ABSTRACT

Immunomodulatory efficacy of Manaxx in the late period after the irradiation could be related with the regulation of impaired expression of functionally active receptors on the surface of antigen-presenting cells and lymphocytes. Elevation of TCR/CD3, HLADR, HLADQ, CD4 expression was detected after the treatment. Monocytes exhibited integrins ICAM-1 and LFA3 expression and CD4+ cells - LFA1. Elevated CD23+ cells proportion was shown in peripheral blood CD19+lymphocytes. Correlations were seen between Interleukin-2 receptor (CD25) expression and Manaxx therapeutic effectiveness in patients with chronic focal infections.

In non-irradiated patients CD3/TCR expression elevation was not detected. Activation was seen of cytotoxic CD4-8+16+56+ cells. In all patients no elevation was seen of somatic mutations in T-cell receptor locus.

INTRODUCTION

Investigation of the ManaXX efficiency in immune deficiencies after radiation exposure was performed in 273 patients with different types of immune disturbances. They included secondary immune deficiency after low-dose radiation exposure (n-84), secondary immune deficiency due to chronic bacterial and viral infections (n-92), immune disturbances related with the metabolic changes (n-32), lymphoid cell proliferation reactions of allergic origin (n-55) and leukemic cell proliferation (acute lymphoid leukemia –3, chronic lymphatic leukemia, n-7). Control groups included 54 non-exposed patients and 20 healthy volunteers.

Surface antigens and DNA distribution analysis were performed by flow cytometry. Monoclonal antibodies (MoAbs) were obtained commercially from Becton Dickinson (CA, USA). IMK Plus, Simulates kits were used for immunophenotyping in two-color assay. Moabs and Anti-human immunoglobulins were used with propidium iodide in cell cycle analysis. Analysis was performed on FACScan flow cytometer. For DNA analysis list mode data were analyzed with G0-G1, M-pikes and S-phase region estimation for different subsets in LYSYS-II and CELLfit software. Anti-viral antibody titers analysis was performed with the use of ABBOTT, Fujirebio Inc.(Japan) and Vector Best (Russia) kits.

ManaXX was prescribed for 25-30 days in daily dosage of 270 mg. In patients with leukemia doses were increased to 450-540 mg daily with treatment duration from 2 to 4 months. Laboratory investigation was performed before treatment, on 14^th, 28^th days, 3, 6 and 12 months after the treatment.

RESULTS

Secondary immune deficiency after low-dose radiation exposure

Follow-up study was performed in patients with secondary stable immune deficiencies with prevalence of cellular, humoral reactions disorders or of mixed type. Doses of irradiation in 1986/87 didn’t exceed 1 Gy. Decreases in the number of lymphocytes and CD4+ cells and in the proportion of CD4+ cells, a low CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects. Changes of immunity were combined with somatic pathology such as circulation changes with encephalopathy and cardiosclerosis, chronic diseases of lungs, liver and digestive tract. Typical was combination of several disorders in one patient. Previous treatment included pathogenetic treatment, tranquilizators, adaptogenic medications, non-specific stimulatory medications etc. Effect on immune system was unstable, laboratory findings changed insignificantly. In all patients and controls these immune parameters were evaluated before and after ManaXX treatment.

ManaXX treatment was performed during the time of clinical remission. Results of investigation showed marked and stable improvement of immune system parameters (fig. 1).
 

Laboratory findings have showed that lymphocyte counts and number of CD4+ and CD8+ cells increased both in patients and in control subjects. The low CD4/CD8 ratio and suppressed NK cell activity were improved as well as CD3-CD16+ cell counts. In contrast, antibody-dependent cell-mediated cytotoxicity, Con A-stimulated lymphocyte proliferation was not changed. Elevation of TCR/CD3, HLADR, HLADQ, CD4 expression was detected after the treatment. Monocytes exhibited integrins ICAM-1 and LFA3 expression and CD4+ cells - LFA1. Elevated CD23+ cells proportion was shown in peripheral blood CD19+lymphocytes while serum levels of immunoglobulins differ insignificantly.

