General Toxic Effects Research Articles

ДОСЛІДЖЕННЯ ВПЛИВУ НАНОКОМПОЗИТНОГО КОМПЛЕКСУ ЦИТОКІНУ ЕМАР II З ДЕКСТРАНОМ 70 НА ОРГАНІЗМ МИШЕЙ ЛІНІЇ BALB/C

The cytokine ЕМАР ІІ is endothelial and monocytic-activating polypeptide II, the precursor of which is the component of the high-molecular complex aminoacyl-tRNA synthetase of the higher eukaryotes of the protein p43, is capable of modulating the properties of endothelial cells, monocytes and leukocytes. In low concentrations the cytokine stimulates and in high concentrations it suppresses the migration of endothelial cells, stimulates their apoptosis, affects the activity of monocytes, neutrophils, macrophages, thus contributing to inflammatory and necrotic processes in malignant tumors. One of the promising directions of targeted therapy of oncological diseases is the use of antiangiogenic, prokoagulative and proapoptic drugs, which became the basis for the selection of an antitumor cytokine ЕМАР ІІ as an object of research. In the Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, the biotechnology of bacterial expression of recombinant ЕМАР ІІ in E.coli BL21 (DE3) cells and isolation of highly purified cytokine preparations in preparative amounts have been developed. In order to increase the stability and reduce the aggregation of recombinant ЕМАР ІІ, scientific and methodological foundations were created and nanocomposite complexes of the cytokine EMAR II with biocompatible polymers with cyclodextrin and dextran 70 were obtained. In this experimental work, the effects of the nanocomposite complex EMAR II and dextran-70 on the animal organism were investigated for the purpose of establishing safety of its use. BALB / C mice were used as an object of research. Experimental studies have shown that acute and chronic administration of the drug to animals at doses of 300 – 10 000 μg / kg does not show the general toxic effects of the nanocomposite complex on the organism of mice. The obtained data open the prospect of further investigation of antitumor properties of the nanocomposite complex EMAR II with dextran-70 with the aim of possible further introduction into pharmacological practice.

ABCI3 Is a New Mitochondrial ABC Transporter from Leishmania major Involved in Susceptibility to Antimonials and Infectivity.

We have identified and characterized ABCI3 as a new mitochondrial ABC transporter from Leishmania major Localization studies using confocal microscopy, a surface biotinylation assay, and trypsin digestion after digitonin permeabilization suggested that ABCI3 presents a dual localization in both mitochondria and the plasma membrane. From studies using parasites with a single knockout of ABCI3 (ABCI3+/-), we provide evidence that ABCI3 is directly involved in susceptibility to the trivalent form of antimony (SbIII) and metal ions. Attempts to obtain parasites with a double knockout of ABCI3 were unsuccessful, suggesting that ABCI3 could be an essential gene in L. majorABCI3+/- promastigotes were 5-fold more resistant to SbIII than the wild type, while ABCI3+/- amastigotes were approximately 2-fold more resistant to pentavalent antimony (SbV). This resistance phenotype was associated with decreased SbIII accumulation due to decreased SbIII uptake. ABCI3+/- parasites presented higher ATP levels and generated less mitochondrial superoxide after SbIII incubation. Finally, we observed that ABCI3+/- parasites showed a slightly higher infection capacity than wild-type and add-back ABCI3+/-::3×FABCI3 parasites; however, after 72 h the number of ABCI3+/- intracellular parasites per macrophage increased significantly. Our results show that ABCI3 is responsible for SbIII transport inside mitochondria, where it contributes to enhancement of the general toxic effects caused by SbIII To our knowledge, ABCI3 is the first ABC transporter which is involved in susceptibility toward antimony, conferring SbIII resistance to parasites when it is partially deleted.

Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos

BackgroundZebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular effects of eight methylxanthines: aminophylline, caffeine, diprophylline, doxofylline, etophylline, 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline and theophylline.MethodsMicroinjections of the eight methylxanthines were performed in 1-2 cell stage zebrafish embryos and the general toxicity and cardiovascular effects were analyzed at different time points. Embryotoxicity and teratogenicity were evaluated to understand the general toxicity of these compounds. Structural and functional alterations of the heart were evaluated to assess the cardiovascular effects.ResultsOur results showed different activity patterns of the methylxanthines drugs. Caffeine, IBMX, pentoxifylline and theophylline were highly embryotoxic and teratogenic; aminophylline, doxofylline and etophylline were embryotoxic and teratogenic only at higher doses, and diprophylline showed a minimal (<10%) embryotoxicity and teratogenicity. Most of these drugs induced structural alteration of the heart in 20-40% of the injected embryos with the maximum dose. This structural alteration was fatal with the embryos ultimately dying within 120 hpf. All the drugs induced a transient increase in heart rate at 48 hpf which returned to baseline within 96 hpf. This functional effect of methylxanthines showed similarity to the studies done in humans and other vertebrates.ConclusionOur results indicate the potential toxicity and teratogenicity of different methylxanthines in the embryos during embryonic development, the most sensitive period of life. Although interspecies differences need to be considered before drawing any conclusion, our study elucidated that a single exposure of methylxanthines at therapeutic range could induce cardiac dysfunction besides causing embryotoxicity and teratogenicity. Of all the drugs, diprophylline appeared to be safer, with lower degree of embryotoxicity, teratogenicity and cardiac toxicity as compared to other methylxanthines.

INDIVIDUAL EXPOSURE LOAD OF FORMALDEHYDE AND ADOLESCENTS’ ORGANISM SENSIBILIZATION

All environmental factors influence on the human directly or indirectly. The biggest influence has the outdoor air, which is one of the major health risk factors associated with the environment. The proportion of 9-18 % of the total hazard index of inhalation exposure belongs to formaldehyde, which has a general toxic, sensibilizing and allergic effect. The frequency of allergic rhinitis and asthma in children living in the industrial cities of Eastern Siberia is 28-36 %. The purpose of the study was to assess the individual load of formaldehyde and detection its relationship with teenagers' organism sensitization. The study was carried out on the territory of two industrial cities with high and moderate levels of air pollution. The individual hazard indices of formaldehyde inhalation exposure were calculated for 373 adolescents. The formaldehyde concentration in urine was determined by HPLC method. The leukocyte migration inhibition test to formaldehyde has been studied. The levels of secretory immunoglobulin IgA, total IgE in serum were determined by ELISA technique. The number of eosinophils in nasal mucus was calculated. Individual hazard indices of formaldehyde inhalation exposure were exceeded in all patients. Elevation of formaldehyde concentration in the urine was found in every third adolescent. More than 30 % of the surveyed had a response to the formaldehyde in leukocyte migration inhibition test, which indicates the presence of sensitization to this chemical. About 20 % of students had a combined increase of total IgE levels in the blood and the number of eosinophils in the nasal mucus and more often these cases are marked in the group of adolescents with the lowest indices of formaldehyde exposure. Reduction of the secretory immunoglobulin A was found in the serum of adolescents with increased risk indices of formaldehyde inhalation exposure.

Changes in blood parameters of patients with laryngeal squamous cell carcinoma during polychemotherapy with cetuximab.

e17579 Background: Our purpose was to evaluate changes in blood parameters in patients with laryngeal squamous cell carcinoma (LSCC) during polychemotherapy (PCT) with cetuximab. Methods: Levels of white blood cells (WBC), immature granulocytes (IG) and neutrophils (Ne), as well as levels of C-reactive protein (CRP), lactate dehydrogenase (LDH) and creatinine were studied in the blood of 20 patients with stage I-III LSCC before therapy with cetuximab/cisplatin+5-fluorouracil and on days 2, 9 and 16 of the therapy. The control group (21 patients) received similar PCT without cetuximab. Treatment was assessed using the RECIST criteria. Results: Partial response was observed in 16 (80%) patients of the main group and in 5 (23.8%) controls, stabilization - 4 (20%) and 12 (57.4%), respectively, progression – in 4 (19%) patients of the control group. Patients of the main group with treatment effect showed WBC increase by 2 times after every cetuximab injection (days 2, 9, 16) compared with the initial levels due to Ne and IG increase by 2.7 and 4 times, respectively. WBC and IG levels measured on days 2, 9 and 16 were 13.40±2.86×109/L, 13.52±1.88×109/L, 12.25±2.08×109/L and 0.044±0.021×109/L, 0.056±0.015×109/L, 0.060±0.008×109/L, respectively (p &lt; 0.001). A transient increase in the indexes was replaced by their decrease to the initial values, with the values similar to the reference ones by the end of the treatment. At the same time, we observed decrease in CRP and creatinine levels up to the reference levels (7.69±3.28 mg/L and 74.75±6.54 umol/L, respectively); LDH did not increase. Stabilization was characterized by unchanged WBC levels, positive dynamics of IG and slow decline of CRP level exceeding the reference one (10.0 mg/L) by the treatment end. Reduction of WBC and increase in IG and CRP levels were noted in the controls regardless of the PCT results which could be explained by severity of intoxication syndrome, partially due to the disease and partially due to PCT toxicity. Conclusions: A dual transient increase in WBC and IG levels, reduction of CRP and creatinine during the treatment and unchanged LDH indicate minimization of myelotoxic and general toxic effects of PCT in combination with cetuximab.

