Search results for: multi drug resistant

Authors: Gajanan M. Sonwane

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Nowadays, the entire pharmaceutical industry is facing the challenge of increasing efficiency and innovation. The major hurdles are the growing cost of research and development and a concurrent stagnating number of new chemical entities (NCEs). Hence, the challenge is to select the most druggable targets and to search the equivalent drug-like compounds, which also possess specific pharmacokinetic and toxicological properties that allow them to be developed as drugs. The present research work includes the studies of developing new anticancer heterocycles by using molecular modeling techniques. The heterocycles synthesized through such methodology are much effective as various physicochemical parameters have been already studied and the structure has been optimized for its best fit in the receptor. Hence, on the basis of the literature survey and considering the need to develop newer anticancer agents, new phenazinamine derivatives were designed by subjecting the nucleus to molecular modeling, viz., GQSAR analysis and docking studies. Simultaneously, these designed derivatives were subjected to in silico prediction of biological activity through PASS studies and then in silico toxicity risk assessment studies. In PASS studies, it was found that all the derivatives exhibited a good spectrum of biological activities confirming its anticancer potential. The toxicity risk assessment studies revealed that all the derivatives obey Lipinski’s rule. Amongst these series, compounds 4c, 5b and 6c were found to possess logP and drug-likeness values comparable with the standard Imatinib (used for anticancer activity studies) and also with the standard drug methotrexate (used for antimitotic activity studies). One of the most notable mutations is the threonine to isoleucine mutation at codon 315 (T315I), which is known to be resistant to all currently available TKI. Enzyme assay planned for confirmation of target selective activity.

Keywords: drug design, tyrosine kinases, anticancer, Phenazinamine

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Authors: Wen Huei Chou, Te Lung Pan, Tsu Wen Yeh

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New media have recently received increasing attention as a new communication form. The COVID-19 outbreak has pushed people’s lifestyles into the digital age, and the drug market has infiltrated formal e-commerce platforms. The self-media boom has fostered growth in online drug myths. To set the record straight, it is imperative to develop new media-based interventions. However, the usefulness of new media on this issue has not yet been fully examined. This study selected 13 articles on the development of new media-based interventions to prevent drug abuse from Airiti Library and Pub-Med as of October 3, 2021. The key conclusions are that (1) new media have a significantly positive influence on skills, self-efficacy, and behavior; (2) most interventions package traditional course learning into new media formats; and (3) new media can create a covert, interactive environment that cannot be replicated offline, which may merit attention in future research.

Keywords: drug abuse, interventions, new media, systematic review

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Authors: Li-Yu Lee, Yu-Shuan Chen, Jun Sheng Wang, I-Ming Chu

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Microneedle patch is a painless transdermal drug delivery method, It could solve some problems in traditional drug delivery such as digestive system causing drug metabolism and subcutaneous injection causing some side effects. Coating drug on or loading drug in microneedle can carry active ingredient through stratum corneum, also can control dose well when microneedle patch apply on localized topical area. We used hyaluronic acid to fabricate dissolvable microneedle patch and encapsulated minoxidil into microneedles. Minoxdil is a drug for exterior use that can be used to treat Androgenetic alopecia, but related commercial products have some shortcomings, for example, propylene glycol which is used to soften stratum corneum cause skin allergic reaction, comparing chemical promotion, microneedle patch provide physical way to make drugs through nature barrier of skin. In this research, we designed a two-step process to fabricate microneedle patch, that can effectively reduce drug waste, and gentle production process could maintain drug activity well. We also do in vitro test on cadaver to make sure patch has enough mechanical strength to penetrate stratum corneum. In the release test and animal test, we found microneedle patch has higher delivery efficiency than tradition way. In this study, we may determine that germinal MNs patch is a potential commodity.

Keywords: dissolving microneedles, androgenetic alopecia, minoxidil, transdermal drug delivery

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Authors: Surajj Sarode, G. P. Vadnere, G. Vidya Sagar

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Compression coating is one of the strategies for delivering drug to the colon based on Gastrointestinal PH and transit time concept. The main aim of these formulations to develop rapidly disintegrating Zaltoprofen core tablets compression-coated with a mixture of time-dependent hydrophilic swellable polymer HPMC K 15 and PH responsive soluble polymer Chitosan and Guar gum in different ratios. The effect of the proportion of HPMC, Chitosan and Guar gum in the coat on premature drug release in upper part (Stomach and small intestine) of GIT and the amount of drug release in colon target area was studied. The formulations are carried out by using Direct Compression method. Sodium starch Glycolate used for rapid disintegration. FTIR used for Drug-Polymer Interaction studies. The prepared tablets were evaluated for hardness, thickness, friability, in-vitro disintegration, in-Vitro dissolution and in-vitro kinetic study.