Treatment of patients exposed to ionizing radiation, in particular, at chronic exposure, has to be performed in conditions of not only changed immunological reactivity, but also increase of somatic cell mutations. The applying of new means for treatment of such patients is possible at absence of mutagen effect. Previous data have indicated antimutagen and tonic activity of Uncaria tomentosa alkaloids (N.Oleinik et al., 1997). Radiogenic T-cell receptor mutations seem to be of major importance for cellular immunity function because of decreased functional ability of aberrant cells and their descendants. In our study we have found for ManaXX none of the promotion effects on a radiation-induced mutagenesis. Quantity of aberrant TCR-4+ lymphocytes in all patients did not differ from normal values during the follow-up (fig. 2).
 

These results indicate that ManaXX might play an important role in cellular immunity.

Secondary immune deficiency due to chronic bacterial and viral infections

Research of ManaXX clinical efficiency was performed in the group of patients with chronic diseases of the bacterial origin accompanied by stable (not less than 1-2 years) changes of laboratory indices. Leukopenia, leukocytosis, lymphocytosis or lymphopenia, monocytosis were screening yardsticks of immunodepressive conditions. Laboratory study showed leukocytosis, neutrophilia with shift to immature granulocytes appearance in a peripheral blood, elevated sedimentation rate. Immunological changes included changes of subset organization, decrease of activation abilities in reply to lectins together with specific hypersensitivity reactions to streptococcal and staphylococcal antigens.

ManaXX clinical effect was accompanied by the normalization of the contents of ?-lymphocytes and mytogen response, re-distribution of the cells in CD8 + subset with the increase of antigen-dependent cytotoxic effector cells and CD56 and CD57 expression on natural killer cells. Humoral immunity was characterized by a decrease of previously elevated B-cell (CD19+sIgM+) counts, thus quantity of differentiated cells expressing surface immunoglobulin G and IgG serum concentration increased (fig. 3).
 

Clinical assessment showed a reliably high therapeutic efficacy of ManaXX in persistent blood viral infections, its total value (excellent and good results) being as high as 82%. The study based on the investigation of patients with Cytomegalovirus and Herpes simplex infection showed that clinical improvement was accompanied by positive changes of cellular and humoral immunity indices, decrease of anti-viral antibody titers. The direction of immunological changes depends on an initial condition of an immunological reactivity- depression or activation changes. For the patients with prevalence of activation reactions ManaXX treatment resulted in a decrease transferrin, IL-2 receptor, HLADR expresison. Monocytes exhibited integrins ICAM-1 and LFA3 expression and CD4+ cells - LFA1. Marked elevation was shown of phagocytosis reactions.

Disorders of infectious and allergic pathogenesis 

Study of patients with hyperlipidemia showed Uncaria tomentosa influence on lipid metabolism (fig. 4). Cholesterol level decrease was demonstrated in all the investigated patients. Patients with elevated parameters before the treatment showed more prominent decrease (p< 0.05) of cholesterol while triglyceride level decrease differences between groups were insignificant.

Explanation of lipid changes under the low-dose exposure could be obtained from the analysis of metabolic processes in a normal (healthy) organism. The parallel changes of membrane receptors of immune cells and activation of a calcium channel, nucleic acids synthesis is related with lipid peroxidation. In normal conditions lipid peroxidation is involved in a regulation of a active and passive ion and surfacce antigen transfer through the cell membrane, modification of their properties. Immune cell proliferation is associated with lipoproteid layer resynthesis, that is reached by activation of a biosynthesis of cholesterol, its aethers, phospholipids and proteins with subsequent blood lipoproteins levels changes. The increase of a lipoproteins level is the trigger of lipid peroxidation. This results in a uncoupling of structurally functional organization of immune cells with respective activation of their biosynthesis. Under some data [I.Kolomijtseva, 1991] at low dose rates intensity of response reaction can be reduced and resulted in metabolic disturbances and cell damage. ManaXX effects on the immune cells could be the result of combined action on this parameters (fig. 5).

SUMMARY

Performed study showed that Peruvian plant Uncaria tomentosa (Willd.) has potent effects on immune system. This effect could be shown on mature cells of peripheral blood and on immature cells as well. We haven’t demonstrated distinct influence of early progenitor hemopoetic cells (CD34+) in healthy volunteers. However significant decrease of early CD34+19+ cells was detected in patients with lymphoid leukemia as well as the decrease of the CD10+ cells who posses the next stage of lymphoid cell differentiation (Bazyka et al., 1999). Parallel decrease of CD5+ blasts was shown in chronic lymphocytic leukemia. Treatment with ManaXX seems also to be effective in control of blast cell counts in acute myelogenous leukemia (V.Klymenko, 1999, personal communication). At present one can suppose that effects on immature cells differ greatly due to the cell place in the proliferation cycle and the state of DNA synthesis.

