IE83685B1 - Use of atipamezole - Google Patents
Use of atipamezoleInfo
- Publication number
- IE83685B1 IE83685B1 IE1992/1735A IE921735A IE83685B1 IE 83685 B1 IE83685 B1 IE 83685B1 IE 1992/1735 A IE1992/1735 A IE 1992/1735A IE 921735 A IE921735 A IE 921735A IE 83685 B1 IE83685 B1 IE 83685B1
- Authority
- IE
- Ireland
- Prior art keywords
- atipamezole
- male
- administration
- ejaculations
- day
- Prior art date
Links
- HSWPZIDYAHLZDD-UHFFFAOYSA-N Atipamezole Chemical compound C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 HSWPZIDYAHLZDD-UHFFFAOYSA-N 0.000 title claims description 22
- 229960003002 Atipamezole Drugs 0.000 title claims description 22
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 230000001568 sexual Effects 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 241000282693 Cercopithecidae Species 0.000 description 8
- 230000006399 behavior Effects 0.000 description 5
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 4
- 230000035492 administration Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 4
- 229960000317 yohimbine Drugs 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 201000001881 impotence Diseases 0.000 description 3
- 230000003042 antagnostic Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000003542 behavioural Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002441 reversible Effects 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- -1 4-(2-ethyl-2,3-dihydro-1H-indenyl)-1H-imidazole Chemical compound 0.000 description 1
- 206010006514 Bruxism Diseases 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 238000006968 MacDonald synthesis reaction Methods 0.000 description 1
- 241000282566 Macaca arctoides Species 0.000 description 1
- 241000282519 Macaca speciosa Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 206010048232 Yawning Diseases 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000027326 copulation Effects 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000003370 grooming Effects 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000002474 noradrenergic Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 230000018052 penile erection Effects 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000001107 psychogenic Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 201000001880 sexual dysfunction Diseases 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Description
‘Use of Atipamezole
This invention relates to use of atipamezole, which is the INN-approved generic name
for 4-(2-ethyl-2,3-dihydro-1H-indenyl)-1H—imidazole or a
acceptable acid addition salt thereof in the manufacture of a medicament for
pharmaceutically
therapeutic treatment of male sexual impotence.
Male impotence is a sexual dysfunction relating to difficulties in achieving and/or
maintaining of sufficient penile erection. It can result from a variety of underlying
causes ranging from purely psychogenic to completely physical dysfunctioning.
Both surgical and pharmacological therapy have been used in the treatment of
impotence. Surgical therapy (implantation of a penile prosthetic device) has been
used successfully mainly in the case of a purely organic disease. A variety of
agents have been suggested for the use as drug therapy in impotence but the
reports of their effectiveness are mainly anecdotal in nature. The use of
pharmacological therapy in impotence has thus not gained any wide acceptance so
far.
A substantial amount of work has been devoted to identifying the neurotransmitters
involved in the facilitation and inhibition of male sexual behaviour (see e.g. Bitran
and Hull 1987, 365-389).
Neuroscience and Behavioural reviews 11,
Noradrenergic neuro-trans mission seems to have an important role.
MacDonald et al (Ann. Clin. Res. 2Q 298-310 (1988)) indicates that a|pha—2—
adrenoceptor antagonists may in the future be evaluated for their ability to treat
male sexual impotence.
Atipamezole is a selective and potent a2-adrenoceptor antagonist which is currently
marketed for the reversal of sedative—analgesic veterinary drugs. Atipamezole has
been disclosed e.g. in the European Patent EP 183492 as useful for the reversal of
detomidlne.
We have now found that this compound is also very effective in increasing male
sexual capacity in a monkey model. These findings suggest that atipamezole
would be an effective therapy in male impotence in humans as well.
Another a2-adrenoreceptor antagonist, yohimbine, is currently used for the
Yohimbine
neurotransmission and has been reported to facilitate the sexual capacity of male
treatment of male impotence. increases noradrenerglc
animals, although the results of different studies are conflicting. Atipamezole is,
however, clearly advantageous over yohimbine for this use because of its excellent
selectivity. The a2/at selectivity ratio of atipamezole is 200-300 times higher than
that of yohimbine.
