Search results for: common drug combinations

Authors: Onur Yaşar, Okan Bilge, Ortaç Onmuş

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The aim of this study is to investigate and compare the locomotion structures, especially the bone structures, of two different dolphin species, the Common bottlenose dolphin Tursiops truncatus and the Harbor porpoise Phocoena phocoena, and to provide a more detailed and descriptive comparison. To compare the structures of bones of two study species; first, the Spinous Process (SP), Inferior Articular Process (IAP), Laminae Vertebrae (LA), Foramen Vertebrae (FV), Corpus Vertebrae (CV), Transverse Process (TP) were determined and then the length of the Spinous Process (LSP), length of the Foramen Vertebrae (LFV), area of the Corpus Vertebrae (ACV), and length of the Transverse Process (LTP) were measured from the caudal view. The spine consists of a total of 61 vertebrae (7 cervical, 13 thoracic, 14 lumbar, and 27 caudal vertebrae) in the Common bottlenose dolphin, while the Harbor Porpoise has 63 vertebrae (7 cervical, 12 thoracic, 14 lumbar, 30 caudal. In the Common bottlenose dolphin, epiphyseal ossification was between the 21st caudal vertebra and the 27th caudal vertebra, while in the Harbor porpoise, it was observed in all vertebrae. Ankylosing spondylitis was observed in the C1 and C2 vertebrae in the Common bottlenose dolphin and in all cervical vertebrae between C1 and C6 in the Harbor porpoise. We argue that this difference in fused cervical vertebrae between the two species may be due to the fact that the neck movements of the Harbor porpoise in the vertical and horizontal axes are more limited than those of the Common bottlenose dolphin. We also think that as the number of fused cervical vertebrae increases, underwater maneuvers are performed at a wider angle, but to test this idea, we think that different species of dolphins should be compared and the different age groups should be investigated.

Keywords: anatomy, morphometry, vertebrae, common bottlenose dolphin, Tursiops truncatus, harbour porpoise, Phocoena phocoena

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Authors: Popy Bora, L. C. Bora, A. Bhattacharya, Sehnaz S. Ahmed

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Microbial bioagents, viz., Pseudomonas fluorescens, Bacillus subtilis, and Trichoderma viride were assessed for their ability to suppress grey blight caused by Pestalotiopsis theae, a major disease of tea crop in Assam. The expression of defense-related phytochemicals due to the application of these bioagents was also evaluated. The individual bioagents, as well as their combinations, were screened for their bioefficacy against P. theae in vitro using nutrient agar (NA) as basal medium. The treatment comprising a combination of the three bioagents, P. fluorescens, B. subtilis, and T. viride showed significantly the highest inhibition against the pathogen. Bioformulation of effective bioagent combinations was further evaluated under field condition, where significantly highest reduction of grey blight (90.30%), as well as the highest increase in the green leaf yield (10.52q/ha), was recorded due to application of the bioformulation containing the three bioagents. The application of the three bioformulation also recorded an enhanced level of caffeine (4.15%) and polyphenols (22.87%). A significant increase in the enzymatic activity of phenylalanine ammonia-lyase, peroxidase and polyphenol oxidase were recorded in the plants treated with the microbial bioformulation of the three bioagents. The present investigation indicates the role of microbial agents in suppressing disease, inducing plant defense response, as well as improving the quality of tea.

Keywords: enzymatic activity, grey blight, microbial bioagents, Pestalotiopsis theae, phytochemicals, plant defense, tea

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Authors: Rajesh S. Mony, Vaidyaratnam Oushadhasala

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An attempt is made in this study to evolve a drug development modality based on classical Ayurvedic knowledge base as well as on modern scientific methodology. The present study involves (a) identification of a specific ailment condition, (b) the selection of a polyherbal formulation, (c) deciding suitable extraction procedure, (d) confirming the efficacy of the combination by in-vitro trials and (e) fixing up the recommended dose. The ailment segment selected is arthritic condition. The selected herbal combination is Kunturushka, Vibhitaki, Guggulu, Haridra, Maricha and Nirgundi. They were selected as per Classical Ayurvedic references, Authentified as per API (Ayurvedic Pharmacopeia of India), Extraction of each drug was done by different ratios of Hydroalcoholic menstrums, Invitro assessment of each extract after removing residual solvent for anti-Inflammatory, anti-arthritic activities (by UV-Vis. Spectrophotometer with positive control), Invitro assessment of each extract for COX enzyme inhibition (by UV-Vis. Spectrophotometer with positive control), Selection of the extracts was made having good in-vitro activity, Performed the QC testing of each selected extract including HPTLC, that is the in process QC specifications, h. Decision of the single dose with mixtures of selected extracts was made as per the level of in-vitro activity and available toxicology data, Quantification of major groups like Phenolics, Flavonoids, Alkaloids and Bitters was done with both standard Spectrophotometric and Gravimetric methods, Method for Marker assay was developed and validated by HPTLC and a good resolved HPTLC finger print was developed for the single dosage API (Active Pharmaceutical Ingredient mixture of extracts), Three batches was prepared to fix the in process and API (Active Pharmaceutical Ingredient) QC specifications.

Keywords: drug development, antiinflammatory, quality stardardisation, planar chromatography

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Authors: U. Borasi, Amit Kr. Jain, Rakesh, Piyush Jain

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Data collection, data preparation, model training, model evaluation, and deployment are all processes in a typical machine learning workflow. Training data needs to be gathered and organised. This often entails collecting a sizable dataset and cleaning it to remove or correct any inaccurate or missing information. Preparing the data for use in the machine learning model requires pre-processing it after it has been acquired. This often entails actions like scaling or normalising the data, handling outliers, selecting appropriate features, reducing dimensionality, etc. This pre-processed data is then used to train a model on some machine learning algorithm. After the model has been trained, it needs to be assessed by determining metrics like accuracy, precision, and recall, utilising a test dataset. Every time a new model is built, both data pre-processing and model training—two crucial processes in the Machine learning (ML) workflow—must be carried out. Thus, there are various Machine Learning algorithms that can be employed for every single approach to data pre-processing, generating a large set of combinations to choose from. Example: for every method to handle missing values (dropping records, replacing with mean, etc.), for every scaling technique, and for every combination of features selected, a different algorithm can be used. As a result, in order to get the optimum outcomes, these tasks are frequently repeated in different combinations. This paper suggests a simple architecture for organizing this largely produced “combination set of pre-processing steps and algorithms” into an automated workflow which simplifies the task of carrying out all possibilities.

