
of female sexual dysfunction comprising one kind of KATP channel opener
selected
from the group consisting of nicorandil, pinacidil and cromakalim as active
ingredient, and a pharmaceutically acceptable carrier. Also, the present
invention
provides a medicament for prevention and treatment of female sexual
dysfunction
comprising papaverin as active ingredient, and a pharmaceutically acceptable
carrier. Further, the present invention provides a medicament for prevention
and
treatment of female sexual dysfunction comprising papaverin and one kind Of
KqTP
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13
channel opener selected from the group consisting of nicorandil, pinacidil and
cromakalim as active ingredients, and a pharmaceutically acceptable carrier.
The present invention provides a medicament for prevention and treatment
of male sexual dysfunction comprising one kind of KATP channel opener selected
from the group consisting of of nicorandil and cromakalim as active
ingredient, and
a pharmaceutically acceptable carrier. Also, the present invention provides a
medicament for prevention and treatment of male sexual dysfunction comprising
papaverin and one kind of KA-rP channel opener selected from the group
consisting
of nicorandil and cromakalim as active ingredients, and a pharmaceutically
acceptable carrier.
Most of potassium channel openers known to date are KATP channel
openers. For example, nicorandil, cromakalim, pinacidil, minoxidil or the like
are
known as potassium channel openers, and they are used as anti-hypertensive
drugs, hair production-promoting agents and therapeutic agents for angina
pectoris (Refer to USP Nos. 4,446,113 and 4,200,640). However, articles in
which they are studied as agents for preventing and treating sexual
dysfunction
are very rare. Only, minoxidil was patented as a therapeutic agent for male
erectile impotence in U.S. (Refer to USP No. 5,336,678). While pinacidil has
been frequently used for treatment of male sexual dysfunction, it has never
been
used for treatment of female sexual dysfunction. Although it was reported that
there was a possibility that minoxidil can be used for treatment of female
sexual
dysfunction, it has not been produced as a commercial product. However, among
potassium channel openers, nicorandil and cromakalim have not been used for
treatment of male or female sexual dysfunction. Papaverin which is used for
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14
treatment of male erectile dysfunction has not been used for treatment of
female
sexual dysfunction. Particularly, it has been not reported that a medicament
comprising potassium channel opener and papaverin in combination has
synergistic effect in treatment of female sexual dysfunction.
In the present invention, effects of nicorandil and minoxidil which is used
as an hair production-promoting agent for topical application were compared.
Both nicorandil and minoxidil when administered alone, have more effective in
relaxing effect than PGE~ does, but have less effective in relaxing effect
than
papaverin does. This may be because there are differences in mechanisms of
action of receptors, innervational structure or the like of clitoral or
vaginal smooth
muscle, unlike smooth muscle of corpus cavernosum penis. Also, the relaxing
effect when minoxidil or nicorandil was pre-treated was greater than the
relaxing
effect when PGE~ or papaverin was administered alone.
Based on the results of the present invention, effective medicaments in
developing therapeutic agents for female sexual dysfunction comprise suitably
nicorandil or papaverin as a single drug, and mixed drugs of nicorandil and
papaverin as mixed drugs. This is because these medicaments have an
excellent relaxing effect of smooth muscle when used as a single drug, and
have
an excellent relaxing effect even at low concentrations when used as mixed
drugs.
When effects of potassium channel openers were tested and compared,
pinacidil has the shortest duration of action, cromakalim has the strongest
effect in
relaxing smooth muscle, and nicorandil has more effective in relaxing effect
of
smooth muscle slices than papaverine does because nicorandil has an effect of
CA 02325930 2000-11-14
accumulating cGMP. When pinacidil was administered at high concentration of
10-6 M or more, even completely depolarized corpus cavernosum became relaxed
in experiments using smooth muscle slices of corpus cavernosum of a rabbit.
