An orally delivered microbial cocktail for the removal of nitrogenous metabolic waste in animal models of kidney failure.

Patients with kidney failure commonly require dialysis to remove nitrogenous wastes and to reduce burden to the kidney. Here, we show that a bacterial cocktail orally delivered in animals with kidney injury can metabolize blood nitrogenous waste products before they diffuse through the intestinal mucosal barrier. The microbial cocktail consists of three strains of bacteria isolated from faecal microbiota that metabolize urea and creatinine into amino acids, and is encapsulated in calcium alginate microspheres coated with a polydopamine layer that is selectively permeable to small-molecule nitrogenous wastes. In murine models of acute kidney injury and chronic kidney failure, and in porcine kidney failure models, the encapsulated microbial cocktail significantly reduced urea and creatinine concentrations in blood, and did not lead to any adverse effects.

Adsorptive therapy as a modificator for tumor-host interaction.

The potential of one of the adsorption methods, enterosorption (ES), using the new generation of carbon adsorbents to correct the negative manifestations of tumor-host interaction in the framework of paraneoplastic syndrome (PNS) as well as systemic toxicity of chemo- and radiation therapy, is discussed. The ES influence on the development of PNS was demonstrated in C57/BL6 mice with transplanted Lewis lung carcinoma. Two-week administration of carbon enterosorbents resulted in a significant suppression of metastasis and correction of tumor-related anemia, activation of granulocytic line in the bone marrow with nearly 3-fold enhancement of its mitotic activity. ES exerted a positive influence on the structural-morphologic indexes and regenerative potential of kidneys and liver, mitigated manifestations of oxidative stress, decreased the level of endogenous intoxication, increased resistance of erythrocyte membranes and decreased ligand loading of blood plasma transport proteins. The effect of ES on anticancer activity and toxic reactions of cisplatin (CP) was evaluated in Guerin carcinoma-bearing rats. ES reduced significantly creatinine and other kidney biochemical indexes elevated in the blood plasma of rats after CP treatment. ES attenuated dystrophic changes in the histological structure of internal organs (kidney, liver, spleen), caused by tumor growth and significantly aggravated under the influence of CP. Such changes were specially traced in the kidneys and well reflect the nephroprotective potential of ES. In rats irradiated with X-ray in sublethal dose, highly activated granulated carbonic enterosorbents facilitated the restoration of white blood cells and lymphocyte count. The results obtained confirm the insights of academician R.E. Kavetsky predicting the future of adsorptive detoxification with activated carbons in the treatment of cancer patients.

Effect of Primary and Secondary Beads of Carbon Enterosorbent on Haematological Parameters and Oxidative Stress Development Caused by Melphalan in Rats.

Background and Objectives: Side effects of anti-cancer drugs are usually accompanied by oxidative stress, including myelotoxicity. We evaluated the potential of oral highly activated micro-/macroporous carbon adsorbents (bulk density of 0.16 g/cm3, surface area calculation by Brunauer-Emmett-Teller model (SBET) > 2200 m2/g, derived from proprietary phenolic resin beads) to alleviate oxidative stress and myelotoxicity in rats. Materials and Methods: A single injection of cytostatic melphalan (L-PAM) at a dose of 4 mg/kg was used for modelling. Two forms of activated carbon were used: AC1-primary beads with the particle size range of 125-250 µm, and AC2-micronized AC1 with a mean particle size of ~1 µm. We measured haematological parameters white blood cells, red blood cells, platelet count, and haemoglobin level. Oxidative stress intensity was evaluated using the following markers: total levels of reactive oxygen species (ROS) in blood plasma; catalase activity (CAT) and pro-oxidant/antioxidant ratio in blood haemolysate samples; level of reduced glutathione (GSH) in liver tissues; oxidative modification of proteins, OPM (APHD, aldehyde-dinitrophenylhydrazone derivatives and KPHD, ketone dinitrophenylhydrazone derivatives) and malonic dialdehyde (MDA) in blood plasma and liver samples. Results: AC2 administration promoted significant myeloprotective effect: 1.5-fold increase in leukocytes, 2-fold in neutrophils, 1.5-fold in lymphocytes, and 1.23-fold in platelet count compared to the experimental Melphalan Group. At the same time, AC1 administration resulted in a slight increase in haematological parameters. Both ACs positively corrected important, but diverse, components of oxidative stress. They significantly reduced oxidative modification of blood and liver proteins (especially the AC1 form), normalized the level of reduced glutathione, pro-oxidant/antioxidant ratio and other markers. For some markers, such as ROS production in blood plasma, the use of enterosorbents resulted in non-significant a shift towards normal parameters. Conclusions: Oral activated carbon adsorbents reduce oxidative stress intensity and myelotoxicity; they can be promising means to combat the adverse effects of chemotherapy in clinical practice.

