Active substance: thiophosphoric acid derivative of Chelidonium majus L.

UKRAIN is a kind of alkaloid which is extracted from great celandine in general. Numberless scientists have demonstrated the method that cancer cells are destroyed in the way of programmed cancer cell death, on the premise of not attacking healthy cells. And the therapeutic dose has no obvious side effects.

The treatment effect brought by UKRAIN is the reaction among properties of numerous types of ingredients. Different from the traditional chemo-treatment, inhibitory action from UKRAIN is within the tumor cells, and the healthy cells are not hurt. That is where UKRAIN's excellent quality comes from.

UKRAIN adjusts the body's immunologic system; therefore, the body's resource can fight with the tumor by itself.

Meanwhile, UKRAIN inhibited the formation of new capillary vessels. Tumors and nutrition are transported through the vessels, and the single tumors spread to other tissues through vessels. In this way, tumor is in a hunger state, and the formation of metastatic tumor is inhibited.

In term of the characteristics antiangiogenic gene, injected before the operation, UKRAIN can encircle the tumors; that's why UKRAIN can improve the applicability of operation greatly. In the late period, the application of UKRAIN can inhibit the formation of metastatic tumors effectively.

191 scientists from 19 countries and 56 universities and research institutes have experimented on UKRAIN, and published their research results in more than 188 kinds of science periodicals, which indicate the importance of UKRAIN in the treatment of cancer.

UKRAIN's clinical trial phase I
19 healthy volunteers mainlined UKRAIN, once every 1-3 days, 5-50 mg every time, and for 7-40 days. The testees did not show any changes, including physiological aspect, such as the temperature, the pulse, blood pressure, electrocardiogram, and so on, and the aspect of laboratory inspections, including blood and urine examination, electrolyte, all kinds of enzymes, antigens, immunoglobulins, plasma protein (consisting of its proportion), microelements and so on. The testees all had very good tolerance, no local reactions, no allergy and other discomforts. Some testees had slight hypersomnia, and the temperature of one or two of the testees went up. Among them, one person, taking this medicine for 3 years, amounting to 3500mg, did not suffer ill-effect.

Control test of UKRAIN with gemcitabine in treating the pancreatic cancer of late stage (phase III clinical trial)
Research unit: Germany ULM University Doc. Frank Gansauge
Object of study: 90 patients, suffering unresectable pancreatic cancer proved by histology
Group A, 30 persons, gemcitabine 1000mg/m2 every week, 7 weeks treatment, 1 week rest, from 2-12 weeks, 3 weeks treatment, and 1 week rest
Group B, 30 persons, UKRAIN 20mg iv, 7 weeks treatment, 1 week rest, from 2 to 12 weeks, 3 weeks treatment, and 1 week rest
Group C, 30 persons, 7 weeks gemcitabine 1000mg/m2, then UKRAIN 20mg iv every week, 1 week rest, from 2 to 12 weeks, 3 weeks treatment, and 1 week rest
Group B and C, first UKRAIN20mg/day, 5 days later, therapy begins

　　All patients were given vitamin.
　　Reaction(3months later)　　　　　 UKRAIN 　　　　　gemcitabine 　　　UKRAIN+ gemcitabine
　　　　CR 　　　　　　　　　　　　　0/20(0%) 　　　　　0/28(0%) 　　　　　　0/28（0%）
　　　　PR 　　　　　　　　　　　　　2/20(10%)　　　　　1/28(4%) 　　　　　　6/28（21%）
　　　　PD 　　　　　　　　　　　　　5/20(25% 　　　　　19/28(68%) 　　　　　5/28（18%）

　　（CR complete remission，PR part remission，SD stable disease，PD pejorative disease）

