[Our and foreign experience in surgical staging of early ovarian cancer].

AIM: The aim of our research work was to assess the influence and effect of pelvic and paraaortic lymph node excision as well as peritoneal biopsies as part of the surgical staging in early ovarian cancer. We tried to evaluate the free of disease survival rate and the overall survival rate in patients with early ovarian cancer treated surgically without adjuvant chemotherapy MATERIAL AND METHODS: We assessed 460 patients operated for early ovarian cancer without adjuvant chemotherapy. The researched period included 1995-2011. Our experience was compared with the foreign experience in the this field. We evaluated 153 patients for whom lymph node sampling or partial pelvic and paraaortal lymph node dissection was performed together with peritoneal biopsies. For the other 307 patients lymph node sampling, partial lymph node dissection and peritoneal biopsies were not performed. There was no difference between the groups of patients according to stage, tumor grading and histological types. RESULTS: We experienced better overall and free of disease survival rate for patients with lymph node sampling, partial dissection and peritoneal biopsies (153 patients) compared to the rest of the patients (307 patients). The five years free of disease survival rate was 82% in the group of patients surgically staged by lymph node sampling, partial resection and peritoneal biopsies (125 p.), compared to 62% in the other group of the patients (190 p.). The overall survival rate in the first group of patients was 90% (138 p.) while for the other group of patients was 68% (209 p.). The recurrences rates were 16% (24 p.) in the group correctly surgically staged (by lymph node sampling, partial lymph node dissection and peritoneal biopsies) compared to 40% (123 p.) for the other group of the patients. CONCLUSIONS: In our research work we found statistically significant differences between the patients correctly surgically staged (pelvic and paraaortal lymph node sampling, partial lymph node dissection, peritoneal biopsies, subdiaphragmatical biopsies) compared to patients, who were not surgically staged. Our results are comparable to the results of the best western clinics and scholars, working in this field.

[Modern tendencies in treatment of endometrial cancer].

AIM: We tried to summarise our and foreign experience in the modern treatment of endometrial cancer. MATERIAL AND METHODS: We evaluated for 10 years period 400 patients treated surgically, as well as treated with postoperative radiotherapy. We tried to give the allgorhythm for treatment of this kind of cancer. All patients with grading 3 tumors, serous-papillary and clear cell endometrial cancers are obligatory are staged surgically. In some of our patients we performed pelvic lymph node dissection with or without paraaortal dissection which brought a more precise information. RESULTS: In patients with pelvic and paraaortal lymph node dissection (200) we had significantly better overall survival rate (p = 0.0003), as well as better survival rate both in low risky and high risky groups (low risky groups p = 0.028, high risky groups p = 0.0007). CONCLUSIONS: The therapeutic benefit of this method is in resecting of the enlarged, positive lymph nodes, which can not be sterilized with radiotherapy. The postoperative intravaginal and percutaneous radiotherapy save these patients from vaginal recurrences.

[Our experience in the surgical treatment of advanced endometrial cancers].

AIM: Our aim was to summarise our experience in the surgical treatment of advanced endometrial cancers for 20 years period. MATERIAL AND METHODS: The patients were treated surgically by extrafascial hysterectomy, radical hysterectomy with pelvic and paraaortal lymph node dissection, by pelvic exenteration and by cytoreductive surgery (350 patients). The radical hysterectomy was applied in patients with stage II endometrial cancer. RESULTS: When cytoreductive surgery was used, we observed difference in the five years survival rate when the residual tumour was < or = 2 cm and > 2 cm in diameter. Better survival rate was observed in the first group with < or = 2 cms in diameter. The five years survival rate in patients treated with radical hysterectomy versus patients treated by extrafascial hysterectomy was 89% vs.68%. In patients with pelvic and paraaortal lymph node dissection the survival was 69%, while in patients only with pelvic dissection was 38%. According to our results the aggressive cytoreductive surgery betters the survival in endometrial cancer stage III-IV. CONCLUSIONS: The improvement in the adjuvant therapy may give an additional light in the treatment of advanced endometrial cancers. The radical hysterectomy with pelvic and paraaortal lymph node dissection improves significantly the overall survival rate of these patients. The optimal cytoreduction also leads to improvement of the survival in patients with advanced endometrial cancers.

[Modern tendencies in HRT of patients treated for endometrial cancer].