Experimental
Three male and one female stumptail macaques (Macaca Arctoides) were studied
in the experiments. The ages of the males were 13, 16 and about 24 years. The
age of the female was 6 years.
During the testing period, the couple being tested was housed in a single cage (0.6
x 0.9 x 1.2 m) with two compartments. Between the sessions and during the first
min of each session, a sliding wall separated the male and the female in the test
cage. The sliding wall was made of iron bars. The monkeys could see and touch
each other through the sliding wall. After the i.m. administration of the studied drug
dose/saline control to the male, the observation of the sexual behaviour began as
described below. Ten minutes after the drug administration, the sliding wall
between the male and the female was pulled away, and the observation of sexual
activity'continued for the next 20 min. At the end of the observation period (=30
min after the drug administration), the sliding wall was replaced. Every time a new
couple was being tested, the first three sessions were done, as above, but without
the drug administrations to allow habituation of the couple to each other. These
first three sessions were not included in the results.
The time of occurrence and duration of the following behaviour was observed:
perineal investigation, mounting, ejaculation, tieing, grooming, direct aggression
towards the female, yawns, self-scratching, teeth grinding, shaking of cage and
masturbation. In the current report, only the number of ejaculations in each
session is given, since it gave the most straightforward index of male sexual
behaviour. For the same reason, the ejaculations obtained by masturbation and
intercourse were pooled in the results.
The experiments were performed once daily seven days a week. Atipamezole was
given every other day and saline control during other days. The preliminary results
in one monkey indicated that there was no difference in the effect of atipamezole
whether it was given every third or other day. Atipamezole doses varied from 0.01
to 0.3 mg/kg (dissolved in saline to get a volume of about 0.2 ml). Each dose was
tested 5-15 times in each monkey. Taking into account the saline days, the testing
of one dose in one monkey took from 10 days to one month. The order of testing
each dose was varied between the monkeys to counterbalance possible serial
effects. The difference in the number of ejaculations obtained at a given
atipamezole dose and the corresponding saline control days was used as an index
of the effect of atipamezole on sexual behaviour. This is how the possible variation
in the baseline sexual activity (represented by ejaculations during saline days)
could be minimised. The incidence of ejaculations (the percentage of saline days
with one or more ejaculations) during saline days was used as an index of baseline
sexual activity of each male. One way analysis of variance (ANOVA) and Student’s
t-test were used in statistical evaluation of the data. P<0.05 was considered to
represent a significant difference.
In the saline (=contro|) conditions, the incidences of sexual activity (percentage of
sessions with ejaculations produced by copulation and/or masturbation) in the three
male monkeys were 7%, 12% and 26%. The oldest male had the lowest and the
youngest male the highest incidence of sexual activity in control (=saline)
conditions. The sexual activity of the males in saline or atipamezole conditions was
not dependent on the estrous cycle of the female.
The results obtained with atipamezole are shown in Figure 1 A—D.
Atipamezole increased the number of ejaculations in a dose-dependent way in all
three male monkeys (for each individual; p<0.05, ANOVA; Figure 1 A-C). The
lowest effective dose of atipamezole varied from 0.01 to 0.08 mg/kg depending on
the individual; the younger the male, the lower the lowest effective dose. The
average atipamezole—induced increase of ejaculations over the three males also
was dose-dependent and significant (p<0.05, ANOVA; Figure 1 D). No other
behavioural effects produced by atipamezole were observed except increased
alertness.
The drug is preferably administrated perorally, transmucosally, intravenously,
intramuscularly or transdermally. The preferable daily dose range is about 0.01 to
1 mg/kg, preferably 0.05 to 0.3 mg/kg for i.v., i.m., transmucosal or transdermal
administration and 0.3 to 10 mg/kg for peroral administration.