Effects on peripheral blood cells show predominant influence on cell activation reactions and, T-cell receptor, HLADR and CD4 molecules that are involved in antigen recognition. Enhancement of anti-bacterial and antiviral response is combined with the decrease of hypersensitivity reactions. Complex effect of ManaXX can be explained by the balanced content of biologically active Uncaria tomentosa compounds that are preserved in lyophilized extract. These properties make this medication from the traditional herb especially useful in new world with elevated levels of ecological loads on the human. It seems to be of positive to Ukraine where not only Chernobyl radiation accident consequences have to be encountered but ecological problems related to the decades of non-controlled development of a hard industry, including metallurgic and chemical works, mines etc. that resulted in an air pollution and complex negative effects on human health. Now at the end of the millenium we were able to find out some scientific background of Peruvian traditional medicine and hope that in a new century new answers will be received and old traditions will help us to counter to a new challenge.
 
 

Problem of clinically observed effects of irradiation and other harmful factors of Chernobyl accident is significant due to the need of health state estimation, prophylaxy and treatment of largepopulation groups, exposed in dose limits fromseveral millisieverts to those inducing acute radiationsyndrome.

As a result of the accident the territory of Ukraine was subjected to considerable radiation contamination and its population was involved to the greatest radiation catastrophes. Kiev, Zhitomir, Rivne and Chernihiv regions with the population of more than 5 million inhabitants.

By the moment of the catastrophe the health state of population in Central-Ukrainian area was influenced by the social and economic peculiarities of the region, by the ecological and anthropogenic load. In rural areas this was wide use of pesticides and mineral fertilizers, in cities- industrial loads with lead, cadmium, manganese etc. One of the peculiarities that greatly influenced the radiation effects especially on thyroid gland was iodine deficiency in Ukrainian Polissia region – the place of Chernobyl nuclear power plant (NPP) location. During the Soviet period special efforts were made to diminish medical consequences, such as hypothyroidism, including the consumption of iodinated salt but the efficiency couldn’t be estimated on the individual level of population in total.

As the result of accident the population of Ukraine was exposed to irradiation from the doses inducing acute radiation effects in those who were on the reactor site and participated in the accident liquidation during the first hours and days, to the low doses that differed several times from the natural levels of radiation.

Acute radiation syndrome (ARS) reconvalescents represented themost severely damaged group of the victims. At the time of first decade after the accident 105 from 145 ARS reconvalescents are the citizens and inhabitants of TheUkraine. Follow-up of patients was organized atResearch Center for Radiation Medicine.During the period ofobservation weregistered the disorders of haemopoiesis and immunity such as transient andstable leukopenia and leukocytosis and increasing number of oncogematological pathology such as leukemia and erythromyelodisplastic syndrome.The somatic state was characterised by prevalence of chronic pathology of different organs and systems.

Before the CPPA and up to 1989 information about the life effectsof radiation exposure in high and especially low doses intervalswas mainly of limited allowance. High centralisation of nuclearpower plants health services and their complete independency fromlocal authorities did not promote to large spread of informationabout possible health effects among general physicians ofsurrounding settlement. Exposure doses under 1 Gy were considered safe, any clinicaleffects weren't recognized.But in the centralized health care systemordinary and accidental instructions were satisfactory.

It's assumed now that late effects in persons who were exposed inthe dose limits under 1 Gy have to be divided into stochastic andnon-stochastic. Correlation of stochastic effects withirradiation could be revealed only statistically.

Special efforts were performed by health careorganisations.Several international and nationalscientific programs were performed during the years after theaccident.Due to the previous results obtained on hibakushi cohorts effortswere made to find the access of stochastic effects leukemia andthyroid cancer in exposed territories of Ukraine, Russia andBjelorus on the base of published information.An increase of leukemia was detectedbut no evidence was obtined whether it's related with theirradiation. An increase of thyroid cancers was shown in Ukraineand Bjelorus, but neither in Russia. Later data was obtainedabout the significant increase of thyroid cancers especially inUkraine. Joint American-Ukrainian program on Thyroid gland inChernobyl victims was elaborated. Also joint US-Ukrainian study is nowperformed on the epidemiology of leukemia. WHO IPHECA projectswere elaborated in 1993-1995 in the clinical fields of hematology(Leukemia ), endocrinology ( Thyroid gland ) and psychoneurology(Brain in utero ) for Ukraine, Bjelorus and Russia. These projects were followed by the similar research in the frame of French-German Initiative from 1998.

