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Mesoscale modelling of radioactive contamination formation in Ukraine caused by the Chernobyl accident.

This work is devoted to the reconstruction of time-dependent radioactive contamination fields in the territory of Ukraine in the initial period of the Chernobyl accident using the model of atmospheric transport LEDI (Lagrangian-Eulerian DIffusion model). The modelling results were compared with available 137Cs air and ground contamination measurement data. The 137Cs atmospheric transport over the territory of Ukraine was simulated during the first 12 days after the accident (from 26 April to 7 May 1986) using real aerological information and rain measurement network data. The detailed scenario of the release from the accidental unit of the Chernobyl nuclear plant has been built (including time-dependent radioactivity release intensity and time-varied height of the release). The calculations have enabled to explain the main features of spatial and temporal variations of radioactive contamination fields over the territory of Ukraine on the regional scale, including the formation of the major large-scale spots of radioactive contamination caused by dry and wet deposition.

Air Movements↗

The antimitotic effects of Ukrain, a Chelidonium majus alkaloid derivative, are reversible in vitro.

Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. We previously failed to confirm this claim and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest. In this study we have found the antimitotic actions of Ukrain to be reversible in low doses in vitro, as shown by flow cytometry and concurrent haematoxylin and eosin stains. We hypothesize that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling cells to overcome the metaphase arrest and survive.

Alkaloids↗

Effect of Ukrain on matrix metalloproteinase-2 and Secreted Protein Acidic and Rich in Cysteine (SPARC) expression in human glioblastoma cells.

Glioblastoma is a highly malignant brain tumor with a highly invasive phenotype and hence an unfavorable prognosis even in response to multidisciplinary treatment strategies. Ukrain, a semi-synthetic thiophosphoric acid derivative of the purified alkaloid chelidonine, has been used in the therapy of several solid tumors, but little is known about its effect on glioblastoma and, in general, about the molecular mechanisms responsible for its effects. We used RT-PCR, Western blot and SDS-zymography to investigate the effects of three doses of Ukrain (0.1, 1 and 10 micromol/l) on the expression of genes and proteins involved in the extracellular matrix remodeling associated with tumor invasion in human cultured glioblastoma cells treated for 24, 48 and 72 h. We analyzed the expression of matrix metalloproteinase-2 and -9, the main mediators of glioblastoma invasiveness, and secreted protein acidic and rich in cysteine (SPARC), involved in the regulation of cell-matrix interactions. There was a significant, dose-related decrease of glioblastoma cell proliferation and a tendency to downregulation of SPARC at the protein level 72 h after 10 micromol/l Ukrain, suggesting the drug may be a useful therapeutic tool for brain tumors.

Antineoplastic Agents↗

Comparative study of the cytostatic effects of Oliphen and Ukrain.

We evaluated the cytostatic effect of the antihypoxic drug Oliphen (Polyoxiarilene) in comparison with the well known cytostatic and immunomodulating agent Ukrain (a semisynthetic compound derived from Chelidonium majus L. alkaloids). We used tumor cell lines M-HeLa and Hep-2/0-6-5, normal cell cultures from human embryo kidney and lung fibroblasts. The cytodestructive effect of Ukrain on both tumor cell lines was more significant at all tested concentrations. Oliphen was cytotoxic only against Hep-2 but not the HeLa cell line. The proliferative activity of both normal cell cultures decreased in the presence of Oliphen and Ukrain concentrations of 0.1 and 0.015% and was stable at 0.0015 and 0.00015%.

Alkaloids↗

Comparative evaluation of the complex treatment of rectal cancer patients (chemotherapy and X-ray therapy, Ukrain monotherapy).

