NIR Research and Product Company Kiev, Ukraine (стр. 3 )

7. Conclusion

The present investigation is a more painstaking phase of studying clinical efficacy of the drug Bipexumâ. Brain cancers have been investigated to which end operation was performed / spared and Bipexumâ therapy was given along with chemotherapy and radiation therapy.

Along with clinical studies and assays, CAT, MR-scanning, echoencephalography and cerebral angiography were performed.

The findings showed that the drug is well tolerated as only 8 patients gave inordinate skin response at the site of administration that disappeared within some hours without resorting to any additional drugs. As administering the drug, no facilitated tumour growth is observed.

Our investigational results demonstrate that it is preferable to administer Bipexumâ jointly with cytostatics such as chlofiden, nitrosoureas and along with gamma teletherapy.

In this way, Bipexumâ is an efficacious drug to use along with cytostatic chemo - and radiation therapy of brain cancers as a preventive against haemopoietic hypoplasia that often curbs using effective doses in radiation and chemotherapy, and a drug improving the patient's quality of life and tolerance to antiblastic therapy.

Researchers:

Second-in-Research Candidate of Medicine	Ye. A. Annin
Key Researcher Candidate of Biology	G. M. Oleynik

BIPEXUM® INJECTION POST-LICENSE USE. BACKGROUND USE OF BIPEXUM® IN NEUROONCOLOGY

Ye. A. Annin, Candidate of Medicine,

Second-in-Research

Practical Research Centre of Endovascular Neuroradiosurgery

Combating brain cancers is one of the most formidable challenges faced by contemporary neurooncology. Glioblastoma and anaplastic astrocytoma are the most common primary brain tumours in adults. The optimal therapy scheme based on information pertaining to the gliomas' biological nature and the relevant clinical experience involves the best safe resection of cancer with subsequent chemo - and radiation therapy. Presently, BCNU, CCNU, procarbazine, vincristine are the most resorted-to anticancer drugs.

Nevertheless, surgical intervention and giving radiation and chemotherapy along with the said drugs produce the following results: survival median for glioblastomas is about 10 months, whereas that for anaplastic astrocytomas totals 2-3 years.

This is why finding new efficacious anticancer drugs. One of these is Bipexumâ. The drug contains the optimal set of free amino acids, native peptides, products of the controlled proteolysis of proteins and embryonal tissues dissolved in isotonic sodium chloride solution with a preservative added. As far as its pharmacological properties are concerned, the drug belongs to metabolic agents having anticancer and immunomodulating action. The mean of fatal outcomes caused by Bipexum'sâ toxicity shows it to be safe irrespective of the mode it is administered. The 'acute' experiment on rodents was carried out to demonstrate that the drug's biologically active properties along with good assimilability (parenteral administration and inhalation) were accompanied by neither skin-irritating, toxic-as-inhaled nor cumulative action. Given Bipexum'sâ subtle species sensitivity factor, the drug's safety-related data can be extrapolated to humans. As administered parenterally to chronic experimental animals, Bipexumâ has biological activity that signals specific stimulation of protective and adaptational mechanisms in organs and systems by influencing the macrophagic system

One hundred forty-four mice were experimented upon. Tissue of cancers (anaplastic astrocytomas) isolated when performing operations was implanted under the capsule of the kidney of mice put to sleep by producing hexenal narcosis using 3-D magnifier under aseptic conditions. At the start, minced tumour weighed 1 mg. Four mice were taken each time to make the experimental group, and 6 operated animals were taken to make the control one. In 3 days, the tumour was tested for its growth and then the animals were treated with Bipexumâ. Afterwards, the drug was administered intraperitoneally at a dose equivalent to LD10 for three days. Having advanced into the seventh day after cancer transplantation, mice were killed by neck dislocation. The effectiveness of treating animal cancers was assayed based on the tumour growth inhibition.

Histologically studying primary tumours, II-III astrocytomas were diagnosed. The cancer was deemed susceptible to the investigational drug, if its growth was inhibited by over 25 %.

Control studies were done to reveal the 98 % growth of material of cancers transplanted under the capsule of the immunocompetent mouse kidney. This is evidenced by the definite increase in cancer's weight up to 2.63 ± 0.079 mg as it advanced into the 7th day after transplantation.

