[Gestagenic and contraceptive activity of new synthetic progesterone analogs in experimental animals].

The gestagenic activity of new 17alpha-hydroxyprogesterone analogs was studied in experiments on infantile female rabbits (Clauberg-McPhail assay) and ovariectomized animals (Comer-Allen assay). The new steroidal preparations produced significant secretory transformations in immature rabbit endometrium. The maximum gestagenic activity was observed for butagest, while the minimum effect was produced by duhydrogesterone (dufaston). Butagest, megestrol capronate, and AMOL isopropyl ester showed the ability to maintain pregnancy in ovariectomized female rabbits. The compositions of gestagens (0.8 mg/kg) with ethinylestradiol (0.04 mg/kg) produced high contraceptive effect in rats.

Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons.

We examined the interaction between ephrins and metabotropic glutamate (mGlu) receptors in the developing brain and cultured neurons. EphrinB2 coimmunoprecipitated with mGlu1a receptors, in all of the brain regions examined, and with mGlu5 receptors in the corpus striatum. In striatal slices, activation of ephrinB2 by a clustered form of its target receptor, EphB1, amplified the mGlu receptor-mediated stimulation of polyphosphoinositide (PI) hydrolysis. This effect was abolished in slices treated with mGlu1 or NMDA receptor antagonists but was not affected by pharmacological blockade of mGlu5 receptors. An interaction among ephrinB2, mGlu1 receptor, and NMDA was supported by the following observations: (1) the NR1 subunit of NMDA receptors coimmunoprecipitated with mGlu1a receptors and ephrinB2 in striatal lysates; (2) clustered EphB1 amplified excitatory amino acid-stimulated PI hydrolysis in cultured granule cells grown under conditions that favored the expression of mGlu1a receptors; and (3) clustered EphB1 amplified the enhancing effect of mGlu receptor agonists on NMDA toxicity in cortical cultures, and its action was sensitive to mGlu1 receptor antagonists. Finally, fluorescence resonance energy transfer and coclustering analysis in human embryonic kidney 293 cells excluded a physical interaction between ephrinB2 and mGlu1a (or mGlu5 receptors). A functional interaction between ephrinB and mGlu1 receptors, which likely involves adaptor or scaffolding proteins, might have an important role in the regulation of developmental plasticity.

[Experimental study of the antitumor properties of acetomepregenol]. / Eksperimental'noe issledovanie protivoopukholevykh svoistv atsetomepregenola.

Antitumor effect on hormone dependent tumors has been demonstrated following oral and parenteral treatment of mice and rats with a gestagenic drug -- acetomepregenol.

[Current trends in the diagnosis and therapy of colorectal cancer]. / Sovremennye napravleniia v diagnostike i lechenii kolorektal'nogo raka.

The report deals with the 30-year experience gained by the Department in the treatment of nearly 5,500 cases of tumors of large bowel. Radical surgery for colonic tumor was followed by lethality in 3.0 and 5-year survival-80.8%; rectal tumor resection-5.3 and 58.2%, respectively. Individually-tailored modalities have been devised for a spectrum of cases of colonic wall invasion and metastatic lesions in regional lymph nodes. A choice of sparing, extended and combined surgical procedures vis-a-vis these factors has been developed, the latter offering most advantage. Therapeutic strategies for hepatic metastasis have been worked out on individual basis.

[The effect of a peptide preparation made from ovaries on reproductive function]. / Vliianie peptidnogo preparata iz iaichnikov na reproduktivnuiu funktsiiu.

A study was done on the action of the low molecular peptide preparation isolated from cow ovaries by the acetic acid extraction, on the rat ovary function. It was revealed that this preparation: 1) does not possess the gonadotrophic activity; 2) enhances the sensitivity of immature rat ovaries to the human chorionic gonadotrophin; 3) increases the number of ovulating oocytes in neonatal androgenized rats in gonadotrophic stimulation of the ovary function; 4) does not influence the character and duration of the estrous cycle in intact adult rats.

[A rational surgical procedure in diffuse polyposis and multiple primary cancer against a background of polyps of the large intestine]. / Ratsional'naia khirurgicheskaia taktika pri diffuznom polipoze i pervichno-mnozhestvennom rake na fone polipov tolstoi kishki.