Claims (1)
- CLAIMS Use of atipamezole or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment of male sexual impotence. Use according to claim 1, in which the treatment comprises intravenous, intramuscular, transmucosai or transderm al administration of atipamezole or _a pharmaceutically acceptable salt thereof in an amount of 0.01 to 1 mg/kg/day. Use according to claim 2 which comprises administration of 0.05 to 0.3 mg/kg/day. Use according to claim 1 in which the treatment comprises peroral administration of atipamezole or a pharmaceutically acceptable salt thereof in an amount of 0.3 to 10 mg/kg/day. Use substantially as hereinbefore described with reference to the drawings. Dk\spec\1-1754retype0ct16/Temp 12 A NUMBER OF EJACULATIONS/SESSION 9
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBUNITEDKINGDOM18/06/1991199100130 | |||
GB919113077A GB9113077D0 (en) | 1991-06-18 | 1991-06-18 | Use of atipamezole |
Publications (2)
Publication Number | Publication Date |
---|---|
IE83685B1 true IE83685B1 (en) | |
IE921735A1 IE921735A1 (en) | 1992-12-30 |
Family
ID=10696833
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE173592A IE921735A1 (en) | 1991-06-18 | 1992-07-01 | Use of atipamezole |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP0589957B1 (en) |
JP (1) | JP3151217B2 (en) |
KR (1) | KR100324447B1 (en) |
AT (1) | ATE144141T1 (en) |
AU (1) | AU661698B2 (en) |
CA (1) | CA2102187C (en) |
CZ (1) | CZ284409B6 (en) |
DE (1) | DE69214647T2 (en) |
DK (1) | DK0589957T3 (en) |
ES (1) | ES2092685T3 (en) |
GB (1) | GB9113077D0 (en) |
GR (1) | GR3021677T3 (en) |
HU (1) | HU220068B (en) |
IE (1) | IE921735A1 (en) |
IL (1) | IL101961A (en) |
MX (1) | MX9202948A (en) |
NO (1) | NO304011B1 (en) |
NZ (1) | NZ242863A (en) |
RU (1) | RU2111749C1 (en) |
WO (1) | WO1992022296A1 (en) |
ZA (1) | ZA923961B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FI20002756A0 (en) * | 2000-12-15 | 2000-12-15 | Orion Yhtymae Oyj | New treatment procedure |
-
1991
- 1991-06-18 GB GB919113077A patent/GB9113077D0/en active Pending
-
1992
- 1992-05-21 IL IL10196192A patent/IL101961A/en not_active IP Right Cessation
- 1992-05-22 NZ NZ242863A patent/NZ242863A/en not_active IP Right Cessation
- 1992-05-29 ZA ZA923961A patent/ZA923961B/en unknown
- 1992-06-17 MX MX9202948A patent/MX9202948A/en not_active IP Right Cessation
- 1992-06-18 DE DE69214647T patent/DE69214647T2/en not_active Expired - Fee Related
- 1992-06-18 RU RU93058537A patent/RU2111749C1/en not_active IP Right Cessation
- 1992-06-18 ES ES92911915T patent/ES2092685T3/en not_active Expired - Lifetime
- 1992-06-18 CZ CS932487A patent/CZ284409B6/en not_active IP Right Cessation
- 1992-06-18 JP JP51106392A patent/JP3151217B2/en not_active Expired - Fee Related
- 1992-06-18 AU AU19724/92A patent/AU661698B2/en not_active Ceased
- 1992-06-18 KR KR1019930703555A patent/KR100324447B1/en not_active IP Right Cessation
- 1992-06-18 EP EP92911915A patent/EP0589957B1/en not_active Expired - Lifetime
- 1992-06-18 DK DK92911915.4T patent/DK0589957T3/en active
- 1992-06-18 HU HU9303636A patent/HU220068B/en not_active IP Right Cessation
- 1992-06-18 AT AT92911915T patent/ATE144141T1/en not_active IP Right Cessation
- 1992-06-18 WO PCT/FI1992/000191 patent/WO1992022296A1/en active IP Right Grant
- 1992-06-18 CA CA002102187A patent/CA2102187C/en not_active Expired - Fee Related
- 1992-07-01 IE IE173592A patent/IE921735A1/en not_active IP Right Cessation
-
1993
- 1993-12-17 NO NO934690A patent/NO304011B1/en not_active IP Right Cessation
-
1996
- 1996-11-15 GR GR960403051T patent/GR3021677T3/en unknown
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