Toxicity of nickel to soil microbial community with and without the presence of its mineral collectors-a calorimetric approach.

The toxicity of nickel and three of its main collectors, sodium isopropyl xanthate (SIPX), sodium ethyl xanthate (SEX), and potassium ethyl xanthate (PEX) to soil microbial activity, was analyzed, individually and as a binary combination of nickel and each of the collectors. The investigation was performed through the microcalorimetric analysis method. For the single chemicals, all power-time curves exhibited lag, exponential, stationary, and death phases of microbial growth. Different parameters exhibited a significant adverse effect of the analyzed chemicals on soil microbial activity, with a positive relationship between the inhibitory ratio and the chemical dose (p<0.05 or p<0.01). A peak power reduction level of 24.23% was noted for 50μgg-1 soil in the case of Ni while for the mineral collectors, only 5μgg-1 soil and 50μgg-1 soil induced a peak power reduction level of over 35 and 50%, respectively, in general. The inhibitory ratio ranged in the following order: PEX>SEX>SIPX>Ni. Similar behavior was observed with the mixture toxicity whose inhibitory ratio substantially decreased (maximum decrease of 38.35%) and slightly increased (maximum increase of 15.34%), in comparison with the single toxicity of mineral collectors and nickel, respectively. The inhibitory ratio of the mixture toxicity was positively correlated (p<0.05 or p<0.01) with the total dose of the mixture. In general, the lesser and higher toxic effects are those of mixtures containing SIPX and PEX, respectively.

Genotoxic effect of Pb and Cd on in vitro cultures of Sphagnum palustre: An evaluation by ISSR markers

In the present work, the genotoxic effect of cadmium and lead supplied in a laboratory trial, was investigated for the first time in the moss Sphagnum palustre, by ISSR molecular markers. A total of 169 reproducible bands were obtained with 12 primers, ten of which gave polymorphisms (i.e., appearance/disappearance of bands), indicating a clear genotoxic effect induced by the metals. Both metals induced a decrease of the genome template stability in a dose dependent manner. At concentration >10−5 Cd also induced a general toxic effect in S. palustre, leading to chlorophyll degradation and moss death. Moreover, we followed the fate of supplied heavy metals into the moss tissue by SEM-EDX to see if they entered the cells. SEM-EDX observations on moss cultures treated with equimolar concentrations of the two metals showed that most Pb precipitated in form of particles on moss surface, while Cd did not aggregate in particles and was not found on moss surface. In light of these findings, we concluded that probably Pb induced a genotoxic effect at lower intracellular concentrations than Cd.

PRESENT ALTERNATIVE STUDY METHODS USED IN PRODUCT SAFETY ASSESSMENT

Alternative toxicological methods used in Russia to assess safety of food and non-food products have been reviewed. Along with traditional toxicological methods of monitoring various alternative toxicological study techniques are used to assess product safety. Those are methods using biological test-objects, so-called biological test methods, or in vitro methods which are allowed to be used from the legislative viewpoint. Alternative toxicological methods are based on risk degree assessment of the studied object by response of living organisms (test-objects) to adverse factor exposure. Information resulting from applied bio-testing methods represents combined toxic effect of all toxicants present in the given medium and their simultaneous presence. When assessing product safety by toxicological indices using alternative biological models, general toxic and irritating effects are to be studied and the test-objects are cattle semen, luminescent bacteria, chick egg chorioallantoic membrane, human and animal cell cultures and isolated organs. In vitro methods with cattle semen and luminescent bacteria playing the role of test-objects are also used to assess alcohol product toxicity, in particular spirits and vodkas. Thus, alternative study methods are widely known and commonly used in practice to prove safety of consumer goods and alcohol-containing foodstuffs.