As studied histologically, the pattern of control heterotransplants in the sub-capsule space was identical to the structure of primary tumours and degree of their anaplasia. Control studies were done to reveal cancer tissue histologically characterised by the dense cell structure formed by cancer cells having markedly polymorphous nuclei. Nucleus chromatin turned out to be fine and dense, with 1-2 pathologic mitoses occurring in a preparation. Cytoplasm was poor and distinctly observable in loose tumoural patches. Tumour cells were triangular or bipolar having short conical processes that represents their astrocytic differentiation. The line where cancers and the underlying kidney met was mostly solid occasionally displaying the infiltrative character of cancer invading the kidney parenchyma.

As demonstrated by this experimental model, the per cent alteration in the weight of treated glioma heterotransplants as compared with the control represents inhibited growth of these tumours. The effectiveness of influencing glioma heterotransplants under the capsule of mouse kidney was measured based on the way their weight varied. The results are presented in table 1.

Table 1

The Way Weight of Sub-Capsular Transplants of Human Brain Gliomas Varies as a Result of Bipexum'sâ Action

No.	Treatment	Cancer Weight, mg (М ± m)
1	Control	2.63 ± 0.079
2	Bipexum®	1.37 ± 0.118

The obtained data show that the weight of cancer heterotransplants exposed to Bipexumâ decreases down to 1.37 ± 0.118 mg that is equivalent to 49.2 % inhibition of their growth.

The way glioma cells and tissues react to the treatment with the potential anticancer drug Bipexumâ when using sub-capsular test was compared and contrasted histologically to display the direct relationship between manifestness of regressive transformations in gliomas and the level of inhibition of their growth.

Based on experiments intended to study the drug Bipexumâ, histological studies showed that superficial parts of cancer heterotransplants newly incorporated no-cell areas, as well as focal and diffuse accumulations of tumour cells displaying toxic damages to nuclei: deformation, pyknosis, chromatolysis. Here and there, the cancer tissue is separated revealing destruction areas in the malignant parenchyma and exposed stroma. Leukocytic infiltrates can be seen around vessels. Infiltrative growth is still signalled by central masses of heterotransplants betraying no mitoses.

In this way, investigational results demonstrated that, as tested by sub-capsular method, II-III gliomas display sharply signalled susceptibility to Bipexumâ by betraying greatly damaged cancer. Histologically, cured gliomas show widely ranging cytotoxic transformations and disorganised microarchitectonics of the glioma’s tissue.

Based on our experimental morphological study using sub-capsular test, there is overt anticancer effect joined by superb growth inhibition that was proved by the morphological control.

Open clinical trial has been conducted by treating 74 patients having brain cancers. Fifteen of these were given therapy by the neurosurgical division in the employ of the I. I. Mechnikov Dnepropetrovsk Oblast Clinical Hospital. The patients received inpatient therapy. As the control group, 40 patients with brain cancers were tested. They received either chemotherapy or radiation therapy. All patients complained of general weakness, sleepiness, headache, nausea. Diagnosis was made based on clinical findings, CAT, MR-scanning, cerebral angiography and echoencephalography.

The effort was put forth using the following investigational methods:

a) clinical assays: complete blood count and urine test, liver function tests, total protein, protein fractions, sulphhydryl groups, blood electrolytes, hematocrit, blood sugar, creatinine, immunologic indices;

b) using clinical instrumentation: computerised axial tomography performed on everybody concerned once two months.

Bipexumâ was administered to combat histologically proved neuroectodermal (glial) brain II-III cancers as identified by the international histological C. N.S. cancer classification. They largely consisted of anaplastic astrocytomas (51 %) and histoblastomas (33 %). Once in a while, anaplastic oligodendrogliomas, cancer metastases, and medulloblastomas were diagnosed.

Bipexumâ has been administered to 74 patients with brain cancers, the figure that was made of 28 women and 46 men at 4 to 46 years of age. Most patients were given multimodality therapy involving surgical removal of cancer and Bipexumâ cure along with chemotherapy (57 individuals) with drugs broteofin, chlofiden and belustin. Given deep-seatedness and no hypertension syndrome betrayed, 17 patients received no operative therapy. Also gamma telemetry was performed on 33 patients.

Two millilitres of Bipexumâ were administered intramuscularly starting from 5-7 days after surgical intervention. The total dose was 20 ml. Administrations were intermitted every 24 hours. Therapeutic effectiveness was assayed based on how life expectancy extended, as well as what was found out by scanning the dynamics of the clinical presentation of the disease, neuroophtalmological monitoring, MR-scanning, computerised axial tomography and echoencephalography.