Keywords: machine learning, automation, AUTOML, architecture, operator pool, configuration, scheduler

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Authors: Husham Bayazed

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A growing number of studies indicate that atherosclerotic coronary artery disease (CAD) has a complex pathogenesis that extends beyond cholesterol intimal infiltration. The atherosclerosis process may involve an immune micro-environmental condition driven by local activation of the adaptive and innate immunity arrays, resulting in the formation of atherosclerotic plaques. Therefore, despite the wide usage of lipid-lowering agents, these devastating coronary diseases are not averted either at primary or secondary prevention levels. Many trials have recently shown an interest in the immune targeting of the inflammatory process of atherosclerotic plaques, with the promised improvement in atherosclerotic cardiovascular disease outcomes. This recently includes the immune-modulatory drug “Canakinumab” as an anti-interleukin-1 beta monoclonal antibody in addition to "Colchicine,” which's established as a broad-effect drug in the management of other inflammatory conditions. Recent trials and studies highlight the importance of inflammation and immune reactions in the pathogenesis of atherosclerosis and plaque formation. This provides an insight to discuss and extend the therapies from old lipid-lowering drugs (statins) to anti-inflammatory drugs (colchicine) and new targeted immune-modulatory therapies like inhibitors of IL-1 beta (canakinumab) currently under investigation.

Keywords: atherosclerotic plagues, immune microenvironment, lipid-lowering agents, and immunomodulatory drugs

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Authors: Hudson Akewe

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In this study, we introduce a modified Jungck (Dual Jungck) iterative scheme and use the scheme to approximate the unique common fixed point of a pair of generalized contractive-like operators in a Banach space. The iterative scheme is also shown to be stable with respect to the maps (S,T). An example is taken to justify the convergence of the scheme. Our result is a generalization and improvement of several results in the literature on single map T.

Keywords: generalized contractive-like operators, modified Jungck iterative scheme, stability results, weakly compatible maps, unique common fixed point

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Authors: Vera Sovkova, Andrea Mickova, Matej Buzgo, Karolina Vocetkova, Eva Filova, Evzen Amler

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PCL (poly-ε-caprolactone) nanofibrous scaffolds with adhered liposomes were prepared and tested as a possible drug delivery system for various synthetic growth factors. TGFβ, bFGF, and IGF-I have been shown to increase hMSC (human mesenchymal stem cells) proliferation and to induce hMSC differentiation. Functionalized PCL nanofibers were prepared with synthetic growth factors encapsulated in liposomes adhered to them in three different concentrations. Other samples contained PCL nanofibers with adhered, free synthetic growth factors. The synthetic growth factors free medium served as a control. The interaction of liposomes with the PCL nanofibers was visualized by SEM, and the release kinetics were determined by ELISA testing. The potential of liposomes, immobilized on the biodegradable scaffolds, as a delivery system for synthetic growth factors, and as a suitable system for MSCs adhesion, proliferation and differentiation in vitro was evaluated by MTS assay, dsDNA amount determination, confocal microscopy, flow cytometry and real-time PCR. The results showed that the growth factors adhered to the PCL nanofibers stimulated cell proliferation mainly up to day 11 and that subsequently their effect was lower. By contrast, the release of the lowest concentration of growth factors from liposomes resulted in gradual proliferation of MSCs throughout the experiment. Moreover, liposomes, as well as free growth factors, stimulated type II collagen production, which was confirmed by immunohistochemical staining using monoclonal antibody against type II collagen. The results of this study indicate that growth factors enriched liposomes adhered to surface of PCL nanofibers could be useful as a drug delivery instrument for application in short timescales, be combined with nanofiber scaffolds to promote local and persistent delivery while mimicking the local microenvironment. This work was supported by project LO1508 from the Ministry of Education, Youth and Sports of the Czech Republic

Keywords: drug delivery, growth factors, hMSC, liposomes, nanofibres

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Authors: Temesgen Sidamo, Prakruti S. Rao, Eleni Akllilu, Workineh Shibeshi, Yumi Park, Yong-Soon Cho, Jae-Gook Shin, Scott K. Heysell, Stellah G. Mpagama, Ephrem Engidawork

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The fluoroquinolones (FQs) are used off-label for the treatment of multidrug-resistant tuberculosis (MDR-TB), and for evaluation in shortening the duration of drug-susceptible TB in recently prioritized regimens. Within the class, levofloxacin (LFX) and moxifloxacin (MXF) play a substantial role in ensuring success in treatment outcomes. However, sub-therapeutic plasma concentrations of either LFX or MXF may drive unfavorable treatment outcomes. To the best of our knowledge, the pharmacokinetics of LFX and MXF in Ethiopian patients with MDR-TB have not yet been investigated. Therefore, the aim of this study was to develop a population pharmacokinetic (PopPK) model of levofloxacin (LFX) and moxifloxacin (MXF) and assess the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24-h (AUC0-24) and the in vitro minimum inhibitory concentration (MIC) (AUC0-24/MIC) in Ethiopian MDR-TB patients. Steady-state plasma was collected from 39 MDR-TB patients enrolled in the programmatic treatment course and the drug concentrations were determined using optimized liquid chromatography-tandem mass spectrometry. In addition, the in vitro MIC of the patients' pretreatment clinical isolates was determined. PopPK and simulations were run at various doses, and PK parameters were estimated. The effect of covariates on the PK parameters and the PTA for maximum mycobacterial kill and resistance prevention was also investigated. LFX and MXF both fit in a one-compartment model with adjustments. The apparent volume of distribution (V) and clearance (CL) of LFX were influenced by serum creatinine (Scr), whereas the absorption constant (Ka) and V of MXF were influenced by Scr and BMI, respectively. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L was 29%, 62%, and 95% with the simulated 750 mg, 1000 mg, and 1500 mg doses, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no difference in the PTA (94.4%) for maximum bacterial kill among the simulated doses of MXF (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention improved proportionately with dose. Standard LFX and MXF doses may not provide adequate drug exposure. LFX PopPK is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Scr and BMI are likely to be important covariates in dose optimization or therapeutic drug monitoring (TDM) studies in Ethiopian patients.