A total of 48 patients suffering from rectum cancer were included in this randomized study conducted at the Proctology Department of the Donetsk Regional Anti-Cancer Center. Patients in group I (24 patients) received an intensive course of high fractional X-ray therapy (cumulative dose up to 25 Gy) with direct protracted endolymphatic chemotherapy with 5-fluorouracil (5-FU) instilled in 600 mg/m2 each day before operation, up to a cumulative dose of 5 g. The 24 patients in group II were treated with Ukrain as monotherapy, 10 mg each second day before operation (up to a cumulative dose of 60 mg) and a total of 40 mg after surgical intervention. Repeated Ukrain courses (100 mg/per course) were also given 6 months after surgical operation. In each ease preoperative treatment was followed by routine surgical operation. Prolongation morbi were found to have developed 14 months later in six patients in group I (25.0%), whereas in group II they were found only in two cases (8.3%). Comparative investigation of objective and subjective signs, analysis of results of instrument and X-ray data, as well as dynamic study of the histological structure of rectal tumors, indicate that Ukrain exerts a more potent malignotoxic and immunomodulating action than other types of anticancer treatment.

Adult↗

The influence of glucose, succinate, pH of the medium and higher temperature on the cytotoxic activity of the preparation Ukrain.

Cells of ascitic forms of Ehrlich's carcinoma and sarcoma 37 transplanted into C57BI/6 mice were used to study the influence of glucose, succinate, and pH of the medium on the cytotoxic activity of the preparation Ukrain. Viability of cells was estimated by the method of intravital staining with tripan blue after the incubation of cell suspension in the presence of the preparation (1.05 x 10(-5) mol and 1.69 x 10(-4) mol). It was established that glucose (5 mmol) reduces the cytotoxic activity of Ukrain, while succinate (5 mmol) increases it. The activity of the preparation was practically absent at pH 6.1-6.7 of the incubation medium and was at a maximum at pH 7.3-8.0. A temperature of 41.5 degrees C has no influence on the effectiveness of Ukrain.

Alkaloids↗

Induced apoptosis in human prostate cancer cell line LNCaP by Ukrain.

Exposure of LNCaP prostate cancer cells to Ukrain (NSC-631570), a novel semisynthetic drug from Chelidonium majus L., results in cell growth inhibition which is concomitant with apoptosis. After 24 h treatment with 3.5 microM of Ukrain as many as 73% cells were found in the G2/M phase. However, at higher drug concentrations (7 microM and 17.5 microM) the changes in cell phase distribution were less dramatic but cell accumulation in the G2/M phase was still evident. The rate of apoptotic cells rose steadily with increased drug concentration in a dose-dependent manner and reached 20% at a dosage of 17.5 microM. To investigate whether the cell cycle control mechanisms are affected in response to Ukrain, we analyzed the expression levels of some cyclins, cyclin-dependent kinases (CDK) and apoptosis-related proteins in drug treated cancer cells. Western blot experiments revealed alterations in levels of CDK1 and CDK2, after treatment. Up-regulation of the CDK inhibitor p27 was observed, which may lead to G2/M cell accumulation, but no substantial changes in expression of Bcl-2 and Bax proteins were found.

Alkaloids↗

Ukrain: acute toxicity after intravenous, intramuscular and oral administration in rats.

The acute toxicity of Ukrain (1 g/30 ml) was determined after a single intravenous, intramuscular or oral administration in rats, performed in accordance with Good Laboratory Practice and the relevant European Community directive. Groups of five (male and/or female) Him:OFA rats were treated once with the following doses: intravenous route: 1.0 ml/kg (males and females), 1.7 ml/kg (males and females) and 3.0 ml/kg (females); intramuscular route: 5.0 ml/kg (males and females); oral route: 15.0 ml/kg (females), 27.0 ml/kg (males and females) and 50 ml/kg (females). The animals were kept for up to 14 days afterwards while clinical observations and body weight determinations were made and were then necropsied. An intravenous injection of Ukrain (1 g/30 ml) induced immediate effects (short-term unconsciousness, followed by cardiovascular signs and, later, signs of general malaise), which if not lethal, disappeared in a short time. It was found that the intravenous LD50 was greater than 43 mg active ingredient/kg body weight in the males and 76 mg active ingredient/kg body weight in the females. An intramuscular injection of Ukrain (1 g/30 ml) in the maximum technically feasible dose induced some transient signs of minor clinical importance which did not become life threatening. In both sexes the intramuscular LD50 was greater than 165 mg active ingredient/kg body weight.