Obtained data led us to the suggestion that significantchanges in the health of the population exposed to amulti-factoral influence of Chernobyl accident had occured duringlast decades. Today we know that the persistent functionaldestabilisation along with the individual reparative andcompensatory insufficience on the various levels of integrationin irradiated patients with dystress and xenobiotic exposure etc.could lead to a total desintegration regulatory syndrome i.e. theprimary formation of the functional and preclinical changes onthe different levels with the subsequent evolution to distinctclinical pathology. Theincrease of functional consequences is originated at least in0,2 - 1 Gy dose limit from the primary initializing defects ofregulation predominatly in central and vegetative nervoussystems, hormonal-humoral regulation and immune systemsinteraction. This stand of view supposes the possibility of the low-doses effects diminishment by the use of individual radiation protection.

Radioprotectors are the substances of different origin that increase body resistance to the radiation exposure. Possibility to decrease radiation damage by pretreatment with sodium cyanide and cysteine amino acid was discovered 50 years ago. Since 1949 a lot of such substances were under expertise including mercaptoalkylamines (cystamine, aminoethyl-isothyuronium, gammaphos), indolylalkylamines (serotonine, mexamin), carbamates etc. and some of them were used by military service for radiation effects protection. Majority of these medications had to be injected or digested from 1 to 2 hours before the irradiation and couldn’t be used for a long time period due to the toxic effects. In the case of Chernobyl none of the radioprotectors were used by the radiation-exposed before the accident and most

The second branch of research was the search of natural compounds that could prevent or diminish radiation effects. Oxidative stress, immunologic deficiency and hemopoetic disorders were revealed as a radiation effects pathways together with elevated frequency of mutations. Additionally disadaptation was the result of psychoemotional stress after the accident and vitamin deficiency due to the nutrition limitations.

Natural compounds and prescriptions possessed actual place in the treatment of radiation exposed during these years due to the several reasons: 

long-time blocking of entry and decorporation of radionuclides,

strengthening of immunity and other defense systems after the exposure,

preventive measures of development or seasonal recidives of chronic disorders in large groups of patients living on the contaminated territories, 

necessity of treatmentside effectsminimization, in particular after cytostaticsandradiotherapy of leukemia, lymphomas and oncologic pathology.

Existence of the established system of health care in our country was supported by the development of the traditional medicine. Its history lasted for thousands of years, scientific examination of medicinal herbs in Ukraine started at the beginning of the XVIII century from the times of Peter the Great. Traditional medicine possessed its actual place and wasn’t replaced by the official pharmacology. To the contrary they interfered and integrated. 192 species of medicinal plants were registered in Ukraine up to 1985. More than 5800 tons of medicinal plants were collected annually since 1975. Botanical characterization, recommendations on collection, preparation and storage were developed and included to the technical documentation such as standards, technical conditions and articles in State Pharmakopea. In our country 45% of all the medications were prepared from the medicinal plants. In treatment of cardiovascular, gastrointestinal, neurological, liver and kidney diseases percentage of medications of natural origin exceeded 80-90%. Investigation of the clinical properties, chemical analysis and characterization were performed on the regular basis before the Pharmacological Committee registration.

RCRM experience includes experimental, preclinical and clinical studies of new medications and nutrition additives in the field of radiation medicine under internationally adopted protocols. Adaptogenous, antioxydative, immunostimulative, antimutagenic and vitaminous preparation were recommended during the first years after the accident. Preparations of ginseng, eleutherococcus, bee poison, beta-carotene, oysters hydrolysate were used during first years. All of them were of complex origin, mild action and practical non-toxicity, so could be used after the exposure.

One of the first tested remedies for the population of the territories, contaminated with the radionuclides was ferrocine (berlin blue), possessing the capacity to reduce cesium - 134 and cesium - 137 entry in a body through gastrointestinal channel. Immunological indices have shown normalization in 28 days and absence of negative changes was reported. Combinations of tropical plants with addition of Echinacea purpurea and Aralia showed their efficiency in transient immunologic deficiencies and infectious and allergic syndrome. Sublimated product of Black Sea mussel’s enzyme hydrolysation also showed antioxydant, radioprotectiveand anti-oncological properties. Investigation showed the balanced assortment of amine acids, glucoproteids, microelements, tiurine and other biologically active substances,that fix actively free radicals in a radiation-exposed.