Investigation of the adsorption capacity of the enterosorbent Enterosgel for a range of bacterial toxins, bile acids and pharmaceutical drugs.

Oral intestinal adsorbents (enterosorbents) are orally administered materials which pass through the gut where they bind (adsorb) various substances. The enterosorbent Enterosgel (Polymethylsiloxane polyhdrate) is recommended as a symptomatic treatment for acute diarrhoea and chronic diarrhoea associated with irritable bowel syndrome (IBS). Since 1980's there have been many Enterosgel clinical trials, however, the detailed mechanism of Enterosgel action towards specific toxins and interaction with concomitantly administered medications has not been fully investigated. Our in vitro study assessed the adsorption capacity of Enterosgel for bacterial enterotoxins and endotoxin, bile acids and interaction with the pharmaceutical drugs; Cetirizine and Amitriptyline hydrochloride. Our data demonstrate the good adsorption capacity of Enterosgel for bacterial toxins associated with gastrointestinal infection, with a lower than the comparator charcoal Charcodote capacity for bile acids whose levels can be raised in IBS patients. Adsorption capacity for the two drugs varied but was significantly lower than Charcodote. These findings suggest that the mechanism of Enterosgel action in the treatment of gastrointestinal infection or IBS is adsorption of target molecules followed by removal from the body. This therapy offers a drug free approach to prevention and treatment of infectious and chronic non-infectious diseases, where intestinal flora and endotoxemia play a role.

Highly activated carbon enterosorbent mediates the suppression of paraneoplastic syndrome associated with Lewis lung carcinoma in mice.

AIM: To investigate the effect of enterosorption on the development of paraneoplastic syndrome in mice with Lewis lung carcinoma (LLC). MATERIALS AND METHODS: The study was performed on male С57/ВL6 mice with transplanted LLC. As an enterosorbent, highly activated powder fraction of HSGD was administered per os daily at a dose of 0.625 g/kg for two weeks starting from the 7th day after tumor cell transplantation. Analysis of hemo- and myelograms, morphological alterations in vital organs, the activities of catalase and superoxide dismutase, biochemical analysis of blood and quantitative analysis of hydroperoxides, malonic dialdehyde, аdvanced oxidation protein products was carried out by standard methods after completing the course of enterosorption. Ligand loading of blood plasma proteins was estimated by the method of differential scanning microcalorimetry. RESULTS: Administration of enterosorbent resulted in inhibition of LLC growth and in nearly 2-fold decrease of lung metastases number (p < 0.05). Activation of granulocytic line in the bone marrow with nearly 3-fold enhancement of mitotic activity took place after enterosorbent administration. Red cell lineage indices and bone marrow cellularity remained unaltered. After enterosorption session, the studied biochemical indices of peripheral blood evidenced on decreasing the endogenous intoxication and oxidative stress levels, improving the functional state of kidneys, increasing the resistance of erythrocyte membranes and lowering the ligand loading of blood plasma transport proteins. Morphological structure of kidneys and liver confirmed significant positive effect of enterosorption. The data of morphologic examination of gastric fundus, small intestine, and large bowel slides after 2-week administration of enterosorbent showed its high safety and proper evacuation from intestine. CONCLUSION: The two-week long enterosorption session in mice with LLC caused the suppression of tumor growth and metastasis, normalization of bone marrow hemopoiesis. Enterosorption exerted a positive influence on the structural-morphologic indexes and regenerative potential of kidneys and liver, mitigated manifestations of oxidative stress, decreased the level of endogenous intoxication, promoted deliganding of albumin molecule and deloading of erythrocyte membranes.

Enterosorption combined with granulocyte colony stimulating factor decreases melphalan gonadal toxicity.

