Ukrain

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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. Chelidonine, like some other celandine alkaloids, is hardly soluble in water. This makes intravenous injections impossible. The preparation of Ukrain together with Thio-TEPA and hydrochlric acid makes the alkaloids water soluble and injectable. addition. It is probable the anti-cancer effect of Ukrain is a result of a combined action of all its constituents. Previously it has been postulated that the active component of Ukrain was a trimeric structure containing three chelidonine molecules connected by a Thiro-thepa skeleton. This has not been confirmed in later investigations.

Licensing Status
Ukrain has obtained drug licenses in Mexico, United Arab Emirates 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 on a large variety of cancer types with very promising results. Ukrain can also have a possible future role in the treatment of Hepatitis C and other viral infections.
Click on this link to go to a summary of all the clinical investigations and case reports on Ukrain.
The Clinical publications on Ukrain have been summarized 2005 in an article by Prof Edzard Ernst, UK.

Other investigations on Ukrain

In vitro investigations on Ukrain of Ukrain has shown effect on a wide variety of cancer cell cultures, a possibleantidepressant and anti-dementia effect and radioprotective properties on normal cells, but not on cancer cells.
It has been shown toinduce apoptosis and to have a selective toxicity for cancer cells. This selective toxicity has been challenged by another research group, which found no selective toxicity for Ukrain in certain cancer cell cultures.

Animal investigations
Animal experiments has shown no acute toxicity in rats,or rabbits and to have effect on a large variety of animal cancers, and bone density in rats.
It seems to have possible interactions with alcohol and morphine and to have a painkilling effect that is antagonized by the morphine blocker Naltrexone. It has been shown to have a selective uptake in tumor tissue in rats and to increase the level of thyroid hormones in Rabbits.
It has been shown to have a protective effect against against bacterial infections and an antiviral effect.

Controversies around Ukrain

Ukrain and its manufacturer Nowicky Pharma has been subject to many controversies. These controvesities will be summarized and debate on this page.
The inventor, Dr Wassil Nowicky describes many events of postulated personal persecution and even a murder attempt in the book, "Who is afraid of Ukrain?", authored together with the austrian journalist, Eleonore Thun-Hohenstein. He has made a summary of his view in a letter, published here.

External Links:

Nowicky Pharma, Austria
Nowicky Pharma, Ukraine
Information for Physicians from the manufacturer.

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Therapeutic Substance(s): 
Disease(s): 

Animal studies on Ukrain

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Studies on anti-cancer effect
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 rat hepatosarcoma
Both Ukrain and the cancer drug Cyclophosphamide were able to induce signs of Apoptosis in a cell culture consisting of liver cancer cells from rats.

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.
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.

Effect on breast cancer in mice
Intravenous, but not subcutaneous or intraperitoneal, administration of Ukrain
was found to be effective in delaying tumour growth in an actual therapeutic
protocol initiated five days after tumour implantation on mice. No untoward side-effects
were observed. Ukrain induced the activation of tumouricidal function of white blood cells from the abdominal cavity(peritoneum) from tumour bearing but not from normal mice.

Radioprotective effects
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 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 , 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.

Drug Interactions
Ukrain have a significant pain-killing effect on mice and interacts with morphine so that the effect of morphine diminishes. This raises concerns about their combined usage.
In another studyUkrain seemd to have pain killing properties only in very high dosis in mice, while
enhancing the effect of morphine in some test settings, and antagonizing the effect in other tests.
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 significantly (p<0.001) enhanced the anticonvulsive action of valproate in a mouse electroshock-induced seizure model. This was observed with UKRAIN doses of 9.5 and 19.0 mg/kg, but not at 4.75 mg/kg. No significant influence on the activity of other anti-epileptics (diazepam, carbamazepine, diphenylhydantoin, phenobarbital) was observed

Ukrain against infections?
Protective effect against bacterial infections
Ukrain increases the survival of mice exposed to letal doses of E.Coli ans Stafylococcus Aureus bacterias.
Antiviral effect on mice and embryos
Ukrain seems to have antiviral effect against the Influenza Virus, when tested on embryos and mice.