Majority of these and other preparations was registered as the nutritive additives and further research was in need to clarify the medical properties and make possible the registration at the Pharmacological Committee.

Uncaria tomentosa (Willd.)DC, was presented in Ukraine in 1996-1997 as a part of different nutritive additives that were supposed to be of immunostimulative, antioxydant and strengthening effect. Common characteristics was the low active substance content and mixture with different other components. So the plant Una de Gato was known but the public and also medical society opinion wasn’t strongly positive at that moment. During 1997 investigations have been started in the hematological and immunological departments of RCRM and Donetsk. Lyophilized extract of Uncaria tomentosa named ManaXX was kindly presented by OMNI-Ukraine the official agent of Liofilizadora del Pacifico Ltda and OMNIAGRO S.A (Peru).

The result was the adoption of the lyophilized extract of a crust of this plant by the Pharmacological Committee as the medical preparation with immunostimulative properties.. The lyophilization seems to be the most effective way of preservation operational a component. 90 mg of an extract are equivalent 3000 ?? of a crust of Uncaria tomentosa. The drug is registered in Ukraine by Pharmacological committee (testimony ?2903 from 25.02.1998 in the medical form of90 mg tablets.

Multicentric study of ManaXX was performed in Research Center for Radiation Medicine of the Academy of Medical sciences of Ukraine, Donetsk state medical university, Ukrainian Institute of Cardiology, Donetsk state university, Donetsk regional Center of immunology and AIDS protection, Donetsk regional oncological center, Cherniakhov district hospital, Donetsk regional center motherhood and childhood care, Hospital of the Cabinet of Ministries of Ukraine.

For research of clinical efficiency of ManaXX in chronic diseases of the bacterial nature the group of the patients was selected with chronic (not less than 1-2 years) changes of laboratory indices - leukopenia, leukocytosis, lymphocytosis or lymphopenia, monocytosis, that are the signs for the screening of immunodepressive conditions. The clinical symptomatology included pneumonias, tracheobronchites, chronic obstructive bronchitis, and also chronic inflammatory processes of a nasopharynx accompanied with an asthenic syndrome, subfebrile temperature.

ManaXX was prescribed for 25-30 days on 90 mg 3 times per day. Complications and side effects during the treatment were not detected, pathologic process in a nasopharynx was stopped. During the 3-12 months follow- up after the treatment recidives weren’t detected. For all the patients normalization of temperature was marked, which was shown for the last two treatment weeks and at the subsequent follow-up it was within the limits of normal values. The conducted semiquantitative estimation of a patients clinical condition by Karnowsky index has shown authentic increase of efficiency of treatment.

Conducted clinical and experimental research showed anti-viral effect of alkaloids of Uncaria tomentosa. It’s established, that the anti-viral activity is connected to action on DNA-polymerase. In Donetsk regional Center of immunology and AIDS ManaXX was prescribed to 34 HIV-infected patients. The treatment was conducted under 3 schemes: (1) - 90 mg once per day - 3 months; (2) – 90 mg 2 times per day - 3 months; (3) 90 mg 3 times per day - 3 months. The treatment under the scheme ?1 was received by 10, scheme ?2 - 14, scheme ?3 - by 10 patients.

Clinical tests have shown positive outcome for the HIV-carriers and patients with clinical signs of AIDS. It was shown at asymptomatic period and lymphoadenopathy stage along with the improvement of a general condition, absence of negative influence on parameters of a blood and biochemical homeostasis. The increase of ?-helper-inducer levels was detected during a treatment.

In this presentation we summarized the outcomes of treatment of 78 patients with viral infections of a different etiology (Cytomegalovirus, relapsing herpes, genital herpes).

The indications for ManaXX therapy at Cytomegalovirus infection were:

1. Clinical development of the infections (decrease of an index of a clinical-functional condition of a patient by Karnowsky scale;unmotivated subfebrile conditions; abortions on early terms of pregnancy, pathological changes of a visual analyzer, nervous system);

2. Laboratory signs of immunological insufficiency.

In herpetic infection the indications were the persistence of the process with an ineffectiveness of preceding courses of therapy (anti-herpetic vaccine, acyclovir).