AIM: Our aim was to evaluate the effect of HRT on endometrial cancer patients MATERIAL AND METHODS: We applied HRT in 250 patients-locally (cream) and in 300 patients in other routes and doses-tablet form, estradermal form, implant form. The research and the follow up were done for 10 years period. RESULTS: When we applied unopposed estrogen (0.3 mg) we had 5 fold increase in the risk of endometrial cancer. The application of local cream with low doses estrogen did not increase the risk of endometrial proliferation and the development of endometrial cancer. The addition of progestogens for 10-14 days led the patients to lower risk of endometrial cancer development. Applying Tibolone lowered the risk of endometrial cancer and had a protective effect on the endometrium. CONCLUSIONS: The application of progestogens for 10-14 days reduced the risk for endometrial cancer and had a protective effect on the endometrium. The HRT was mostly applied in early endometrial cancer grade 1,2.

[Preoperative and intraoperative evaluation of myometrial invasion in endometrial cancer by progesterone-challenge test, CT scan, magnetic resonance imaging, PET scan and intraoperative visual evaluation and Frozen section].

AIM: Our aim was to compare the diagnostic value and accuracy of progesterone-challenge test combined with TVS, CT scan, MRI, Pet scan and Visual and histologic evaluation (Frozen section) for assessment of Myometrial invasion of the endometrial cancer. METHODS: Our research work includes 300 patients with endometrial cancer for the period of 1999-2009. All of them were found by Progesterone challenge test combined with TVS, Collor-doppler sonography, who additionally were examined by CT MRI and Pet scan. In the time of surgery was evaluated visually and histologically the Myometrial invasion of the tumor: a) As superficial cancer b) Infiltration up to 50% c) Infiltration more than 50% of the myometrium. Frozen section was also performed, which gave the final diagnosis of the infiltration in the myometrium. RESULTS: The Progesteron-challenge test combined with TVC, CT scan, MRI, Visual assessment and Frozen section did not give significant differences in assessment of the depth of myometral invasion. A small advantage we detect in the frozen section evaluation without strong statistical significance. The positive value of the intratumor blood flow was higher in deep myometrial invasion without any statistical significance. The median level of RI index was lower in patients with deep myometrial invasion. CONCLUSIONS: The Progesterone-challenge test combined with TVS is a cheap, easily performed and repeated technique for evaluation of deep myometral invasion in endometrial cancer patients. The CT scan, MRI and PET scan we offer in patients with bad quality of TVS. The Visual evaluation and Frozen section help additionally the diagnosis of myometrial infiltration in endometrial cancer patients.

[Clinical application of Bionect (Hyaluronic Acid Sodium Salt) in wound care by cesarean section and episiotomy].

UNLABELLED: Hyaluronic acid is an important component of extracellular matrix and plays crucial role in wound healing by stimulation of neutrophil migration, fibroblasts proliferation and neoangiogenesis. OBJECTIVE: To study the efficacy of topical application of of Bionect (Hialuronic Acid Sodium Salt) in wound care in cases of episiotomy and cesarean section surgical wounds. MATERIALS AND METHODS: 27 patients, delivered by cesarean section and 20 patients with vaginal delivery with episiotomy were included in a prospective study. In 15 cases from cesarean section group and 10 cases from episiotomy group daily application of Bionect was performed. Standard wound care was applied in 12 cesarean section wounds and 10 episeotomies. All patients were monitored for wound healing disturbances on daily basis. RESULTS: The incidence of edema, infiltration, exudation and superficial blood collections was significantly lower in cases of Bionect application. No wound dehiscence was observed in cases, in which Bionect was used for wound care. One partial episiotomy dehiscence (10%) and one total cesarean section wound dehiscence were observed in standard wound treatment group. Excellent results in patients, treated with Bionect makes it a reasonable wound care option, especially in cases, when wound complications are expected.

Optical plastic refractive measurements in the visible and the near-infrared regions.

Some new refractometric results are obtained in the visible and the near-infrared spectral regions. The main optical plastics are analyzed: poly(methyl methacrylate), polystyrene, polycarbonate, and styrene acrylonitrile. New materials, such as methyl methacrylate styrene copolmer, CTE-Richardson, Zeonex, Optorez, and Bayer are examined. The refractive indices are measured for wavelengths from 435.8 to 1052 nm with a new device. Abbe constants and dispersion coefficients are calculated. The measured and computed data is intended for designers and technologists.

Effects of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride on acute gastric lesions, acid secretion in rats and on some hemodynamic parameters in cats.

