TRIBESTAN
1. Preparation trade name
2. Manufacturer
3. Active Substance Generic Name (in
English and Latin)
4. ATC code:
5. Formulation and Active Substance
Content
6. Properties of the Preparation: Pharmacological
Effects, Mechanism of Action
7. Pharmacokinetics: Absorption, Distribution,
Elimination
8. Indications
9. Dosage and Mode of Application
10. Contraindications: none
11. Use during Pregnancy or Lactation
12. Adverse Drug Reactions
13. Drug Interactions of Clinical
Significance
14. Cautions and Specific Warnings
15. Overdose: Symptoms, Treatment
16. Storage Conditions
17. How Supplied
REFERENCES
1. Preparation trade name: Tribestan
2. Manufacturer: Sopharma AD
3. Active Substance Generic Name
(in English and Latin): Proprietary extract of the
plant Tribulus Terrestris L. Bulgaricum.
4. ATC code: G 04 B X 00
5. Formulation and Active Substance
Content
Tribestan is an original non-hormonal preparation
of plant origin. Its active components are steroid
saponins of furostanol type isolated from the epigeous
part of the Tribulus terrestris L. plant. The preparation
has been standardized on a base of the predominating
compound, protodioscine, not less than 45%. The
structural formula of protodioscine is R = glucose
: ramnose
(2:1) - 26-0-beta-1-glucopiranosil, 22-hydroxifurost-5-en-3-beta,
26-diol, 3-0-beta-diglucoramnoside.
6. Properties of the Preparation:
Pharmacological Effects, Mechanism of Action
Spermatogenesis is a complex process including
a proliferation of the spermatogonia, a long-term
process of tissue division (meiosis) and multiple
cytological alteration of the spermatids during
their proliferation. The effect upon the germ cells
may be realized either during their reproductive
period (a mitotic division of the spermatogonia),
or during the maturation of the spermatocytes. The
effect of the preparation upon the division and
maturation of the germ cells has been investigated
by means of a series of quantitative cytological
methods in rat testes. Tribestan considerably increases
the number of spermatogonia, spermatocytes and spermatids
in rat testes without producing any effect upon
the diameter of the seminiferous tubules whatsoever.
The effect of the preparation upon the DNA synthesis
in the germ cells is a significant one and shows
an increase of the spermatogonia in the S-period
of the animals treated. In parallel, an enhanced
number (measured by density) of the Sertoli cells
in the rat testes has been observed (a 40% increment).
The cytological investigations show no difference
in the Leydig cell numbers between the experimental
and control animals.
The oral administration of the preparation results
in an intensification of the spermatogenesis and
an improvement of the spermatozoa quality in sexually
mature rats. It enhances the percentage of the mobile
spermatozoa, improves their motion characteristics
and simultaneously prolongs their viability period.
Tribestan stimulates the sexual behavior (libido
sexualis) when administered to male animals (boars).
The effect of the preparation upon the serum
concentration of hormones produced by the pituitary-gonadal
axis is expressed in an enhancement of the Lutenizing
hormone and testosterone levels following the oral
administration to healthy men. FSH (follicle-stimulating
hormone) is not affected.
In women, FSH and estradiol serum concentrations
are elevated by the preparation while testosterone
is only mildly affected. The results show that the
preparation has an effect upon the pituitary-gonadal
axis hormones but it does not interfere with the
hormonal balance of the body at all. This peculiarity
enables the administration of Tribestan as a reproductive
function-stimulating agent.
So far, the mechanism of action of Tribestan
remains vague. Following clinical trials, Koumanov
et al (1982) launched the hypothesis of a central
effect of the preparation as prompted by the elevated
Lutenizing hormone level. Alternatively, Tribestan
may realize its effects by being metabolized in
the body into androgen-like products or stimulating
the physiological transformation of testosterone
into dehydrotestosterone (DHT), androstenediol or
estrogens. There exists a possibility that Tribestan
may exert a direct action on the hypothalamus and
maybe also upon other superior brain structures.
On the other hand, a peripheral effect is assumed
to be present as well; most probably, it produces
the effect of the preparation on the pelage. The
treatment of patients suffering of a secondary hypogonadism
is associated with an enhanced axillary and genital
pelage. The increased quantity of DHT is related
to it as well.
The reduction of serum cholesterol under the
action of the preparation provided the ground for
the same investigators (Koumanov et al., 1982) to
assume that it affects the cholesterol metabolism.