Other effects
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.
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.

Long term effects on rodents
A three month treatment with Ukrain significantly depressed the spontaneous locomotor
activity and did not affect the motor coordination of mice and rats of both
sexes. Ukrain did not affect the body weight gain as well as the mass of internal
organs; the exception was an increase in the mass of the spleen in rats.
Biochemical studies indicated that the three month treatment depressed
the whole brain dopamine concentrations and did not affect the noradrenaline
(NA) and Serotonin(5-HT) concentrations.
In another investigation, Ukrain showed no clinical signs of toxicity in hamsters and rats
and no teratogenic effect could be noted in either species. Slight embryotoxic effects were noted in
hamsters exposed to Ukrain at doses which were otherwise not embryotoxic to rats.
Ukrain was found to be non-mutagenic and non-genotoxic in a standardized genotoxicity experiment.
Ukrain did not show any tendences to induce any signs of allergic shock in a standardized animal experiment on mice.

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Clinical Investigations on Ukrain

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Here you can add Data on Clinical Investigations on Ukrain by clicking on "edit" above..

Short Summaries:

Ukrain against Pancreatic Cancer

Gemcitabine and Ukrain against Pancreas Cancer 2007
30 patients with pancreatic cancer received chemotherapy with Gemcitabine, combined with Ukrain after their cancer operations. Mild side effects were observed in 53%, no severe side effects occurred. In 80% of the patients recurrence of the disease was observed. The survival rates were 86.7% after one year, 76.6% after two years, 46.7% after three years and 23.3% after five years, which is much better than any previosuly known treatment results. The median survival time was 33.8 months.

Gemcitabine Versus Ukrain versus Ukrain/Gemcitabine 2002
90 patients with non-operapable pancreatic cancer were randomized into three different treatment arms. Patients in arm A received Gemcitabine, those in arm B received Ukrain, and those in arm C received gemcitabine and Ukrain.
In all three arms therapy was well tolerated and toxicity was moderate. 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.

Ukrain against Pancreatic Cancer 2002
21 patients were treated with 10 mg ukrain every second day x10. The control group received supportive treatment only. Ukrain treatment was well tolerated. Mean values on pain measure and
[url]=http://en.wikipedia.org/wiki/Performance_status]Karnofsky index[/url] were significantly better in the ukrain group than in controls (P<0.05). One-year survival was 76% in the ukrain group, compared to 9.5% in the control group.
Median survival after treatment with ukrain was 574 days, compared to 197 days in the control group.

Ukrain against Pancreatic Cancer 2000
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
Ukrain against Breast Cancer 2000
75 patients with histologically confirmed breast cancer were divided into three groups of 25. The control group received symptomatic corrective therapy prior to their breast operation. The two other groups were given neoadjuvant therapy with Ukrain injections. The first group received a total course dose of 50 mg and the second group received a total Ukrain dose of 100 mg. Five to seven days after the last injection patients from all groups were subjected to operation. Practically all patients who were administered Ukrain noticed remarkable positive changes in the second half of treatment: 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 operation. Changes in the tumor tissue were one-sided in their qualitative differences in comparison to the control group and were not dose-dependent. The results of this study showed the efficiency of both doses (50 and 100 mg) of Ukrain with the higher dosage performing slightly better.

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.

Colorectal Cancer 1996
96 patients with colorectal carcinomas were included in a randomised study. 48 patients were treated with UKRAIN (15 of them with metastasising and 33 with non-metastasising colorectal tumours) and 48 patients were treated with the chemotherapeutic drug 5-FU and radiotherapy. The survival rate after 21 months was 78% in the group treated with UKRAIN and 33% in the group treated with 5-FU and radiotherapy.