Under examination there were 292 patients. An analysis of results of treatment enabled the authors to conclude that surgical treatment of patients with diffuse polyposis of the colon is the method of choice. The method and volume of operations must be determined according to the involvement of the colon in polyposis, the age and state of the patients. The best method of surgery is a one-step radical operation-subtotal resection of the colon. Polyps concomitant to cancer of the colon should be ablated before the main operation since their histological analysis can change the volume of the planned radical operation. When choosing the method of surgical intervention for patients with primary-multiple cancer against the background of polyps the total portion of the colon with polyps should be ablated.

[The surgical treatment of polyps and early forms of cancer of the large intestine]. / Khirurgicheskoe lechenie polipov i rannikh form raka tolstoi kishki.

The article describes the present-day principles of surgical treatment of polyps and early forms of colorectal carcinoma appearing against their background. The investigation performed has shown that all benign adenomas of the colon can be successfully treated by local dissection. Sessile tumors located on the lower- and middle-ampullar portions of the rectum, are liable to endorectal dissection, in pedicular tumors endoscopic polypectomy is most expedient. In cases with carcinoma against the background of adenoma, the main criterion determining choice of the method of surgical intervention is the degree of ingrowth of the tumor into the colon walls. An analysis of long-term results of treatment shows that in carcinoma of the colon developing against the background of adenoma, local dissection is not inferior in efficiency to typical radical operations.

[3-phase-usage contraceptives]. / Kontratseptivy trekhfaznogo primeneniia.

The main trends of improving methods of usage of oral steroidal contraceptives are reviewed. The data characterizing the features of the pharmacodynamics of three-phase usage steroidal agents, their side effects are presented.

[Comparative study of the progestagenic action of 16 alpha, 17 alpha-cyclohexanoprogesterones (pregna-D'6-pentarans) when administered by different routes]. / Sravnitel'noe izuchenie progestagennogo deistviia 16 al'fa, 17 al'fa-tsiklogeksanoprogesteronov (pregna-D'6-pentaranov) pri razlichnykh putiakh vvedeniia.

A comparative study of the progestational activity of modified pentarans depending on the dose and the route of administration was carried out. It was shown that modification of the molecule of 16 alpha, 17 alpha-cyclohexanoprogesterones by introducing and additional double bond in positions 6, 7 and methyl group in position 6 provided a high gestational effect, being particularly pronounced at intramuscular administration.

[Relation of the progestagenic activity and conformation of the 17beta-acetyl side chain in the D'6-pentarane series]. / Zavisimost' progestagennogo deistviia v riadu pregna-D'6-pentaranov ot konformatsii 17beta-atsetil'noi bokovoi tsepi.

The synthesis of 2' beta-methyl-16 alpha,17 alpha-cyclohexanoprogesterone and its MM2 conformational analysis have been performed. The acetyl side chain was shown to have an unusual conformation with the torsion angle C13-C17-C20-O20 being -32.1 degrees. This conformation is by 5.4 kJ.mol-1 more stable than the usual one with the torsion angle 130.3 degrees. 2' beta-Methyl-16 alpha,17 alpha-cyclohexanoprogesterone proved to be inactive as a progestogen (pregnancy maintenance and McPhail tests). The lack of the activity may be due to the additional methyl group in D'-ring causing a change of the conformation of the 17 beta-acetyl side chain, thus hindering the formation of the conformation necessary for binding to the progesterone receptor.

[Prolonged-action contraceptives]. / Kontratsevtivy prolongirovannogo deistviia.

