|Title of Invention||
PHARMACEUTICAL COMPOSITION COMPRISING GAMA-BUTYROBETAINE
|Abstract||There is disclosed a pharmaceutical composition for stimulation of sexual activity and potency in male mammals comprising gamma-butyrobetaine in association with pharmaceutically acceptable diluent or carrier such as herein described, with or without 3-(2,2,2- trimethylhydrazinium)-propionate as free base or pharmaceutically acceptable salt, such as herein described.|
|Full Text||A PHARMACEUTICAL COMPOSITION FOR STIMULATION
OF SEXUAL ACTIVITY AND POTENCY IN MALE MAMMALS
The present invention relates to a pharmaceutical composition for stimulation of
sexual activity and potency in male mammals. The invention discloses novel effects of
known substances, showing combination unexpected level of pharmacological activity. In
particular, a pharmaceutical composition is disclosed, comprising as active ingredients
gamma-butyrobetaine (GBB) in combination with 3-(2,2,2-trhnethylhydrazinium)
propionate (THP) or phosphodiesterase inhibitor.
GBB (actiniae), an intermediate in the synthesis of. camitine in
mammalian organism, initially was characterised as a toxic substance, inducing
tachypnea, salivation and lacrimation, mydriasis, vasoconstriction and cardiac
arrest in diastole (Linneweh W. Z physiol Chem., 1929;42:181). Further
research demonstrated that the toxicity of GBB is extremely low (LD50 = 7000
mg/kg subc.) (Rotzsch W, Lorenz I, Strack E. Acta biol med ger 1959;3:28-36).
The cardiovascular effect's of GBB were compared to that of acetylcholine
(Hosein EA, McLennan PL Pharmacological action of gamma-butyrobetaine.
Nature 1959;183:328), but later the data were renounced by the same author,
who had in fact investigated the effects of the GBB methyl esther. Another
investigators held, that GBB is pharmacologically inert (Hosein EA, Proulx P.
Isolation and probable functions of betaine esters in brain metabolism. Nature
1960;187:321. Burgen ASV, Hobiger'F. Brit J Pharmacol. 1949;4:229. Strack
E, Foesterling-K. Z physiol Chem. 1953;295:377). Contrary to that, radical
scavenger properties (Akahira M, Hara A, Abiko Y. Effect of MET-88, a
gamma-butyrobetaine hydroxylase inhibitor, on myocardial derangements
induced by hydrogen peroxide in the isolated perfused rat heart. Fundam Clin
Pharmacol. 1997;11(4):356) and cardioprotective activity (Kalvins I, Veveris
M. Latvian patent Nr. 11727) were later demonstrated for GBB. It was also
disclosed, that pharmaceutical composition, comprising GBB as the active
principle, is useful for treating of carnitine deficiency (Cavazza C.
Phamiaceutical composition comprising gamma-butyrobetaine. UK Patent
Application GB 2 091 101 (1982)). There are no data on the influence of GBB
on sexual activity and potency of mammals.
3-(2,2,2-Trimethylhydrazinium)propionate (THP) is known also as a
medicine Mildronate or Quaterine (UK patent 2105992). It interferes with
carnitine biosynthesis and, consequently, limits the transporting of long-chain
fatty acids through mitochondrial membranes (Simkhovich BZ, Shutenko ZV,
Meirena DV et al. 3-(2,2,2-trimethylhydrazinium)propionate (THP) - a novel ?-
butyrobetaine inhibitor with cardioprotective properties. Biochem Pharmacol
1988;37:195). It has therefore found application as metabolic corrector in
ischemic diseases of different origin and cytoprotector in hypoxic conditions.
A pharmaceutical composition for the treatment of cardiovascular
diseases, containing 3-(2,2,2-trimethylhydrazinium)propionate and gamma-
butyrobetaine was disclosed in Latvian patent LV 11728.
However, there are no data on the influence of 3-(2,2,2-
trimethylhydrazinium)propionate (THP) or combinations thereof with other
substances on sexual activity and potency of mammals.
We have surprisingly discovered that gamma-butyrobetaine and/or THP
induce substantial and long-lasting increase of sexual activity in laboratory
animals. Moreover, the combination of both substances produce a more
prolonged and higher increase of the intracavernous pressure than each of the
constituent substances separately. Moreover, GBB or combination thereof with
THP, exert a positive influence on intracavernous pressure, induced by
reflectory stimulation. Thus we have unexpectedly discovered that GBB or
combination thereof with THP, are useful for stimulating of both the sexual
activity and potency of mammals. This activity can not be attributed to the
known effects of GBB and/or THP on the fatty acids turnover or other known
physiological effects of said substances.
The pharmacological effects of GBB, THP and their combination on the
sexual activity of mammals was investigated by a model based on rat
copulating behaviour in state of physiological depression.
