Talk:Ukrain/Temp

Ukrain, also called NSC 631570 is an experimental anticancer drug invented by the Ukrainian researcher Wassil Nowicky and tested clinically for the first time in 1978. It is a product that results from a reaction of alkaloids from greater celandine with the classic cancer medicine Thio-TEPA in the presence of hydrochloric acid.

Content
Ukrain contents mixture of alkaloids. Chelidonine is generally considered the most important one. The preparation of Ukrain together with Thio-TEPA and hydrochloric acid makes the alkaloids water soluble and injectable. It is probable the anti-cancer effect of Ukrain is a result of a combined action of all its constituents

Boyko VN, Zholus RB. Previously it has been postulated that the active component of Ukrain was a trimeric structure containing three chelidonine molecules connected by a Thio-thepa skeleton. This has not been confirmed in later investigations

Licensing Status
Ukrain has obtained drug licenses in Mexico and several states of the former Soviet Union. Recently, Ukrain has got the orphan drug status for the treatment of pancreatic cancer in Australia and in the United States of America.

Clinical Investigations
Ukrain has been investigated in multiple phase I and phase II clinical trials with very promising results. Below follows a summary:

Ukrain against Pancreatic Cancer
The effect of combining the cancer drug Gemcitabine and Ukrain in the adjuvant treatment of resected advanced pancreatic cancer on 30 Cancer patients who was receiving chemotherapy after their cancer operations. In 80% of the patients recurrence of the disease was observed. The relapse-free survival time was 21.7 months. The actuarial survival rates were 86.7% after one year, 76.6% after two years, 46.7% after three years and 23.3% after five years. The median survival time according was 33.8 months.

90 patients with histologically proven non-operapable pancreatic cancer were given 1000 mg of the cancer medicine gemcitabine/m2(Gemzaar), 20 mg Ukrain, weekly, or 1000 mg gemcitabine/m2 and 20 mg Ukrain weekly. In all three arms therapy was well tolerated and toxicity was moderate. At the first re-evaluation in arm A 32%, in arm B 75%, and in arm C 82% showed no change or partial remission according to WHO criteria (arm A versus arm B: P<0.01, arm A versus arm C: P<0.001). Median survival was in arm A 5.2 months, in arm B 7.9 months, and in arm C 10.4 months. Actuarial survival rates after 6 months were 26%, 65% and 74% in arms A B and C, respectively (arm A versus arm B: P<0.05, arm A versus arm C

21 patients were treated with 10 mg ukrain every second day x 10. The control group received supportive treatment only. Ukrain treatment was well tolerated. Mean values on pain measure and Karnofsky index were significantly better in the ukrain group than in controls (P<0.05). .

42 patients with advanced symptomatic pancreas cancer were randomly assigned to receive either vitamin C and Ukrain, or vitamin C and normal saline. The one-year survival was 81% in the Ukrain group compared with 14% in the control group. The 2-year survival was 43% in the Ukrain group compared with 5% in the control group. Median survival was 17.17 months for Ukrain-treated patients and 6.97 months for the control group.

Breast Cancer
75 patients with histologically confirmed breast cancer were divided into three groups of 25. The control group received symptomatic corrective therapy prior to mastectomy. The two other groups were given neoadjuvant therapy with Ukrain injections. Five to seven days after the last injection patients from all groups were subjected to operation. Practically all patients who were administered Ukrain noticed improvement in appetite, normalization of sleep, disappearance of general weakness and the appearance of confidence in recovery. After the course of treatment with Ukrain, the contours of the tumorous node became more clearly defined, which facilitated mastectomy.

Bladder Cancer
Mechanism in Bladder Cancer 2000 Ukrain prevents active free amino acid transport into urinary bladder tumor tissue, inhibiting the activities of protein biosynthesis, gluconeogenesis and energy production. The combined decrease in Glutamine and Leucine levels in urinary bladder tumor tissue is a specific sign of the antitumor effect of Ukrain and a mechanism of its cancerostatic action by controlling the processes of amino acid pool formation in the tumor.

Ukrain in Bladder Cancer 1998 28 patients with relatively small bladder cancer tumors were divided in three groups. The first group was treated with a total dose of 100 mg Ukrain, the second group received 200 mg Ukrain, and the third group was treated with 300 mg Ukrain. In all patients Ukrain was administered i.v. at a dose of 10 mg per day. Ukrain, at a total dose from 100-300 mg as neoadjuvant therapy in patients with T1N0M0 bladder cancer, resulted in either complete or partial regression of tumors in 60.7 +/- 9.2% of cases. The best treatment regime included three courses of Ukrain at 2-week intervals.