Also, when acetylcholine, L-arginine and PGE~ were in vivo administered
5 to corpus cavernosum penis of a living cat which was pretreated with
pinacidil, 35
115 % of internal pressure of corpus cavernosum increased additionally
depending on kinds of drugs than when the erection inducer was alone
administered. Further, in vitro experiments using vaginal wall slices of a
rabbit
showed that pinacidil was effective in relaxing vaginal smooth wall. A
10 medicament comprising one kind of potassium channel opener selected from
the
group consisting of nicorandil, pinacidil and cromakalim, and/or papaverin has
been used in the present invention for prevention and treatment of female
sexual
dysfunction for the first time, and it was confirmed that the medicament was
effective in prevention and treatment of female sexual dysfunction. Also, in
the
15 present invention, when a medicament comprising one kind of potassium
channel
opener selected from the group consisting of nicorandil and cromakalim, and
optional papaverin was topically applied to penis, it was reported that
erection
inducing effects was great in male sexual dysfunction patients.
In a medicament for prevention and treatment of sexual dysfunction
according to the present invention, a medicament comprising one kind Of KqTP
channel opener selected from the group consisting of nicorandil, pinacidil and
cromakalim, and/or papaverin as active ingredients) can be used for prevention
and treatment of female sexual dysfunction, and a medicament comprising one
kind of KArP channel opener selected from the group consisting of nicorandil
and
CA 02325930 2000-11-14
16
cromakalim, and optional papaverin as active ingredients) can be used for
prevention and treatment of male sexual dysfunction. In the medicament for
prevention and treatment of sexual dysfunction according to the present
invention,
the active ingredients) is(are) preferably contained in amount of 0.1 ~ 20 %
by
weight based on total weights of the medicament, and more preferably, in
amount
of 1 ~ 10 % by weight based on total weights of the medicament.
The daily dose of KATP channel opener compound of the present
invention for prevention and treatment of female sexual dysfunction is
generally in
the range of from about 10 to 30 mglday for the average adult woman patient
(60
kg), and may be administered in single or divided doses.
The daily dose of KA-rP channel opener compound of the present invention
for prevention and treatment of male sexual dysfunction is generally in the
range
of from about 20 to 50 mg/day for the average adult man patient(70 Kg), and
may
be administered in single or divided doses.
The daily dose of papaverin of the present invention for prevention and
treatment of female sexual dysfunction is generally in the range of from about
10
to 30 mg/day for the average adult woman patient (60 kg), and may be
administered in single or divided doses.
The daily doses of papaverin and KATP channel opener compound in the
medicament of the present invention as mixed drugs for prevention and
treatment
of female sexual dysfunction are generally in the range of from about 10 to 30
mg/day and about 10 to 30 mg/day, respectively, for the average adult woman
patient (60 kg), and may be administered in single or divided doses.
The daily doses of papaverin and KATP channel opener compound in the
CA 02325930 2000-11-14
17
medicament of the present invention as mixed drugs for prevention and
treatment
of male sexual dysfunction are generally in the range of from about 20 to 50
mg/day and about 20 to 50 mg/day, respectively, for the average adult man
patient
(70 kg), and may be administered in single or divided doses.
The concrete dosage will be determined depending on the age and body
weight of the subject being treated, response, administration route, duration
of
treatment and the like. In practice the physician will determine the actual
dosage
which will be most suitable for an individual patient and it will vary with
the age,
weight and response of the particular patient. The above dosages are exemplary
of the average case but there can, of course, be individual instances where
higher
or lower dosage ranges are merited, and all such dosages are within the scope
of
this invention.
The active compounds of the present invention can be administered alone,
but will generally be administered in an admixture with a pharmaceutical
diluent or
carrier selected with regard to the intended route of administration and
standard
pharmaceutical practice.
The medicament for prevention and treatment of sexual dysfunction
according to the present invention may comprise a pharmaceutically acceptable
base in addition to the above-described active ingredient(drug). Bases which
can
be used in the present invention include for example, alcohols, esters of
fatty acids,
biocompatible fats, fatty oils, wax, lanolin, paraffin, vaseline, glycerin,
starch,
cellulose derivatives, polyethylene glycol, silicone oils, bentonite, and
mixtures
thereof.