Lung Cancer
Lung Cancer 1992
Lymphocyte subsets were evaluated in nine men (aged 42-68 years, mean 57 years) with histologically proven lung cancer, previously untreated. Ukrain was applied as an intravenous injection every three days. One course consisted of 10 applications of 10 mg each. The results showed a restoration of cellular immunity that was accompanied by an improvement in the clinical course of the disease. This effect was particularly pronounced in patients who responded to
further chemotherapy. Objective tumour regression (CR+PR) was seen in 44.4% of
treated patients. Four out of nine patients (44.4%) died of progressive disease
during the course of this study.

Cervix Cancer
Cervix Cancer 1992
Nine women with a stage IB voluminous uterine cervical cancer received Ukrain before and after operation. Three out of nine eligible cases had partial responses after operation, while six cases remained stable. There were signs of activation of the immune defence. Two patients were treated with adjuvant radiotherapy due to lymphatic involvement and all nine patients were still alive at least six months after follow-up.

Meta-analysis
Ernst ans Schmid 2005
Ernst et al. searched for all relevant randomised clinical trials Ukrain .
Seven trials met the inclusion criterias. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was considered poor. In addition, the interpretation of several trials was impeded by other problems. The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, they meant that numerous caveats prevented a positive conclusion, and that independent rigorous studies are urgently needed

Case Reports
Kidney Cancer with Liver metastasis from 2000
A 52-year-old man with renal cell carcinoma was treated with surgery and chemotherapy (vinblastine). Ukrain was administered after tumor progression to the vena cava inferior and appearance of liver metastasis. The drug induced a complete remission, which has lasted 32 months since the first therapy course.

Synovial Sarcoma from 2000
A 23-year-old woman, diagnosed with a synovial sarcoma of the peritoneum, underwent an operation for tumor extraction, and got Ukrain afterwards. Nearly 4 years after Ukrain therapy, the patient is in complete remission.

Breast Cancer from 2000
A 50-year-old female patient with breast cancer (stage IV) was treated with Ukrain because of the impossibility of radiotherapy and chemotherapy. 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.

Case Series from 2000
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.

Treatment of Kaposis Sarcoma and AIDS from 1996
Two case reports are presented of therapy with Ukrain for the treatment of AIDS patients with Kaposi's sarcoma. During treatment the Kaposi's sarcoma lesions diminished in size, showed decolouration and no lesion appeared in the 30-day interval after the beginning of treatment. Both patients tolerated Ukrain well and showed an improved immunohaematological status: an increase in total leukocytes, T-lymphocytes and T-suppressor numbers. In one case T-helper lymphocytes were also increased.

Treatment of Astrocytoma from 1996
Ukrain, a semisynthetic thiophosphoric acid compound of alkaloid chelidonine from Chelidonium majus L. (1) causes regression of various tumours. Among other effects, its action seems to depend on the stimulation of the immune system which very often is deficient in cancer patients. Its use in a patient with subtotal extirpation of a frontal anaplastic grade III astrocytoma seems to have reduced growth speed significantly

Urethral Carcinoma from 1996
In a patient with low grade differentiated urethral carcinoma (histologically: urothelial carcinoma G2 and G3, pT1 with low grade differentiation) operation was carried out, with recurrence after two months. Instead of reoperation the patient was given Ukrain as monotherapy. No carcinoma was detected four months later by histological examination or during examinations three years later.

Oesophageal carcinoma from 1996
A poorly differentiated squamous cell oesophageal carcinoma was diagnosed in a patient after an 11 month history of difficulty in swallowing. The condition was inoperable according to clinical and X-ray contrast examinations. Radiation therapy with three courses of chemotherapy was carried out, but no amelioration was obtained. Ukrain therapy (course of 46 ampoules) was undertaken; this changed the situation entirely: all the subjective problems disappeared and no residual cancer was seen on the X-rays. Complete remission is seen nearly four years after Ukrain therapy.

Ovary cancer from 1996
A patient with adenocarcinoma in the right ovary with lymphangitis carcinomatosa, staged as G II-G III pT3, pNX, pMX, was treated after palliative surgery by chemotherapy and, simultaneously, with Ukrain. Two and a half years after treatment the patient is without any signs of tumour recurrence.