　　
　　UKRAIN cures pancreatic cancer of late stage

　　Distribution of the patients contracting colorectal cancer according to TNM staging
　
　　Control test of UKRAIN with 5-Fu and radiotherapy in treating the colorectal cancer (Clinical Trail PhaseIII )
　　Research Unit: Ukrainian national University
　　5-Fu+Radiation: 5Gy/day radiation for 5 day, 600 mg/m2/day 5-Fu for as much as 5 g.
　　UKRAIN: 10 mg iv on every other day for as much as 40 mg before the operation; 10 mg iv on every other day after the operation; 10 mg on every other day 10 times.
　　Patients' reaction towards the UKRAIN therapy
　　Group I: After injection for 5-6 times, the conditions of all the cases' body(100%) become better all over, the toxity begins to bring less effect, their fatigue becomes less, they vomit less and reobtain their appetite. They feel less subpycetogenic and have a better sleep. 10 patients hemorhage less in their intestinum rectum, have easier defecation and the topalgia abates after 2 courses of UKRAIN treatment, Karnofsky index goes up from 60.7 to 72.9.
Group II: the conditions of 30 cases' body become better. (90.9%)
　　In the 2 above groups, UKRAIn has no toxity according to WHO Standard. The temperatures of 3 patients go up to 38℃ at the time of the first 3 injections, but after the injections, they went down to normal.
　　Patients' reaction towards 5-Fu therapy
　　14/15(93.3%) of the control group I, and 29/33(87.3%) of the control group II have a worse appetite and sleep, and toxity effects, such as fatigue, nausea, or lethargy, appear. Local effect takes place in 3 patients who receive X-ray therapy (9.1%). Kamofsky index drops after the 5-Fu treatment. The index of group I goes down from 63.6 to 55, and group II from 70.3 to 65.6. The toxity could be tested out in the liver, kidney, and nerve of the body of 32/48(67%) patients; 3 cases die from toxity after only 1 course of 5-Fu treatment.

　　Average value of the variation in the hematology, immunology, and biochemistry
　　
　　Average value of the variation in the hematology, immunology, and biochemistry
　　

　　Average value of the variation in the hematology, immunology, and biochemistry

　　
　　Variation of parameter of haematology, immunology and biochemistry after the UKRAIN therapy for the colorectal cancer (the average value)
　　1. The amount of peripheral blood lymphocytes increases.
　　2. The amount of T-lymphocytes and B-lymphocytes increases.
　　3. The amount of T accessory lymphocytes and T suppressors increases.
　　4. The activity of NK cells increases.
　　5. The amount of large granular lymphocytes increases.
　　6. Phagocytic activity and index increases.
　　7. Biochemical parameter does not drop.

　　Control test of UKRAIN with 5-Fu and radiotherapy in treating colorectal cancer(Clinical Trail Phase III)
　　
　　203 patients suffering from all kinds of tumor of late stage were treated by UKRAIN therapy. Professor Aschholf in Villamedica Hospital in Germany treated 203 patients of all kinds of cancer of late stage which have treated unsuccessfully in traditional way. Local deep hyperthermal therapy is also taken to treat 76 patients(37.4%) at the same time, heating the tumor tissues to more than 42.5℃. The tumor treatment is also supplemented with Selen, Cimedidine, the extract from Grass Bouquet Perfume Compound and Vitamin A. Outcome of the treatment: 41patient (20.2%) get complete remission, 122 patients (60.1%) partial remission. And only 40(19.7%) have no response to the therapy. The reaction rate of apermatocytoma(3/4 CR, 1/4 PR) and prostate cancer(70% CR, 5% PR) are the highest.

　　UKRAIN is used to treat Ewing's sarcoma.9-year-old girl suffering from Ewing's sarcoma had been treated unsuccessfully by radiotherapy. And later she was treated by radiochemtherapy for 1.5 years altogether (2 EVAIA, 12 VAIA), but the exacerbation of the tumor was brought on. From this time on, the UKRAIN therapy was taken, in one course of which 15 mg iv was used for 10 times on every other day in addition to local heating. Treatment of 3 courses was taken during 8 months, and 6 weeks later the tumor did not show signs of growth. 8 months later she came to complete remission.

　　UKRAIN's effect on killing tumor cells The tumor cells concentration is between 7.6μg/ml and 76.0μg/ml. 5-Fu does not show inhibiting activity when its concentration is higher than that of 100-1000 times, and does not show lathality even at a quite high concentration. But UKRAIN begins to show lathality at about 760μg/ml.

