Composition
1 ampoule contains 5 mg Chelidonium majus L. alkaloid - thiophosphoric acid derivative in 5 ml bidistilled water for injection, with a pH range of 3.5 to 5.5.

Properties and efficacy
UKRAIN? is a compound synthesized from Chelidonium majus L. alkaloids and thiophosphoric acid triaziridide. It is malignotoxic (only toxic for malignant cells), immunomodulating and has the following properties:
In vitro experiments demonstrate a direct cytostatic and cytolytic effect of UKRAIN? on malignant cell populations of various origin through the induction of apoptosis (programmed cell death), the inhibition of DNA, RNA and protein synthesis. UKRAIN? influences the apoptosis enzymes through the inhibition of topoisomerases I and II and the activation of Me2+ dependent endodesoxyribonucleases of the lymphocytes in animals and cancer patients. However, this influence is not shown on thrombocytes. UKRAIN? influences oxygen consumption of normal and malignant cells in different ways. In both healthy and tumor cells oxygen consumption is initially increased. The oxygen consumption of healthy cells returns to normal within a short time whereas that of malignant cells stops completely.

In a test panel of the NCI (National Cancer Institute, Bethesda, Maryland USA) UKRAIN? (NSC 631570) 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) with an effective concentration range of approximately 4 mg/ml. Mammary adenocarcinomas in mice (induced by DMBA) can be successfully treated with UKRAIN?.
Laser scanner microscopy has demonstrated that UKRAIN? becomes highly concentrated in the nuclei of malignant cells, especially in the nucleoli. Under the same experimental conditions the concentration of UKRAIN? in normal cells was considerably lower. The characteristic fluorescence of UKRAIN? under UV light can be observed in patients with primary skin cancer and cutaneous metastases.
Activation (modulation or stimulation) of parts of the immune system (effector-target systems) has also been demonstrated on human and animal spleen cells, peripheral lymphocytes and macrophages. A normalisation of the reduced immunological parameters is often observed in oncological patients, such as an improvement in the T4/T8 ratio, activation of NK cells and increases in the migrating and phagocyting abilities of certain leukocyte subpopulations. These properties also classify UKRAIN? as a Biological Response Modifier (BRM).
Reproduction studies on rodents have shown no evidence of cumulative toxicity or any embryotoxic, teratogenic, carcinogenic or mutagenic properties of UKRAIN?. It is not allergenic. The acute toxicity (LD50) of UKRAIN? is between 350 and 400 mg/kg/BW in rodents. UKRAIN? has caused no kinds of toxic, allergic or anaphylactic reactions in patients until now. UKRAIN? therapy has caused no damage to fast proliferating tissue and is not myelosuppressive. No leukopenia, erythrocytopenia, thrombocytopenia, mucosa bleeding or hair loss has been observed. The therapeutic index of UKRAIN? is 1250.
UKRAIN? does not damage normal cell cultures.
The lethal concentration for cancer cells can be increased hundreds of times without demonstrating any damaging effect on normal cells in vitro.
Oncological patients may show a fluctuation of tumor marker values during a UKRAIN? therapy. These changes are indications for the effectiveness of the therapy. UKRAIN? can induce complete or partial regression of tumors and metastases in patients without any cytotoxic effects on normal cells. Sometimes it only induces a long-term stabilisation of the disease process.
During the therapy the tumor tissues show a high selective accumulation with UKRAIN?. In many cases shortly after i.v. or i.m. administration, UKRAIN? can be detected in the area of the malignant process by means of autofluorescence under UV light (strong tumor-affinity of UKRAIN?).
Distribution, metabolism and elimination of UKRAIN? are not fully cleared up in humans. The effect of a kidney or liver deficiency on the elimination of UKRAIN? was not examined.

Applications
Therapy for: adenocarcinomas, especially in the colorectal area, mammary, bladder, prostate, ovary, cervix, endometrium, plate epithelial carcinomas, small cell and non-small cell lung cancer, tumors in head - neck area, testicles carcinomas, sarcomas, malignant melanomas and lymphomas.

Method of administration
UKRAIN? may be administered intravenously or intramuscularly. Intravenous application is to be preferred, if possible.

Guidance on administration
Inject slowly! Not more than 5 ml should be injected in one minute. UKRAIN? should not be added to other injection or infusion solutions.