ManaXX was prescribed in 270 mg daily dosage. The duration of therapy varied from 1 about 3 months. As a result of the conducted therapy positive changes of clinical and laboratory parameters were shown in all patients. At cytomegalovirus infection the improvement of a general condition, normalization of temperature within 10-14 days of the treatment was shown. In female patients with early abortions conception occurred and pregnancy finished by birth of healthy children. At 62% of simple herpes patients relapses were not observed during the term of observation (6-9 months), and in 38%relapses were detected after 3 to 5 months. Repeated course of therapy was in need.

The clinical improvement was accompanied by positive dynamics of parameters of cellular and humoral immunity, decrease of titers of virus-specific antibodies, normalization of cell activation.

ManaXX efficiency was demonstrated in patients with pathology of infectious-allergic origin. Previously positive effect of Uncaria tomentosa extracts was found in a number of experimental inflammatory conditions and in clinical practice as well (Cabieses, 1994; Obregon Vilches, 1995); with the highest efficiency at extracts application before the influence of an inflammation inducer. These experimental data led to the presumption that ManaXX treatment had to most effective as a prophylaxis drug. Our results in patients with infectious-allergic arthritis have shown ManaXX clinical efficiency as a anti-relapse drug of a preventive maintenance. Complex anti-viral, anti-bacterial and immunomodulatory effect gives chance to check the perspectives of its application at infectious-allergic myocardites caused by herpes simplex virus, cytomegalovirus, enteroviruses and bacterial infections infections. Recent investigations showed that ManaXX implementation in cardiovascular diseases could be wider. Positive effect was demonstrated in patients with rheumatic disease of 1-2 activity grade. 

Clinical chemistry analysis showed cholesterol levels decrease. These findings showed the possibility of action complex action not only on immunological parameters but also on lipid metabolism. Clinical investigation was performed in patients with ischemic heart disease and atherosclerosis. Investigation group received basic treatment and ManaXX 270 mg dayly for 3 weeks. Control group received the basic treatment for the same period. 

Experimental research has allowed to establish, that anti-oncologic effect of Uncaria tomentosa is connected with polyphenol alkaloids, including - epicatechines, procyanidines ?1, ?1, ?2, ?4, isorhynchophilline etc. (Kreutzkamp et al., 1984). It’s revealed that oxyindole alcaloids have the combined effect of oncogenesis and phagocytosis stimulation. Also it was demonstrated that lyophilized extracts have higher efficiency, than separate alkaloids. 

All the data about new methods of oncological patients treatment have to be re-evaluated for several times due to the extreme importance of this problem. We have gained some experience about ManaXX in different kinds of benign and malignantprolipherative disordersand hope that it would be of interest to scientific audience.

Clinical data from our hematology department have shown that ManaXX can be used as a means of auxiliary therapy at chronic lymphatic leukemia after chemotherapy. It’s efficacy was also seen in patients with CLL 3^rd stage who could stand the chemotherapy courses. Cytological research of blast and residual normal cells has found none of the negative effects and no stimulation of leukemia cell clones.

The experience of solid cancer patientstreatment with ManaXX at Donetsk regional oncological center since 1997 had demonstrated no negative side effects, its anti-inflammatory and hemostimulative action after chemotherapy. In a number of patients immunostimulation and analgesive effect was registrated.

Clinical investigation has shown ManaXX efficiency in fibromyoma, especially of interstitial type. Treatment course lasted from 28 to 40 days with daily dosage of 270 mg. Control study in a period of 60-90 days after the treatment has shown clinical improvement and in 11 from- 15 - normalization of menstrual cycle. The clinical efficiency was accompanied by reduction of the node size at ultrasonic investigation from 40 to 70%. 

Clinical data about the Uncaria tomentosa action in oncological disorders arise the problem of action mechanisms in such pathology. Is this action a result of immune system activation and anti-oncological defence? Are immune effects related with the endocrine system changes, there is a complex action? Do these effects predominate or there is some direct action on the malignant cells? The possible answer could include all the possibilities but sophisticated research has to be performed. Experimental chemical studies showed many similar effects of oncosuppression in Uncaria tomentosa derivatives and taxanes. 

The expansion of experimental and clinical efforts would include special program elaboration for antitumor effect studies, injection form preparation, experimental toxicity estimation of new derivatives and full scale preclinical and clinical trials.