　　UKRAIN has the property of following the trail of tumor cells then killing them. UKRAIN can give out fluorescence. The check of fluorescence to the malignant cells shows that UKRAIN has a strong affinity for the material in cancerous nuclei, but no affinity for that in normal cells. Seen with ultraviolet microscope, the nuclei of malignant tumor cells have a strong affinity for UKRAIN, but no affinity for that of normal cells.

　　UKRAIN has selective toxic effect on tumor cells. UKRAIN of different dosage (0.1, 1.0, 10, and 100) was put into human and animal cell lines of different origins (including normal cells and cancer cells). The effect of UKRAIN on the synthesis of the cell DNA, RNA, and protein was studied by means of putting the maker thymidine, uridine, and lececine into the cell lines. The cell DNA, RNA, and protein are more conspicuous than that of normal cell DNA, RNA, and protein. UKRAIN of different dosage brings no toxic effect on normal cells (even those of high copy rate), but the growth inhibiting phenomenon was always seen with regard to the cancer cell lines.

　　UKRAIN arrests angiogenesis. In-tro test: UKRAIN (about 15-75μg/ml) can also arrest angiogenesis. UKRAIN has strong inhibiting effect on the in-vitro formation of capillary from endothelium. This inhibiting effect is reversible-endothelium can form into capillary when put into fresh culture medium without UKRAIN.
UKRAIN of high concentration(50μg/ml) could almost inhibit the angiogenesis totally(＞90%), but has no toxic effect on the normal cells.

　　UKRAIN induce apoptosis of tumor cells
　　Roublevskaia,etc（2000）have reported that after the treatment of UKRAIN（3.5-17.5μm） , the LNCAPcells of human prostate cancer cell line had a cancer cell growth inhibition rate of 75% and stopped at G2/M phase, while only 10% of those of the control group were at G2/M phase. The function that UKRAIN can increase the number of apoptotic tumor cells are correlative to dose.
　　The immuno-modulating effect of UKRAIN
　　The effect of UKRAIN to normal human lymphocyte have been proved in both in-vivo and in-vitro tests. Incubating UKRAIN together with lymphocyte can generate direct immuno-modulating effect and make lymphocyte express more T-accessary cells phenotype and less T-suppressor cells phenotype.
　　After repeated injection of UKARIN to 138 thymectomized mice, the number of T lymphocyte in peripheral blood increased three times; granular lymphocyte increased 5.5 times. The activity of NK cells increased notably(p<0.05), and phagocytosis was also strengthened. There were also a remarkable increase in interferon-alfa and antibody secretion cells. The dosage corresponds to the 5mg therapeutic dosage for human(computed in 70kg/weight), revealing positive immuno-modulating effect.
　　UKRAIN did have mice in-vivo tests to prove its immuno-modulating effect. After prophylactic injection of UKRAIN, there were still a high level of survival rate of mice that have infected staphylococcus aureus of diploid LD50, peccant Escherichia coli and Influenzavirus.

　　In-vivo tests on animals
　　showing UKRAIN's apoptotic effect to cancer cells
　　The DI-DMBA-3 model of rat's rapidly proliferating breast cancer is used to observe UKRAIN's effect to the growth of D1-DBMA-3 breast cancer. The 14th day after inoculating tumor, inject 4mg UKRAIN each day through intravenous administration. Fourteen days after that, it can be observed that the growth of the tumor was inhibited effectively（P<0.05）, while the tumor in control group kept growing. As to mice that were implanted with Lewis cancer cells, UKRAIN can inhibit the growth and transfer of primary tumor. After 25-30 days of UKRAIN treatment(1mg/kg weight, subcutaneous injection), the volume of the tumor in the mice became much smaller than those of the control group. On the 33rd day, the number and volume of the shifted tumor in the lung decreased largely in comparison with the control group. The growth inhibition and transfer inhibition index of the tumor are respectively 71.5% and 73.07%. Pharmecokinetics study showed that after intramuscular injection of UKRAIN to 44 rats, UKRAIN was distributed in an instance into body fluid (t1/2 α=13.5+0.84min). About 65% of UKRAIN is in blood and humor (Vd=34.72+0.447). UKRAIN is a kind of rapidly clearing medicine ( t1/2β =114.62min）, which is discharged mainly from kidney. The output from kidney each day is, on average, 55% of the medication. Half of the output can be discharged in the first 7-10 hours. The latter has the same situation with the disappearance of UKRAIN from blood plasma(5 hours after injecting UKRAIN, it can not be detected in blood plasma). Therefore, it can be presumed that UKRAIN does not undergo metabolism in human body.
　　In various researches about UKRAIN's effect to the central nervous system, it is evidenced that UKRAIN could permeate blood-brain barrier.
　　Research on the pharmacokinetics of W-256 tumor-bearing rats
　　After injecting one dose of UKRAIN through intravenous administration, that is 0.25mg/kg, it did not fix on to the surfaces of plasma proteins or blood corpuscles. Its concentration ratios in cor, liver, brain, lung and muscles are all very low, similar to that of plasma, or even lower. Its concentration in kidney is relatively high, probably due to the reason of excretion. The highest level of concentration is in tumor tissues, reaching 2.84 times as high as that of plasma.