Keywords: population PK, PTA, moxifloxacin, levofloxacin, MDR-TB patients, ethiopia

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Authors: Kwaku Damoah

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This study presents a comprehensive data-driven analysis to understand the evolution of adverse events (AEs) in pharmacovigilance. Utilizing data from the FDA Adverse Event Reporting System (FAERS), we employed three analytical methods: rank-based, frequency-based, and percentage change analyses. These methods assessed temporal trends and patterns in AE reporting, focusing on various drug-active ingredients and patient demographics. Our findings reveal significant trends in AE occurrences, with both increasing and decreasing patterns from 2000 to 2023. This research highlights the importance of continuous monitoring and advanced analysis in pharmacovigilance, offering valuable insights for healthcare professionals and policymakers to enhance drug safety.

Keywords: event analysis, FDA adverse event reporting system, pharmacovigilance, temporal trend analysis

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Authors: Sophio Kobauri, Temur Kantaria, Nina Kulikova, David Tugushi, Ramaz Katsarava

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The elaboration of effective drug delivery vehicles is still topical nowadays since targeted drug delivery is one of the most important challenges of the modern nanomedicine. The last decade has witnessed enormous research focused on synthetic cationic polymers (CPs) due to their flexible properties, in particular as non-viral gene delivery systems, facile synthesis, robustness, not oncogenic and proven gene delivery efficiency. However, the toxicity is still an obstacle to the application in pharmacotherapy. For overcoming the problem, creation of new cationic compounds including the polymeric nano-size particles – nano-containers (NCs) loading with different pharmaceuticals and biologicals is still relevant. In this regard, a variety of NCs-based drug delivery systems have been developed. We have found that amino acid-based biodegradable polymers called as pseudo-proteins (PPs), which can be cleared from the body after the fulfillment of their function are highly suitable for designing pharmaceutical NCs. Among them, one of the most promising are NCs made of biodegradable Cationic PPs (CPPs). For preparing new cationic NCs (CNCs), we used CPPs composed of positively charged amino acid L-arginine (R). The CNCs were fabricated by two approaches using: (1) R-based homo-CPPs; (2) Blends of R-based CPPs with regular (neutral) PPs. According to the first approach NCs we prepared from CPPs 8R3 (composed of R, sebacic acid and 1,3-propanediol) and 8R6 (composed of R, sebacic acid and 1,6-hexanediol). The NCs prepared from these CPPs were 72-101 nm in size with zeta potential within +30 ÷ +35 mV at a concentration 6 mg/mL. According to the second approach, CPPs 8R6 was blended in organic phase with neutral PPs 8L6 (composed of leucine, sebacic acid and 1,6-hexanediol). The NCs prepared from the blends were 130-140 nm in size with zeta potential within +20 ÷ +28 mV depending on 8R6/8L6 ratio. The stability studies of fabricated NCs showed that no substantial change of the particle size and distribution and no big particles’ formation is observed after three months storage. In vitro biocompatibility study of the obtained NPs with four different stable cell lines: A549 (human), U-937 (human), RAW264.7 (murine), Hepa 1-6 (murine) showed both type cathionic NCs are biocompatible. The obtained data allow concluding that the obtained CNCs are promising for the application as biodegradable drug delivery vehicles. This work was supported by the joint grant from the Science and Technology Center in Ukraine and Shota Rustaveli National Science Foundation of Georgia #6298 'New biodegradable cationic polymers composed of arginine and spermine-versatile biomaterials for various biomedical applications'.

Keywords: biodegradable polymers, cationic pseudo-proteins, nano-containers, drug delivery vehicles

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Authors: Nicholas Abdilmasih, Habib Rezanejad

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This study investigates the gene expression induction efficiency of single versus multiple guide RNAs (gRNAs) targeting the NGN3 gene using the CRISPR activation system in HEK293 cells. Our study aimed to contribute to optimizing the use of gRNAs in gene therapy applications, particularly in treating diseases like diabetes, where precise gene regulation is essential. The experimental design involves culturing HEK293 cells, and once they reach approximately 70-80% confluence, cells were transfected with specific gRNAs targeting the NGN3 gene promoter. Specific gRNAs targeting the NGN3 promoter that was previously designed, incorporated into plasmid clone cassettes and introduced into HEK293 cells through co-transfection using pCAG-DDdCas9-VP192-EGFP transactivator. Post-transfection, cell viability, and fluorescence were monitored to assess transfection efficiency. RNA was extracted, converted to cDNA, and analyzed via qPCR to measure NGN3 expression levels. Results indicated that specific combinations of fewer gRNAs led to higher NGN3 activation compared to multiple gRNAs, challenging the assumption that more gRNAs result in synergistic gene activation. These findings suggest that optimized gRNA combinations can enhance gene therapy efficiency, potentially leading to more effective treatments for conditions like diabetes.

Keywords: CRISPR activation, Diabetes mellitus, gene therapy, guide RNA, Neurogenin3

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Authors: Muhammet Baldan, Emel Timuçin

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Generally, absorption and bioavailability increase if solubility increases; therefore, it is crucial to predict them in drug discovery applications. Molecular descriptors and Molecular properties are traditionally used for the prediction of water solubility. There are various key descriptors that are used for this purpose, namely Drogan Descriptors, Morgan Descriptors, Maccs keys, etc., and each has different prediction capabilities with differentiating successes between different data sets. Another source for the prediction of solubility is structural features; they are commonly used for the prediction of solubility. However, there are little to no studies that combine three or more properties or descriptors for prediction to produce a more powerful prediction model. Unlike available models, we used a combination of those features in a random forest machine learning model for improved solubility prediction to better predict and, therefore, contribute to drug discovery systems.

Keywords: solubility, random forest, molecular descriptors, maccs keys

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Authors: Kedar J. Mahadeshwar