CA 02325930 2000-11-14
18
Also, one kind of KATP channel opener selected from the group consisting
of nicorandil, minoxidil, pinacidil and cromakalim, and/or papaverin, and a
pharmaceutically acceptable skin absorption enhancer can be mixed in various
amounts and formulated. Skin absorption enhancers were added in order to pass
the active ingredient through clitoris, vaginal tissue or albuginea of penis
surrounding corpus cavernosum penis and penis skin to facilitate sexual
excitement or erection inducing effects when the active ingredient(drug) was
topically applied to clitoris, vagina or penis. Skin absorption enhancers
which can
be used in the present invention may include for example, fatty alcohols,
fatty
acids, esters of fatty acids, surfactants, fatty alcohol ethers, propylene
glycol or
mixtures thereof.
The medicament according to the present invention may comprise
additives such as pharmaceutically acceptable solvents, propellants, anti-
septives,
preservatives, aromatic agents, stabilizers, suspending agents, colorants,
emulsifiers, consistency agent or the like, if necessary.
The medicament for prevention and treatment of sexual dysfunction
according to the present invention may be used in dosage forms of spray,
solution,
cream, gel, ointment, lotion, powder, suppository, patch, implant or the like
using
conventional preparation methods of dosage forms following mixing the above-
described KATP channel opener and/or papaverin, pharmaceutically acceptable
base, skin absorption enhancer and additives with specific ratios. The
medicament according to the present invention may be administered via the
oral,
parenteral or topical routes. Preferably, the medicament according to the
present
invention may be a medicament for topical application.
CA 02325930 2000-11-14
19
Preferably, the medicament for prevention and treatment of female sexual
dysfunction according to the present invention may be directly administered to
clitoris, vagina or vicinity thereof. Also, the medicament for prevention and
treatment of male sexual dysfunction according to the present invention may be
preferably directly administered to penis or vicinity thereof.
A dosage form of the medicament for prevention and treatment of female
sexual dysfunction according to the present invention may be spray, solution,
cream, get, ointment, lotion, powder, patch, suppository or implant. A dosage
form of the medicament for prevention and treatment of male sexual dysfunction
according to the present invention may be spray, solution, cream, gel,
ointment,
lotion, powder or patch.
The medicament according to the present invention may be preferably for
prevention and treatment of vasculogenic female or male sexual dysfunction.
Although correct mechanism for pharmacological action of the
medicament for treatment of sexual dysfunction according to the present
invention
is not established, when the medicament for treatment of sexual dysfunction
according to the present invention was used, potassium channels became open,
blood flow into clitoris and vagina increased and both smooth muscle of
vaginal
wall and smooth muscle of corpus cavernosum penis became relaxed. Therefore,
the medicament according to the present invention make diagnosis and treatment
of male and female patients having sexual dysfunction possible. For example,
it
is effective to directly apply the medicament to clitoris or vagina in case of
treating
female sexual dysfunction, and it is effective to directly apply the
medicament to
CA 02325930 2000-11-14
the penis or vicinity thereof in case of treating male sexual dysfunction.
The previously described versions of the present invention have many
advantages including providing a medicament for prevention and treatment of
sexual dysfunction which can treat sexual dysfunction, and providing a
5 medicament for prevention and treatment of sexual dysfunction which has
excellent treatment effects of sexual dysfunction and no side effect.
In case of female sexual dysfunction patients who have problems in sexual
arousal or excitement, sexual dysfunction can be treated by increasing blood
flow
into clitoris or vagina, thereby increasing a secretion from vagina and
elevating the
10 sense by means of applying the medicament for prevention and treatment of
sexual dysfunction according to the present invention is applied to clitoris
and
vagina immediately before sexual intercourse. Also, the medicament for
prevention and treatment of sexual dysfunction according to the present
invention
are applicable to male sexual dysfunction patients. Further, since preferably,
the
15 medicament according to the present invention is directly absorbed to
target organ
via topical application of the minimum thereof, the effect of the medicament
according to the present invention is excellent and the medicament according
to
the present invention is practically free from systemic or local side effects.
Since the medicaments according to the present invention have
20 prevention and treatment effects of sexual dysfunction and no side effect,
they are
thought to be suitable in maintaining satisfactory sex life between man and
wife.
The present invention will now be described in more detail in connection
with the following examples, which should be considered as being exemplary
only
and not limiting the present invention.