The effectiveness of 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (AN12) on acute ulcer models and gastric acid secretion in rats was compared with the action of the histamine H2-receptor antagonist roxatidine (R). AN12 or R given orally, produced significant, dose-dependent decreases in stress- and indomethacin-induced ulcers. The ED50 value of AN12 and R were 0.40 (0.27-0.60) and 13.27 (9.13-19.29) mg/kg, respectively, for stress ulcers and 0.68 (0.17-2.61) and 25 mg/kg, respectively, for indomethacin ulcers. The length and number of ethanol-provoked gastric damages were significantly reduced by R (50 and 100 mg/kg p.o.) but not by AN12 (0.5-2 mg/kg p.o.). In pylorus-ligated rats, AN12 (2 mg/kg p.o.) and R (50 and 100 mg/kg p.o.) significantly inhibited basal gastric acid secretion, increased pH and decreased acidity. The influence of AN12 (2 mg/kg) on the volume of stomach juice was close to that of R (100 mg/kg), AN12 (0.1-1.0 mg/kg i.v.) did not significantly affect the hemodynamics of anesthesized cats. It is suggested that the influence of some CNS amine neurotransmitters may be included in part, in the effects of AN12.

Effect of roxatidine bismuth citrate (MX1) against acetylsalicylic acid- and indomethacin-induced gastric mucosal damage in rats.

We have studied the effect of the newly synthesized agent, roxatidine bismuth citrate (N-[3-(3-(1-piperidinyl-methyl)phenoxy)propyl]-hydroxyacetamide-2- hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex), code name MX1, against acetylsalicylic acid (ASA)- and indomethacin-induced gastric mucosal damage in rats. Effects of MX1 (12.5, 50, 125, 184, 250 mg/kg) were compared to the effects of equimolar doses of roxatidine and bismuth subcitrate. Effect of MX1 (10(-6) M) on mucin biosynthesis measured by [3H] glucosamine incorporation in rat gastric corpus has been determined. MX1-pretreatment dose-dependently decreased the mean ulcer number and length in all doses used in an extent similar to that of roxatidine and more pronounced in comparison with bismuth subcitrate. The morphometrical results have been confirmed histomorphologically. The biosynthesis of mucin was found to be significantly enhanced after MX1 addition. The results of the present study suggest that MX1 has a gastroprotective effect against ASA- and indomethacin-induced ulcers which might be due both to its H2-blocking and mucus-stimulating activity.

Gastroprotective effect of MX1 (a novel salt of the active metabolite of roxatidine with a complex of bismuth and citric acid) against stress ulcers in rats.

We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ -2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization). The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg-1) were compared with the effects of equimolar doses of roxatidine (6.5, 25, 70, 100 and 140 mg kg-1) and bismuth subcitrate (6.5, 25, 70, 100 and 140 mg kg-1). The results show that MX1-pre-treatment, at all the doses used, significantly reduces the mean number and size of ulcers. Even at the lowest dose the number of ulcers was reduced by 64.3% and the size of the ulcer by 55.9%. Roxatidine (25, 70, 100 and 140 mg kg-1) dose-dependently reduces ulcer size and number by 24.6, 55.6, 85.3 and 89.0% and by (+7.2), 14.3, 57.1 and 67.9%, respectively. Bismuth subcitrate significantly reduces ulcer size and number only at the highest dose employed (-28.5 and -44.8%, respectively). The morphometric results have been confirmed histomorphologically. The results suggest that MX1 has a gastroprotective effect against stress-induced ulcers which is similar to that of the parent compound and more pronounced than that of bismuth subcitrate.

Synthesis, gastroprotective, antisecretory and anti-Helicobacter effect of N-[3-(3-(1-piperidinylmethyl) phenoxy)propyl]-hydroxyacetamide 2-hydroxypropane-1,2,3-tricarboxylate bismuth (3+) complex (MX1)-MX1.

MX1 (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ 2-hydroxypropane-1,2,3-tricarboxylate bismuth (3+) complex) is a novel salt of the active metabolite of H2-antagonist roxatidine with a complex of bismuth with citric acid. In a model of ethanol-induced ulcers in male Wistar rats, both roxatidine and the bismuth salt reduced the number and the total length of lesions. Comparison of roxatidine and MX1 at equimolar doses of 160 mumol kg-1 showed a more potent cytoprotective effect of MX1. The potency of anti-secretory and antiacidic effects of MX1 was more than twice that of roxatidine on histamine-stimulated secretion in female Wistar pylorus-ligated rats. Microbiological tests with the reference bismuth preparation De-Nol showed prominent anti-Helicobacter properties of MX1 in-vitro. Both test compounds had similar range of MICs to Helicobacter pylori, from 4 to 64 microgram bismuth mL-1. The cytoprotective, antisecretory, anti-acidic and anti-Helicobacter properties of the new agent MX1 warrant further more extensive pharmacological and clinical trials.