Safety of a proteoliposome from Neisseria meningitides as adjuvant for a house dust mite allergy vaccine

The proteoliposome (PL) of Neisseria meningitidis serogroup B has been reported as a safe and potent vaccine adjuvant, inducing a TH1-skewed response. The present study describes a pre-clinical safety evaluation of an allergy therapeutic vaccine candidate based on purified allergens from Dermatophagoides siboney house dust mite and PL as adjuvant, both components adsorbed onto aluminum hydroxide gel. Two separate studies of acute toxicity evaluation were performed in mice and rabbits, and two repeat-dose studies were conducted in non-sensitized and allergen-sensitized Balb/c mice, respectively. The study in sensitized mice intends to model a therapeutic setting. Aerosolized allergen challenge was used in both settings to model natural respiratory exposure. In the therapeutic setting, mice were administered with three doses containing 2 μg allergen at weekly intervals [subcutaneous route] and subsequently challenged with aerosolized allergen for 6 consecutive days. Parameters of general toxicity effects were assessed via measures of behavior, body weight, food and water consumption, and macroscopic evaluation of organs. Histological examination of organs and the injection site was performed. Potential immunotoxicity effects at the systemic level were assessed by blood eosinophil counting and serum allergen specific IgE by ELISA The vaccine did not produce general or functional toxic effects of significance, at a dose up to 100 μg allergen per kg body weight. An expected local reaction at the injection site was observed, which could be attributed mostly to the immunological effect of aluminum hydroxide. The models implemented here suggest an acceptable safety profile of this vaccine for testing in clinical trials of allergy immunotherapy.

Оценка риска здоровью населения Самары и Новокуйбышевска от загрязнения атмосферного воздуха

There are presented results of the analysis of a risk to public health of cities of Samara and Novokuibyshevsk. We assessed the content of harmful substances in the air at fixed stations located within the city boundaries on a well-ventilated area. The risk to health is calculated in accordance with the R 2.1.10.1920-04. During the period 2014-2015 we fixed the impurity concentration in excess of the average daily maximal permissible concentrations of carcinogens of the first and second classes of danger (benzo[a]pyrene and formaldehyde), as well as ammonia, which has a general toxic effect. The average concentration of phenol and formaldehyde within the territory of the city of Novokuibyshevsk were in the range of the average daily maximal permissible concentrations. Within the city of Samara in the air annual average concentrations of formaldehyde, only slightly exceeding the daily maximal permissible concentrations value of 1.39 in 2015 were registered. The total cancer risk to public health in the city of Samara as a whole for the period 2014-2015 amounted to 2.77·10-4, the total hazard index - 18.35. For the health of the population of the city of Novokuibyshevsk the level of total cancer risk is equal to 1.37·10-4, the total hazard index - 14.64. Hexavalent chromium, formaldehyde and benzene seem to be main pollutants that form the total level of carcinogenic risk to public health in the cities of Samara and Novokuibyshevsk. Copper (I place ranking), contained in large quantities in the emissions of non-ferrous metallurgy is the priority chemical, forming the total index of the risk of developing non-carcinogenic effects in the population of the city of Samara and Novokuibyshevsk. Petrochemicals are related with the values of the total cancer risk and total hazard index unacceptable for public health in cities of Samara and Novokuibyshevsk and require planned measures aimed at improving the environment in the near future.

Electrophysiological alterations and general toxic signs obtained by subacute administration of titanium dioxide nanoparticles to the airways of rats.

Particles of titanium dioxide (TiO2) with typical size below 100 nm have gained a broad range of application by now, partly involving direct human exposure. Their known properties - high specific surface, mobility within the organism, induction of oxidative stress, release of inflammation mediators etc. - raise the possibility of nervous system damage but the available data regarding this are scarce and contradictory. Based on that, and the experiences with other metal oxide nanoparticles, the aim of the present study was to investigate certain general end nervous system toxic effects of TiO2 nanoparticles applied in the airways of rats. Young adult Wistar rats (5 groups of 10 rats each) received, daily for 28 days, intratracheal instillations of titanium dioxide nanoparticles of ca. 10 nm diameter, suspended in 1% hydroxyethyl cellulose dissolved in phosphate-buffered saline, in the doses of 1, 3, and 10 mg/kg b. w. Vehicle controls received the suspension medium and there was also an untreated control group. During treatment, the rats' body weight was measured, and their clinical state observed, daily. After the 28 days, spontaneous cortical activity, sensory evoked potentials and tail nerve action potential was recorded in urethane anesthesia, then the rats were dissected and tissue samples were taken for Ti level determination and biochemical measurements of some oxidative stress indicators. The two higher doses reduced the rate of body weight gain significantly. Sensory evoked potentials and tail nerve action potential were significantly slowed, but the change in the spectrum of spontaneous cortical activity was not significant. Correlation of moderate strength was found between certain evoked potential parameters and brain Ti level and oxidative stress data. Our results underlined the possible neurotoxicity of TiO2 NPs but also the need for further investigations.