Cervix cancer from 1996
A grade IV cervical cancer was treated with endocervical cone biopsy (electrocoagulation) in a 28 year-old lady. Three years later examination revealed cervical carcinoma in situ and a conization was recommended, which the patient refused. She was treated with Ukrain instead. The grading regressed steadily and after one year of Ukrain therapy all stagings were normal. Three years after the start of Ukrain therapy she gave birth to a healthy child. Eight years later she has no recurrence and is healthy.

Breast Cancer from 1996
A patient with breast cancer who was not previously given any therapy before receiving Ukrain had a full clinical remission with 12 years without any oncopathological symptoms.

Breast Cancer with lung metastasis from 1996
A recurrent breast cancer with lung metastases was treated with the new anticancer drug Ukrain. Lymph nodes and lung metastases disappeared. The patient showed a full clinical remission.

Rhabdomyosarcoma from 1996
A six year old child was diagnosed to have a rhabdomyosarcoma of the muscles of the right buttock. Because of impossibility of radiotherapy and chemotherapy, treatment with Ukrain 10 mg i.v. once every two days, 10 injections (100 mg) was instituted. The following clinical effects were recorded: reduced pain in joints, improved appetite and condition, increased physical activity, reduced fever.

Malignant Melanoma from 1996
A patient with a metastasizing malignant melanoma (stage III) was treated with Ukrain monotherapy. Before and during the first Ukrain course of treatment the patient excreted melanin in the urine. After the third course melanin was no more detectable and the patient has been without any symptoms of disease for the last 12 years.
A female patient was treated for a metastatic malignant melanoma. She was treated chemotherapeutically, with interferon, and surgically. After recurrence two years later the chemotherapy regime was changed and Ukrain therapy was administered between the chemotherapy series. The patients multiple metastases in the lungs and a complete remission which lasted at least more than one year was achieved.

Case Series from 1992 with sedative and anti-allergic effects
Preliminary clinical observations and studies on immunological
response-indicators were made in eight patients with malignant tumours, who had been administered parenteral injections of Ukrain. The results suggest that the preparation is a non-toxic immunostimulator inducing production of thymodependent
T lymphocytes. The preparation improves general health of patients, has anti-allergic action, and sedative and anti-inflammatory effects. It can inhibit growth of malignant tumours.

Case Series from 1992, II
Thirty six stage III cancer patients were treated with Ukrain injected intravenously every second day in a dose of 10 mg per
injection. Each patient received 300 mg of the drug (30 injections). The results obtained indicate that Ukrain, in a concentration not cytostatic in normal cells, is cytostatic for malignant ones, and may suppress
the growth of cancer. The compound also has immunoregulatory properties,
regulating the T lymphocyte subsets

Case Reports from 1992
More than 400 documented patients with various cancer types have been treated with Ukrain.The authors report on a 9 year old girl with "untreatable" Ewing Sarcoma, a 58 year old woman with colon cancer with lymph node metastasis and a 69 year women with breast cancer with skeleton metastasis. All were treated with Ukrain with complete remission lasting at least several years as a result.
Case Reports from 1991
Twenty-seven patients with various malignancies were treated with
Ukrain.The study showed an activation of the immune defence in the treated patients as well as a favourable course of their disease and in general well-being.

Other Publications
Debate in the Lancet about how to set up a phase II study 2000-2001
Two english researchers proposed to set up a phase II study on 8 different cancer types with 15 patients in each group testing the effect of ukrain. They claim that the manufacturer of Ukrain, Nowicky pharma refused to participate in this project unless the made a dose finding study on pancreatic cancer instead. One of the issues would be who would fund an independent investigation comittee. The english researchers suspect accuse Nowicky pharma of being afraid performing an objective evaluartion. In the end both sides publicly agreed that tehy want to perform the investifation, but we are still waiting for it the investigation to happen....

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.

Ukrain in healthy volunteers 1992
Phase I of a clinical study of Ukrain was performed in 19 healthy outpatient volunteers. 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.