UNLABELLED: Today due to improvements in cancer treatment there is an increasing number of long-term cancer survivors, many of whom suffer from infertility caused by malignancy itself and chemo- or radiotherapy. Also, anticancer therapy may cause myelosuppression. Presently granulocyte colony stimulating factor (G-CSF) is used for prevention and treatment of myelosuppression. Another treatment option used to decrease intoxication and ameliorate side effects of cancer therapy is sorption technology. The aim of our investigation was to study the efficiency of combined use of enterosorption and G-CSF to decrease gonadal toxicity of chemotherapy. MATERIALS AND METHODS: Melphalan (L-PAM) injected i.v. at a single dose of 4 mg/kg to white inbred rats was used as gonadotoxic and myelosuppressing agent. Carbon enterosorbent C2 was administered by intragastric route as a suspension in saline at a dose of 5 ml per 1 kg of rats' body weight (or 900 mg/kg of the dry mass of enterosorbent) daily for 3 days before and for 7 days after L-PAM injection. G-CSF was injected once a day for 4 days starting from the next day after L-PAM administration at a dose of 50 µg/kg. Histological preparations of testicular tissues were examined by light microscopy. RESULTS: Our findings have shown that melphalan caused marked damage of testicular tissues and seminiferous, especially spermatogenic epithelium. The most expressed protection of the histological structure of testes was observed when enterosorbent and G-CSF were used in combination. CONCLUSION: Gonadal toxicity of chemotherapy could be efficiently decreased by the combined use of enterosorption and G-CSF.

Effect of enterosorption on paraneoplastic syndrome manifestations in mice with highly angiogenic variant of Lewis lung carcinoma.

AIM: To study the correcting effects of microgranulated HSGD enterosorbent on hematological, morphological and biochemical indices of paraneoplastic syndrome in mice with highly angiogenic variant of Lewis lung carcinoma LLC/R9. METHODS: The study was performed on male С57/ВL6 mice with transplanted LLC/R9. Enterosorbent HSGD was administered daily at a dose of 0.625 g/kg for 2 weeks starting from 7(th) day after tumor cell transplantation. When enterosorption was completed, an analysis of peripheral blood, biochemical indices and morphological structure of tumor, lung, liver, spleen and thymus was carried out by standard methods. RESULTS: It has been shown that administration of enterosorbent did not affect LLC/R9 growth but resulted in nearly two fold decrease of the volume of lung metastases (p < 0.05). Erythrocyte number and hemoglobin level were higher by 30.0% (p < 0.05) and 23.3% (p < 0.05), respectively, in mice treated with enterosorbents as compared to untreated animals. In addition sorbent treatment completely normalized the thrombocyte index resulting in elevation of platelet number by 54.5% (p < 0.01) up to their level in intact mice. The morphological examination of liver and biochemical analysis of peripheral blood evidenced on significant positive correcting effect of enterosorption on histological structure of this organ and its functional activity. Normalization of total proteins and serum albumin level as well as significant decrease of total lipid concentration by 29% (p < 0.01) in blood of treated mice were observed. CONCLUSION: Positive influence of microgranulated carbon sorbent on some hematological, morphological and biochemical indices of tumor associated symptoms in LLC/R9-bearing mice denotes that enterosorption-based therapy can be considered as a prospective treatment for correction of some paraneoplastic syndrome signs in cancer patients.

Prevention of myelosuppression by combined treatment with enterosorbent and granulocyte colony-stimulating factor.

UNLABELLED: Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. AIM: To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). MATERIALS AND METHODS: Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. RESULTS: The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. CONCLUSION: Simultaneous administration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy.

[Prophylaxis and correction of inflammatory complications in peritonitis, depending on severity of enteral insufficiency].

There were examined 54 patients, in whom peritonitis of various etiology was diagnosed. Clinical, biochemical, immunological and other investigations were conducted for estimation of the enteral insufficiency syndrome severity. Basing on the analysis of the data obtained and criterions of the patient common state there was determined the occurrence risk for inflammatory complications (IC). Complex of prophylactic and therapeutic measures for reduction of the IC rate was proposed.

[Prophylaxis of adhesive process in patients with extended peritonitis].

The results of treatment of 378 patients, suffering extended peritonitis, were analyzed. For prophylaxis of adhesions formation intraoperatively an adequate surgical correction and measures, directed on elimination of endotoxicosis, were applied; postoperatively--the preparations, suppressing the adhesions formation, were applied. Conduction of intracorporeal and extracorporeal therapy extremely high frequency irradiation in complex of treatment have promoted a trustworthy improvement of motor-evacuatory function stomach and intestinal due to impact on system of coagulation and blockade of the oxidative reactions cascade, as well as due to bacteriostatic effect.

The influence of enterosorption on some haematological and biochemical indices of the normal rats after single injection of melphalan.