Keywords: zaltoprofen, chitosan, formulation, drug delivery

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Authors: Athini Ntloko

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Mycobacterium bovis and other species of Mycobacterium tuberculosis complex (MTBC) can result to a zoonotic infection known as Bovine tuberculosis (bTB). MTBC has members that may contaminate an extensive range of hosts, including wildlife. Diverse wild species are known to cause disease in domestic livestock and are acknowledged as TB reservoirs. It has been a main study worldwide to deliberate on bTB risk factors as a result and some studies focused on particular parts of risk factors such as wildlife and herd management. The significance of the study was to determine the incidence of Mycobacterium tuberculosis complex that is associated with soil, hayfeed and water. Questionnaires were administered to thirty (30) smallholding farm owners in the two villages (kwaMasele and Qungqwala) and three (3) three commercial farms (Fort Hare dairy farm, Middledrift dairy farm and Seven star dairy farm). Detection of M. tuberculosis complex was achieved by Polymerase Chain Reaction using primers for IS6110; whereas a genotypic drug resistance mutation was detected using Genotype MTBDRplus assays. Nine percent (9%) of respondents had more than 40 cows in their herd, while 60% reported between 10 and 20 cows in their herd. Relationship between farm size and vaccination for TB differed from forty one percent (41%) being the highest to the least five percent (5%). The highest number of respondents who knew about relationship between TB cases and cattle location was ninety one percent (91%). Approximately fifty one percent (51%) of respondents had knowledge about wild life access to the farms. Relationship between import of cattle and farm size ranged from nine percent (9%) to thirty five percent (35%). Cattle sickness in relation to farm size differed from forty three (43%) being the highest to the least three percent (3%); while thirty three percent (33%) of respondents had knowledge about health management. Respondents with knowledge about the occurrence of TB infections in farms were forty-eight percent (48%). The frequency of DNA isolation from samples ranged from the highest forty-five percent (45%) from water to the least twenty two percent (22%) from soil. Fort Hare dairy farm had the highest number of positive samples, forty four percent (44%) from water samples; whereas Middledrift dairy farm had the lowest positive from water, seventeen percent (17%). Twelve (22%) out of 55 isolates showed resistance to INH and RIF that is, multi-drug resistance (MDR) and nine percent (9%) were sensitive to either INH or RIF. The mutations at rpoB gene differed from 58% being the highest to the least (23%). Fifty seven percent (57%) of samples showed a S315T1 mutation while only 14% possessed a S531L in the katG gene. The highest inhA mutations were detected in T8A (80 %) and the least was observed in A16G (17%). The results of this study reveal that risk factors for bTB in cattle and dairy farm workers are a serious issue abound in the Eastern Cape of South Africa; with the possibility of widespread dissemination of multidrug resistant determinants in MTBC from the environment.

Keywords: hayfeed, isoniazid, multi-drug resistance, mycobacterium tuberculosis complex, polymerase chain reaction, rifampicin, soil, water

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Authors: K. Ali, M. F. Qamar, M. A. Zaman, M. Younus, I. Khan, S. Ehtisham-ul-Haque, R. Tamkeen, M. I. Rashid, Q. Ali

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This study centers on molecular identification of Haemonchus contortus and isolation of Benz-imidazoles (BZ) resistant strains. Different abattoirs’ of two geographic regions of Punjab (Pakistan) were frequently visited for the collection of worms. Out of 1500 (n=1500) samples that were morphologically confirmed as H. contortus, 30 worms were subjected to molecular procedures for isolation of resistant strains. Resistant worms (n=8) were further subjected to DNA gene sequencing. Bio edit sequence alignment editor software was used to detect the possible mutation, deletion, replacement of nucleotides. Genetic diversity was noticed and genetic variation existing in β-tubulin isotype 1 of the H. contortus population of small ruminants of different regions considered in this study. H. contortus showed three different type of genetic sequences. 75%, 37.5%, 25% and 12.5% of the studied samples showed 100% query cover and identity with isolates and clones of China, UK, Australia and other countries, respectively. Interestingly the neighbor countries such as India and Iran haven’t many similarities with the Pakistani isolates. Thus, it suggests that population density of same genetic makeup H. contortus is scattered worldwide rather than clustering in a single region.