PIP: Various aspects of injectable prolonged-action steroid contraceptives are reviewed with special emphasis on the effectiveness of depo- medroxyprogesterone (depo-provera) and norethisterone enanthate (NE). Both preparations have progestogen activity. Depo-provera was 1st used for the treatment of endometriosis and threatened abortion. As a contraceptive, 150 mg depo-provera is given every 90 days (once every 3 months). NE is also given 200 mg during the 1st 5 days of a cycle; injections are repeated 2 months later and then every 3 months. The incidence of pregnancy following depo-provera use did not exceed 1/100 women-years. Clinical trials of NE indicated the incidence of pregnancy ranging from 1-3.6/100 women-years (depending upon drug administration schedule). The contraceptive effect of both depo-provera and NE was shown to be associated with inhibition of ovulation. The majority of women treated with depo-provera or NE developed various disorders of the menstrual cycle. Amenorrhea development was found to depend upon duration of administration, and was more frequent after depo-provera than after NE. Metabolic effects of depo-provera and NE included decrease in the blood level of cholesterol in high-density lipoproteins, and an increase in the fasting levels of glucose and insulin. Depo- provera did not affect liver function. Epidemiological studies did not show an increase in cancer incidence following the use of depo-provera. Restoration of fertility occurred about 5.5 months after termination of depo-provera administration. Injectable contraception recommended primarily in young women who want to increase the intervals between childbirths. Women older than 40 years should use other methods of contraception.^ieng

[The use of peptides for contraception]. / Ispol'zovanie peptidov s tsel'iu kontratseptsii.

PIP: Potential use of luteinizing hormone releasing hormone (luliberin) analogs as contraceptive agents is briefly reviewed. Physiological effects of luliberin are associated with calcium-dependent stimulation of secretion of pituitary gonadotropins. Synthetic analogs of luliberin were shown to have both agonistic and antagonistic properties. Biological activity of luliberin analogs depended upon their chemical structure. Substitutions in positions 6 and 10 led to creation of agonists, while antagonists were synthesized by substituting D-amino acids in positions 1,2,3 and 6. The most promising contraceptive properties were detected in luliberin agonists. Administration of luliberin agonists in large doses was shown to have a paradoxical, pituitary-medicated antifertility effect. Several luliberin agonists were found to have a direct inhibitory effect on steroidogenesis in ovarian and testicular cells. The contraceptive effect of the luliberin agonist HOE-766 was demonstrated in animal studies and in clinical trials. Following intranasal administration of HOE-766 (200-400 mcg/day, for 6 months and longer), 25% of women retained a normal menstrual cycle, while 50% had oligomenorrhea and 25% had amenorrhea. The use of agonists during an early follicular phase was shown to cause dysfunction of corpus luteum. Daily postovulatory administration of agonists caused decrease in blood progesterone levels but did not shorten the duration of luteal phase. Experiments in rats indicated that administration of luliberin agonists during the first 7 days or from day 8 to day 12 of pregnancy induced miscarriage. Peptides failed to induce miscarriage in women. Ability of luliberin analogs to inhibit testosterone secretion indicates that these substances can be used as male contraceptives.^ieng

[Clinico-laboratory research on the pharmacodynamic characteristics of Rigevidon]. / Kliniko-laboratornoe issledovanie osobennostei farmakodinamiki rigevidona.

A contraceptive effect of Rigevidon depends on the drug influence on cyclic secretion of gonadotropic hormones. Rigevidon fails to exert a significant effect on prolactin secretion. The drug withdrawal results in a comparatively rapid restoration (within the first three months) of the generative function.

PIP: The effect of the new combined oral contraceptive agent Rigevidon on the hypothalamo-hypophyseal-ovarian system was studied in 50 women (age not specified). Rigevidon was given for 21 days with subsequent 7-day interval. Duration of administration was 10-12 cycles. Functional state of the ovaries and gonadotropic function of the pituitary gland was evaluated by measuring the blood levels of estradiol, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). During Rigevidon administration in doses producing the contraceptive effect, all women showed the monophasic type of basal temperature. FSH levels on days 7-9 and 20-23 of cycle 3, 6 and 10-12 did not differ significantly from those in controls; there was a 2.8 times decrease FSH levels on days 14-16 of cycle 3 and a 3.8 times decrease on days 14-16 of cycle 10-12. Marked decrease in LH levels was observed on days 14-16 of cycle (5 times) and during the 6th cycle (9.2 times). Significant decrease in estradiol levels was recorded on days 7-9 and 14-16 of cycle 3,6 and 10-12. Progesterone levels were decreased significantly on days 7-9 and 20-23 of cycle 3, 6 and 10-12; significant decrease in progesterone levels on days 14-16 was observed only during cycle 3. Prolonged administration of Rigevidon (10-12 cycles) produced no changes in prolactin secretion. After cessation of Rigevidon administration, the LH and estradiol levels were decreased only on days 14-16 of cycle 1. The test with LH releasing hormone (100 mc) on days 12-14 after Rigevidon cessation showed normal sensitivity of the pituitary gland to hypothalamic stimulation. The results of this study indicate that the contraceptive effect of Rigevidon is associated with inhibition of ovulation and cyclic secretion of FSH and LH.