Dosage
Tests have shown that smaller doses (5 mg) have an immune modulating effect and larger doses (20 mg) a malignocytolytic effect. Because UKRAIN? accumulates in tumor or metastases areas very quickly after injection and influences the immune system of different patients in different ways, the dosage is not selected according to body weight or surface, but according to the immune status of the patient. A single dosage is 5 to 20 mg per injection depending on tumor mass, speed of growth, the extent of the disease and the immune status of the patient.
Injections are normally given twice a week for 5 weeks, followed by a therapy pause of 1 or 2 weeks. Individual variations on this schedule can prove to be useful in certain cases.
In order to establish the optimal dosage for the respective case, one may begin with 5 mg of UKRAIN?. If reactions are observed (see side effects) this dosage should be continued. If reactions decrease or do not appear at all, then the dose is increased by 5 mg per day (up to a maximum of 20 mg twice a week) and the reactions observed. There are also indications that alternate doses of 20 mg and 5 mg twice a week can be successfully applied. Therapy should be carried out until there is a complete tumor remission and reactions and side-effects have disappeared, but not less than 9 series of treatment. Further 6 series of therapy should then be carried out with a pause of 2 to 4 months between each series.

Combination treatment
UKRAIN? therapy can be carried out immediately before and after an operation. The same dosage scheme applies if administered with simultaneous radiotherapy. UKRAIN? can be used in combination as well as adjuvant to chemotherapy.

Contraindications
Pregnancy. Highly febrile status. Expansive processes within the central nervous system should be treated cautiously and only in the clinic because of possible reversible tumor swelling.
Caution is indicated with children in the growing phase.
UKRAIN? should not be applied in conjunction with cortisone derivatives or other immune-suppressive medicaments since these neutralise the immune-stimulating effect of UKRAIN?.
Oncological patients in the terminal stages of the disease with pronounced kachexia have little prospect of successful treatment.

Pregnancy and breast feeding
During pregnancy the application of UKRAIN? should not be carried out, although, until now, no evidence for any kind of injury to the embryo has been found. During and after the UKRAIN therapy, male as well as female patients should take care of reliable contraception. It is not known whether UKRAIN? passes into the mother's milk, that is why breast feeding should be avoided during therapy.

Side effects
UKRAIN? tests on healthy probands showed no side effects.
Side effects in cancer patients during therapy may be explained by the action of tumor degradation products. These disappear when the tumor is in complete remission.
After the first injection some of the following side effects may appear:
local: reddening, swelling and pain at the site of an intramuscular injection
systemic: dizziness, depression, insomnia, sleepiness, general fatigue, restlessness, apathy and especially at the beginning of therapy, increased fluid requirement, increased urination, tension, tingling sensations, stabbing pains, itching, feeling of warmth, burning and/or dragging pains in the tumor area, heavy perspiration and shivering.
In some cases a slight nausea occurs at the beginning of therapy. A temporary swelling and/or hardening of tumors may also occur. These side effects vary from individual to individual and indicate that the patient is responding to therapy. They fade away as the tumor mass regresses. These side effects can be explained by the release of tissue toxins as the tumor decomposes. Therapy should be continued until these side effects have completely disappeared, even when there is no further evidence of a tumor.

Interactions
UKRAIN? may increase or decrease the mechanism of action of other medicaments. Medicaments containing sulphur such as antidiabetica (sulfonyl-urea-derivates) may cause hypoglycemia and lead to fainting. Preparations containing digitalis may cause serious ECG changes and sulphonamides may lose their effect.
Animal tests have demonstrated a reduction in the pharmacological action of morphine derivatives. The use of this group must be considered cautiously.

Acquired tolerance
None known at present.

Special warnings for safe application
In phase 1 tests with high-dosage UKRAIN? therapy healthy probands were injected with 5 - 50 mg injections. No signs of intolerance appeared.
Especially in the case of large tumors, indirect signs of intoxication can appear as a result of the decomposition products from the tumor. This can lead to especially strong side-effects such as itching and skin rashes. Patients with kidney deficiencies should be well observed. In such cases the breaks between injections should be lengthened.
Apart from the risk of swelling and/or increased pressure in cases of tumors in the central nervous system during the application of UKRAIN? as well as a possible reduction in the state of consciousness, no warnings are necessary.
A quiet style of life with abstinence from nicotine and alcohol is to be specially recommended during and after therapy. Healthy nutrition and the possible substitution of vitamins and trace elements can assist the healing process. Stress must be avoided, since the adrenaline release has a negative effect on UKRAIN?. If at all possible, the patient should take time off work, at least during the first series of therapy. All physical activities, either at work or in sports should be avoided during treatment.
Attentiveness and reaction times (the ability to operate machines or to drive vehicles) may be impaired. Caution is required in all activities which require concentration. The patient must be advised about this.
Although there are no signs of impairment of growth or other disturbances in children and young people, the indication conditions must be considered very carefully.
Pre-treatment with UKRAIN? may considerably facilitate surgery in many cases by demarcation and/or a reduction in tumor mass. Treatment should be continued after the operation.

Package size
1 ampoule
10 ampoules

Shelf life
48 months

Storage instructions
Do not store above 25 °C. Protect from light and store in the outer package. When temporarily stored at low temperatures a precipitate may develop. Cautious warming to 60 °C and shaking will dissolve it.