Keywords: Haemonchus contortus, Benzimidazole resistant, β-tubulin-1 gene, abattoirs

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Authors: Neslihan Demirci, Serdar Durdağı

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Mycobacterium tuberculosis is still a worldwide disease-causing agent that, according to WHO, led to the death of 1.5 million people from tuberculosis (TB) in 2020. The bacteria reside in macrophages located specifically in the lung. There is a known quadruple drug therapy regimen for TB consisting of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Over the past 60 years, there have been great contributions to treatment options, such as recently approved delamanid (OPC67683) and bedaquiline (TMC207/R207910), targeting mycolic acid and ATP synthesis, respectively. Also, there are natural compounds that can block the tryptophanyl-tRNA synthetase (TrpRS) enzyme, chuangxinmycin, and indolmycin. Yet, already the drug resistance is reported for those agents. In this study, the newly released TrpRS enzyme structure is investigated for potential inhibitor drugs from already synthesized molecules to help the treatment of resistant cases and to propose an alternative drug for the quadruple drug therapy of tuberculosis. Maestro, Schrodinger is used for docking and molecular dynamic simulations. In-house library containing ~8000 compounds among FDA-approved indole-containing compounds, a total of 57 obtained from the ChemBL were used for both ATP and tryptophan binding pocket docking. Best of indole-containing 57 compounds were subjected to hit expansion and compared later with virtual screening workflow (VSW) results. After docking, VSW was done. Glide-XP docking algorithm was chosen. When compared, VSW alone performed better than the hit expansion module. Best scored compounds were kept for ten ns molecular dynamic simulations by Desmond. Further, 100 ns molecular dynamic simulation was performed for elected molecules according to Z-score. The top three MMGBSA-scored compounds were subjected to steered molecular dynamic (SMD) simulations by Gromacs. While SMD simulations are still being conducted, ponesimod (for multiple sclerosis), vilanterol (β₂ adrenoreceptor agonist), and silodosin (for benign prostatic hyperplasia) were found to have a significant affinity for tuberculosis TrpRS, which is the propulsive force for the urge to expand the research with in vitro studies. Interestingly, top-scored ponesimod has been reported to have a side effect that makes the patient prone to upper respiratory tract infections.

Keywords: drug repurposing, molecular dynamics, tryptophanyl-tRNA synthetase, tuberculosis

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Authors: Nungki Rositaningsih, Emil Budianto

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Starch has been widely used as an encapsulation material for drug delivery system. However, starch hydrogel is very easily degraded during metabolism in human stomach. Modification of this material is needed to improve the encapsulation process in drug delivery system, especially for gastrointestinal drug. In this research, three modified starch-based hydrogels are synthesized i.e. Crosslinked starch hydrogel, Semi- and Full- Interpenetrating Polymer Network (IPN) starch hydrogel using Poly(N-Vinyl-Pyrrolidone). Non-modified starch hydrogel was also synthesized as a control. All of those samples were compared as biomaterials, floating drug delivery, and their ability in loading drug test. Biomaterial characterizations were swelling test, stereomicroscopy observation, Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared Spectroscopy (FTIR). Buoyancy test and stereomicroscopy scanning were done for floating drug delivery characterizations. Lastly, amoxicillin was used as test drug, and characterized with UV-Vis spectroscopy for loading drug observation. Preliminary observation showed that Full-IPN has the most dense and elastic texture, followed by Semi-IPN, Crosslinked, and Non-modified in the last position. Semi-IPN and Crosslinked starch hydrogel have the most ideal properties and will not be degraded easily during metabolism. Therefore, both hydrogels could be considered as promising candidates for encapsulation material. Further analysis and issues will be discussed in the paper.