Administration, Oral↗

Clinical aspects of cancer treatment and new biochemical mechanisms of the drug Ukrain.

A random group of 50 patients in tumor stages T1-3N0-2M0 was selected from breast cancer patients and given Ukrain therapy by intravenous injection. Twenty-five patients received a total dose of 50 mg Ukrain (5 mg every second day, 10 injections altogether). Twenty-five patients received a total dose of 100 mg Ukrain (10 mg every second day, 10 injections altogether).

Alkaloids↗

Ukrain treatment in a patient with breast carcinoma. Case report.

A 50-year-old female patient with breast cancer (stage IV) was treated with Ukrain because of the impossibility of radiotherapy and chemotherapy. The first course led to a subjective improvement in her general condition, objective changes such as the appearance of border between the tumor and healthy tissues and a decrease in tumor size. Ukrain facilitated the surgeon in performing an operation to remove the primary tumor as well as the metastatic lymph nodes. After the second and third courses of Ukrain, the patient demonstrated clinical remission.

Alkaloids↗

Ukrain treatment of a patient with retroperitoneal synovial sarcoma. Case report.

A 23-year-old woman, diagnosed with a synovial sarcoma of the peritoneum, underwent an operation for tumor extraction. In the postoperative period, Ukrain was injected i.v. at a dose of 10 mg on alternate days, for a total of 10 injections. After a 2-month break, this schedule was repeated. Ukrain treatment was well tolerated by the patient and there were no complications in the postoperative period. The following changes in immunohematological parameters were observed: increased total leucocytes, T lymphocytes and T helpers. Nearly 4 years after Ukrain therapy, the patient is in complete remission.

Adult↗

Radiomodification effects of Ukrain, a cytostatic and immunomodulating drug, on intracellular glucocorticoid reception during short-term gamma-irradiation.

The ability of Ukrain, a cytostatic and immunomodulating semisynthetic compound of thiophosphate-modified alkaloids of Chelidonium majus L., to modify the effects of irradiation on intracellular glucocorticoid reception in female rat liver was evaluated after intraperitoneal administration of the drug at 0.4 mg/kg of body weight. Ukrain caused the normalization of the intracellular glucocorticoid-receptor system, influenced by short-term whole-body gamma-irradiation of rats with 1 Gy, beginning on the 10th day after administration of the drug. It was found that Ukrain minimized the consequences of irradiation in the endocrine system of the experimental animals.

Adjuvants, Immunologic↗

Intermittent three-month treatment with Ukrain in intact and ovariectomized rats. Part II: Effect on bone mineral density of the femur.

Ukrain, an acid alkaloid derivative of Chelidonium majus L., was administered intraperitoneally to ovariectomized and control sexually mature female rats at doses of 7, 14 and 28 mg/kg once daily for 10 days, followed by 10-day break. This procedure was repeated five times. At the end of the Ukrain treatment (24 h after the last dose of the drug) the right femora of the rats were harvested and the bone densitometric parameters of the whole bone and distal metaphysial and intertrochanteric subregions were assessed using the dual energy x-ray absorptiometry densitometric method. The results showed no apparent decrease in bone mineral density in groups of rats studied. A nearly significant (p = 0.08) decrease of bone mineral content was observed in ovariectomized rats treated with 14 mg/kg of Ukrain.

Absorptiometry, Photon↗

Teratological evaluation of Ukrain in hamsters and rats.