Investigation of cardiotoxic effect of A-1 apo + D actinomycin complex on isolated rat heart

Aim. Chemotherapy is one of the main methods of treating malformations. However, this technique causes a great deal of side effects, among which are complications related to cardiac toxicity. Development of new anticancer drugs is directly related to a decrease in the general toxic effect on the organism and the cardiovascular system in particular. The aim of the study was to investigate the capability of apolipoprotein A-1 together with an anticancer drug, actinomycin D, to induce functional disturbances in the performance of an isolated rat heart and to compare the effect with that of pure actinomycin D. Methods. For experiments use was made of Wistar male rats weighing 220-250 g. A modified Krebbs-Henseleit buffer saturated with carbogene (95 % O2 and 5 % CO2, solution temperature 37.5 °C) was used as perfusate. Experiments were conducted on isolated rat hearts. The isolated rat hearts were perfused retrogradely by a standard procedure, with isovolumic pressure registered in the left ventricle. Apolipoprotein A-I was isolated of human high-density lipoprotein by delipidating followed by separation of the proteins mix by means of column chromatography. In the experiment, apolipoprotein A-I- was mixed with actinomycin D, with concentration of the anticancer drug in the complex being 0.1 µg/ml.Results. Actinomycin D with concentration 1 µg/ml aggravates the functional indicators of the heart and enhances energy load on the myocardium. Decreasing the concentration of cytostatic down to 0.1 µg/ml of perfusate brings the indicators to the baseline values. Apolipoprotein A-I combined with actinomycin D offsets the changes introduced by the cytostatic without a carrier. The complex improves hemodynamics, which can be interpreted by the presence of a protein component.Conclusion. An isolated rat heart model shows that apolipoprotein A-I in combination with 0.1 µg/ml actinomycin D does not cause cardio toxicity. The complex improves myocardial efficiency through the use of the protein component as a carrier of the anticancer drug.Received 15 November 2016. Accepted 30 November 2016.Funding: The research was supported by the federal budget project implemented by Research Institute of Biochemistry, Reg. R-085.Conflict of interest: The authors declare no conflict of interest.Author contributionsConceptualization and study design: Kolpakov AR. Сбор и обработка материала: Knyazev R.A., Trifonova N.V.Statistical data processing: Knyazev R.A.Article writing: Knyazev R.A.Review &amp; editing: Polyakov L.M.

Stimulation of Diethylnitrosamine Metabolism Reduces Its General Toxic and Hepatocarcinogenic Effects.

The general toxic and hepatocarcinogenic effects of diethylnitrosamine after stimulation of its metabolism with 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) were studied. The hydroxylating activity of liver microsomes of C57Bl/6Mv mice towards p-nitrophenol increased more than 4-fold 3 days after injection of TCPOBOP. Injection of diethylnitrosamine 3 days after TCPOBOP caused a lesser body weight loss and decrease of food consumption in C57Bl/6Mv mice than in response to diethylnitrosamine without preinduction. Injection of diethylnitrosamine to suckling ICR mice after TCPOBOP induction of cytochrome P450 2e1 activity led to development of 2-fold lesser number of tumors and pretumorous nodes in the liver in comparison with animals injected with diethylnitrosamine without induction. These data indicated that metabolism stimulation reduced the general toxic and hepatocarcinogenic effects of diethylnitrosamine.

Mono- and Combined Therapy of Metastasizing Breast Carcinoma 4T1 with Zoledronic Acid and Doxorubicin.