　　The research on UKRAIN's acute toxicity
　　
　　Judging from the LD50 numbers, the acute toxicity of UKRAIN is very low. The therapeutic dosage for human is between 5mg and 20mg, equals to the dosage of 0.07-0.3mg/kg weight, which is much lower than the LD50 numbers detected from animal tests. Therefore, the dosage for human is safe.

　　The speed of intravenous injection should be slow
　　In preliminary tests, when using intravenous injection to 136 rats in order to observe the acute toxicity of UKRAIN, we found that the speed of injection was also associated to the response of toxicity. When rats were injected 50mg/kg weight UKRAIN at a high speed, their breathing time decreased from 110/min t o 35/min. But if they were injected at a lower speed (more than half minute) the same dosage, the rats were generally in a stable state.
The toxicity after repeated medication (three months)
　　
　　 Results after three months' toxicity test
　　Mortality: at the highest level of dosage, 3 masculine and 3 feminine animals died respectively on the 3rd, 4th, 14th day and 1st, 4th, 6th day. The cause of death has not been reported. Blood cell counting shows that with the increase of dosage, blood disks and segmented white blood cells with statistic sense decreased. The total amount of white blood cells increased with the increase of dosage, only seen in masculine animals, and the increase of dose related lymphocyte and monocyte were seen in both sexes.
　　Histology (3 months): one animal from each of the 0.3mg and 1.5mg groups showed mild dural hemorrhage, and two from the 1.5mg group and one from the 3mg group developed the phenomenon that the microglia cells aggregated slightly around blood vessels. In spite of these, there were no other changes related to treatment.
　　6 months' research on rabbits (vein): apply intravenous injection every day for 6 months. The lower dosage is 0.07mg/kg, middle level dosage is 0.30mg/kg, and higher dosage is 0.70mg/kg. Each dosage group includes 12 rabbits. Both masculine and feminine animals constitute half of a group.
　　Important outcomes: all the following had no change after treatment: weight, heart rate, respiration rate, food consumption, general activity and response, audition, vision, hemology parameter and blood chemical parameter. The ingestion of water did not change in lower and middle level dosage groups, but in higher dosage group, it increased at a certain time point. The situation happened on both masculine and feminine animals, during convalescence or not. Most animals had no change in urinalysis after treatment, only several of higher dosage group had a high rate of "white urine". In histopathology, the medulla(breast bone): low cellulous(both masculine and feminine in middle level dosage group, masculine in high dosage group), megacaryocyte lost activity(masculine in higher dosage group), compaction(masculine in middle level dosage group), cytolysis(masculine in middle level dosage group). The kidney: there were no obvious difference between higher dosage group and control group during convalescence in proximal convoluted tubule and spondylosis of epithelial cells(both masculine and feminine in higher dosage group). This shows that the above changes are reversible. The weights of organs had no change on the whole after treatment. But compared with those of control group, the weight of brain, cor, liver and level of adrenaline in higher dosage group were a little bit higher during convalescence.
　　Pharmacologic and toxicologic results
　　UKRAIN could be toleranced very well in all the tests. But it should be paid attention to that the spleens of rats were enlarged obviously and dopamine in brain tissue decreased. The decrease of automatic movement that were observed can be considered as a sign of retardation of response though the coordinated action was not affected. This should, as recommended, be listed in the warnings of the product. There were observable however rather low decrease of platelet in middle and higher dosage groups, which should also be paid attention to.