Keywords: biomaterial, drug delivery system, interpenetrating polymer network, poly(N-vinyl-pyrrolidone), starch hydrogel

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Authors: Mustafa Malki, Ewan R. Pearson

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Tools utilized by health care practitioners to flag potential adverse drug reactions secondary to drug-drug interactions ignore individual genetic variation, which has the potential to markedly alter the severity of these interactions. To our best knowledge, there have been limited published studies on the impact of genetic variation on drug-drug interactions. Therefore, our aim in this project is the discovery of previously unrecognized, clinically important drug-drug-gene interactions (DDGIs) within the list of most commonly used drug combinations in the UK. The UKBB database was utilized to identify the top most frequently prescribed drug combinations in the UK with at least one route of interaction (over than 200 combinations were identified). We have recognised 37 common and unique interacting genes considering all of our drug combinations. Out of around 600 potential genetic variants found in these 37 genes, 100 variants have met the selection criteria (common variant with minor allele frequency ≥ 5%, independence, and has passed HWE test). The association between these variants and the use of each of our top drug combinations has been tested with a case-control analysis under the log-additive model. As the data is cross-sectional, drug intolerance has been identified from the genotype distribution as presented by the lower percentage of patients carrying the risky allele and on the drug combination compared to those free of these risk factors and vice versa with drug tolerance. In GoDARTs database, the same list of common drug combinations identified by the UKBB was utilized here with the same list of candidate genetic variants but with the addition of 14 new SNPs so that we have a total of 114 variants which have met the selection criteria in GoDARTs. From the list of the top 200 drug combinations, we have selected 28 combinations where the two drugs in each combination are known to be used chronically. For each of our 28 combinations, three drug response phenotypes have been identified (drug stop/switch, dose decrease, or dose increase of any of the two drugs during their interaction). The association between each of the three phenotypes belonging to each of our 28 drug combinations has been tested against our 114 candidate genetic variants. The results show replication of four findings between both databases : (1) Omeprazole +Amitriptyline +rs2246709 (A > G) variant in CYP3A4 gene (p-values and ORs with the UKBB and GoDARTs respectively = 0.048,0.037,0.92,and 0.52 (dose increase phenotype)) (2) Simvastatin + Ranitidine + rs9332197 (T > C) variant in CYP2C9 gene (0.024,0.032,0.81, and 5.75 (drug stop/switch phenotype)) (3) Atorvastatin + Doxazosin + rs9282564 (T > C) variant in ABCB1 gene (0.0015,0.0095,1.58,and 3.14 (drug stop/switch phenotype)) (4) Simvastatin + Nifedipine + rs2257401 (C > G) variant in CYP3A7 gene (0.025,0.019,0.77,and 0.30 (drug stop/switch phenotype)). In addition, some other non-replicated, but interesting, significant findings were detected. Our work also provides a great source of information for researchers interested in DD, DG, or DDG interactions studies as it has highlighted the top common drug combinations in the UK with recognizing 114 significant genetic variants related to drugs' pharmacokinetic.

Keywords: adverse drug reactions, common drug combinations, drug-drug-gene interactions, pharmacogenomics

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Authors: Kamel Abd Elaziz Mohamed

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Introduction: Drug related problems (DRPs) are of major concern, affecting patients of both sex. They impose considerable economic burden on the society and the health-care systems. Aim of the work: The aim of this work was to identify and categorize drug-related problems in adult intensive care unit. Patients and methods: The study was a prospective, observational study as eighty six patients were included. They were consecutively admitted to ICU through the emergency room or transferred from the general ward due to DRPs. Parameters included in the study as length of stay in ICU, need for cardiovascular support or mechanical ventilation, dialysis, as well as APACHE II score were recorded. Results: Drug related problems represent 3.6% of the total ICU admission. The median (range) of APACHE II score for 86 patients included in the study was 17 (10-23), and length of ICU stay was 2.4 (1.5-4.2) days. In 45 patients (52%), DRP was drug over dose (group 1), while other DRP was present in the other 41 patients (48%, group 11). Patients in group 1 were older (39 years versus 32 years in group 11), with significant impaired renal function. The need of inotropic drugs and mechanical ventilation as well as the length of stay (LOS) in ICU was significantly higher in group 1. There were no significant difference in GCS between both groups, however APACHE II score was significantly higher in group 1. Only four patients (4.6%) were admitted by suicidal attempt as well as three patients (3.4%) due to trauma drug-related admissions, all were in (group 1). Nineteen percent of the patients had drug related problem due to hypoglycaemic medication followed by tranquilizer (15%). Adverse drug effect followed by failure to receive medication were the most causes of drug problem in (group11).The total mortality rate was 4.6%, all of them were eventually non preventable. Conclusion: The critically ill patients admitted due to drug related problems represented a small proportion (3.6%) of admissions to the ICU. Hypoglycaemic medication was one of the most common causes of admission by drug related problems.