Prostate Cancer
Prostate Cancer 2000 15 patients with newly diagnosed prostate cancer received Ukrain at a total dose of 100 mg After two to three injections of Ukrain, all the patients noted considerable subjective improvements in their state. Ukrain increased the amount of total T-lymphocytes, including “active” T-lymphocytes, decreased the content of T-suppressors and increased that of T helpers, correspondingly raising the T helper/T-suppressor ratio.

Colorectal Cancer
Rectal Cancer 1998 48 patients suffering from rectum cancer were included in a randomized study were 24 patients received an intensive course of X-ray therapy together with chemotherapy with 5-fluorouracil before operation. The 24 patients in group II were treated with Ukrain as monotherapy, 10 mg each second day before operation and a total of 40 mg after surgical intervention. Repeated Ukrain courses were also given 6 months after surgical operation. Recurrence were found to have developed 14 months later in six patients in group I 25.0%, 8.3% in group II.

Case Reports
A total of 203 advanced-stage cancer patients suffering from different types of cancer who had exhausted all conventional forms of therapy were treated with the Ukrain. Forty-one patients (20.2%) achieved total remission, 122 (60.1%) partial remission and only 40 (19.7%) did not respond to treatment.

There have been numerous published case reports about succesful treatments of Kaposis Sarcoma and AIDS, Astrocytoma, Urethral Carcinoma, Oesophageal carcinoma, ovary cancer, cervix cancer, breast cancer, rhabdomyosarcoma, malignant melanoma and ewing sarcoma.

Other effects of Ukrain
Treatment of Hepatitis C Ukrain can be used in the treatment of Chronic hepatitis C, alone or in combination with Interferon, preparations; in the cases with Hepatit C Virus genotype 1b, Ukrain seems more promising than IFN. Individual therapy with Ukrain and IFN increased the efficacy of treatment 2.5-fold in comparison with standard monotherapy with the same preparations, significantly decreased the number of side effects and dramatically improved cost-effectiveness.Drugs Exp

Stimulation of immune defence Ukrain stimulates the immune defence and has cell killing and growth inhibition effects on various cancer cells. Ukrain induced programmed cancer cell death in womb cancer cells cultures by activating the so-called intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.

Antidepressant and anti-dementia effect? Chelidomium Majus alkaloids, Ukrain and the pharmaceutical compound Sanguirythrine seems to diminish the breakdown of the Neurotransmitters Serotonin and Acetylcholin. This could be a theorethical explanation to the many reported about better mood and concentration ability when taking Ukrain, as this is typical actions for antidepressants and anti dementia medicines.

Radioprotective properties on normal cells, but not on cancer cells. Exponentially growing human tumour cell lines from breast, pancreas, colorectal, glioblastoma, and human skin and lung fibroblastic cells when exposed to Ukrain and radiation, Ukrain cytotoxicity was time- and dose-dependent. The combination of Ukrain plus radiation gave enhanced toxicity in colorectal cancer and glioblastoma cells, but not in breast cancer and pancreatic cancer cells. Most strikingly, Ukrain managed to protect normal skin and lung cells from the harmful effects of radiation.

induktion of apoptosis Ukrain was found to be capable of the in vitro induction of apoptosis in different cancer cell lines. The effect was less expressed in cells with multiple drug resistance. Exposure of a prostate cancer cells culture to Ukrain resulted in cell growth inhibition which is concomitant with apoptosis Selective toxicity for cancer cells In a test panel of the NCI (National Cancer Institute, Bethesda, Maryland USA) Ukrain demonstrated cytostatic and cytolytic activity against all 60 human cancer cell lines tested from 8 main cancer types (brain, ovary, colon and kidney carcinomas, small cell and non-small cell lung carcinomas, melanomas, leukaemia and lymphoma). It had no damaging effect on normal cells in the terapeutic dose range. Ukrain selectively inhibits growth of ME180 and A431 cancer cells at a concentration range from 3.5 microM to 7.0 microM and induces apoptosis. In contrast, normal human skin cells showed no damaging effect of Ukrain. . ''' Other scientists failed to confirm the selective toxicity and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest.

