Experimental Evaluation of Long-Term Toxic Effects of Methotrexate on Male Reproductive System.

The morphological and functional state of the reproductive system was studied in male outbred rats (SD stock) and male F1(CBA×C57BL/6) mice after long-term (3 months) methotrexate administration. The drug was administered subcutaneously once a week for 4 weeks, the dose for male rats was 1 mg/kg, for male mice 2.2 mg/kg. It was found that male rats retained the ability to conceive, their reproductive potential was not limited by increased risk of embryo death. At the same time, signs of astheno- and pathospermia were revealed. The testicular tissue was characterized by reduced content of the sources of the proliferative pool of spermatogenesis. In mice treated with methotrexate, increased content of DNA breaks was detected in the testicular cells.

Reproductive Toxicity of Theobroma cacao: Increase in Survival Index, Nongenotoxic, and Proimplantation Potential.

Unsweetened natural cocoa (UNCP) was evaluated for reproductive toxicity in rats. A preliminary genotoxic potential was evaluated by the DNA comet assay test using C57Bl/6 mice. Both therapeutic dose (TD; 900 mg/kg) and high dose (HD; 9000 mg/kg) of UNCP were used. White Wistar rats were used in two experimental groups. The females received UNCP 15 days before crossing with untreated males. The males received UNCP for 48 days before mating with untreated females. Subacute toxicity was observed during a 14-day oral administration of UNCP. Results show that a high tail DNA% was observed with methyl mesylate administration in all tissues analysed. The lowest tail DNA% value was observed in the liver (1.64 ± 0.26) and kidney (1.63 ± 0.30) during UNCP (TD) administration. UNCP did not induce observable physical congenital malformations on the pubs of treated female and male rats, lacks genotoxic potential, and did not adversely affect pregnancy index, pub weights, and survival index, but UNCP exhibited proimplantation potential (p > 0.05).

Effectiveness of Phenolic Antioxidants in Experimental Model of Benign Prostatic Hyperplasia.

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.

Experimental Study of the Effectiveness of Phenolic Antioxidants in Male Infertility Caused by Pathospermia.

The effect of phenolic antioxidants (dihydroquercetin, p-tyrosol, dibornol) on the morphology, functions, and redox processes in the reproductive cells of male rats was studied on the model of experimental pathospermia. All antioxidants reduced the percentage of degenerative forms of spermatozoa. Dibornol was most effective. Dihydroquercetin and p-tyrosol did not increase the total number of spermatozoa and the percentage of their mobile forms. These indicators were improved only by dibornol. After administration of all test drugs, the antioxidant potential of spermatozoa increased and did not significantly differ from the baseline values.

Experimental Assessment of the Effect of Kagocel on Reproductive Function in Pubertal Male Rats.

We studied possible toxic effects of antiviral drug Kagocel on reproductive function in pubertal male rats. The drug was administered in therapeutic and 10-fold higher doses throughout the spermatogenesis cycle (48 days). Kagocel did not reduce mating and fertilizing capacities, did not suppress spermatogenesis, and had no toxic effects on the offspring. The results characterize Kagocel as a drug with a broad reproductive safety profile and demonstrate that the age limits for using Kagocel in pediatric practice can be extended.

Effect of Granulocyte Colony-Stimulating Factor Immobilized by the Electron-Beam Synthesis Nanotechnology on Reparative Regeneration of Spermatogenous Tissue.

Effectiveness of the granulocyte colony-stimulating factor immobilized by using electronbeam synthesis nanotechnology was investigated on the model of experimental testicular failure caused by the toxic effect on stem spermatogonia. Administration of the drug to experimental paclitaxel-treated animals increased the number of sources of the proliferative pool of spermatogenesis and its productivity. The effectiveness of immobilized granulocyte colony-stimulating factor was based on its ability to stimulate reparative regeneration of the spermatogenic tissue, which manifested in a decrease in spermatogenic layer maturity and increase in the number of microenvironment cells. Effectiveness of the immobilized form of the drug was superior to that of non-immobilized form.

Responses of Spermatogenous Tissue and Mechanisms of Their Development Upon Cytostatic Exposure.