CA 02325930 2000-11-14
21
EXAMPLE 1
To test the medicament for prevention and treatment of sexual dysfunction
according to the present invention, among women patients who came to
outpatient
department of urology in Hospital, 18 patient volunteers, who consented after
S explanations of objects and test methods of this study were evaluated. The
average age of 18 volunteers was 41.3 years old, and they have neither a
history
of sexual dysfunction nor diseases which cause sexual dysfunction.
First, the size of clitoris in basal state was measured with caliper. The
size of clitoris, diameter of clitoral artery and clitoral blood flow of peak
systolic
velocities(PSV) and end diastolic velocities (EDV) were measured by color
Doppler ultrasonography.
Then, 2% minoxidil solution was applied to the 18 volunteers, and changes
in the size of clitoris, diameter of clitoral artery and clitoral blood flow
of peak
systolic velocities(PSV) and end diastolic velocities (EDV) were measured
using
the same method. Thereafter, 2% minoxidil solution was completely washed out.
After a long time passed, 5% nicorandil solution was applied to the 18
volunteers, and changes in the size of clitoris, diameter of clitoral artery
and clitoral
blood flow of peak systolic velocities(PSV) and end diastolic velocities (EDV)
were
measured using the same method.
The size of clitoris and diameter of clitoral artery after application of the
drug increased compared with those of the basal state. However, there was no
statistically significant difference because of personal differences and
deficiency in
discriminant ability of measurement apparatus and measurement standard.
Mean scores of peak systolic velocities(PSV) and end diastolic velocities
(EDV) of
CA 02325930 2000-11-14
22
clitoral artery in basal state were 5.40 ~ 0.78 cm/s and 1.76 ~ 0.44cm/s,
respectively.
After application, both 2% minoxidil solution and 5% nicorandil solution
significantly increased clitoral blood flow of PSV to 9.88 ~ 2.76 cm/s and
16.87 ~
3.53 cm/s, respectively (p<0.05). Also, clitoral blood flow of EDV after
applying
2% minoxidil solution and 5% nicorandil solution was increased to 3.52 ~ 1.26
cm/s and 4.69 ~ 2.21 cm/s, respectively. Also, it was found that relaxing
effect of
5% nicorandil solution was much superior to that of 2% minoxidil solution. In
the
meantime, questions regarding changes of sense were given to the volunteers.
However, answers to the questions were different and inconsistent due to
personal
differences and differences in test methods.
From the above results, it can be known that when 2% minoxidil solution
was topically applied to clitoris, the blood flow rate of clitoral artery
significantly
increased, and when 5% nicorandil solution was topically applied to clitoris,
the
blood flow rates of clitoral artery significantly increased.
Therefore, KArP channel opener solutions can be used to improve clitoral
artery of female sexual dysfunction patients, and they are expected to be
effective
in male sexual dysfunction patients.
2o EXAMPLE 2
Using slices(0.1 x 1.2 x 3 mm) obtained from vaginal smooth muscle of
New Zealand white rabbits(2.5 ~ 3.5 Kg), isometric contraction was measured.
Relaxation responses of the slices contracted with phenylephrine pretreatment
against L-arginine, PEGS and acetylcholine were compared. In each response,
CA 02325930 2000-11-14
23
using apamin, kaliotoxin, glibenclamide, tolbutamide, 4-aminopyridine and TEA
which are potassium channel blocker as well as minoxidil and pinacidil which
are
KarP channel openers, effects of the above compounds on contraction and
relaxation response of vaginal smooth muscle were tested.
As a result, there was no spontaneous contraction of slices in basal state,
biphasic response consisting of relaxation following contraction by electrical
field
stimulation (Grass SD9 stimulator, Frequency: 200 Hz, Delay: 1 msec, duration:
20
msec, 60 volts) was shown. The relaxation following contraction by electrical
field
stimulation was not inhibited by atropine pretreatment. However, it was
inhibited
by bretyllium or acetylcholine pretreatment. Slices were contracted
proportional
to the concentration of phenylephrine. Magnitude order of relaxation of slices
contracted with phenylephrine (1 ~ 5 wM) pretreatment was Pinacidil >
acetylcholine >_ minoxidil >_ PEGS >_ L-arginine. Relaxation effect of L-
arginine (1
100 mM) and PEGS (1 ~ 100 mM) even at high concentration were 5 ~ 10 % and 5
~ 20 %, respectively. Relaxation effect of acetylcholine (5 ~ 50 ~.M) was
approximately 60% and similar to that of minoxidil (10 ~M). However, duration
of
action of acetylcholine was short and strength of relaxation effect of
acetylcholine
was weak, and therefore, the slices became re-contracted following temporary
relaxation when treated with acetylcholine. Pinacidil (10 ~M) made the slices
completely relax, and some slices was relaxed to values below the basal
values.