AIM: One of the most prominent side effects of intensive cancer chemotherapy is bone marrow suppression which is an independent negative prognostic factor for the time to tumor progression. The aim of the study was to evaluate the myeloprotective possibilities of carbon enterosorbents in the case of usage of alkilating drug melphalan (L-PAM). MATERIALS AND METHODS: L-PAM was injected intravenously to healthy inbred rats to cause the myelosuppression. 3 days before and 7 days after this, suspension of two types of carbon granulated enterosorbents were administered per os one time per day. On 8(th) day after L-PAM injection, the rats were weighted and blood and liver tissue were taken under Ketamine general anesthesia for biochemical examination. Peripheral blood smears were made also. RESULTS: Melphalan at a dose of 3 mg/kg causes expressed myelotoxic reaction: leucopenia, decreasing of erythrocytes, hemoglobin and platelets counts. Even on 8(th) day after single injection of this cytostatic we can detect expressed signs of oxidative stress like increasing of hydroperoxides, TBA-reactive substances, and decreasing of activity and level of main endogenic antioxidants - superoxide dismutase (SOD), catalase and reduced glutathione. L-PAM causes also the violation of kidney function such as increase of urea and creatinine level; and rising of endogenic intoxication with elevation of middle mass molecules level. In a dose of 3 mg/kg melphalan has no negative influence on liver function on 8(th) day of experiment. Enterosorption with carbon enterosorbents C1 (bulk density γ = 0.28 g/cm(3), granules diameter 0.15-0.25 mm, BET pore surface 1719 m(2)/g, therapeutic dosage 1400 mg/kg) and C2 (bulk density γ = 0.18 g/cm(3), granules diameter 0.15-0.25 mm, BET pore surface 2162 m(2)/g, therapeutic dosage 900 mg/kg) diminishes and mitigates negative side effects caused by single intravenous injection of melphalan. Carbon enterosorbent C2 have rather more expressed positive effect than C1 for practically all indices. The most important curative effect due to C2 administration is prominent myeloprotection of bone marrow of experimental animals. CONCLUSION: Carbon enterosorbent C2 is promising and perspective sorbent for prophylaxis and treatment of side effects of cytostatic chemotherapy including myelotoxicity, mucositis, kidney injuries, gonadotoxicity, etc.

[Conservative treatment of patients with intermittent claudication].

The article deals with the analysis of the results of randomized placebo-controlled studies of various therapeutic agents currently available in Russia, as well as the results of meta-analyses and Cochrane reviews of medicamentous treatment of patients with intermittent claudication. The results of these studies gave grounds to recommend the most efficient agents in the new edition of the "National Guidelines on management of patients with lower-limb arterial disease" (2013).

Analysis of medical use of carbon adsorbents in China and additional possibilities in this field achieved in Ukraine.

The review is devoted to analysis of the use of carbon sorbents for medicinal purposes in China and description of some innovative technologies in this field in Ukraine. The review underlines the presence of common roots of sorption therapy development in these two countries determined by pioneer works of Prof. T.M.S. Chang, created to the concept of artificial cells. High level of works of Chinese scientists on sorption purification of blood and combined extracorporeal methods has been mentioned. At the same time, by author's opinion, two other methods of sorption therapy, namely enterosorption and sorption therapy of wounds and burns, has not been properly developed in China. In the review, there are also described the essential results of Ukrainian scientists in the field of blood purification from protein-bound toxins and other harmful compounds what is important for treatment of many serious human pathologies, and also the important data on the use of oral sorbents and dressings from activated carbon materials, which could be considered as a useful addition to achievements of Chinese scientists in the field of the development and use of sorbents for medicinal purposes.

[Peculiarities of enterosorption via nasointestinal probe using sorbent diosmectite].

Peculiarities of conduction of enterosorption, using sorbent diosmectit via nasointestinal probe, were analyzed in patients, suffering peritonitis in acute ileus. The data obtained witness positive dynamics of indices of endogenic intoxication and antiendotoxic immunity while application of sorbent.

Optimization of physico-chemical properties of carbon enterosorbents and evaluation of their sorption activity for use in the treatment of paraneoplastic syndrome and other endogenous intoxications in cancer patients.

AIM: Development of carbon enterosorbents with optimal physical-chemical properties and high adsorptive capacity for their usage in the treatment of paraneoplastic syndrome and other endogenous intoxication in cancer patients. METHODS: physical-chemical and biochemical methods of investigation. RESULTS: In the work it has been shown that performance of additional steam activation on pilot plant developed in R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, allows produce highly active granulated and fibrous carbon enterosorbents which possess well developed porous surface providing potent sorption potential toward compounds of hydrophilic and hydrophobic nature. Being placed in gastro-intestinal tract lumen these sorbents may cause certain effect on functional activity of detoxifying body systems and regeneration potential of many organs and tissues. CONCLUSION: The usage of carbon enterosorbents with optimal physical-chemical properties and high adsorptive capacity could be very perspective for correction of biochemical, immunologic, morphologic and hematological manifestations of paraneoplastic syndrome.

