Computer-aided Evaluation of Polyvalent Medications' Pharmacological Potential. Multiphytoadaptogen as a Case Study.

Many human diseases including cancer, degenerative and autoimmune disorders, diabetes and others are multifactorial. Pharmaceutical agents acting on a single target do not provide their efficient curation. Multitargeted drugs exhibiting pleiotropic pharmacological effects have certain advantages due to the normalization of the complex pathological processes of different etiology. Extracts of medicinal plants (EMP) containing multiple phytocomponents are widely used in traditional medicines for multifactorial disorders' treatment. Experimental studies of pharmacological potential for multicomponent compositions are quite expensive and time-consuming. In silico evaluation of EMP the pharmacological potential may provide the basis for selecting the most promising directions of testing and for identifying potential additive/synergistic effects. Multiphytoadaptogen (MPhA) containing 70 major phytocomponents of different chemical classes from 40 medicinal plant extracts has been studied in vitro, in vivo and in clinical researches. Antiproliferative and anti-tumor activities have been shown against some tumors as well as evidence-based therapeutic effects against age-related pathologies. In addition, the neuroprotective, antioxidant, antimutagenic, radioprotective, and immunomodulatory effects of MPhA were confirmed. Analysis of the PASS profiles of the biological activity of MPhA phytocomponents showed that most of the predicted anti-tumor and anti-metastatic effects were consistent with the results of laboratory and clinical studies. Antimutagenic, immunomodulatory, radioprotective, neuroprotective and anti-Parkinsonian effects were also predicted for most of the phytocomponents. Effects associated with positive effects on the male and female reproductive systems have been identified too. Thus, PASS and PharmaExpert can be used to evaluate the pharmacological potential of complex pharmaceutical compositions containing natural products.

[Possibilities of in silico estimations for the development of pharmaceutical composition phytoladaptogene cytotoxic for bladder cancer cells]. / Vozmozhnosti otsenok in silico dlia razrabotki farmkompozitsii fitoladaptogen, tsitotoksichnoi dlia kletok raka mochevogo puzyria.

Based on the prediction of biological activity spectra for several secondary metabolites of medicinal plants using the PASS computer program and validation in vitro of the predictions results the priority direction of the pharmaceutical composition Phytoladaptogene (PLA) development was determined. PLA is a complex of structurally diverse small organic compounds including biologically active substances of phytoadaptogenes (ginsenosides from Panax ginseng, rhodionin from Rhodiola rosea and others) compiled considering previously developed pharmaceutical compositions. Two variants of the pharmaceutical composition were studied: - the major and minor variants included 22 and 13 compounds, respectively. The probability of activity exceeds the probability of inactivity for 1400 out of 1945 pharmacological effects and mechanisms predicted by PASS for the major variant of PLA. The wide range of predicted activities is mainly due to the low structural similarity of constituent compounds. An in silico prediction indicates the possibilities of antitumor properties against bladder, stomach, colon, ovarian and cervical cancers both for minor and major PLA compositions. It was found that the highest probability values of activity were predicted for three mechanisms: apoptosis agonist, caspase-3 stimulant, and transcription factor NF-κB inhibitor. According to the PharmaExpert program they are associated with the antitumor effect against bladder cancer. Experimental validation was using the human bladder cancer cell line RT-112. The results of the MTT test have shown that the cytotoxicity of the major PLA variant is higher than that of the minor PLA variant. In vitro experiments performed using two methods (double staining with annexin V and propidium iodide and detection of active caspase-3 in cells) confirmed that the death of bladder cancer cells occurred via the apoptotic mechanism. The data obtained correspond to the results of the prediction and indicate advantages of the major PLA composition. Thus, PLA can become the basis for the development of a drug with the antitumor activity against bladder cancer. The antitumor activity predicted by PASS for other cancers may be the subject of further studies.

Effect of Phytoadaptogen Administration during Early Ontogeny on Lifespan and Somatic Status of CBA Mice with High Incidence of Tumors.

We studied the influence of nontoxic phytoadaptogen complex on the lifespan and somatic status (body weight, coat state, and motor activity) of CBA mice predisposed to spontaneous hepatomas. Administration of the complex phytoadaptogen during the first month of postnatal ontogeny increased mean animal lifespan by 17.1% (p<0.001) and median of survival by 25.6% (p<0.001) and promoted maintenance of satisfactory physical status of CBA mice during spontaneous hepatocarcinogenesis.

Morphological Studies of Hepatocellular Carcinomas in Male CBA Mice with High Liability to Cancer under the Effect of Phytoadaptogen.

Treatment of CBA mice predisposed to cancer with a complex phytoadaptogen in the therapeutic and preventive modes led to the appearance of moderate and low-differentiation hepato-cellular carcinomas infiltrated by leukocytes. Destructive signs were detected in tumor tissue.

Effects of Phytoadaptogen on Hepatoma Development in Cancer-Prone CBA Mice.

The incidence, size, and number of hepatocarcinomas decreased in cancer-prone male CBA mice under the effect of preventive and therapeutic treatment with a complex phytoadaptogen.

Integrins LFA-1 and Mac-1 and cytokines IL-6 and IL-10 in high-cancer mice under the influence of phytoadaptogen.