In men, Tribestan exerts a complex action:
- it stimulates the libido and
improves the spermatogram;
- it increases the ejaculate volume by 1 - 2 ml,
enhances the spermatozoa concentration by 30 millions/ml,
increases the mobile spermatozoa by 30%.
An important feature in the pharmacodynamics
of Tribestan is the evidence that the preparation
regulates the body hormonal balance without any
interference with its functional mechanisms.
7. Pharmacokinetics: Absorption,
Distribution, Elimination
The pharmacokinetic evidence about Tribestan
is based on the investigation of N. Dikova and V.
Ognyanova (1981) in albino Wistar rats.
Their results show the active substance of protodioscine
to be rapidly eliminated away from the plasma since
its concentration at the 180th minute is insignificant.
The tests investigating the 24-hour excretion
of Tribestan show that 12 and 14% of the preparation
is being excreted with the bile whereas the urinary
excretion of Tribestan is about 6 and 7% for 50
and 200 mg/kg b.m. single I.V. administered doses
respectively. Following oral administration of the
same doses of Tribestan, a considerably smaller
quantity of protodioscine is being excreted with
the bile over 24 hours in rats - from 2 to 5% of
the administered dose. Following oral administration,
no measurable concentration of any unaltered protodioscine
was detected with the 24 hour urine.
The experimental evidence obtained show that
the hepatic excretory route is the preferred one
for the excretion of Tribestan as unaltered protodioscine.
It may be assumed that protodioscine participates
in the enterohepatic cycle of rats.
The rapid elimination of protodioscine away from
the plasma, as well as the lower percentage of the
excreted unaltered protodioscine in relation to
the doses administered, supports the opinion that
protodioscine undergoes an intensive biotransformation
within the body.
8. Indications
In men: an impotentio coeundi in Klinefelter
syndrome, a varicocele, a cryptorchism, a hypotrophy
of the testes, the Noonan syndrome, an idiopathic-azoospermia-based
sterility.
The evidence of M. Protich's clinical trial of
Tribestan treatment of male sterility (1981) established
that the preparation exerted a stimulating effect
upon spermatozoa mobility in men suffering of an
idiopathic oligoasthenozoospermia as well as in
men undergone an internal testicular vein resection
as a varicocele treatment. The following investigated
parameters were of a major significance: the increased
ejaculate volume by 1 - 2 ml, the enhanced spermatozoa
concentration by 30 millions/ml, the 30% increment
of the mobile spermatozoa. In patients with an idiopathic
oligoasthenozoospermia, the average mobile spermatozoa
number in the test group prior to treatment was
29% whereas it reached 36.^% following the treatment.
The velocity of the spermatozoal motion prior to
treatment was 1.95 mm/sec whereas it reached 3.76
mm/sec following the therapy.
The treatment of patients with an unilateral
or bilateral hypotrophy of the testes associated
with the spermogram disorders is of a definite interest.
Following a 60-day Tribestan treatment, the libido
augments and spermogram improves. In patients with
a primary or secondary hypogonadism, there is a
libido recovery and enhancement, and an improved
and prolonged erection following the administration
of the preparation.
The patients treated for one of several forms
of male hypogonadism (Klinefelter syndrome) due
to a chromosomopathy (supernumerary chromosomes)
reported an increased libido whereas erections were
registered, and coituses and masturbation were practiced
by two patients. An increment of the Lutenizing
hormone was measured in these patients. The quantity
of the other hormones and cholesterol was reduced.
The treatment of patients with a high gonad insufficiency
(Noonan syndrome) resulted in an improved libido,
appearing erections, a genital pelage and an improved
self-confidence.
The results of treatment of patients suffering
of a cryptorchism showed an improved libido and
a more frequent masturbation practice.
In patients of different nosologic groups, the
testosterone rose from the lower to the upper normal
range limit. In patients having a subnormal pretreatment
testosterone level, the hormone reached the physiologic
levels whereas in cases with normal pretreatment
values of the testosterone level changed insignificantly
following treatment.
In conclusion, it may be summarized on the base
of the clinical trials carried out so far that Tribestan
possesses a very good therapeutic effect on all
forms of impotentio coeundi et generaldi in men.
It showed a very good therapeutic effect in the
idiopathic oligoasthenospermia as well. The preparation
is distinguished for its very good tolerance and
a lack of any adverse drug reactions whatsoever.