Synthesis, antiulcer and antidepressive activity of 4-(4-halophenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolines.

4-(4-halophenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolines 2a-c have been synthesized by two methods and their biochemical and pharmacological properties have been studied. Biochemical investigations showed that all the compounds are strong inhibitors of DA, NE and 5-HT reuptake, the strongest effect being observed with compound 2b (R = Br). 2a-c exhibited a strong antiulcer activity on an experimental model of stress-induced ulcers with minimal doses (0.1 to 3.0 mg/kg), the effect of 2b being 30 times higher as compared to the H2-antagonist Ranitidin. At higher doses (10 to 30 mg/kg) 2b and 2c inhibited the Reserpinptosis. The most active compound in the reuptake inhibition 2b, expressed a high antidepressive activity in some other tests, comparable to that of the antidepressant Nomifensin. 2b has been selected for further pharmacological testing under the code name AN12.

Resolution and absolute stereochemistry of 6,7-dimethoxy-4-phenyl- 1,2,3,4-tetrahydroisoquinoline. The crystal structure of the R-hydrochloride salt form.

Stereospecific multistep synthesis and resolution of 6,7-dimethoxy-4- phenyl-1,2,3,4-tetrahydroisoquinoline (3) has been achieved from its racemic base. The absolute configurations of the optical antipodes converted into their hydrochloride salt forms have been determined by X-ray diffractometric analysis, thus permitting assignment of the antipodes as the (+)-(4R)-3 and (-)-(4S)-3 enantiomers. The crystal structures of the two enantiomers are related as mirror images and only the (4R)-3.HCl form has been fully determined by three-dimensional X-ray diffraction. In the solid state, the carbon atoms of the two methoxy groups deviate slightly from the benzene-ring plane and the chirally oriented phenyl substituent is almost perpendicularly tilted out of conjugation with the isoquinoline system. Examination of the enantiomers in several biochemical tests for 5-HT, NE and DA uptake inhibition-activity revealed an exclusive preference for the (4S)-enantiomer. These results are in accord with previous suggestions that the S-configurational state of the 4-phenyl substituent is important for biological activity.

[Racemic and optically active 2-chloroethylcarbamoyl derivatives of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine: a new structural type of DA, NE and 5-T uptake inhibitors]. / Racemische und optisch aktive 2-Chlorethylcarbamoyl-derivate des 7,8-Dimethoxy-1-phenyl-1H-3-benzazepins: Neue Strukturtypen von DA, NE und 5-HT Uptake Inhibitoren.

The racemic and optically active 2-chloroethylcarbamoyl derivatives of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines 6 and 8 were synthesized. The enantiomers of the benzazepine 5 were obtained by consecutive treatment of (+/-)-5 with (-) and (+)-dibenzoyl-tartaric acids. Compounds 6 are strong DA and NE uptake inhibitors while 8 exhibits inhibition towards 5-HT. The inhibitory effect of 6 is characterized by clearly expressed enantioselectivity. So 1-S-6 is a 26, resp. a 40 times stronger inhibitor of DA and NE uptake than 1-S-6. (+/-)-6 shows moderate antiulcer activity on water-immersion stress ulcer.

A new class of antiulcer drugs. I. Antiulcer effect of AN5, a 4-phenyl-tetrahydroisoquinoline derivative, on different experimental models of ulcer in rats.

The action of AN5 on experimental models of gastric ulcers induced by water-immersion stress, indomethacin and reserpine, or by pylorus ligation in rats has been studied. AN5 supresses the formation of ulcers in all experimental models. The strongest antiulcer effect is shown in relation to water-immersion stress-induced ulcers. From the broad pharmacological studies of AN5 on this model it can be seen that even a dose of 0.100 mg/kg has a high antiulcer activity. The increase of the dose leads to a regular increase of the antiulcer activity, the highest suppression of the ulcer index being reached at a dose of 1 mg/kg (86.15%). The comparative studies with ranitidine and cimetidine on the same experimental models of gastric ulcers show that AN5 possesses an antiulcer activity many times higher than that of the above-mentioned drugs.

Effects of compound IS-35 on intraocular pressure.