The expression of leukocyte integrins LFA-1 and Mac-1 and cytokines IL-6 and IL-10 was studied in mice predisposed to spontaneous hepatocarcinomas. The efficacy of a phytoadaptogen in correcting these parameters was evaluated. The role of adhesive interactions between immune cells and target cells in the recovery of antitumor regulatory mechanisms was estimated.

[Investigation of multyphytoadaptogene anti-radiation activity in mice].

The aim of the work was to elucidate the radioprotective activity of multyphytoadaptogene (MPA) in mice in various conditions of gamma radiation and MPA application. Males of CBA x C57BL/6 F1 mice were given 15% MPA solution with drinking water 2 weeks before the radiating (preventive application), 2 weeks before and 2 weeks after the radiating (preventive and therapeutic application) and also 2 weeks after the radiating only (therapeutic application). Animals of control groups received radiation or were given 5% ethanol solution in drinking water in the same application schemes. MPA increased the mice survival in preventive, preventive and therapeutic as well as therapeutic applications after 7.5 Gy radiation (66.7: 66.4 and 40.2% correspondingly). After 11.0 Gy radiation MPA increased the mice survival in preventive as well as preventive and therapeutic applications (75.0 and 76.9% correspondingly). MPA administration improved the somatic state, weight of animals, quality of life. MPA has no side effects. The data suggest the radioprotective activity of MPA.

[Investigation of multyphytoadaptogene anti-radiation efficacy in dogs experiments].

The purpose of the work was to elucidate the radioprotective efficacy of multyphytoadaptogene (MPA) in dogs in various conditions of gamma radiation and MPA application. Dogs were given 15% MPA solution with drinking water in 3,6 ml/kg dose per day 2 weeks before the radiating (preventive application), 2 weeks before and 2 weeks after the radiating (preventive and therapeutic application) as well as 2 weeks after the radiating only (therapeutic application). Animals of control groups received radiation. Dogs were exposed to 3,5 Cy acute radiation and 8,0 Gy prolonged radiation. There were no survived dogs in control groups. At the same time MPA increased dogs survival in preventive, preventive and therapeutic as well as therapeutic applications after 3,5 Gy acute radiation and after 8,0 Gy prolonged radiation. MPA improved the somatic state, interfere with leukocytes amount in blood. The data obtained suggest the radioprotective efficacy of MPA.

[Antimutagenesis of multiphytoadaptogene in yeast saccharomyces].

Multiphytoadaptogene (MPA) consists of plant extracts components including adaptogenes. Genotoxicity analysis revealed the antimutagenic activity of MPA. MPA decreased the direct mutations frequency in ADE4-ADE8 loci induced by UV radiation and nitrous acid by 3.7 and 33 times, respectively. The lethal effect of UV radiation was inhibited when the preparation was used. MPA had no effect on replicative mutagenesis. At the same time it depressed mutagenesis caused by repair errors. The data obtained suggest the antimutagenic activity of multiphytoadaptogene is associated with postreplicative repair activation.

Therapeutic efficacy of the neuroprotective plant adaptogen in neurodegenerative disease (Parkinson's disease as an example).

Therapeutic efficacy of the plant neuroprotector Phytomix-40 in Parkinson's disease was demonstrated. This preparation consists of the components from extracts of 40 plants, including some adaptogens (ginseng, eleutherococcus, Rhodiola rosea, etc.). The preparation normalized immune, antioxidant, and hormonal parameters in patients. The neuroprotective plant adaptogen can be used in complex therapy for Parkinson's disease for improving its efficacy.

[Neuroprotective features of phytoadaptogens].

In the article the authors demonstrated that phytoadaptogens (Panax ginseng, Eleutherococcus senticosus, Rhodiola rosea) take part in protecting brain neurons from various injuries. Ability of phytoadaptogens to have influence on neurodegenerative mechanisms at Parkinson's disease is discussed. Phytoadaptogens should be proposed for study or use as therapeutic modulators in neurodegenerative disorders including Parkinson's disease.

Effect of complex phytoadaptogen on MPTP-induced Parkinson's syndrome in mice.

Oral administration of 10% solution of Phytomix-40 (multicomponent plant phytoadaptogen) to C57Bl/6 mice with MPTP-induced Parkinson's syndrome alleviated symptoms (oligokinesia and muscle rigidity), compensated for the deficiency of dopamine and its metabolites (DOPAC and homovanillic acid), and reduced the level of lipid peroxides in the striatum. In vitro Phytomix-40 in a concentration of 3.3 x 10(-2) g/liter exhibited a pronounced antioxidant effect (5-fold decreased MDA level in mouse brain homogenate in Fe(2+)-ascorbate-dependent LPO).

[A toxicological study of the preparation Phytomix-40]. / Toksikologicheskoe izuchenie preparata Fitomiks-40.

The results of toxicological evaluation of the new plant preparation Phitomix-40 (PM-40) used in the treatment of cancer are presented. To prevent a patient's individual immunological responsiveness to some phytoadaptogens, the preparation comprises 40 plant extracts (Rhodiola r. L.; Juniperus C. L.; Helichrysum a. L; Viburnum o. L., etc.). Animal experiments demonstrated that PM-40 had a low toxicity; LD50 was more than 20 and 15 ml/kg for rats and mice, respectively.