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Concept introduction: This paper talks about how an innovative cloud based analytics enabled solution that could address a major industry challenge that is approaching all of us globally faster than what one would think. The world of supply chain for drugs and devices is changing today at a rapid speed. In the US, the Drug Supply Chain Security Act (DSCSA) is a new law for Tracing, Verification and Serialization phasing in starting Jan 1, 2015 for manufacturers, repackagers, wholesalers and pharmacies / clinics. Similarly we are seeing pressures building up in Europe, China and many countries that would require an absolute traceability of every drug and device end to end. Companies (both manufacturers and distributors) can use this opportunity not only to be compliant but to differentiate themselves over competition. And moreover a country such as UAE can be the leader in coming up with a global solution that brings innovation in this industry. Problem definition and timing: The problem of counterfeit drug market, recognized by FDA, causes billions of dollars loss every year. Even in UAE, the concerns over prevalence of counterfeit drugs, which enter through ports such as Dubai remains a big concern, as per UAE pharma and healthcare report, Q1 2015. Distribution of drugs and devices involves multiple processes and systems that do not talk to each other. Consumer confidence is at risk due to this lack of traceability and any leading provider is at risk of losing its reputation. Globally there is an increasing pressure by government and regulatory bodies to trace serial numbers and lot numbers of every drug and medical devices throughout a supply chain. Though many of large corporations use some form of ERP (enterprise resource planning) software, it is far from having a capability to trace a lot and serial number beyond the enterprise and making this information easily available real time. Solution: The solution here talks about a service provider that allows all subscribers to take advantage of this service. The solution allows a service provider regardless of its physical location, to host this cloud based traceability and analytics solution of millions of distribution transactions that capture lots of each drug and device. The solution platform will capture a movement of every medical device and drug end to end from its manufacturer to a hospital or a doctor through a series of distributor or retail network. The platform also provides advanced analytics solution to do some intelligent reporting online. Why Dubai? Opportunity exists with huge investment done in Dubai healthcare city also with using technology and infrastructure to attract more FDI to provide such a service. UAE and countries similar will be facing this pressure from regulators globally in near future. But more interestingly, Dubai can attract such innovators/companies to run and host such a cloud based solution and become a hub of such traceability globally.

Keywords: cloud, pharmaceutical, supply chain, tracking

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Authors: Syed Beenish Rufai, Sarman Singh

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Background: Performance of Genotype MTBDRsl (Hain Life science GmbH Germany) for detection of mutations associated with second-line drug resistance is well known. However, less evidence regarding the association of mutations and genetic background of strains is known which, in the future, is essential for clinical management of anti-tuberculosis drugs in those settings where the probability of particular genotype is predominant. Material and Methods: During this retrospective study, a total of 259 MDR-TB isolates obtained from pulmonary TB patients were tested for second-line drug susceptibility testing (DST) using Genotype MTBDRsl VER 1.0 and compared with BACTEC MGIT-960 as a reference standard. All isolates were further characterized using spoligotyping. The spoligo patterns obtained were compared and analyzed using SITVIT_WEB. Results: Of total 259 MDR-TB isolates which were screened for second-line DST by Genotype MTBDRsl, mutations were found to be associated with gyrA, rrs and emb genes in 82 (31.6%), 2 (0.8%) and 90 (34.7%) isolates respectively. 16 (6.1%) isolates detected mutations associated with both FQ as well as to AG/CP drugs (XDR-TB). No mutations were detected in 159 (61.4%) isolates for corresponding gyrA and rrs genes. Genotype MTBDRsl showed a concordance of 96.4% for detection of sensitive isolates in comparison with second-line DST by BACTEC MGIT-960 and 94.1%, 93.5%, 60.5% and 50% for detection of XDR-TB, FQ, EMB, and AMK/CAP respectively. D94G was the most prevalent mutation found among (38 (46.4%)) OFXR isolates (37 FQ mono-resistant and 1 XDR-TB) followed by A90V (23 (28.1%)) (17 FQ mono-resistant and 6 XDR-TB). Among AG/CP resistant isolates A1401G was the most frequent mutation observed among (11 (61.1%)) isolates (2 AG/CP mono-resistant isolates and 9 XDR-TB isolates) followed by WT+A1401G (6 (33.3%)) and G1484T (1 (5.5%)) respectively. On spoligotyping analysis, Beijing strain (46%) was found to be the most predominant strain among pre-XDR and XDR TB isolates followed by CAS (30%), X (6%), Unique (5%), EAI and T each of 4%, Manu (3%) and Ural (2%) respectively. Beijing strain was found to be strongly associated with D94G (47.3%) and A90V mutations by (47.3%) and 34.8% followed by CAS strain by (31.6%) and 30.4% respectively. However, among AG/CP resistant isolates, only Beijing strain was found to be strongly associated with A1401G and WT+A1401G mutations by 54.5% and 50% respectively. Conclusion: Beijing strain was found to be strongly associated with the most prevalent mutations among pre-XDR and XDR TB isolates. Acknowledgments: Study was supported with Grant by All India Institute of Medical Sciences, New Delhi reference No. P-2012/12452.

Keywords: tuberculosis, line probe assay, XDR TB, drug susceptibility

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Authors: Ramesh Subramani, Mathivanan Narayanasamy, William Aalbersberg

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It is well accepted by last 35 years of research and on-going programmes that marine environment harbours abundant and unique biodiversity, which is currently playing as an important source in bioprospecting. It has become apparent that marine microorganisms are lead in the biodiscovery. Among marine organisms, actinobacteria are a target phylum for discovering novel antibiotics against increasing the multi-drug resistant human pathogens because of these taxa representing for novel genera and species. Marine actinomycetes are a proven source of new antibiotic leads and novel enzymes with important industrial applications. A total of 183 streptomycete and 25 non-streptomycete strains were isolated from different marine samples collected from north-eastern part of the Indian Ocean. Among them, 111 isolates displayed antibacterial activity against human pathogens and 151 exhibited antifungal activity against phytopathogens. Importantly, most of them produced various extracellular enzymes and 58 of them produced exopolysaccharides. Totally eight small bioactive compounds and a thermostable alkaline protease have been purified from a selected strain, Streptomyces fungicidicus. Besides, our on-going studies on non-streptomycete strains (rare actinomycetes) are most likely promising resource for new and unique compounds against current emerging drug-resistant pathogens. We have just recognised the chemical diversity in marine microorganisms. Therefore it is worthwhile to continue the exploration of marine microorganisms for new drug leads, novel enzymes and other bioprospecting research.

Keywords: bioactive compounds, industrial enzymes, marine actinobacteria, microbial metabolites, marine natural products

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Authors: Richa Mardianingrum, Srie R. N. Endah

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In this research, we have designed four isoniazid derivatives i.e., isonicotinohydrazide (1-isonicotinoyl semicarbazide, 1-thiosemi isonicotinoyl carbazide, N '-(1,3-dimethyl-1 h-pyrazole-5-carbonyl) isonicotino hydrazide, and N '-(1,2,3- 4-thiadiazole-carbonyl) isonicotinohydrazide. The docking and molecular dynamic have performed to them in order to study its interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA). Based on this research, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (INHA) receptor, so they could be used as an anti-tuberculosis drug candidate.