A decrease in the total number of sperm cells and reduction of spermatogonium population were observed upon cytostatic damage of spermatogenous tissue caused by single paclitaxel administration. It was established that the paclitaxel-induced damage to the testicular tissue is underlain by reduction of its regenerative potential consisting in depletion of regional precursor pool. Changes in functional activity of progenitor cells were caused not only by direct action of paclitaxel, but also by suppression of the secretory function of the tissue microenvironment.

Dihydroquercetin effects on the morphology and antioxidant/prooxidant balance of the prostate in rats with sulpiride-induced benign hyperplasia.

A course of dihydroquercetin (antioxidant) injections to 5-month-old Wistar rats with sulpiride-induced benign prostatic hyperplasia led to reduction of proliferative activity in the glandular structures and to attenuation of the inflammatory reaction in the tissue. Prostatic antioxidant/prooxidant balance returned to normal after the treatment.

Pharmacological stimulation of the regenerative capacity of rat testes damaged by paclitaxel.

Productivity of spermatogenesis and the population of spermatogonial cells were substantially reduced in male Wistar rats 3 months after administration of cytostatic drug paclitaxel, damaging stem spermatogonia. However, signs of reparative regeneration appeared in the testicular tissue. In animals receiving paclitaxel in combination with granulocyte CSF, the same period of observation, the number of spermatogonia and the efficiency of spermatogenesis at the same terms of the study did not differ from those in intact animals. Intensive recovery processes started 1 month earlier than after administration of paclitaxel alone. These data attest to pronounced potentiating effect of granulocyte CSF on reparative regeneration of the testicular tissue.

Mechanisms of reparative regeneration of rat testis after injection of paclitaxel.

Population of spermatogonia was reduced in 2, 3, and 6 months after single intravenous injection of antitumor drug paclitaxel in maximum tolerated dose (MTD). The count of Sertoli cell increased in 3 months after the start of the experiment. The maturity of the seminiferous tubule epithelium was lower than in intact rats. Spermatogenesis productivity did not differ from that in intact animals 6 months after start of the experiment. These data indicate that regeneration of the spermatogenous tissue after paclitaxel treatment is realized via renewal of the spermatogenic epithelium, but considering the amount of spermatogonial cell population, the recovery rate would be low.

[An experimental study of the effectiveness of the drug afalaza in chronic aseptic prostatitis].

A pilot study evaluated the efficacy of the drug afalaza (mixture of affinity purified antibodies to PSA and endothelial NO-synthase) compared with the Serenoa repens extract in a model of chronic abacterial prostatitis in Wistar rats caused by suturing of prostate tissue by silk thread. Except for the animals of intact group, rats (n = 13 in each group) underwent intraperitoneal injection of distilled water (10 ml/kg), afalaza (at a doses of 5, 7.5 and 10 ml/kg) or an Serenoa repens extract (50 mg/kg) 1 month after surgery for 45 days. After infusion, the mass, volume, and prostate weighting factor were evaluated, and prostate tissue was examined histologically. 2.5 months after surgery, development of chronic abacterial prostatitis was observed in the control group. Compared with intact group, significant increase in weight, weighting factor, and volume of prostate were detected in control group. Against the background of administration of Serenoa repens extract and afalaza, these parameters were not significantly different from control values. The use of Serenoa repens extract prevented the development of atrophic processes and slowed the development of sclerotic processes. Administration of afalaza at all studied doses prevented the development of sclerotic changes, and a dose of 7.5 ml/kg prevented the development of atrophic processes with the effectiveness matching to Serenoa repens extract. Taking into account the high safety of afalaza, this drug is a promising treatment for chronic prostatitis.

Comparative evaluation of the efficiency of prostatotropic agents of natural origin in experimental benign prostatic hyperplasia.

Comparative evaluation of the efficiency of prostatotropic agents was carried out in rat experiments. Serenoa repens plant preparation and polypeptides isolated from the cattle prostate were used for the treatment of benign hyperplasia. Drugs in parallel with sulpiride similarly led to shrinkage of the acinar epithelial area and to emergence of a trend to an increase of the stromal/epithelial proportion, more so after Serenoa repens treatment.

Experimental study of the efficiency of impaza on the model of chronic aseptic prostatic inflammation.

We compared the efficacy of Impaza (antibodies against endothelial NO-synthase in ultra-low doses) and Serenoa repens on the rat model of chronic aseptic prostatic inflammation. Administration of Serenoa repens in a dose of 50 mg/kg for 1.5 months prevented the development of prostate sclerosis and increased luminal area, but did delay the development of atrophic processes. In animals treated with Impaza (3 ml/kg for 1.5 months), atrophic changes in the prostate gland were practically absent. These findings indicate that Impaza can be used in complex therapy of abacterial prostatitis.