The investigational effort showed that condition of the control group receiving no Bipexumâ naturally deteriorated in the course of radiation and chemotherapy that appeared in increasingly aggravated obnubilation, poor appetite, nausea, vomiting, advanced general weakness. The group showed statistically confident decrease in the number of blood leukocytes, as well as somewhat reduced haemoglobin, lymphocytes and ESR.

The main group's habitus was fairly good and moderately impaired. As receiving the drug therapy, patients showed no aggravated condition. After Bipexumâ therapy, based on CAT and MR-scanning, brain edema and dislocation syndrome got relieved, appetite was invigorated and motor performance improved. Five patients receiving Bipexumâ relapsed 3 months after performing the operation for sub-total cancer removal. The way Bipexumâ therapy influenced the status of blood profile factors in brain cancer patients was studied to display marked alterations neither in haemoglobin, number of erythrocytes / leukocytes nor ESR. Stability of these factors proves Bipexumâ having no ghost effect on haemopoietic processes. After Bipexumâ therapy, complete urine test factors did not go beyond normal values.

Mean values of biochemical plasma indices measured in patients with brain cancers after their receiving Bipexumâ therapy displayed no statistically confident alterations as compared with those before therapy.

The control group’s biochemical plasma indices did not statistically changed either, however, some decrease in hematocrit and electrolytes and increase in creatinine and non-protein nitrogen were noted.

Based on the level of the activity of AST and ALT enzymes, the soundness of liver function is found out. Significant increase in the said enzymes' activity in the blood, as a rule, signals severe liver damages, death of the large number of hepatocytes or badly impaired permeability of cell membranes.

Individually analysing alterations in parameters of the main group after administering Bipexumâ it was found that the activity of plasma transaminases reduced in 80 % of those concerned to show that liver function improved.

Plasma AST and ALT activity in the brain cancer control group has been studied to disclose statistically confident increase in the activity of the said enzymes.

Findings of plasma protein exchange in patients with brain cancers assigned to the main group were studied to signal slackened processes engaged in protein synthesis and the drug having anticancer activity. Bipexumâ-caused alterations in plasma protein fractions of the main group have been individually analysed to display, in 80 % of those concerned, increase in both albumin content proving healthier liver function, and γ-globulin fraction of immunoglobulins that can be regarded as a factor contributing to strengthened klendusity.

Studying immunologic indices it was shown that individuals assigned to the main group had no negative dynamics of such, whereas those from the control group betrayed manifested negative dynamics as chemotherapy and radiation therapy suppress bodily immunoprotection.

In general, clinical assays show that Bipexumâ therapy for brain cancers had marked impact neither on haemopoietic processes nor nitrogen-isolating function of kidneys, but rather demonstrated moderate hepatoprotective and anticancer effect and strengthened immunity.

In this way, Bipexumâ is an efficacious drug to use along with cytostatic chemo - and radiation therapy of brain cancers as a preventive against haemopoietic hypoplasia that often curbs using effective doses in radiation and chemotherapy, and a drug improving the patient's quality of life and tolerance to antiblastic therapy.

USE OF THE DRUG BIPEXUM® IN TREATING BRAIN AND SPINAL CORD METASTASES

S. A. Sivkovich

M. D.

Head of Systemic Cancer Clinic

Academy of Medical Sciences of Ukraine's

Institute of Oncology

Combating cancers is a complex and, now and then, hard-to-be-solved problem. Nevertheless, the research state of the art allows oncologists to successfully deal with this challenge. For example, speaking about a heterogeneous group of diseases such as cancers of hematopoietic and lymphoid tissues, it can be said with every confidence that, if the pathological process advances not beyond the first or second stage, the full recovery from this severe morbus can be attained.

The most vigorous treatment is characteristic of diseases when tumourous process invades the brain and the cancer metastasises in the spinal cord. In these cases, therapy calls for multimodality approach administering, along with conventional anticancer drugs, those belonging to various pharmacological groups, for example, fetotherapeutic drugs.

Combating different cancerous brain and spinal cord damages, we are widely using Bipexumâ, an example of the fetoformulated drug. The drug's base makes it well tolerated and, what is the main point, has no damaging impact upon organs and systems.