Relaxation response by acetylcholine was partly inhibited by high
concentration of
K,aTP channel blockers or voltage-sensitive potassium channel blockers. Also,
relaxation response by acetylcholine was completely inhibited by apamin or
kaliotoxin even at a low concentration (1 ~M). Relaxation response by
pinacidil
CA 02325930 2000-11-14
24
(10 ~.M) was completely inhibited by TEA or 4-aminopyridine pretreatment.
However, relaxation response by pinacidil (10 ~M) was not inhibited by apamin
or
kaliotoxin pretreatment
From the above results, it was found that neurotransmitters involved in
relaxation response of vaginal smooth muscle of a lapin exhibit relaxation
effects
via potassium channels like in other smooth muscle, and relaxation response by
pinacidil was the greatest.
EXAMPLE 3
After enucleating clitoris, vagina, urethra, cystis and uterus from a matured
New Zealand female rabbit (3.0 ~ 4.0 kg), slices consisting of smooth muscle
of
clitoris (1 x 1 x 5 mm) and distal vaginal wall (2 x 3 x 8 mm) were prepared
while
removing surrounding tissues under a microscope for microsurgery. Tension of
slices were measured through a polygraph (SD9, Grass Instrument, Quincy, MA,
USA) connected to a force displacement transducer. Firstly, Tension was
applied
to each slice using a weight of 1.0 g and each slice was incubated for over 30
minutes. Then, after administering 100 pl of phenylephrine (10-6 M), tension
of
1.0 g was added repeatedly until isometric tension appears. Time in which
difference in maximum contraction tensions of before and behind contraction
curves was below 10% was considered as state where isometric tension was
accomplished by measuring amplitudes of contraction curve after administering
phenylephrine. Relaxing responses of slices to drugs administered were
evaluated as follows. After contracting slices by adding 100 pl of
phenylephrine
(10-4 M) to the slices in which isometric tension was accomplished, effective
CA 02325930 2000-11-14
concentration, maximum relaxation tension and maximum relaxation concentration
were significantly measured by administering the drug in from low
concentration to
high concentration (concentration in bath, 10-8 ~ 3 x 10-5 M ), respectively
into
contracted slices.
5 As the drug, nicorandil, minoxidil, papaverin and PGE~ were cumulatively
administered in from low concentration (10-8 M) to high concentration (3 x
10'5 M).
As a result, relaxation ratio increased proportionally to the concentration of
the
drug, respectively, in both slices of clitoris and vaginal wall. The results
were
shown in Figure 1 a and 1 b.
10 From the above results, it was found that magnitude order of maximum
relaxation ratio of slices of clitoral and vaginal smooth muscle by single
drug was
follows: papaverin, nicorandil, minoxidil, and PEGS. The results were shown in
Table 1 below.