In women, the treatment with Tribestan is indicated
in frigidity, endocrine ovarial sterility, climacteric
and postcastrational syndrome with marked vasomotor
and neurasthenic manifestations.
The evidence of P. Tabakova, M. Dimitrov and
B. Tashkov's clinical trial of Tribestan in women
suffering of a climacteric syndrome (19..) established
a complete or quasi-complete relief of all or most
of the symptoms in 98% of the treated patients.
The disappearance of the neurovegetative and neurophsychic
manifestations, and of some complaints related to
the cardiovascular system as well, explains the
considerable rise of libido sexualis in almost 2/3
to 3/4 of the treated women as well. In this case,
the effect of Tribestan is equivalent, and sometimes
- even superior, to the effect of the estrogen-testosterone
hormonal preparation Ambosex. In addition, the frequent
adverse drug reactions (for Ambosex) as a virilization
and a weight gain tendency are not present when
Tribestan is administered.
The preparation can be used with a success to
treat the natural or an artificial postmenopausal
syndrome in women as well. The administration of
Tribestan to treat sterility mostly in women, but
very often in men as well, is recommended in cases
of impaired gamete formation due to stress situations,
a long-standing sterile life, an impaired or absent
libido, and any other causes resultant in an anovulatory
menstrual cycle, dyskinetic Fallopian tube changes,
and/or qualitative alterations of the sperm (in
men).
The mechanism of action is a complex one: the
hormonal stimulation of the ovulation is being combined
with an enhanced libido and an improved general
and psycho-emotional state of the sterile pair,
particularly when conforming to our recommendation
Tribestan to be taken by the husband as well.
The combination of Tribestan with any appropriate
hormonal preparations results in a potentiation
of its positive effect providing the ground for
its administration in the routine therapy of sterility.
9. Dosage and Mode of Application
In men: The dosage and duration of treatment
are being determined by the character and severity
of the illness. Most often, the dose is 1 - 2 tablets
of 250 mg 3 times a day with meals. The duration
of the therapy in the case of impotentio coeundi
should be at lease 40 - 50 days.
It is known that a period of at least 80 days
is needed between the spermatogonial division and
the formation of a mature spermatozoon. This imposes
the necessary minimal therapeutic cycle in the case
of sterility to be a complete germinative cycle
of spermatogenesis, i.e. 80 - 90 days.
In women: The treatment is strictly individually
adjusted and depends upon the severity of the illness.
The usual dose is 1 - 2 tablets of 250 mg 3 times
a day with meals. In the case of sterility, the
preparation is administered from day 1 to day 12
of the menstrual cycle. The combined administration
of Tribestan with ovulation stimulating preparations
in the sterile female patients results in a better
effect.
The treatment should be strictly individually
realized in postcastrational and climacteric syndrome.
Nevertheless, there are some guidelines to follow:
1. Tribestan is usually prescribed
in a dose of 2 tablets 3 times per day for 20 days.
Thereafter, the dose is being reduced by 1 tablet
every 4 - 5 days to reach maintenance dose of 1
tablet 2 times a day whereas the term of treatment
depends upon the achieved effect.
2. Alternatively, Tribestan may also be administered
in a dose of 2 tablets 2 times per day for a 30-day
course with a following dose reduction to 1 tablet
2 times daily every 4 - 5 days.
3. Tribestan may be administered in a dose of 1
tablet 3 times a day continuously for a longer period
of time (up to one year).
10. Contraindications: none
11. Use during Pregnancy or
Lactation
The animal experiments showed that Tribestan
possesses a very low toxicity. No evidence of any
carcinogenic, embryotoxic and/or teratogenic effect
were found. However, the preparation must be discontinued
whenever a pregnancy is established.
12. Adverse Drug Reactions
None have bee observed so far.
All clinicians, engaged in the trials, report
a very good tolerance and an absence of any adverse
reactions related to the preparation. The clinical-laboratory
evidence in Tribestan treated patients or test animals
show no deviations of blood count, flocculation
tests and urine analysis.
13. Drug Interactions of Clinical
Significance
The combination of Tribestan with ovulation stimulating
hormones in sterile women results in a mutual potentiation
of the drug effects.
14. Cautions and Specific Warnings
In treatment of women with natural or an artificial
climacteric syndrome, the transition from the effect-achieving
to the maintenance dose must be gradually realized.