Keywords: drug related problems, ICU, cost, safety

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Authors: Simon Nyarko

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This study examined the microbial flora contamination of the Ghanaian paper currency notes and antibiotic resistance in Ejura Municipal, Ashanti Region, Ghana. This is a descriptive cross-sectional study designed to assess the profile of microflora contamination of the Ghanaian paper currency notes and antibiotic-resistant in the Ejura Municipality. The research was conducted in Ejura, a town in the Ejura Sekyeredumase Municipal of the Ashanti region of Ghana. 70 paper currency notes which were freshly collected from the bank, consisting of 15 pieces of GH ¢1, GH ¢2, and GH ¢5, 10 pieces of GH ¢10 and GH ¢20, and 5 pieces of GH ¢50, were randomly sampled from people by exchanging their money in usage with those freshly secured from the bank. The surfaces of each GH¢ note were gently swabbed and sent to the lab immediately in sterile Zip Bags and sealed, and tenfold serial dilution was inoculated on plate count agar (PCA), MacConkey agar (MCA), mannitol salt agar (MSA), and deoxycholate citrate agar (DCA). For bacterial identification, the study used appropriate laboratory and biochemical tests. The data was analyzed using SPSS-IBM version 20.0. It was found that 95.2 % of the 70 GH¢ notes tested positive for one or more bacterial isolates. On each GH¢ note, mean counts on PCA ranged from 3.0 cfu/ml ×105 to 4.8 cfu/ml ×105. Of 124 bacteria isolated. 36 (29.03 %), 32 (25.81%), 16 (12.90 %), 20 (16.13%), 13 (10.48 %), and 7 (5.66 %) were from GH¢1, GH¢2, GH¢10, GH¢5, GH¢20, and GH¢50, respectively. Bacterial isolates were Escherichia coli (25.81%), Staphylococcus aureus (18.55%), coagulase-negative Staphylococcus (15.32%), Klebsiella species (12.10%), Salmonella species (9.68%), Shigella species (8.06%), Pseudomonas aeruginosa (7.26%), and Proteus species (3.23%). Meat shops, commercial drivers, canteens, grocery stores, and vegetable shops contributed 25.81 %, 20.16 %, 19.35 %, 17.74 %, and 16.94 % of GH¢ notes, respectively. There was 100% resistance of the isolates to Erythromycin (ERY), and Cotrimoxazole (COT). Amikacin (AMK) was the most effective among the antibiotics as 75% of the isolates were susceptible to it. This study has demonstrated that the Ghanaian paper currency notes are heavily contaminated with potentially pathogenic bacteria that are highly resistant to the most widely used antibiotics and are a threat to public health.

Keywords: microflora, antibiotic resistance, staphylococcus aureus, culture media, multi-drug resistance

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Authors: Agnese Natali, Francesco Morelli, Walter Salvatore

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Automated Rack Supported Warehouses (ARSWs) are storage buildings whose structure is made of the same racks where goods are placed. The possibility of designing dissipative seismic-resistant ARSWs is investigated. Diagonals are the dissipative elements, arranged as tense-only X bracings. Local optimization is numerically performed to satisfy the over-resistant connection request for the dissipative element, that is hard to be reached due the geometrical limits of the thin-walled diagonals and must be balanced with resistance, the limit of slenderness, and ductility requests.

Keywords: steel racks, thin-walled cold-formed elements, structural optimization, hierarchy rules, dog-bone philosophy

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Authors: Zohreh Bayat, Dariush Minai-Tehrani

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Lipases constitute one of the most important groups of industrial enzymes that catalyze the hydrolysis of triacylglycerol to glycerol and fatty acids. Muscarinic antagonist relieves smooth muscle spasm of the gastrointestinal tract and effect on the cardiovascular system. In this research, the effect of a muscarinic antagonist on the lipase activity of Pseudomonas aeruginosa was studied. Lineweaver–Burk plot showed that the drug inhibited the enzyme by competitive inhibition. The IC50 value (60 uM) and Ki (30 uM) of the drug revealed the drug bound to the enzyme with high affinity. Determination of enzyme activity in various pH and temperature showed that the maximum activity of lipase was at pH 8 and 60°C both in presence and absence of the drug.