[Luliberin analogs--a new class of contraceptive agents]. / Analogi liuliberina--novyi klass kontratseptivnykh sredstv.

PIP: Pharmacological activity of endogenous luliberin and its analogs is reviewed with special emphasis on their potential use as contraceptive agents. The contraceptive effect of inhibitors of the hypothalamo-hypophyseal-ovarian system can be associated with the following: neutralization of endogenous luliberin in the portal system of the pituitary with antibodies; blocking of luliberin receptor with synthetic antagonists; and inhibition of the cyclic release of endogenous luliberin after prolonged administration of agonists. Experiments with immunological contraception showed that immunization of normal rats during early proestrus with antisera against luliberin caused complete inhibition of the preovulatory release of gonadotropins, prolongation of the diestrus phase, and blocking of ovulation. The maximum neutralization of luliberin was observed 2-3 months after immunization. The disadvantage of this method of contraception was a significant decrease of estrogen levels typical for the postmenopausal period. Depending upon the dose, timing of administration, and phase of the ovulatory cycle, synthetic luliberin can have a contraceptive effect (inhibition of luteotropin peak, decrease of plasma estradiol level, prevention of the rise of progesterone level during the 2nd half of the menstrual cycle, inhibition of the ovulation). Biological activity of various synthetic analogs of luliberin was found to depend upon the chemical structure. In general, substituting amino acids in positions 6 and 10 produced agonists, while substituting amino acids in positions 1, 2, 3, and 6 produced antagonists. Administration of luliberin antagonists (usually in mg doses) produced an antiovulatory effect via the decrease in the plasma levels of gonadotropins with subsequent inhibition of gonad function). Synthetic luliberin agonists in large doses have a "paradoxical" effect mediated via hypophysis, although certain agonists were found to have a direct inhibitory effect on the gonads.^ieng

[Progestagenic activity and the mechanism of the contraceptive action of mecygeprone]. / Progestagennaia aktivnost' i mekhanizm kontratseptivnogo deistviia metsigeprona.

Progestagenic activity of a modified analog of progesteron-6 alpha-methyl-cyclogexan-[1', 2', 16 alpha, 17 alpha]-pregn-4-en-3,20-dion including into mecygepron composition has been studied; its activity is proved to be 5 times as great as that of progesteron at any way of administration. Mecygepron affects processes of ovogenesis and early embryogenetic development in rats. A decreased number of washed out embryos is observed, while the number of lutein bodies specific for intact rats remains the same, decelerated rate of cleavage and increased number of unfertilized ova. In the mechanism of the changes observed an essential role plays a decreased secretion of lutropin resulting in a prolonged estrol cycle and, evidently, in intrafollicular overmaturation of the ova, which loose their ability to be fertilized. Besides, the disturbed hormonal balance under mecygepron influence can affect the character of the oviduct and uterine contents and, thus, prevent the normal development of the fertilized gametes.

[Experience of the use of histoautoradiography in vitro, using 3H-thymidine, for assessing the degree of radiation damage to rectal adenocarcinoma]. / Opyt ispol'zovaniia gistoavtoradiografii in vitro s 3H-timidinom dlia otsenki stepeni luchevogo povrezhdeniia adenokartsinom priamoi kishki.

In vitro thymidine histoautoradiography was employed to measure labeling index in 18 moderately- and well-differentiated adenocarcinomas of the rectum before and after radiotherapy. After radiation labeling index fell from 13.8 +/- 3.2 to 3.9 +/- 1.4% while mitotic index--from 8 to 1%.