The systemic cancer division uses Bipexumâ along with radiotherapy and chemotherapy for malignant lymphomas damaging the brain and spinal way of example, let us scan the case history of female patient S. admitted to the division in extremely grave, as a matter of fact, hopeless condition. Apart from totally damaged bony tissue (backbone, hip bones, skull), she revealed brain parietal lobe cancer. She presented with staccato speech, headache, episodic amnesia. After multimodality therapy using Bipexumâ, she left and, presently, is put on rehabilitation.

In this way, introducing Bipexumâ into the therapy for malignant lymphomas damaging the brain and spinal cord augurs well for combating this group of diseases.

ASPECTS OF TREATING MALIGNANT LYMPHOMAS*

S. A. Sivkovich

M. D.

Head of Systemic Cancer Clinic

Academy of Medical Sciences of Ukraine's

Institute of Oncology

The standard therapy for malignant lymphomas is aimed at stabilising malignant process, as well as curing the patient suffering from this severe morbus.

Numerous prolonged polychemotherapy programmes, remote gamma teletherapy, besides a positive effect of reducing the tumour, as well has general toxic action vis-a-vis the macro-organism. This appears in arising of agranulocytosis, allergic hepatitis, chronic pyelonephritis. Therefore, in order to effectively cure malignant lymphomas (attaining enduring remissions, healing patients, minimising toxic effect of chemo - and radiotherapy), various drugs are used that, although they represent different pharmacological groups (vitamins, enzymes, mediated-action anticoagulants, antioxidants, hepatoprotectors), are brought together under the "accompanying therapy" rubric.

Drugs whose formulation is based on fetotherapy are special in performing this function.

Scientists have been putting forth long-standing efforts to make it possible to use biologically active components of animal embryo cells. It is enough to say that only patents in this area number many hundreds. Virtually all developments are based on the following methods: mincing individual organs and embryonal tissues and then extracting soluble proteins from obtained homogenate using physiological solution; adding preservatives of different kinds; ultrafiltration.

Great part of patent authors propose using extracts of individual organs and tissues to cure specific human diseases.

As a rule, to extract the embryonal tissue, researchers largely use recently pregnant animals, that is when already formed embryo is intensively growing. Naturally, in this period the availability of factors stimulating the growth process is necessary. At the same time, factors are needed to control cell differentiation that prevent the process from turning into uncontrolled.

Therefore, using extracts of animal embryo tissues in practical medicine is possible only after their treatment by inactivating factors that stimulate growth processes and isolating active tissue differentiation control factors. Otherwise, using drugs based on embryo tissue extracts is pregnant with too high risk of arising and generalisation of neoplastic processes, including malignant ones.

It was fulfilling these conditions that laid the groundwork for formulating anticancer drugs (Propesum® and Bipexum®) manufactured by the NIR Company. All starting extracts are treated by two steps: irreversible inactivation of factors stimulating growth processes and isolation of active differentiation factors from precursor proteins. Only after that, drugs having necessary therapeutic effect are manufactured. In other words, the basis is provided for massive fetotherapeutic effort to be put forth in preventing and curing cancers in humans.

The effectiveness of the drug therapy to combat cancers hinges on the patient's life expectancy. Therefore, it should be specially noted that all 20 patients that 9 years ago were assigned Propesum® as part of clinical trials, are alive. The drug Propesum® is approved by the Ministry of Health of Ukraine's Pharmacological Committee (Reg. No. 95.245.7). The drug is indicated intramuscularly for various site-specific cancers, cancer of lung, kidneys, gastrointestinal tract, liver, soft tissue and bone sarcomas, as well as melanomas. The drug is intended to prevent and treat malignant neoplasms. The mechanism of the drug's action is based on antigen marking malignant cells and starting the mechanism of their rejection.

Propesum® has been assigned to patients with malignant lymphomas: 343 had lymphogranulomatosis, 114 had non-Hodgkin's lymphomas.

As part of primary or relapse therapy, Propesum® has been administered to 222 patients, and to 125 in remote gamma therapy.

On 110 patients in remission, Propesum® has been used without any accompanying therapy.

Two millilitres of Propesum® were administered intramuscularly adhering to three regimens. Regimen I used 2 ampoules (4 ml) every other day for 20 days. Regimen II used 2 ml every day for 10 days. Regimen III used 2 ml twice a day for initial 5 days, and then 2 ml once a day for 10 days.