Keywords: anti-tuberculosis, docking, Inhibin alpha subunit, InhA, inhibition, synthesis, isonicotinohydrazide

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Authors: Sutapa Som Chaudhury, Chitrangada Das Mukhopadhyay

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Alzheimer’s disease is a well-known form of dementia since its discovery in 1906. Current Food and Drug Administration approved medications e.g. cholinesterase inhibitors, memantine offer modest symptomatic relief but do not play any role in disease modification or recovery. In last three decades many small molecules, chaperons, synthetic peptides, partial β-secretase enzyme blocker have been tested for the development of a drug against Alzheimer though did not pass the 3rd clinical phase trials. Here in this study, we designed a PEGylated, aminogenic, tripeptidic polymer with two different molecular weights based on the aggregation prone amino acid sequence 17-20 in amyloid beta (Aβ) 1-42. Being conjugated with poly-ethylene glycol (PEG) which self-assembles into hydrophilic nanoparticles, these PEGylated tripeptides constitute a very good drug delivery system crossing the blood brain barrier while the peptide remains protected from proteolytic degradation and non-specific protein interactions. Moreover, being completely aminogenic they would not raise any side effects. These peptide inhibitors were evaluated for their effectiveness against Aβ42 fibrillation at an early stage of oligomer to fibril formation as well as preformed fibril clearance via Thioflavin T (ThT) assay, dynamic light scattering analyses, atomic force microscopy and scanning electron microscopy. The inhibitors were proved to be safe at a higher concentration of 20µM by the reduction assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Moreover, SHSY5Y neuroblastoma cells have shown a greater survivability when treated with the inhibitors following Aβ42 fibril and oligomer treatment as compared with the control Aβ42 fibril and/or oligomer treated neuroblastoma cells. These make the peptidic inhibitors a promising compound in the aspect of the discovery of alternative medication for Alzheimer’s disease.

Keywords: Alzheimer’s disease, alternative medication, amyloid beta, PEGylated peptide

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Authors: Eslam Dabbish, Fortuna Ponte, Stefano Scoditti, Emilia Sicilia, Gloria Mazzone

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The medical techniques based on the use of light for activating the drug are occupying a prominent place in the cancer treatment due to their selectivity that contributes to reduce undesirable side effects of conventional chemotherapy. Among these therapeutic treatments, photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) are emerging as complementary approaches for selective destruction of neoplastic tissue through direct cellular damage. Both techniques rely on the employment of a molecule, photosensitizer (PS), able to absorb within the so-called therapeutic window. Thus, the exposure to light of otherwise inert molecules promotes the population of excited states of the drug, that in PDT are able to produce the cytotoxic species, such as 1O2 and other ROS, in PACT can be responsible of the active species release or formation. Following the success of cisplatin in conventional treatments, many other transition metal complexes were explored as anticancer agents for applications in different medical approaches, including PDT and PACT, in order to improve their chemical, biological and photophysical properties. In this field, several crucial characteristics of candidate PSs can be accurately predicted from first principle calculations, especially in the framework of density functional theory and its time-dependent formulation, contributing to the understanding of the entire photochemical pathways involved which can ultimately help in improving the efficiency of a drug. A brief overview of the outcomes on some platinum and ruthenium-based PSs proposed for the application in the two phototherapies will be provided.

Keywords: TDDFT, metal complexes, PACT, PDT

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Authors: Itze Coronel Salomon

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The rise of organized crime and violence related to drug cartels in Mexico has created serious challenges for the authorities to provide security to those who live within its borders. However, to achieve a significant improvement in security is absolute respect for fundamental human rights by the authorities. Irregular migrants in Mexico are at serious risk of abuse. Research by Amnesty International as well as reports of the NHRC (National Human Rights) in Mexico, have indicated the major humanitarian crisis faced by thousands of migrants traveling in the shadows. However, the true extent of the problem remains invisible to the general population. The fact that federal and state governments leave no proper record of abuse and do not publish reliable data contributes to ignorance and misinformation, often spread by the media that portray migrants as the source of crime rather than their victims. Discrimination and intolerance against irregular migrants can generate greater hostility and exclusion. According to the modus operandi that has been recorded criminal organizations and criminal groups linked to drug trafficking structures deprive migrants of their liberty for forced labor and illegal activities related to drug trafficking, even some have been kidnapped for be trained as murderers . If the victim or their family cannot pay the ransom, the kidnapped person may suffer torture, mutilation and amputation of limbs or death. Migrant women are victims of sexual abuse during her abduction as well. In 2011, at least 177 bodies were identified in the largest mass grave found in Mexico, located in the town of San Fernando, in the border state of Tamaulipas, most of the victims were killed by blunt instruments, and most seemed to be immigrants and travelers passing through the country. With dozens of small graves discovered in northern Mexico, this may suggest a change in tactics between organized crime groups to the different means of obtaining revenue and reduce murder profile methods. Competition and conflict over territorial control drug trafficking can provide strong incentives for organized crime groups send signals of violence to the authorities and rival groups. However, as some Mexican organized crime groups are increasingly looking to take advantage of income and vulnerable groups, such as Central American migrants seem less interested in advertising his work to authorities and others, and more interested in evading detection and confrontation. This paper pretends to analyze the introduction of this new trend of kidnapping migrants for forced labors by drug cartels in Mexico into the forms of contemporary slavery and its implications.

Keywords: international law, migration, transnational organized crime

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Authors: Trina Isabel D. Santiago, Juan Raphael M. Perez, Maria Angelica O. Soriano, Teresita B. Suing, Jumee F. Tayaban