20
CA 02325930 2000-11-14
26
Table 1. Maximal relaxation (%) of each strip
Clitoris Vagina
Single dnig
Mi 34.79 10.01 9, n=12) 40.83 9.89 (N=8,11
(N= n= )
Ni 65.25 18.54 9, n=13) 68.01 17.12 (N=7,=8)
(N= n
PG 27.05 12.18 10, n=10)27.75 11.95 (N=8,=14)
(N= n
PA 80.81 7.83 =7, n=9) 75.19 10.39 (N=7,=11)
(N n
Double mixture
Mi + PG 37.31 15.42 (N=7,12) 42.49 16.05 (N=9,
n= n=17)
Ni + PG 43.32 16.16 (N=7,8) 46.61 20.04 (N=8,
n= n=15)
Mi + PA 87.93 18.83 (N=7,11) 73.06 24.0 (N=7,
n= n=16)
Ni + PA 103.06 12.75 (N=7,=9) 91.84 20.44 (N=7,
n n=10)
Triple mixture
Mi+pG+PA 94.31~ 10.88 (N=4, n=8) 93.48~ 15.96 (N=4, n=6)
Ni+pG+PA 99.01~ 15.31 (N=4, n=8) 105.8~ 5.58 (N=4, n=S)
_________________________________________________________________________
Mi; minoxidil, Ni; nicorandil, PG; prostaglandin E1, PA; papaverine,
N; number of animals,
n; number of strips
CA 02325930 2000-11-14
27
EXAMPLE 4
Following the procedure as described in Example 3 except that nicorandil
and papaverin; minoxidil and papaverin; nicorandil and prostaglandin; and
minoxidil and prostaglandin were used as mixed drugs, relaxation ratio of each
slice was measured.
After contracting slices of clitoral corpus cavernosum smooth muscle and
vaginal smooth muscle with 100 pl of phenylephrine (10-4 M) and pre-treating
the
contracted slices with nicorandil (10-5 M), papaverin was cumulatively
administered
from low concentration (10-8 M) to high concentration (3 x 10-5 M ). As a
result,
relaxation ratio increased proportionally to the concentration of the mixed
drugs,
respectively, in the above two slices. The results were shown in Figure 2a and
2b.
In the mixed drugs, pre-treatment with nicorandil significantly increased
maximum relaxation ratio of the drug which followed rather than pre-treatment
with
minoxidil did. Papaverin exhibited stronger relaxation effect than
prostaglandin.
Also, the mixed drugs had stronger relaxation effect than the medicament
comprising a single drug. Among the mixed drugs, mixture of nicorandil and
papaverin exhibited the strongest relaxation effect. The results were shown in
Table 1 below.
CA 02325930 2000-11-14
28
Table 1. Maximal relaxation (%) of each strip
Clitoris Vagina
Single dmg
Mi 34.79 10.01 9, n=12) 40.83 9.89 (N=8,
(N= n=11)
Ni 65.25 18.54 9, n=13) 68.01 17.12 (N=7,
(N= n=8)
PG 27.05 12.18 10, n=10)27.75 11.95 (N=8,
(N= n=14)
PA 80.81 7.83 =7, n=9) 75.19 10.39 (N=7,
(N n=11)
Double mixture
Mi + PG 37.31 15.42 (N=7, n=12)42.49 16.05 (N=9, =17)
n
Ni + PG 43.32 16.16 (N=7, n=8)46.61 20.04 (N=8, =15)
n
Mi + PA 87.93 18.83 (N=7, n=11)73.06 24.0 (N=7, 16)
n=
Ni + PA 103.06 12.75 (N=7, 91.84 20.44 (N=7, =10)
n=9) n
Triple mixture
Mi+PG+PA 94.31~ 10.88 (N=4, n=8) 93.48~ 15.96 (N=4, n=6)
Ni+pG+PA 99.01~ 15.31 (N=4, n=8) 105.8~ 5.58 (N=4, n=S)
_________________________________________________________________________
Mi; minoxidil, Ni; nicorandil, PG; prostaglandin E1, PA; papaverine,
N; number of animals,
n; number of strips
CA 02325930 2000-11-14
29
A medicament comprising nicorandil or papaverin as a single drug, or a
medicament comprising mixed drugs of nicorandil and papaverin as mixed drugs
exhibited an excellent relaxation effect of clitoral and vaginal smooth
muscle.
Therefore, these medicaments can be developed as topical therapeutic agents
for
female sexual dysfunction. Especially, in results of table 1 above, a
medicament
comprising a potassium channel opener and papaverin in combination exhibited a
synergistic effect in treatment of sexual dysfunction.
Although the present invention has been described in detail with reference
to the above specific embodiments, other embodiments are possible. Therefore,
it should be apparent to those skilled in the art that various modifications
and
changes thereof can be made without departing from the spirit and scope of the
invention and that such modifications and changes be included in the scope of
the
following claims.