Effect on HA-1 hepatoma in mice Treatment by antitumor drug Ukraine increased life span of mice with HA-1 hepatoma (transplanted intravenously), decreased the increment of tumor weight. In the abdominal fluid such treatment caused a decrease of number of tumor cells and an increase of number of macrophages. Ukrain increased cystatin C level, revealing protective mechanism of action. Another study also showed similar results.

Multiple effects on mice A marked progressive anticancer and antimetastatic effect was observed on Lewis carcinoma in mice. The antimetastatic effect of the drug manifested as a decrease in both number and volume of lung metastases. Ukrain also made an increase in the endocrine function of the thymus (a central organ of the immune system), an increase in serum interferon, adhesion of peritoneal macrophages and formation of antibodies against thymus-dependent antigen by spleen plasma cells. It increased the number of lymphoid cells and monocytes in peripheral blood. In addition to the increase in lymphocytes, the number of large granular lymphocytes also increased, i.e., cells possessing natural cytotoxic activity.

Effect on bone density in rats Ukrain was shown to affect bone tissue metabolism in rats. Its action could be slightly osteopenic at the highest doses administered to intact animals for a prolonged period of time. By far, the most important finding seems to be the anabolic effect of Ukrain on bone in ovariectomized rats, which is most probably related to induced increase in the production of sex hormones, predominantly estrogens. This means it is likely that Ukrain can counteract the loss of bone due tp estrogen deficiency in postmenopausal women.

Interactions with Alcohol? Ukrain seems to inhibit the enzyme thay breaks down alcohol in rats. This means that there is reason to be careful when combining alcohol and Ukrain.

Radioprotective effects on the glucocorticoid and thyroid systems in rats Ukrain minimized the consequences of radiation therapy on parts of the endocrine system in rats. Two hundred and sixty rats were infected by tularemia and the equine encephalomyelitis (EEM) virus 24 hours after irradiation. Irradiation prior to infection was found to decrease the survival rate. Preventive administration of Ukrain increased the survival rate. Ukrain decreases bone-marrow suppression [/b] in rats exposed to gamma radiation by improving hemopoiesis and immunogenesis. The radioprotective effects of Ukrain are far superior to all its components taken separately [/b], both measured by survival of mice irradiated by different doses, and by the protection coefficient a. These observations suggest that the influence of Ukrain on radiation effects does not result from the antiradiation properties of its components but rather from the concerted action of the specific combination found in Ukrain.  Selective uptake in tumor tissue in rats Ukrain penetrates into tissues after injection in labaratory rats by active transport or by favored diffusion. A relatively higher affinity for Ukrain was observed in tumor tissue and liver, while affinity was lowest in the brain and muscles. The presence of tumors decreased Ukrain concentrations in plasma and normal tissues in comparison with those in control animals.

Interactions with morphine? The interaction between Ukrain and Naltrexone, a nonselective opioid receptor antagonist, was studied in the ‘writhing syndrome’ test in mice. The results show that the antinociceptive effect of both single dose and prolonged administration of Ukrain is completely antagonized by Naltrexone. Ukrain interacts with morphine in mice so that the effect of morphine diminishes. This raises concerns about their combined usage.

Ukrain and Thyroid Hormones in Rabbits The influence of Ukrain on serum levels of thyroid hormones was studied in rabbits of both sexes. An increase in the thyroxine level was found at a dose of 1.5 and 3.0 mg/kg i.v. in male rabbits, whereas increased triiodothyronine was noted when Ukrain was given at all studied doses. In females the thyroxine level was not altered by Ukrain administration, whereas the triiodothyronine concentration was increased following Ukrain at 0.3, 1.5 and 3.0 mg/kg i.v. It is probable the altered thyroid hormone levels as a result of Ukrain application may contribute to the drug’s potent immunomodulatory action.

Lack of toxicity in Rabbits 6 week Ukrain application to rabbits did not change their body organs and total body weight. The drug did not affect biochemical parameters of peripheral blood, except for a minor reduction in the total plasma level and increases in serum uric acid and urea indicating enhanced catabolism of proteins and minor changes in white blood cells.

Effect on sarcoma-45 in rats The effect of Ukrain on the growth kinetics of the experimental tumor sarcoma-45 in rats was studied. Ukrain was proved to be an effective antitumor agent on biological and mathematical models in accordance with standardized instructions for screening.

Protective effect against bacterial infections Ukrain increases the survival of mice exposed to letal doses of E.Coli ans Stafylococcus Aureus bacterias.

Antiviral effect Ukrain seems to have antiviral effect against the Influenza Virus, when tested on embryos and mice.