The efficiency of monotherapy with zoledronic acid (Resorba), doxorubicin, and their combination was studied on the model of metastasizing breast carcinoma in BALB/c mice. Doxorubicin monotherapy was accompanied by a significant increase in median survival up to 57 days (vs. 34 and 35 days in control groups); 27% animals survived for 90 days (duration of the study). Bioluminescence area of the primary tumor significantly decreased on days 21 and 28; the total number of visceral metastases also decreased according to magnetic-resonance imaging data. Resorba monotherapy produced no general toxic effect, the median survival increased to 64 days, and 90-day survival was 33%. Imaging techniques (magnetic-resonance imaging, microtomography, bioluminescent analysis) showed that Resorba delayed the development of the primary tumor (regression of luminescence area on days 21 and 28, regression of standardized bioluminescence intensity on day 28) and significantly reduced the number of visceral metastases in comparison with the control. Combination therapy was less effective than monotherapy with the same medications. Median survival was 55 days, 90-day survival was 13%, but magnetic-resonance imaging and bioluminescence analysis after combination therapy also showed delayed growth of the primary tumor and reduced number of visceral metastases. Microtomography revealed bone metastases in ~30% animals of the control group; in experimental groups, no bone metastases were found. The experiment with periosteal (distal epiphysis of the femur) injection of 4T1-Luc2 tumor cells demonstrated pronounced selective effectiveness of Resorba in relation to bone metastases. Monotherapy with Resorba can prevent the development of not only bone, but also visceral metastases of breast cancer.

In Ukrainian

Nowadays one of the perspective trends in manufacturing technology of prolonged release surgical materials is introduction of bioactive substances into the polymer matrix. Earlier we synthesized the nanocomposite material Polydens, which is an interpenetrating polymer network of polyurethane and poly(2-hydroxyethyl methacrylate) filled with silica modified by antimicrobial substances, namely metronidazole, decametoxin and silver nitrate. In this work we examined medical and biological properties of the synthesized material. The release kinetics of antimicrobial substances into the aqueous medium was studied by absorption spectrophotometry and chemical methods. The influence on the vital activity of yeast cells, antimicrobial properties, general toxic effect and reaction of the surrounding tissues of Polydens were investigated microscopically, by agar diffusion method and after subcutaneous implantation of material Polydens to test animals, respectively. It has been found that the nanocomposite is non-toxic, causes no severe local inflammatory reaction, and the release kinetics of bioactive substances does not inferior to the standard samples. Research of antimicrobial properties has shown that considered material significantly suppresses the vital activity of yeast cells and is characterized by a prolonged antibacterial effect. Polymer-based nanocomposite Polydens is a promising material in manufacturing of different medical devices, such as implants, catheters, drainages etc.

Effect of 4-benzylidenamino-5-phenyl-4Н-1,2,4-triazole-3-thiones and salts of 2-(4-amino-5-phenyl-4Н-1,2,4-triazole-3-ylthio)acetic acid on central component of nociceptive system

Aim. To study the effect of 4-benzylideneamino-5-phenyl-4H-1,2,4-triazole-3-thiones and salts of 2-(4-amino-5-phenyl-4H-1,2,4-triazole-3-yltio)acetic acid on central component of nociceptive system on condition of thermal stimulation of limbs of rats, and also to explore patterns related with the chemical structure and pharmacological activity of 1,2,4-triazole derivatives.Materials and methods. The newly synthesized derivatives of 4-benzylideneamino-5-phenyl-4H-1,2,4-triazole-3-thiones and salts of 2-(4-amino-5-phenyl-4H-1,2,4-triazole-3-ylthio)acetic acid (Table. 1) have been used in the studies. General toxic effect and acute toxicity of compounds had been previously studied by express method of V.B. Prozorovskiy to determine the conditions of test-substance dosing [4]. The study has been conducted on a group of non-linear white rats of both sexes weighing 185-229 g.Results. The compound that is close to the reference medication – analgin, by its activity, has been revealed. This compound exhibits analgesic activity at considerably lower doses than the proposed reference medication.Conclusions. Some relations between chemical structure and pharmacological activity of the investigated 1,2,4-triazole derivatives have been established. Thus, condensation of 4-amino-5-phenyl-4H-1,2,4-triazole-3-thione with 4- hydroxybenzaldehyde causes almost no effect on analgesic action of starting thione and 4-(4-hydroxybenzylideneamino)-5-phenyl-4Н-1,2,4-triazole-3-thione, whereas the replacement of 4-hydroxybenzylideneamino substituent by 2-hydroxybenzylideneamino substituent reduces the sensitivity of rats to thermal stimulus. The replacement of morpholine cation in the molecule of morpholine salt of 2-(4-amino-5-phenyl-4H-1,2,4-triazole-3-ylthio)acetic acid by piperidinium cation leads to sudden appearance of analgesic activity.