One hundred ten patients in remission have been cured put on the first regimen, 231 by receiving the second one, and 226 put on the third.

The patients showed disappearance of general intoxication symptoms and diminution of tumour masses along with improved physiological and instrumental (roentgenological, ultrasonic, endoscopic) data bearing on internal organs, that was characteristic of improved habitus and relieved symptoms of general intoxication. Biochemical blood indices held steady throughout the Propesum® administration, and bilirubin even decreased from 11.5±4.0 μmol/l at the start to 10.4±3.2 μmol/l at the end of the therapy. The cellular composition of peripheral blood also displayed stability. Urine specimen did not change significantly.

Throughout the administration of Propesum®, neither subjective nor objective conditions of patients showed any alterations. No relapses in the fundamental illness or exacerbations of associated pathology emerged.

General intoxication symptoms and resorption of tumour masses slackened in the investigational group much faster than in the control one. Peripheral blood indices, in spite of chemo - and radiotherapy administered, held steady and decreased insignificantly. For example, erythrocytes made an average of (3.80±0.13)х1012/l before and (3.85±0.61)х1012/l after therapy.

The absolute number of leukocytes, especially, large granular lymphocytes, increased from 40.61±0.67 cells to 66.12±0.75 cells. What with chemo - and radiotherapy, the cellular composition of blood, as well as the number of large granular lymphocytes of control patients naturally decreased by an average of 30.8 %.

When using Propesum®, neither of the groups with lymphogranulomatosis or non-Hodgkin's lymphomas showed any complications irrespective of the administration programme.

Thirty-two patients with complicated course (neuroleukemia) were given chemotherapy and radiation therapy along with administering the drug Bipexum® (Reg. No. 06.99/00797) at the dose of 2.0 intramuscularly every day for 10 days. The patients tolerated cytostatic therapy better than those to whom the drug was not administered (10 individuals). Improved tolerance manifested itself in satisfactory habitus along with positive effect of cytostatic therapy (relieved pain syndrome displayed by 80 % of patients, enhanced motor performance, touch sensibility in 35 %, improved vision in 4 %).

In this way, the basic haematological indices of patients with malignant lymphomas as they were undergoing cytostatic therapy along with the fetotherapeutic drugs Propesum® and Bipexum® did not change significantly, which enabled radiation and chemotherapy to be performed to the full extent within optimal time points. Furthermore, the way patients felt took turn for the better that gave a chance to improve quality of life when giving vigorous anticancer therapy.

Bipexum®: Medical Instructions

Reg. certificate No. P.06.99/00797 of the 25th of June, 1999

General characteristic: Bipexumâ contains the optimal set of free amino acids, native peptides and products of the controlled proteolysis of proteins and embryonal tissues in isotonic sodium chloride solution with a preservative added. The drug is a transparent light yellow liquid.

Composition: products of the proteolysis of the bovine embryo soft tissues and brain (1.3 %) in solution (0.9 % sodium chloride solution) with a preservative added (0.1 % quinosol solution)

Available as 2.0 ml ampoules.

Pharmacological group. A metabolic drug having anticancer and immunomodulating action.

Pharmacological properties: Bipexumâ is an efficacious drug to use along with cytostatic and radiation therapy of brain cancers. The drug is used as a preventive against haemopoietic hypoplasia as well as to improve the patient's quality of life and tolerance to antiblastic therapy. The drug stimulates the functional activity of T-helpers and T-lymphocytes, has sharply signalled antitoxic effect, improves liver function and inhibits tumour process.

Indications. To be used along with cytostatic and radiation therapy of brain cancers.

Administration and dosage. 2.0 ml (1 ampoule) to be administered intramuscularly once a day for 10 days along with providing multimodality care (chemo - and radiation therapy), and as part of renewed recourses.

Pathogenesis. Bipexumâ is well tolerated and has damaging impact neither upon organs nor systems.

Contraindications. Hypersensitivity to the drug, pregnancy.

Interaction. Not presented.

Special notes. Not to be administered otherwise than intramuscularly.

Storage. B type. Keep in dark place at +4 oC to +8 oC for not over 2 years.

Dispensed by prescription.

Package.ml ampoules.

Manufacturer. NIR Limited.

Location. 50 Kharkovskoye Shosse, 02160 Kiev, Ukraine

tel./fax: +6

tel.: +0 /

* Provisor, 19, 2002, 43-44