 TRIBESTAN 1. Preparation trade name 1. Preparation trade name: Tribestan 3. Active Substance Generic Name (in English and Latin): Proprietary extract of the plant Tribulus Terrestris L. Bulgaricum. 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; 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. 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. 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. 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. Store at a controlled room temperature (15° - 30°C) and protect from direct sunlight. Film-tablets of 250 mg active ingredient in a package of 60 tablets. 1. Vankov, S. Apropos of Tribestan pharmacology.
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