　　The increasing total amount of white blood cell in blood united with other research results on its proportional distribution shows that the immuno-modulating effect of UKRAIN could be seen as a positive effect.
　　Reproduction toxicity
　　The embryotoxicity and teratogenesis of UKRAIN were tested on hamsters and rats. The dosage is 0.1, 1.67 and 28mg/kg weight. The higher dosage is 100 times as much as the therapeutic dosage of human. Results: rats, no embryotoxicity or teratogenesis were observant. No teratogenesis was observed on hamsters, but low embryotoxicity (P<0.05) was observed in lower and higher dosage groups. And the amounts of corpus luteum, implantation and fetus all decreased.
　　Genotoxicity:
　　including the following experiment results:
　　-- AMES-test on salmonella typhosa TA97A，TA98，TA100，TA102，TA15335
　　-- Transformation test, using the embryo cells of hamsters for primary cultivation
　　-- Micronucleus test results on mice
　　Results: all the above tests results are negative. Local irritation observation: observe the irritation response of rabbits after one intravenous, intra-arterial, perivenous or intramuscular injection. Research shows that intravenous of intra-arterial injection of 5mg/5ml could be tolerated. But perivenous injection can cause mild to moderate irritation response, and the muscular after injection can appear mild to moderate local inflammation.
　　Stability test of UKRAIN
　　Three UKRAIN ampoule of continuous lot numbers, with the density of 5mg/5ml.
　　Tests were conducted by placing UKRAIN in a climate-control chamber set according to the ICH standard. Temperature 25℃, humidity 60%, 60 months indoor.
　　Results: it was observed that after the 60 months' stability test, UKRAIN was stable in the first 48months：the pH is 3.12-3.30，the density is 0.99999，asepsis；injectable volume is 5.057ml；no pyrogen；UKRAIN TLC analysis：content in 48 months≥100%. No sediment. Sediment appeared after 60 months.
　　A summary of UKRAIN
　　1. UKRAIN has selective toxic effect on all kinds of cancer cells. It inhibits the microtubule polymerization of cancer cells, making the cancer cells stay at the G2/M phase and accelerating the apoptosis of cancer cells. The inhibiting effect on synthesis of malignant cells RNA, DNA, and protein is more conspicuous than that of normal cells. The toxic effect of UKRAIN on cancer cells is 100 times stronger than that on normal cells. Generally, there is only a subtle difference between therapeutic dose and toxic dose of inhibiting-cell medicine, but the therapeutic index of UKRAIN is 1250.
　　2. UKRAIN has the effect of targeting tumor cells. Intravenously injected UKRAIN assembles in the tumor locus. When the tumor locus in the operation or the skin carcinoma is irradiated by ultraviolet rays, it can be seen with naked eye the fluorescence given out by UKRAIN that assembled in the tumor locus. Meanwhile, normal tissues do no show fluorescence.
　　3. UKRAIN inhibits the angiogenesis in the tumor locus. After 2-4 weeks of treatment, the envelop was formed around the bigger tumor, so it became easier to resect the tissue.
　　4. UKRAIN has the effect of strengthening the function of immune system. During treatment, the total amount of the peripheral lymphocyte of the patients increased. The proportion of T-accessary cells to T-suppressor cells also increased. And the effect of macrophage was also strengthened.
　　5. Patients' quality of life were improved. During treatment, their appetite increased, their sleeping state were improved, and there was no bone marrow transplantation phenomenon. UKRAIN has the effect of relieving the pains, leading to the reduction of dosage of morphine.
　　6. UKRAIN has special affinity to tumor cells. Consequently, we can adopt other calculation methods other than calculating the dosage according to the body surface area. Therefore, the dosage needed is relatively low.
　　7. During the treatment, the discomfort that patients may go through should be imputed to the toxicity produced in the process of degradation of tumor necrosis. Because these symptoms can not seen in the healthy people tests and would disappear along with the disappearance of tumor.