Keywords: bacteria, inhibition, kinetics, lipase

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Authors: Soroosh Torabi, Brad Berron, Ren Xu, Christine Trinkle

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Microfluidics integrated with 3D cell culture is a powerful technology to mimic cellular environment, and can be used to study cell activities such as proliferation, migration and response to drugs. This technology has gained more attention in cancer studies over the past years, and many organ-on-a-chip systems have been developed to study cancer cell behaviors in an ex-vivo tumor microenvironment. However, there are still some barriers to adoption which include low throughput, complexity in 3D cell culture integration and limitations on non-optical analysis of cells. In this study, a user-friendly microfluidic multi-well plate was developed to mimic the in vivo tumor microenvironment. The microfluidic platform feeds multiple 3D cell culture sites at the same time which enhances the throughput of the system. The platform uses hydrophobic Cassie-Baxter surfaces created by microchannels to enable convenient loading of hydrogel/cell suspensions into the device, while providing barrier free placement of the hydrogel and cells adjacent to the fluidic path. The microchannels support convective flow and diffusion of nutrients to the cells and a removable lid is used to enable further chemical and physiological analysis on the cells. Different breast cancer cell lines were cultured in the device and then monitored to characterize nutrient delivery to the cells as well as cell invasion and proliferation. In addition, the drug response of breast cancer cell lines cultured in the device was compared to the response in xenograft models to the same drugs to analyze relevance of this platform for use in future drug-response studies.

Keywords: microfluidics, multi-well 3d cell culture, tumor microenvironment, tumor-on-a-chip

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Authors: Ephrem Mebratu Dagnew, Mohammed Biset Ayalew, Gizework Alemnew Mekonnen, Alehegn Bishaw Geremew, Ousman Abubeker Abdela

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Objective: To assess the prevalence of drug-related problems and associated factors among adult psychiatric inpatients. Method: Hospital-based multicenter cross-sectional observational study was conducted from April to July 2021 at five randomly selected hospitals in North-west Ethiopia. A total of 325 consecutively sampled patients participated in the study. Clinical pharmacists assessed the DRPs based on clinical judgment supported by updated evidence-based diseases guidelines. A Medscape drug-interactions checker was used to check drug-drug interactions. The results were summarized using descriptive statistics, including frequency, mean, and standard deviation. Odds ratio (OR) with 95% confidence interval were also computed for each variable for the corresponding P-value. The value of P ≤ 0.05 was considered statistically significant. Result : From the total of 325 study participants, more than half of them (52.9%) were females and the mean age ± (standard deviation) was 30.8±11.3 years. At least one drug-related problem was recorded from 60.9%, 95% CI (55.7-65.8) of study participants with a mean of 0.6±0.49 per patient. Need additional drug therapy was the most common DRP (22.8%), followed by non-adherence to medicine (20.6%) and adverse drug reactions (11%), respectively. Factors independently associated with drug-related problems were rural residence [AOR=1.96,95%CI:1.01-2.84, P-value=0.046], self-employed [AOR=6.0 ,95% CI: 1.0-36.9, P-value=0.035] and alcohol drinkers [AOR=6.40,95%CI:1.12-37.5, p-value=0.034]. Conclusion: The prevalence of drug-related problems among adult psychiatric patients admitted to psychiatric wards was high. Healthcare providers give more attention to tackling these problems. Being a rural residence, self-employed, and Alcohol drinkers were associated with drug-related problems.

Keywords: psychiatric patients, drug-relatedproblems, multicenter, Ethiopia

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Authors: Judith Stein, Elfriede Friedmann

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The injection of a drug into the vitreous body for the treatment of retinal diseases like wet aged-related macular degeneration (AMD) is the most common medical intervention worldwide. We develop mathematical models for drug transport in the vitreous body of a human eye to analyse the impact of different rheological models of the vitreous on drug distribution. In addition to the convection diffusion equation characterizing the drug spreading, we use porous media modeling for the healthy vitreous with a dense collagen network and include the steady permeating flow of the aqueous humor described by Darcy's law driven by a pressure drop. Additionally, the vitreous body in a healthy human eye behaves like a viscoelastic gel through the collagen fibers suspended in the network of hyaluronic acid and acts as a drug depot for the treatment of retinal diseases. In a completely liquefied vitreous, we couple the drug diffusion with the classical Navier-Stokes flow equations. We prove the global existence and uniqueness of the weak solution of the developed initial-boundary value problem describing the drug distribution in the healthy vitreous considering the permeating aqueous humor flow in the realistic three-dimensional setting. In particular, for the drug diffusion equation, results from the literature are extended from homogeneous Dirichlet boundary conditions to our mixed boundary conditions that describe the eye with the Galerkin's method using Cauchy-Schwarz inequality and trace theorem. Because there is only a small effective drug concentration range and higher concentrations may be toxic, the ability to model the drug transport could improve the therapy by considering patient individual differences and give a better understanding of the physiological and pathological processes in the vitreous.