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To achieve universal healthcare for everyone, the World Health Organization has emphasized the importance of National Medicines Policies for increased accessibility and utilization of high-quality and affordable medications. In the Philippines, significant challenges have been identified surrounding the sustainability of essential medicines, resulting in limited access such as high cost and dominance and market dominance and monopoly of multinational companies (MNCs) in the Philippine pharmaceutical industry. These identified challenges have been addressed by several initiatives, such as the Philippine National Drug Policy and Generics Act of 1988 (Republic Act 6675), to attempt to reduce drug prices. Despite these efforts, the concerns with drug accessibility and affordability continue to persist; hence, Republic Act 9502 was enacted. This paper attempts to review RA 9502 in the pursuit of making medicines more affordable for Filipinos, analyze and critique the problems and challenges associated with the law, and provide recommendations to address identified problems and challenges. A literature search and review, as well as an analysis of the law, has been done to evaluate the policy. RA 9502 recognizes the importance of market competition in drug price reduction and quality medicine accessibility. Contentious issues prior to enactment of the law include 1) parallel importation, pointing out that the drug price will depend on the global market price, 2) contrasting approaches in the drafting of the law as the House version focused on medicine price control while the Senate version prioritized market competition, and 3) MNCs opposing the amendments with concerns on discrimination, constitutional violations, and noncompliance with international treaty obligations. There are also criticisms and challenges with the implementation of the law in terms of content or modeling, interpretation and implementation, and other external factors or hindrances. The law has been criticized for its narrow scope as it only covers specific essential medicines with no cooperation with the national health insurance program. Moreover, the law has sections taking advantage of the TRIPS flexibilities, which disallow smaller countries to reap the benefits of flexibilities. The sanctions and penalties have an insignificant role in implementation as they only ask for a small portion of the income of MNCs. Proposed recommendations for policy improvement include aligning existing legislation through strengthened price regulation and expanded law coverage, strengthening penalties to promote law adherence, and promoting research and development to encourage and support local initiatives. Through these comprehensive recommendations, the issues surrounding the policy can be addressed, and the goal of enhancing the affordability and accessibility of medicines in the country can be achieved.

Keywords: drug accessibility, drug affordability, price regulation, Republic Act 9502

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Authors: Rady A., Elsheshai A., Eltawel M.

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Introduction and Aim of work: Literature suggest that antipsychotic medications may decrease cortisol level, an effect that seems to be more present with second generation antipsychotic. Our study aims at assessing effect of long term use of antipsychotics on cortisol level Subjects and Methods: 30 chronic schizophrenic patients on antipsychotics compared to 20 drug naive schizophrenic patients as regards serum cortisol level Results: Cortisol level was significantly lower in chronic schizophrenic patients receiving antipsychotics compared to drug naive patients (P=0.002 <0.05) Conclusion: Antipsychotic medications seem to have the potential to decrease cortisol level in blood. Among hypothesis proposed in literature is the good control of pseudo stress due to psychotic features.

Keywords: schizophrenia, antipsychotic, cortisol, HPA

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Authors: Zakiul Fuady, Ismail AB, Fauzi, Zulfian

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This research was conducted to analyze the absorption coefficients of sound at several types of materials as well as its combinations. The aim of this research was to find the value of sound absorption coefficients on the materials and its combinations. The materials used in this research were gypsum panel, gypsum-fibre palm, fibre palm-gypsum, and foamed concrete-fibre palm. The test was conducted by using a method of reverberation chamber based on the ISO 354-1985 with the types of the sound source: white noise and pink noise at the frequency of 125 Hz - 8000 Hz. Based on the test results of white noise, it was found that the panel of gypsum-fibre palm has α = 0.93 at low frequency; the panel of fibre palm has α = 0.97 at a medium frequency; and the panel of foamed concrete-fibre palm has α = 0.89 at high frequency. Further, for the sound source of pink noise, it was found that the panel of gypsum-fibre palm has α = 0.99 at low level; the panel of fibre palm-gypsum has α = 0.86 at medium level; and the panel of fibre palm-gypsum has α = 0.64 at high level. The fibre palm panel could absorb the sounds well since this material has bigger airspace (pore) than the foamed concrete and gypsum. Consequently, when the sounds wave enters to this material it will be trapped in the space. The panel of fibre palm affected an increasing of sound absorption coefficient value at the combination materials when the panel of fibre palm was placed under another panel. However, the absorption coefficient values of both fibre palm and fibre palm-gypsum panels are about the same.

Keywords: coefficient of sound absorption, pink noise, white noise, palm

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Authors: Leandra Prempeh, Emily Malugen

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Prenatal drug exposure can have a molecular impact on the hypothalamic and reward genes that regulate feeding behavior. This can impact feeding regulation, resulting in feeding difficulties and growth failure. This was potentially seen in “McKayla,” a 19- month old girl with a history of in-utero drug exposure, patent ductus arteriosus, and gastroesophageal reflux disease who presented for intensive day treatment feeding therapy. She was diagnosed with Avoidant Restrictive Food Intake Disorder, described as total food refusal and meeting 100% of her caloric needs from a gastrostomy tube. The primary goals during intensive feeding therapy were to increase her oral intake and decrease her reliance on supplementation with formula. Several behavioral antecedent manipulations were implemented to establish consistent responding and make progress towards treatment goals. This included multiple modified bolus placements (using underloaded and Nuk brush), reinforcement contingencies, and variety fading before stability was finally achieved. Following, increasing retention of bites then increasing volume and variety were goals targeted. From treatment onset to the last 3 days of treatment, McKayla's rate of rapid acceptance of bite presentations increased significantly from 33.33% to 93.13%, rapid swallowing went from 0.00% to 92.32%, and her percentage of inappropriate mealtime behavior and expels decreased from 58.33% and 100% to 2.31% and 7.68%, respectively. Overall, the treatment team successfully introduced and increased the bite size of 7 pureed foods, generalize the treatment to caregivers with high integrity, and began facilitating tube weaning. She was receiving about 33.42% of her needs by mouth at the time of discharge. Other nutritional concerns addressed during treatment included drinking a nutritionally complete drink out of an open cup and age appropriate growth. McKayla continued to have emesis almost daily, as was her baseline before starting treatment; however, the frequency during mealtime decreased. Overall, McKayla responded well to treatment. She had a very slow response to treatment and required a lot of antecedent manipulations to establish consistent responding. As the literature suggests, [drug]-exposed neonates, like McKayla, may be at increased risk for nutritional and growth challenges that may persist throughout development. This supports the need for longterm follow-up of infant growth.

Keywords: behavioral intervention, feeding problems, in-utero drug exposure, intensive multidisciplinary intervention

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Authors: Madhuresh Dwivedi, Navneet Singh Deora, H. N. Mishra

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In the context of bakery products, the gluten component of wheat has a crucial role in stabilizing the gas-cell and crumb structures, appearance, mouth feel and maintaining the rheological properties, thus the acceptability of these products. However, because of coeliac disease, some individuals cannot tolerate the protein gliadin present in the gluten fraction of wheat flour. Also termed as gluten-sensitive enteropathy, it is a common chronicle disorder in populations throughout the world with average prevalence of 0.37%. The safest way for celiac sufferers is to stay away from gluten-containing foods such as wheat, rye, barley as well as durum wheat, spelt wheat, and triticale. Thus, in view of the current increasing incidence of gluten intolerant sufferers (due to improved diagnostic procedures), the development of gluten-free cereal-based bakery products suitable for celiac patients represents a challenging and serious task, but also very demanding call for food technologists as well as for the bakers. The use of alternative cereal starches (like rice, soy, maize, potato and so on), gums, hydrocolloids, dietary fibres, alternative protein sources, prebiotics and combinations of them represent the most widespread approach used as replacement to mimic gluten in the manufacture of industrial processable gluten-free bakery products due to their structure-building and water binding properties.