Enterosorption as a method to decrease the systemic toxicity of cisplatin.

UNLABELLED: A perspective adsorptive method to minimize systemic toxic effects of chemotherapy is enterosorption (ES). However, the capabilities of this method are far from being completely studied. The question remains opened - should ES be initiated in the first hours on completing cytostatic infusion without the risk of their anticancer activity to be decreased. AIM: to analyze ES influence on anticancer activity and toxic reactions of cisplatin (CP) upon the use of carbon enterosorbent in 1 h after intravenous administration of cytostatic. METHODS: CP at the dose of 1 mg/kg body weigh (BW) was administered to Guerin carcinoma-bearing rats each second day for two weeks. Enterosorbents on the basis of highly activated carbon fibers were administered by per os daily 1 h after CP injection. 3 days after the last CP administration the rats were weighted and blood under ether narcosis has been taken for biochemical examination. Tumors and innate organs were isolated, weighted, and fixed in 4% buffered formalin for morphologic examination. RESULTS: In rats administered with CP at the background of ES, BW loss was in 1.6 times lower than in animals after CP session. Relative kidney weight in CP-treated rats was 33.9% higher than in normal ones (p ≤ 0.05). No significant differences were detected between relative kidney weights in the CP + ES-treated and intact animals. Introduction of ES allowed prevent an 30% increase of creatinin content observed in blood plasma after CP treatment (р ≤ 0.05). Urea content was 1.7 times lower in blood plasma of CP + ES-treated rats than after CP treatment. CP caused significant toxic injuries in kidneys, liver, and spleen tissues. Morphologic structure of organs in rats treated with CP at the background of ES was affected at much lower degree. In tumors, large areas of newly formed connective tissue and blood vessels have been fixed after the CP+ES action instead of large necrotic area observed after CP treatment. ES caused insignificant suppression of Guerin carcinoma growth and had additional impact to inhibitory action of CP. CONCLUSION: Active carbon enterosorbents which are administrated just 1 h after CP administration possesses detoxicating potential sufficient for significant elimination of toxic effect of the cytostatic at the background of complete preservation of its antitumor activity.

[Effect of mesenchymal stem cells and entero-absorbent on cardiac function in rats following local irradiation of the chest].

Cardiac function in Wistar male rats was assessed by ECG records for 28 days following exposure of the chest to γ-rays at a dose of 6 Gy, dose rate 4 Gy/min. The exposed rats experienced a moderate cardiac ischemia and a certain increase in the load on the atria. The use of clay of Kaluga deposit and mesenchymal stem cells reduced the adverse radiation effects.

[Possibility of the liver ultrastructure recovery in intoxication with heavy metals salts].

Experimental studies helped to reveal ultrastructural changes in hepatocytes, caused by prolonged exposure to heavy metals salts taken in combination and ratios characteristic to soil contents near Almalyk mining and smelting enterprise. The authors demonstrated possibility of liver structural recovery via enterosorption with additional antioxidant therapy.

[Clinical aspects of intestinal dysbacteriosis].

The article presents data of domestic and foreign literature on intestinal dysbacteriosis. It is evident that intestinal dysbiosis always secondary and its correction should take into account the reasons that caused the violation of the microbial composition of the intestinal flora and the clinical manifestations of this syndrome. The characteristic of the normal intestinal microflora and its significance for the human body. It was emphasized that the resident microflora influences the development of the immune response of the intestinal mucosa, epithelial differentiation and proliferation, motility, is actively involved in the digestion and absorption, and synthesis of vitamins and bioactive substances. It was described factors leading to violation of the microbial composition of intestine, as well as methods of diagnosis and treatment of dysbiosis. Therapeutic measures for dysbiosis conducted according to the nature and severity of underlying disease and were in compliance with dietary recommendations and the use of drugs, normalizing the intestinal microflora. In order to remove from the intestinal lumen conditionally pathogenic microorganisms and toxins using different chelators. One of the members of this group of drugs is Laktofiltrum. Laktofiltrum drug effective in treating patients with bowel diseases, accompanied by dysbiosis, as a monotherapy and in combination with other drugs.