Keywords: coupled PDE systems, drug diffusion, mixed boundary conditions, vitreous body

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Authors: Esra Cansever Mutlu, Muge Sennaroglu Bostan, Fatemeh Bahadori, Ebru Toksoy Oner, Mehmet S. Eroglu

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Paclitaxel is used in treatment of different cancer types mainly breast, ovarian, lung and Kaposi’s sarcoma. It is poorly soluble in water; therefore, currently used formulations tremendously show side-effects and high toxicity. Encapsulation of the drug in a nano drug carrier which causes both reducing side effects and increasing drug activity is a desired new approach for the nano-medicine to target the site of cancer. In this study, synthesis of a novel nano paclitaxel formulation made of a new amphiphilic monomer was followed by the investigation of its pharmacological properties. UV radical polymerization was carried out by using the monomer Lecithin-2-Acrylamido-2-methylpropane (L-AMPS) and the drug-spacer, to obtain sterically high stabilized, biocompatible and biodegradable phospholipid nanoparticles, in which the drug paclitaxel (Pxl) was encapsulated (NanoPxl). Particles showed high drug loading capacity (68%) and also hydrodynamic size less than 200 nm with slight negative surface charge. The drug release profile was obtained and in vitro cytotoxicity test was performed on MCF-7 cell line. Consequently, these data indicated that paclitaxel loaded Lecithin-AMPS/PCL-MAC nanoparticles can be considered as a new, safe and effective nanocarrier for the treatment of breast cancer.

Keywords: paclitaxel, nanoparticle, drug delivery, L-AMPS

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Authors: Christy Rosaline, Rathankar Roa, Waheeta Hopper

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Persistence of tuberculosis, emergence of multidrug-resistance and extensively drug-resistant forms of the disease, has increased the interest in developing new antitubercular drugs. Developing inhibitors for 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis (MtbDAH7Ps), an enzyme involved in shikimate pathway, gives a selective target for antitubercular agents. MtbDAH7Ps was screened against ZINC database, and shortlisted compounds were subjected to induce fit docking. Prime/Molecular Mechanics Generalized Born Surface Area calculation was used to validate the binding energy of ligand-protein complex. Molecular Dynamics analysis for of the lead compounds–MtbDAH7Ps complexes showed that the backbone of MtbDAH7Ps in their complexes were stable. These results suggest that the shortlisted lead compounds ZINC04097114, ZINC15163225, ZINC16857013, ZINC06275603, and ZINC05331260 could be developed into novel drug leads to inhibit DAH7Ps in Mycobacterium tuberculosis.

Keywords: MtbDAH7Ps, Mycobacterium tuberculosis, HTVS, molecular dynamics

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Authors: Kunal Shah, Swati Patel

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Many real world problems involve data which can be considered as multi-label data streams. Efficient methods exist for multi-label classification in non streaming scenarios. However, learning in evolving streaming scenarios is more challenging, as the learners must be able to adapt to change using limited time and memory. Classification is used to predict class of unseen instance as accurate as possible. Multi label classification is a variant of single label classification where set of labels associated with single instance. Multi label classification is used by modern applications, such as text classification, functional genomics, image classification, music categorization etc. This paper introduces the task of multi-label classification, methods for multi-label classification and evolution measure for multi-label classification. Also, comparative analysis of multi label classification methods on the basis of theoretical study, and then on the basis of simulation was done on various data sets.

Keywords: binary relevance, concept drift, data stream mining, MLSC, multiple window with buffer

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Authors: Zunnu Raen Akhtar, U. Irshad, M. Majid

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Due to the widespread cultivation of transgenic cotton, intense selection pressure resulted in resistant allele in pink bollworm, Pectinophora gossypiella (Gelechiidae: Lepidoptera). A resistant strain of pink bollworm against transgenic cotton has become a challenge to Integrated Resistance Management (IRM) in the World. Laboratory and field studies were conducted to determine the resistant strains of pink bollworm by performing bioassay, extracting the DNA, conducting PCR of both laboratory as well as field collected pink bollworms to observe the developed resistance. In all of the studies, two Bt varieties FH-142 and FH-118 expressing Cry1Ac compared to non-Bt (Control) were tested against pink bollworm. In the laboratory, bioassay results showed that there was no significant mortality difference between Bt and non-Bt varieties. Similar mortality percentage was observed in transgenic and non-transgenic (control) variety. Insects which were survived after bioassay, as well as those collected from the Bt cotton fields, were selected for further molecular studies. DNA extraction followed by PCR was conducted to check the resistant strains in pink bollworm. In field studies, we also observed the population dynamics of pink boll worms on Bt as compared to non-Bt varieties. Laboratory and field studies confirmed that resistant strains occurs in Pakistani Bt cotton fields. Different strategies should be adopted to combat that serious prevailing resistance issues.