The compound Ukrain, containing thiophosphoric acid alkaloid derivatives from the plant Chelidonium majus L., was given intramusculary (i.m.) on days 6-11 of gestation to hamsters and on days 6-15 of gestation to rats in doses of 0.1, 1.67 and 28 mg/kg daily. No clinical signs of toxicity were found in treated animals and no teratogenic effect could be noted in either species. Such parameters as the number of corpora lutea, implantation sites, pre and post-implantation losses, number of live foetuses per litter, placental weight, foetal weight and crown-rump length were not significantly different between the Ukrain treated rats and the controls. Slight embryotoxic effects (increased post-implantation losses) and in consequence decreased number of average litter size were noted in hamsters exposed to Ukrain at doses which were otherwise not embryotoxic to rats.

Alkaloids↗

Evaluation of mutagenic, genotoxic and transforming properties of Ukrain.

Evaluation of mutagenic and genotoxic properties of Ukrain was on the basis of the Ames and micronucleus tests. Ukrain was investigated for its ability to induce morphological transformation of embryonic cells of the Syrian hamster. Under the experimental condition used in this study, Ukrain was found to be non-mutagenic and non-genotoxic, and furthermore did not induce morphological cell transformation.

Alkaloids↗

Clinical studies of Ukrain in healthy volunteers (phase 1).

Phase I of a clinical study of Ukrain was performed in 19 healthy outpatient volunteers. Their general clinical conditions were evaluated, as well as the following parameters: biochemical, haematological, immunological, electrolyte and trace elements, neopterin, immune complexes and non specific blocking factors. Ukrain was administered intramuscularly (i.m.) or intravenously (i.v.) every one, two or three days in doses of 5 to 50 mg for 7 to 40 days. In one case the drug was administered for three years in the dose of 5 to 50 mg/injection in repeated courses. During the investigation no significant changes were found in clinical states. During the intramuscular injections the volunteers felt only localized pain; some reported drowsiness, increased thirst and polyurea. There was a slight, insignificant increase in body temperature and negligible decrease of blood pressure in some cases. In conclusion, it can be said that Ukrain is well tolerated in healthy volunteers in the doses of 5, 10, 20, and 50 mg/injection, even during prolonged (up to three years) administration.

Adult↗

Effect of single and prolonged administration of Ukrain on prolactin concentration in rats.

The effect of single and prolonged administration of Ukrain on the serum prolactin concentrations in rats of both sexes was investigated. One hour after intraperitoneal (i.p.) administration of Ukrain in rats, in doses of 7, 14 and 28 mg/kg, the drug did not affect their serum prolactin concentration. Only in a dose of 28 mg/kg did this drug decrease serum prolactin in a group of female rats. Repeated i.p. treatment (once daily for three months) with 7, 14 and 28 mg/kg of Ukrain significantly increased the serum prolactin concentration in rats of both sexes. The most marked effect was observed in the group of female rats.

Alkaloids↗

Evaluation of thiophosphoric acid alkaloid derivatives from Chelidonium majus L. ("Ukrain") as an immunostimulant in patients with various carcinomas.

This paper summarizes the preliminary results of two independent clinical trials conducted with the preparation "Ukrain", containing thiophosphoric acid alkaloid derivatives from the plant Chelidonium majus L. (greater celandine), in order to investigate whether it has immunopotentiating properties in cancer patients. A total of twenty-seven patients with various malignancies were treated with "Ukrain" given intravenously in a dose of 10 mg every three days. In all patients the cellular and humoral immune response was studied. There was an increase in both total T-cells and T-helper lymphocytes, a decrease in T-suppressor cells, and normalization of the helper/suppressor (HIS) ratio. A significant increase in erythrocyte-rosette-forming T-cells and NK cells was also demonstrated. Serum immunoglobulin levels, complement components (C3 and C4), and acute phase proteins were not significantly enhanced. Restoration of cellular immunity was accompanied by an improvement in the patients' performance status and in the clinical course of the disease. The treatment was generally well tolerated. The present study shows that some therapeutic benefit from the use of Chelidonium majus ("Ukrain") as an immunostimulant in cancer patients can be achieved.

Acute-Phase Proteins↗