Phase II trial from 1992
70 patients, ranging in age from 14 to 80 years, were given Ukrain to determine the appropriate dose range for
and the clarification of dose/response relationships, in order to provide
an optimal background for wider therapeutic trials. The patients were treated with different dosages and with different dosage intervals. All patients were at terminal stages of their disease.

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Pre-Clinical Investigations on Ukrain

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Here you can Publish Data on Pre-Clinical Investigations on Ukrain by clicking on "Add child page" below.

Effect on Glioblastoma
Glioblastoma is a very dangerous brain tumor with small chances of survival. Ukrain modulates the activation of certain genes and proteins involved in tumor invasion. After treatment with high dose Ukrain, the concentration of the so-called glial fibrillary acidic protein increased within the cancer cells. There was no effect on the Connexin 43 protein. Ukrain-induced programmed cancer cell death(Apoptosis) were in 4.63 % in low concentration, 10.9 % at medium concentration and 28.9% in high concentration. The Apoptosis was likely to be mediated by release of the substance cytochrome c in the cell cytoplasm(Cell fluids).

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.

Active Substance?
Habermehl with co-workers found Ukrain to be a potent inducer of apoptosis. However, mass spectrometric analysis of Ukrain failed to detect the suggested Ukrain molecule that has been postulated yto mediate the effect of Ukrain. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain.
The potent proapoptotic effects of Ukrain seems not to be due to the suggested "Ukrain-molecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine.Panzer[/b]] with co-researchers also made a study, were
chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry failed to demonstrate the proposed trimeric structure of Ukrain.

Ewing tumors
Using the MTT assay, the cytotoxicity of Ukrain was compared with the cytotoxicity of Chelidonium majus L. alkaloids, and the cancer drugs thiothepa, doxorubicin, cyclophosphamide and etoposide against four human [url=Ewing tumor cell cultures. The sensitivity profile of Ukrain was comparable to that of the C. majus L. alkaloids, and different from that of thioTEPA, cyclophosphamide, etoposide and doxorubicin. This indicates that ukrain might be of use in the treatment of Ewing tumors.

Antidepressant ant 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.

MAO-inhibiting effect
It has been shown that the major alkaloids from plants Chelidonium majus L. and Macleaya (Bocconia) are irreversible inhibitors of oxidative deamination reaction of serotonin and tyramine as substrates, catalyzed by rat liver mitochondrial monoamine oxidase (MAO). Among the examined agents, alkaloid chelidonine and drug "Ukrain" were the strongest inhibitors of the reaction. As it is well known, the MAO inhibitors appear to be, as a rule, pronounced antidepressants. The combination of malignotoxicity and antidepressive activity in drug "Ukrain" seems to be favourable for its clinical applications.

Resistance to ionizing radiation
This studydata give the first mechanistic insights into specific cellular resistance mechanisms behind the cytotoxic and radiosensitivity-modifying effects of the drug Ukrain by showing that fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro.

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.

Effect on alcohol dehydregonase
Ukrain seems to inhibit the enzyme thay breaks down alcohol. This means that there is reason to be careful when combining alcohol and Ukrain.

induktion of apoptosis
The induction of apoptosis by Ukrain was studied in Chinese hamster ovary cells. Ukrain was found to be capable of the in vitro induction of apoptosis in the cell lines studied. The effect was less expressed in cells with multiple drug resistance. Ukrain enhanced the effects of etoposide, i.e., the combined effect of both agents was evident at significantly reduced concentrations. This suggests that pharmacological compositions of the drugs may reduce the effective doses used in chemotherapy and thus significantly diminish its toxic side effects.

Exposure of a prostate cancer cells culture to Ukrain resulted 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 a state of beginning apoptosis. 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.

A method for determination of Ukrain in blood plasma
the main fluorescent component of Ukrain was determined by liquid chromatography . Ukrain was resolved from fluorescent peaks of the sum of alkaloids of Chelidonium majus L. although several peaks of alkaloids were retained in Ukrain as traces. The height of the main peak was nearly constant, while the alkaloid peaks varied depending on the series of the preparation; chelidonine and ThioTEPA gave no peaks. Ukrain possesses neither significant stable binding to plasma proteins nor adsorption in blood cells.