Investigation of low recovery in the free drug assay for antibody drug conjugates by size exclusion-reversed phase two dimensional-liquid chromatography.

Antibody drug conjugates (ADCs) are complex therapeutic agents combining the selectivity of monoclonal antibodies and highly efficacious small molecule drugs to successfully eliminate tumor cells while limiting the general toxicity and side effects of the therapeutic to protect patient safety. One unique attribute critical to the safety of ADCs is the residual content of unconjugated small molecule drug present from either incomplete conjugation or degradation of the ADC. Typically for quality control assays, quantifying the amount of the free drug is performed through precipitation of the protein species using an organic solvent and then assaying the amount of free drug left in the supernatant. During the validation of an assay of this type for a maleimide based linker drug, issues were experienced with low and variable recovery in the spiked samples of the drug substance and drug product. A two-dimensional heart-cutting method coupling Size Exclusion Chromatography (SEC) with Reverse Phase (RP) chromatography was utilized to explore possible mechanisms leading to the low recovery of the free linker drug. The results of the investigation indicated that the spiked linker drug reacts with residual reactive groups on the ADC; a conclusion which was confirmed by the observed increase of average Drug to Antibody Ratio (DAR) determined by Hydrophobic Interaction Chromatography (HIC). Finally, several approaches were evaluated to minimize the recovery loss. Capping the residual reactive groups on the ADC with maleimide containing reagents effectively mitigated the low recovery issue.

The Problem of Nephropathy Induced by Endocavitary Administration of Iodine-Containing X-ray Contrast Agents

It is known that there is a high risk of progression of side effects in kidneys, so-called nephropathy induced with X-ray contrast agents, at applying of water-soluble X-ray contrast agents in medical practice. New water-insoluble compounds of orthotantalates of rare-earth elements are offered as new X-ray contrast agents for endocavitary administration. The achieved results have shown the absence of general toxic effect on bodies of animals, high X-ray contrast properties in vitro and in vivo experiments. The investigations were performed on white nondescript mice, rats Wistar subtype and Chinchilla rabbits.

Reproductive toxicity of Samanea tubulosa on rats

&lt;p&gt;&lt;em&gt;Samanea tubulosa&lt;/em&gt; é uma planta utilizada na fitoterapia e na alimentação animal. Entretanto, a ingestão de vagens de &lt;em&gt;S. tubulosa&lt;/em&gt; tem sido associada à ocorrência de abortos em bovinos. Assim, o objetivo do trabalho foi investigar os efeitos da dieta contendo 5% de vagens de &lt;em&gt;S. tubulosa&lt;/em&gt; em ratos machos e fêmeas Wistar. A dieta foi administrada para ratos machos (n = 10) por 60 dias antes do acasalamento. Ratos fêmeas (n = 10) receberam o tratamento por 30 dias, durante a coabitação e do dia gestacional (GD) 0 ao GD 20. As fêmeas tratadas foram acasaladas com ratos não tratados. Em machos, o consumo da planta causou diminuição no consumo de ração e redução de 20% no índice de fertilidade. A prole de machos tratados apresentou menor ganho de peso e comprimento cabeça cauda. Fêmeas tratadas com a planta apresentaram aumento do consumo de ração e água e do peso corporal. Ainda, foram observadas diminuição na fertilidade, fecundidade e no índice de gestação e aumento do peso da placenta e no número médio de corpos lúteos. Desse modo, em decorrência aos possíveis efeitos tóxicos sistêmicos e reprodutivos, o consumo prolongado de &lt;em&gt;S. tubulosa&lt;/em&gt; não é recomendado para fins fitoterápicos ou alimentar.&lt;/p&gt;

The effect of changes in CYP2E1 activity in the liver on toxicity and carcinogenicity of diethylnitrosamine in mice

In this work, the biological effects of diethylnitrosamine (DENA) have been studied under controlled conditions of its metabolism in mice of different ages. The results indicate that the general toxic and hepatocarcinogenic effects of DENA are mostly due to the parent compound, whereas the alkylating metabolites cause hepatic cell damage. Our findings cast doubt on the conventional understanding of the exclusive role of mutagenic activation in the carcinogenic action of chemicals.