The influence of compound IS-35 on intraocular pressure of unanesthetized rabbits was studied. In some cases intraocular pressure was measured with either the tonometer of Schiotz and was calculated in mmHg according to Leydhecker's scale (1973), or with the tonometer of Maclakov. Intraocular pressure was measured before and at 30, 60, 120, 180, 240 and 360 min after topical application of IS-35, timolol and trimetoquinol. It was established that IS-35 applied locally in the eye as 0.5% solution or collyrium decreases statistically significantly intraocular pressure. This effect was similar to that of timolol and exceeded significantly the effect of trimetoquinol. The experimental study on the beta-adrenergic adenylate cyclase showed that the mechanism of action of IS-35 on ophthalmotonus most probably is similar to the effect of timolol and is due to the suppression of aqueous humor formation.

[The effect of the beta adrenomimetic trimethoquinol and its rigid tetrahydroberberine conformer on histamine liberation induced by compound 48/80 in mast cells]. / Einfluss des beta-Adrenomimetikums Trimethoquinol und seines rigiden Tetrahydroprotoberberin-Konformers auf die durch Substanz 48/80 induzierte Histaminfreisetzung aus Mastzellen.

The effects of the beta 2-adrenomimetic trimethoquinol (TMQ) and one of its rigid tetrahydroprotoberberin conformer - compound Is-35 - on the histamine content and the compound 48/80 induced histamine release have been studied. The histamine content in skin parts of ears and in the whole heart of male rats has been determined spectro-photofluorometrically. TMQ and Is-35 were injected in doses of 3 mumol/kg and compound 48/80 in increasing doses (1, 2 and 3 mg/kg) during 3 successive days. It has been found that the antagonizing effect of TMQ on the mast cell histamine release is tissue-dependent: it prevents the release of 20% of the compound 48/80-releasable histamine in ears and of 40% in heart. Is-35 has not effect on the compound 48/80 induced histamine release in ears and prevents the release of only 12% of the compound 48/80-releasable histamine in heart. The morphological studies show quantitative and qualitative changes in the heart mast cell population which are in good agreement with the biochemical data obtained. The fixation of the flexible part of the TMQ molecule in a tetrahydroprotoberberin configuration results in a reduction of the antagonistic activity towards the compound 48/80 induced histamine release. On the basis of this finding it could be suggested that an aporphin-like conformation of the TMQ molecule is responsible for its activity established.

Some analogies between prebiotic thermal conversions of glycine and metabolic pathways.

The reaction schemes suggested earlier for thermal transformation of glycine into amino acids and carboxylic acids are considered in detail. Close analogy with some wide-spread biochemical reactions of amino acids is observed. The pathway suggested has some common stages with the tricarboxylic acid cycle and other metabolic processes. The possible role of alpha-imino or alpha-keto acids as prebiological analogs of pyridoxal-phosphate-containing enzymes is discussed. The thermal transformations of glycine under primitive Earth conditions could be considered as evolutionary precursors of some present-day metabolic pathways.

A study of the interaction of glycine and its oligohomopeptides with formaldehyde and acetaldehyde under possible primitive earth conditions.

It is established that glycine and glycine oligohomopeptides interact with formaldehyde and acetaldehyde in a homogeneous weak acid medium (pH 3.3-3.7) at mild temperatures (60-80 degrees C) in the absence of inorganic solid substances. Together with the expected serine and threonine, the formation of alanine, glutamic and aspartic acid, norvaline and isoleucine, as well as four non-protein amino acids is also established. It is suggested that the non-protein amino acids are hydroxymethylserine, hydroxymethylthreonine, hydroxymethylaspartic acid and gamma-amino-delta-hydroxyvaleric acid. The modes of formation of all protein and non-protein amino acids are discussed. These results strengthen the probability that similar processes may have been one of the pathways for the prebiotic synthesis of amino acids on primitive Earth.

Some evidence for the universality of structural periodicity in proteins.

A new simple and sensitive method for detecting small periodicity (repetition of a small segment along the chain) in proteins is developed, based on the repetition of identical residues. 38 proteins from organisms representing different levels of evolutionary development have been tested for small periodicity. The same is done with the nodal ancestors of 25 of them. The results are presented graphically (the periodicity curves). The statistical significance of the observed periodicity is confirmed by a modified version of the chi-square test. All the results obtained support the conception that the small periodicity of the contemporary proteins is a reflection of their evolutionary history and that the most ancient proteins have arisen through a polycondensation of short peptides or through transcription and translation of satellite-type repeat sequence DNA.