The abrupt reduction of the dose that achieved the
effect results in a renewed triggering of the whole
complex of climacteric signs and symptoms.
15. Overdose: Symptoms, Treatment
A special attention should be paid to the evidence
about the safety of the preparation. Under experimental
conditions, no evidence of any acute, subchronic
and/or chronic toxicity (behavioral, hematological,
functional, biochemical and/or morphologic investigations)
have been established whatsoever. There is no evidence
of any carcinogenic, teratogenic and/or embryotoxic
effect either.
The performed experiments showed that Tribestan
possesses no toxic effect upon the animals. In rats,
LD50 toxicity for intraperitoneal administration
is 750-mg/kg b.m. whereas for the oral administration
it is more than 10,000 mg/kg b.m. that is why, no
symptoms of overdose and/or toxicity have been observed
during the clinical trials.
16. Storage Conditions
Store at a controlled room temperature (15° -
30°C) and protect from direct sunlight.
17. How Supplied
Film-tablets of 250 mg active ingredient in a
package of 60 tablets.
REFERENCES
1. Vankov, S. Apropos of Tribestan pharmacology.
Scientific-technical Report, 1980.
2. Viktorov, Iv., D. Kaloyanov, Al. Lilov, L. Zlatanova,
Vl., Kasabov. Clinical investigation on Tribestan
in males with disorders in the sexual function MBI,
1982 (in print).
3.Gyulemetova, R., M. Tomova, M. Simova, P. Pangarova,
S. Peeva Apropos of Tribestan standardization. Die
Pharmazie, 1982, 37, 4.
4. Gendjeiv, Z. Studies on Tribestan carcinogenicity.
Scientific-technical report, 1981.
5. Dikova, N., V. Ognyanova. Pharmacokinetic studies
on Tribestan. Anniversary Scientific Session '35
Years Chemical Pharmaceutical Research Institute'
Sofia, March 22-23, 1983.
6. Ilieva, Z., Embryotoxic and teratological studies
on Tribestan. Scientific-technical report., 1981.
7. Koumanov, F., E. Bozadjieva, M. Andreeva, E.
Platonova, V. Ankov. Clinical trial of Tribestan.
Exper. Med. 1982, 2.
8. Milanov, S., E. Maleeva, M. Tashkov. Tribestan
effect on the concentration of some hormones in
the serum of healthy subjects (Company documentation).
9. Nikolov, R. Neuropharmacological Study on Tribestan.
Scientific-technical report, 1981.
10. Protich, M., D. Tsvetkov, B. Nalbanski, R. Stanislavov,
M. Katsarova. Clinical trial of Tribestan in infertile
males. Scientific-technical Report, 1981.
11. Tanev, G., S. Zarkova, Toxicological studies
on Tribestan. Scientific-technical Report, 1981.
12. Tomova, M., R. Gyulemetova, S. Zarkova. An agent
for stimulation of sexual function. Patent (11)
27584 A61K35/1978.
13. Kerr, J.B., D.M. de Krester. Cyclic variation
in Sertoli cell lipid content throughout the spermatogenic
cycle in the rat. J. Repod. Fertil., 1975, 43/1,
1-8.
14. Kruger, P.M., C.D. Hogden, K.I. Sherins. New
evidence for the role of the Sertoli cells and spermatogonia
in feed-back control of FSH-secretion in male rat.
Endocrinology, 1974, 95/4, 955-962.
15. Lacy, D. The seminiferous tubule in mammals.
Endeavor, 1967, 26, 101-108.
16. Leblond, C., P.Y. Clermont. Definition of the
stages of the cycle of the seminiferous epithelium
in the rat. Annals of the New York Acad. Sci., 1952,
55, 548-573.
17. Mancini, R.E., A.C. Seiguer. Histological localization
of the follicle stimulating and Lutenizing hormones
in the rat testes. J. Histochem. Citochem. 1967,
15/9, 516-526.
18. Tomova, M., R. Gyulemetova. Steroid saponins
and Steroidsapogenine VI. Furastanol bisglykosid
aus Tribulus terrestris L., Planta medica, 1978,
34, 188-191.
19. Tomova, M., R. Gyulemetova, S. Zarkova - License
(11) 27584 AGIR 35/1978.
20. Tomova, M., R. Gyulemetova, S. Zarkova at al.,
License 68428/18.I.1985.
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