Keywords: gluten-free, coeliac disease, alternative flour, hydrocolloid, crumb structure

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Authors: M. A. Spielmann, L. Schebek

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In order to reach the long-term national climate goals of the German government for the building sector, substantial energetic measures have to be executed. Historically, those measures were primarily energetic efficiency measures at the buildings’ shells. Advanced technologies for the on-site generation of heat (or other types of energy) often are not feasible at this small spatial scale of a single building. Therefore, the present approach uses the spatially larger dimension of a quarter. The main focus of the present paper is the long-term economic-ecological assessment of available decentralized heat-generating (CHP power plants and electrical heat pumps) technologies at the quarter level for the German unrefurbished residential buildings. Three distinct terms have to be described methodologically: i) Quarter approach, ii) Economic assessment, iii) Ecological assessment. The quarter approach is used to enable synergies and scaling effects over a single-building. For the present study, generic quarters that are differentiated according to significant parameters concerning their heat demand are used. The core differentiation of those quarters is made by the construction time period of the buildings. The economic assessment as the second crucial parameter is executed with the following structure: Full costs are quantized for each technology combination and quarter. The investment costs are analyzed on an annual basis and are modeled with the acquisition of debt. Annuity loans are assumed. Consequently, for each generic quarter, an optimal technology combination for decentralized heat generation is provided in each year of the temporal boundaries (2016-2050). The ecological assessment elaborates for each technology combination and each quarter a Life Cycle assessment. The measured impact category hereby is GWP 100. The technology combinations for heat production can be therefore compared against each other concerning their long-term climatic impacts. Core results of the approach can be differentiated to an economic and ecological dimension. With an annual resolution, the investment and running costs of different energetic technology combinations are quantified. For each quarter an optimal technology combination for local heat supply and/or energetic refurbishment of the buildings within the quarter is provided. Coherently to the economic assessment, the climatic impacts of the technology combinations are quantized and compared against each other.

Keywords: building sector, economic-ecological assessment, heat, LCA, quarter level

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Authors: Sarah Crawford, Gerry Lesley

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This research is a pre-clinical assessment of anti-cancer effects of novel non-steroidal diethyl stilbestrol-like estrogen analogs in estrogen-receptor positive/ progesterone-receptor positive human breast cancer microtumors of MCF 7 cell line. Tamoxifen analog formulation (Tam A1) was used as a single agent or in combination with therapeutic concentrations of 4-hydroxytamoxifen, currently used as a long-term treatment for the prevention of breast cancer recurrence in women with estrogen receptor positive/ progesterone receptor positive malignancies. At concentrations ranging from 30-50 microM, Tam A1 induced microtumor disaggregation and cell death. Incremental cytotoxic effects correlated with increasing concentrations of Tam A1. Live tumor microscopy showed that microtumos displayed diffuse borders and substrate-attached cells were rounded-up and poorly adherent. A complete cytotoxic effect was observed using 40-50 microM Tam A1 with time course kinetics similar to 4-hydroxytamoxifen. Combined treatment with TamA1 (30-50 microM) and 4-hydroxytamoxifen (10-15 microM) induced a highly cytotoxic, synergistic combined treatment response that was more rapid and complete than using 4-hydroxytamoxifen as a single agent therapeutic. Microtumors completely dispersed or formed necrotic foci indicating a highly cytotoxic combined treatment response. Moreover, breast cancer microtumors treated with both 4-hydroxytamoxifen and Tam A1 displayed lower levels of long-term post-treatment regrowth, a critical parameter of primary drug resistance, than observed for 4-hydroxytamoxifen when used as a single agent therapeutic. Tumor regrowth at 6 weeks post-treatment with either single agent 4-hydroxy tamoxifen, Tam A1 or a combined treatment was assessed for the development of drug resistance. Breast cancer cells treated with both 4-hydroxytamoxifen and Tam A1 displayed significantly lower levels of post-treatment regrowth, indicative of decreased drug resistance, than observed for either single treatment modality. The preclinical data suggest that combined treatment involving the use of tamoxifen analogs may be a novel clinical approach for long-term maintenance therapy in patients with estrogen-receptor positive/progesterone-receptor positive breast cancer receiving hormonal therapy to prevent disease recurrence. Detailed data on time-course, IC50 and tumor regrowth assays post- treatment as well as a proposed mechanism of action to account for observed synergistic drug effects will be presented.

Keywords: 4-hydroxytamoxifen, tamoxifen analog, drug-resistance, microtumors

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Authors: Marianne Miguet, Gaël Plantard, Yves Jaeger, Vincent Goetz

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The contamination of groundwater is a major concern. A common pollutant, the perchloroethylene, is the target contaminant. Water treatment process as Granular Activated Carbons are very efficient but requires pilot-scale testing to determine the full-scale GAC performance. First, the batch mode was used to get a reliable experimental method to estimate the adsorption capacity of a common volatile compound is settled. The Langmuir model is acceptable to fit the isotherms. Dynamic tests were performed with three columns and different operating conditions. A database of concentration profiles and breakthroughs were obtained. The resolution of the set of differential equations is acceptable to fit the dynamics tests and could be used for a full-scale adsorber.