Acute toxicity in rats
The acute toxicity of Ukrain was determined after a single intravenous, intramuscular or oral administration in rats. 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. . In both sexes the intramuscular LD50 was greater than 165 mg active ingredient/kg body weight.

Selective toxicity for cancer cells
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.
Exposure of cultured carcinoma cells to Ukrain resulted in cell growth inhibition and apoptosis at doses as low as 7 microM. In contrast, the same drug concentrations were not affective towards normal human keratinocytes. In order to investigate whether cell cycle control mechanisms are effected in response to Ukrain, we analyzed cell cycle distribution and levels of cyclins and cyclin-dependent kinases in drug treated carcinoma cells. We found alterations in levels of mitotic cyclins A and B1, and cyclin-dependent kinases CDK1 and CDK2, after treatment. We also observed an upregulation of CDK inhibitor p27 in both cancer cell lines which may lead to the G2/M cells accumulation, which in turn leads to apoptosis.

Selective cytotoxic effect on cancer cells
The inhibitory effect of Ukrain on malignant cells and on normal cells, in vitro,
has been compared. To obtain a 50% inhibition of cell growth, a tenfold
concentration had to be used with normal endothelial cells compared to a human
osteosarcoma cell line. A laser scanning microscope showed a high uptake of
Ukrain in malignant cells, while the content in normal cells under the same
experimental conditions was substantially lower.

No selective toxicity for Chelidonine
Chelidonine is one of the major alkaoids found in Greater Celandine.
The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study.

No selective toxicity for Ukrain?
Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. Panzer 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 Panzer have found the antimitotic actions of Ukrain to be reversible in low doses in vitro. He hypothesizes that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling normal cells to overcome the metaphase arrest and survive.

In vitro effect on multiple tumors
A comparative in vitro study between the effects of Ukrain and antitumor drugs cyclophosphamid and cisplatin on total thiol content in Guerin carcinoma, Guerin/cis-DDP carcinoma, and in animal livers was carried out. The cancer cell cytotoxicity of Ukrain was found similar to that of known antitumor drugs.

Effect of Glucose, succinate and temperature on Ukrain activity
The influence of glucose, succinate, and the pH of the medium on the cytotoxic activity of the preparation Ukrain was studied. 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.

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Ukrain: Debated Subjects

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There are many viewpoints of Ukrain, and this is the place were you really can find out what you believe is the truth by turning all the coins and looking at all the arguments.
The Main subjets of debate have been

1. What is the active substance of Ukrain?

2. Do Nowicky Pharma refuse to participate in independent evaluations?

3. Has Ukrain been unfairly blocked to obtain license in Austria and the EU?

4. Do Ukrain have selective toxicity for cancer cells?

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Ukrain Debate 1: What is the active Substance of Ukrain?

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This is a debate about the active substance of Ukrain.
Nowicky Pharma firts proposed that the active substance is a trimeric structure, that in later tests by Panzer and Habermehl have been postulated not to be present.
Panzer says that "Chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry was inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine)", Habermehl is saying that "mass spectrometric analysis of Ukrain failed to detect the suggested Ukrain molecule that has been postulated yto mediate the effect of Ukrain. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain". Nowicky Pharma, the manufacturer of Ukrain declares in their EMEA Orphan Drug License application: "Chelidonine, like some other celandine alkaloids, is hardly soluble in water. This makes intravenous injections impossible. For this reason drugs derived from celandine alkaloids are always administered only orally. In addition, these drugs cannot accumulate in cancer tissue. Ukrain is a Chelidonium majus L.-thiophosphoric acid derivative, a complex reaction mixture of Chelidonium majus L. alkaloids with triethylene-thiophosphoric acid triamide (Thio- TEPA). The injection solution contains Ukrain in a concentration of 1 mg/ml. No Thio-TEPA or free aziridine ring compounds can be detected. The finished product contains still alkaloids, however, in contrast to the starting material, in a water-soluble, injectable, active form".

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