Experiments were conducted on adult Wistar rats of both sexes with
initial body weight of 300 - 330 g. During the experiment, the animals were
kept in standard crates in groups of 6. The feed was a standartized diet R70
(LABFOR, Lactamin AB, Sweden). The room temperature was kept at 21 - 23
°C, relative humidity at 65 ± 10%, 12 hour light/darkness cycle. During one
week before the experiment it was established that the average water
consumption by the rats was 8.2 - 12% (average -10%) of their body mass.
Male rats were distributed randomly into 4 groups, each of 6 animals, and
supplied for 6 weeks with the following aqueous solutions:
Group 1 (Control Group) - drinking water without any additives;
Group 2 (GBB Group) - drinking water was supplemented by gamma-
butyrobetaine (0.015% by weight), resulting in the average daily gamma-
butyrobetaine intake of 15 mg/kg;
Group 3 (THP Group) - drinking water was supplemented by THP (0.06% by
weight), resulting in the average daily THP intake of 60 mg/kg;
Group 4 (GBB + THP Group) - drinking water was supplemented by THP
(0.06% by weight) and gamma-butyrobetaine (0.015% by weight), resulting in
the average daily THP intake of 60 mg/kg and gamma-butyrobetaine intake of
The copulating activity, of male rats was tested four times: after one week,
after four weeks, after six weeks and 48-50 hours after the discontinuation of
substance intake, when all animals were receiving drinking water without
The tests were conducted -between 10 and 12 a.m. 6 male rats of one
group were placed into a clean, well illuminated crate (box). After 5 min.
adaptation period 2 female rats were placed into the box for 10 minutes. For
each male rat the following data were collected:
1) copulating intensity (number of copulations during the exposition period);
2) arousal period, with separate registration of the delay time - the period until
the male rat displays interest in female rat, and number of
approachmg/mounting attempts during the exposition period;
3) postcoital period - the behaviour of male rats during 5 min. period after the
removal of females. The postcoital behaviour was characterized by following
marks: 0 - the animal is passive, lays down; 1 - the rat is quiet, grooming; 2 -
the rat is mobile, rutting; 3 - the animal is active, aggressive.
The female rats used were in the estrus phase, induced by i.p. injection of
0.2 ml 0.1% estradiol dipropionate:48 h before the test.
There were no substantial changes in water consumption attributable to
experimental substances, while the sexual behaviour of rats in experimental
groups was substantially different from that of control group.
Already a week after the start of the experiment, animals receiving GBB
or GBB+THP displayed substantially higher sexual interest and activity in
sexual contacts, as well as longer postcoital agitation period. The continuing
application of GBB resulted in increase of sexual activity, reflected in higher
copulation intensity, while rutting and general activity of animals was relatively
less influenced (Tables 1 - 4).
The combined use of GBB and THP resulted in hightened sexual interest
and copulating activity during all experimental period. After the discontinuing
of medication, only the GBB + THP Group displayed higher copulating activity
compared with controls.
Thus we have experimentally. demonstrated, that GBB alone and in
combination with THP after 6 week treatment period produces a substantial and
lasting increase of copulating activity in male rats. Moreover, we found a
surprising increase of efficiency for the combination of two substances as
compared to their activity when used separately.
In further experiments the novel compositions were compared with a
known potency stimulator papaverine (Sarosdy MF, Hudnall CH, Erickson DR,
Hardin TC, Novicki DE. A prospective double-blind trial of intracorporeal
papaverine versus prostaglandin E1 in treatment of impotence. J Urol,
1989;141:551), which is an efficient erection stimulant at intracorporeal
Adult male rats, weighing 300 - 410 g were used. The influence of the
experimental substances on the penile erection was evaluated using the
experimental model, where changes of intracorporeal pressure was measured
(Chen KK et al. J Urol, 1992;147:1124).
Rats were anesthetized by sodium pentobarbital (50 mg/kg i.p. plus
additionally 8 mg/kg/h i.v.). Body temperature was kept at 37 - 37.4 °C (rectal
control) by heating lamp. Endotracheal tube was inserted to assure adequate
respiration under anesthesia. Number 25 needle filled with heparinized saline
was connected to pressure transducer and introduced into corpus cavemosum
penis. Intracavernous pressure and II standard lead on an ECG was
continuously recorded on physiograph DMP-4B (Narco Bio-Systems, USA). In
some experiments arterial pressure in common carotid artery was also recorded.
The effects of experimental substances were detennined both at intravenous and
intracavernous introduction route. For the intracorporeal injection the
substances were dissolved in isotonic (0.9%) NaCl solution and the dose,
introduced in 0.05 ml of liquid. Papaverine hydrochloride, used in clinics for
potency testing, served as the positive standard (intracavernous injection 0.2 mg
per rat; intravenously 2.0 mg/kg). Gamma-butyrobetaine (GBB) was introduced
separately and in combination with THP or phosphodiesterase inhibitor, in
Gamma-butyrobetaine (GBB) (intracavernous injection 0.02 - 0.1 mg per
rat, usually 0.05 mg per rat; intravenously 2.0 mg/kg) and THP (intracavernous
injection 0.2 mg per rat; intravenously 10.0 mg/kg) were introduced separately
and as combination (GBB+THP).