Keywords: activated carbon, groundwater, perchloroethylene, full-scale

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Authors: Sudhir Kumar, V. R. Sinha

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Background: The topical and systemic toxicity associated with present nonmelanoma skin cancer (NMSC) treatment therapy using 5-Fluorouracil (5-FU) make it necessary to develop a novel delivery system having lesser toxicity and better control over drug release. Solid lipid nanoparticles offer many advantages like: controlled and localized release of entrapped actives, nontoxicity, and better tolerance. Aim:-To investigate safety and efficacy of 5-FU loaded solid lipid nanoparticles as a topical delivery system for the treatment of nonmelanoma skin cancer. Method: Topical solid lipid nanoparticles of 5-FU were prepared using Compritol 888 ATO (Glyceryl behenate) as lipid component and pluronic F68 (Poloxamer 188), Tween 80 (Polysorbate 80), Tyloxapol (4-(1,1,3,3-Tetramethylbutyl) phenol polymer with formaldehyde and oxirane) as surfactants. The SLNs were prepared with emulsification method. Different formulation parameters viz. type and ratio of surfactant, ratio of lipid and ratio of surfactant:lipid were investigated on particle size and drug entrapment efficiency. Results: Characterization of SLNs like–Transmission Electron Microscopy (TEM), Differential Scannig calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Particle size determination, Polydispersity index, Entrapment efficiency, Drug loading, ex vivo skin permeation and skin retention studies, skin irritation and histopathology studies were performed. TEM results showed that shape of SLNs was spherical with size range 200-500nm. Higher encapsulation efficiency was obtained for batches having higher concentration of surfactant and lipid. It was found maximum 64.3% for SLN-6 batch with size of 400.1±9.22 nm and PDI 0.221±0.031. Optimized SLN batches and marketed 5-FU cream were compared for flux across rat skin and skin drug retention. The lesser flux and higher skin retention was obtained for SLN formulation in comparison to topical 5-FU cream, which ensures less systemic toxicity and better control of drug release across skin. Chronic skin irritation studies lacks serious erythema or inflammation and histopathology studies showed no significant change in physiology of epidermal layers of rat skin. So, these studies suggest that the optimized SLN formulation is efficient then marketed cream and safer for long term NMSC treatment regimens. Conclusion: Topical and systemic toxicity associated with long-term use of 5-FU, in the treatment of NMSC, can be minimized with its controlled release with significant drug retention with minimal flux across skin. The study may provide a better alternate for effective NMSC treatment.

Keywords: 5-FU, topical formulation, solid lipid nanoparticles, non melanoma skin cancer

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Authors: Ranjot Kaur, Om P. Katare, Anupama Sharma, Sarah R. Dennison, Kamalinder K. Singh, Bhupinder Singh

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Respiratory microbial infections being among the top leading cause of death worldwide are difficult to treat as the microbes reside deep inside the airways, where only a small fraction of drug can access after traditional oral or parenteral routes. As a result, high doses of drugs are required to maintain drug levels above minimum inhibitory concentrations (MIC) at the infection site, unfortunately leading to severe systemic side-effects. Therefore, delivering antimicrobials directly to the respiratory tract provides an attractive way out in such situations. In this context, current study embarks on the systematic development of lung lia pid-modified chitosan nanoparticles for inhalation of voriconazole. Following the principles of quality by design, the chitosan nanoparticles were prepared by ionic gelation method and further coated with major lung lipid by precipitation method. The factor screening studies were performed by fractional factorial design, followed by optimization of the nanoparticles by Box-Behnken Design. The optimized formulation has a particle size range of 170-180nm, PDI 0.3-0.4, zeta potential 14-17, entrapment efficiency 45-50% and drug loading of 3-5%. The presence of a lipid coating was confirmed by FESEM, FTIR, and X-RD. Furthermore, the nanoparticles were found to be safe upto 40µg/ml on A549 and Calu-3 cell lines. The quantitative and qualitative uptake studies also revealed the uptake of nanoparticles in lung epithelial cells. Moreover, the data from Spraytec and next-generation impactor studies confirmed the deposition of nanoparticles in lower airways. Also, the interaction of nanoparticles with DPPC monolayers signifies its biocompatibility with lungs. Overall, the study describes the methodology and potential of lipid-coated chitosan nanoparticles in futuristic inhalation nanomedicine for the management of pulmonary aspergillosis.

Keywords: dipalmitoylphosphatidylcholine, nebulization, DPPC monolayers, quality-by-design

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Authors: Yuliya E. Leshchenko, Tatyana S. Ostapenko

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Language variation is a widespread linguistic phenomenon which can affect different levels of a language system: phonological, morphological, lexical, syntactic, etc. It is obvious that the scope of possible standard alternations within a particular language is limited by a variety of its norms and regulations which set more or less clear boundaries for what is possible and what is not possible for the speakers. The possibility of lexical variation (alternate usage of lexical items within the same contexts) is based on the fact that the meanings of words are not clearly and rigidly defined in the consciousness of the speakers. Therefore, lexical variation is usually connected with unstable relationship between words and their referents: a case when a particular lexical item refers to different types of referents, or when a particular referent can be named by various lexical items. We assume that the scope of lexical variation in bilingual speech is generally wider than that observed in monolingual speech due to the fact that, besides ‘lexical item – referent’ relations it involves the possibility of cross-language variation of L1 and L2 lexical items. We use the term ‘cross-language variation’ to denote a case when two equivalent words of different languages are treated by a bilingual speaker as freely interchangeable within the common linguistic context. As distinct from code-switching which is traditionally defined as the conscious use of more than one language within one communicative act, in case of cross-language lexical variation the speaker does not perceive the alternate lexical items as belonging to different languages and, therefore, does not realize the change of language code. In the paper, the authors present research of lexical variation of adult Komi-Permyak – Russian bilingual speakers. The two languages co-exist on the territory of the Komi-Permyak District in Russia (Komi-Permyak as the ethnic language and Russian as the official state language), are usually acquired from birth in natural linguistic environment and, according to the data of sociolinguistic surveys, are both identified by the speakers as coordinate mother tongues. The experimental research demonstrated that alternation of Komi-Permyak and Russian words within one utterance/phrase is highly frequent both in speech perception and production. Moreover, our participants estimated cross-language word combinations like ‘маленькая /Russian/ нывка /Komi-Permyak/’ (‘a little girl’) or ‘мунны /Komi-Permyak/ домой /Russian/’ (‘go home’) as regular/habitual, containing no violation of any linguistic rules and being equally possible in speech as the equivalent intra-language word combinations (‘учöтик нывка’ /Komi-Permyak/ or ‘идти домой’ /Russian/). All the facts considered, we claim that constant concurrent use of the two languages results in the fact that a large number of their words tend to be intuitively interpreted by the speakers as lexical variants not only related to the same referent, but also referring to both languages or, more precisely, to none of them in particular. Consequently, we can suppose that bilingual mental lexicon includes an extensive ‘fused’ zone of lexical representations that provide the basis for cross-language variation in bilingual speech.

Keywords: bilingualism, bilingual mental lexicon, code-switching, lexical variation

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