Modification of sulpiride model of benign prostatic hyperplasia for evaluation of the effectiveness of drug therapy.

Specific effects of ultra-low doses of antibodies to prostate-specific antigen obtained from laboratory rats of late reproductive age with sulpiride model of benign prostatic hyperplasia were compared with the results of clinical application of the preparation. Clinical reproducibility of experimental data was proven, which suggests that the developed model is adequate for pilot testing of the effects of pharmacotherapy of this disease.

[Influence of taxan-containing cytostatic preparations on the progeny].

In experiments designed to study effect of taxan-containing agents on the progeny of Wistar rats, one of the parents was given a single intravenous injection of the antineoplastic drug paclitaxel 1, 3 and 6 months before crossing with the untreated partner. The number of systemic pathological changes in the off-springs of paclitaxel-treated females was significantly greater and their spectrum wider than in those of the treated males. Severity of toxic effects depended on the time of crossing after drug administration. The optimal time for obtaining less affected off-springs of treated females and males was 3 and 6 months after administration of paclitaxel.

The stage of offspring of female rats after treatment with cytostatics of various groups.

We examined the offspring of female rats that were mated with intact males in the delayed period after administration of cytostatic drugs Farmorubicin, platidiam, carboplatin, etoposide, and paclitaxel (1, 3, and 6 months post-treatment). Toxicity of these drugs in the offspring decreased in the following order: paclitaxel > etoposide > carboplatin > platidiam > Farmorubicin. The toxic effect depended not only on the type of cytostatic treatment, but also on the period of conception.

Effect of vepeside on the function of reproductive system in rats.

Experiments on adult rats showed that a single intravenous injection of antitumor drug vepeside in a MTD (maximum tolerable dose) reduced the reproductive status during periods corresponding to exposure of mature sex cells, spermatocytes, and spermatogonia in male rats and exposure of oocytes in ovulating, mature, and primordial follicles in female rats. Reduction of the male and female reproductive function manifested in increased antenatal mortality of the progeny. The toxic effects of the drug on mature male sex cells caused temporary partial infertility.

Morphological and functional state of rat ovaries in early and late periods after administration of platinum cytostatics.

Experiments on Wistar rats showed that cisplatin and carboplatin induced similar morphological alterations in the ovaries. Both agents reduced the number of structural and functional elements, but the effect of cisplatin was more pronounced. Morphological changes observed in the early period after injection of the preparations were accompanied by prolongation of the estrous cycle, which was longer in rats treated with carboplatin. Partial and reversible sterility was observed in females at the early terms after cisplatin treatment.

Status of the progeny of rats treated with platinum-containing cytostatics.

Wistar rat pups from rats treated with first- and second-generation platinum-containing cytostatics (platidiam, carboplatin) 1, 3, and 6 months before mating with intact partners had similar disorders. The severity of these disorders depended in many cases on the chemical structure of the drug and sex of the parent treated with the cytostatic. The severity of toxic effects in the progeny of intact females mated with cytostatic-treated males decreased with prolongation of the period elapsing between the treatment and mating. Carboplatin produced a more potent toxic effect on the reproductive function of rats compared to platidiam.

[Preclinical toxicological study of ecorsin]. / Doklinicheskoe toksikologicheskoe izuchenie ékorsina.

A new drug preparation ecorsin based on the dry aspen bark extract was studied for toxicological safety on a preclinical stage. The drug exhibited no toxicity upon a single administration to rats and mice (both male and female). The intragastric administration of ecorsin for 3 months to rats (at a daily dose of 50, 250, and 500 mg/kg) and rabbits (25 and 50 mg/kg) led to neither functional not morphological changes in hemopoietic and lymphoid organs, liver, kidney, heart, digestive system, and CNS. The long-term administration resulted in a partial atrophic modification of convoluted seminiferous tubules in impuberal male rats, while not affecting the testes of aged animals. The administration of ecorsin at 50, 250, and 500 mg/kg led to dose-dependent changes in some characteristics of the reproductive capacity in rats. Ecorsin did not modify the extent of allergic reactions and produced no immunotoxicant and mutagen effects.