Sildenafil (intracavernous injection 0.15 mg per rat, intravenously 3.0
mg/kg) was introduced separately and in combination (GBB + sildenafil).
It was discovered that intracavernous injection of GBB produces a
pronounced dose-dependent, but relatively short-termed increase of
intracorporeal pressure (Table 5).
THP did not produce significant changes of intracorporeal pressure. The
activity of GBB in this test was also inferior to that of papaverine. Surprisingly,
the effect of the combination of GBB with THP or sildenafil was equal or
superior to that of papaverine. Both the effect produced by the combination, and
its duration was superior to that induced by each of the ingredients separately.
Since the intracavemous injection is not popular due to inconvenience to
patient, intravenous route was selected for further evaluation.
It was demonstrated that intravenous papaverine and THP display little
effect on intracorporeal pressure, while GBB and GBB-THP composition are
highly efficient in increasing the intracorporeal pressure (Table 6).
It is important to notice, that the GBB-THP in combination and GBB plus
sildenafil sustains its effect 2.25 times or even, correspondingly, 5.46 times
longer than the GBB alone. It is also essential to note that only GBB-THP in
combination induced a pronounced positive response to reflex penis stimulation
resulting in increase of intracorporeal pressure, a response untypical for
Thus it was demonstrated, that pharmaceutical compositions containing
GBB or combination thereof with THP or sildenafil produced an increase of
intracorporeal pressure not only at intracavemous injection, but also, contrary to
papaverine, at intravenous route. We demonstrated the surprising efficiency of
the composition comprising the combination of GBB and THP and GBB plus
sildenafil in inducing the rise of intracorporeal pressure and the unexpected
sustained duration of effect, compared to that of each component of the
combination used alone, as well as restoration of positive reflex response to
mechanical penis stimulation.
Considering the positive effects the substances displayed orally, they are
useful for stimulation of sexual activity and erection both at norm and at
physiological depression of erectile function, being introduced both enterally
In cases when the active ingredients are administered parenterally by
injections or orally as drops, syrup or beverage, the pharmaceutical composition
contains the combination of gamma-butyrobetaine with THP or gamma-
butyrobetaine with sildenafil in the summary amount of 0.5-40% by total weight
of pharmaceutical form and distilled water, physiologic saline solution, glucose
solution, or buffer solution as a pharmaceutically acceptable solvent.
In cases when the combination of active ingredients is administered as
tablets, caplets, capsules, pills, granules, or powders, the pharmaceutical
composition contains the combination of gamma-butyrobetaine with THP or
gamma-butyrobetaine with sildenafil in the summary amount of 0.5 to 5 g by
weight per tablet, caplet, capsule, pill, granule, or powder dosage unit.
In cases when the active ingredients are administered transcutaneously,
topically, sublingually, intrauretrally or intranasally their content is 0.5-40% by
total weight of pharmaceutical form.
The pharmacutical composition, in addition, may include other
pharmacutical agents, such, as for example, other phosphodiesterase type V
inhibitors (vardenafil, tadalafll and related).
1. A pharmaceutical composition for stimulation of sexual activity and potency in male
mammals comprising gamma-butyrobetaine in association with pharmaceutically acceptable
diluent or carrier such as herein described, with or without 3-(2,2,2-trimethylhydrazinium)-
propionate as free base or pharmaceutically acceptable salt, such as herein described.
2. The pharmaceutical composition as claimed in Claim 1 optionally having a
phosphodiesterase inhibitor, such as herein described.
3. The pharmaceutical composition as claimed in Claim 2 wherein the phosphodiesterase
inhibitor is type V inhibitor, such as herein described.
4. The pharmaceutical composition as claimed in Claim 3 wherein the phosphodiesterase
inhibitor of type V is selected from the group consisting of sildenafil, vardenafil, tadalafil.
There is disclosed a pharmaceutical composition for stimulation of sexual activity and
potency in male mammals comprising gamma-butyrobetaine in association with pharmaceutically
acceptable diluent or carrier such as herein described, with or without 3-(2,2,2-
trimethylhydrazinium)-propionate as free base or pharmaceutically acceptable salt, such as herein
|Indian Patent Application Number||446/KOLNP/2004|
|PG Journal Number||20/2010|
|Date of Filing||02-Apr-2004|
|Name of Patentee||KALVINSH IVARS|
|Applicant Address||LIBIESHU 25, LV-5052 IKSHKILE|
|PCT International Classification Number||A61K 31/519|
|PCT International Application Number||PCT/LV2002/00004|
|PCT International Filing date||2002-03-04|