Keywords: transgenic cotton, resistance, pectinophora gossypiella, , integrated resistance management (IRM), polymerase chain reaction (PCR)

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Authors: Al-Hindi Rashad, Alotibi Ibrahim

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The aim of this study was to examine the antibacterial activity of the peroxide components of some locally produced honeys: Toran, Zaitoon (Olive), Shaflah, Saha, Jizan, Rabea Aja, Fakhira, Sedr Aljanoob, Tenhat, Karath and Bareq against two of the drug resistant bacteria; i.e., methicillin resistant Staph. aureus (MRSA, ATCC 43330) and Acinetobacter baumannii. Measurement of the antibacterial activity of honey samples by using the agar well diffusion method was adopted as follows: by using turbidity standard McFaraland 0.5, suspensions of bacterial strains MRSA ATCC 43330 and Acinetobacter baumannii were prepared. By the spreading plate method, 100 µl of the suspension was inoculated onto Muller-Hinton agar medium. On the inoculated agar medium, five wells were made using a sterile cork borer (diameter 5 mm).100 µl of honey dilutions (10%, 30%, 50%, 70% and 100%) were used. The study indicated that the highly effective activity was in some local honey samples such as Toran honey against MRSA, and Shafalah honey against MRSA and Acinetobacter baumannii which showed bactericidal effects at concentrations 70 % to 100 % as well. The majority of local honey samples recorded bacteriostatic effects on MRSA and Acinetobacter baumannii at consternations 50 % and above. In conclusion this investigation indicated that in regard to the majority inhibitory effect on microorganisms, the existing of H2O2 in honey samples together with phenolic content greatly provide a strong antibacterial activities among different types of honey, because in some previous studies the H2O2 content of honey interacts with phenolic content and showed better inhibitory effect than in absent of H2O2.

Keywords: antibacterial activity, honey, hospital acquired, Saudi Arabia

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Authors: Rostyslav Horbay, Nick Korolis, Vahid Anvari, Rostyslav Stoika

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Introduction: Giant cancer cells (GCC) are common in all types of cancer, especially after poor therapy. Some specific features of such cells include ~10-fold enlargement, drug resistance, and the ability to propagate similar daughter cells. We used murine NK/Ly lymphoma, an aggressive and fast growing lymphoma model that has already shown drastic changes in GCC comparing to parental cells (chromatin condensation, nuclear fragmentation, tighter OXPHOS/cellular respiration coupling, multidrug resistance). Materials and methods: In this study, we compared morpho-functional changes of GCC that predominantly show either a cytostatic or a cytotoxic effect after treatment with drugs. We studied the effect of a combined cytostatic/cytotoxic drug treatment to determine the correlation of drug efficiency and GCC formation. Doses of G1/S-specific drug paclitaxel/PTX (G2/M-specific, 50 mg/mouse), vinblastine/VBL (50 mg/mouse), and DNA-targeting agents doxorubicin/DOX (125 ng/mouse) and cisplatin/CP (225 ng/mouse) on C57 black mice. Several tests were chosen to estimate morphological and physiological state (propidium iodide, Rhodamine-123, DAPI, JC-1, Janus Green, Giemsa staining and other), which included cell integrity, nuclear fragmentation and chromatin condensation, mitochondrial activity, and others. A single and double factor ANOVA analysis were performed to determine correlation between the criteria of applied drugs and cytomorphological changes. Results: In all cases of treatment, several morphological changes were observed (intracellular vacuolization, membrane blebbing, and interconnected mitochondrial network). A lower gain in ascites (49.97% comparing to control group) and longest lifespan (22+9 days) after tumor injection was obtained with single VBL and single DOX injections. Such ascites contained the highest number of GCC (83.7%+9.2%), lowest cell count number (72.7+31.0 mln/ml), and a strong correlation coefficient between increased mitochondrial activity and percentage of giant NK/Ly cells. A high number of viable GCC (82.1+9.2%) was observed compared to the parental forms (15.4+11.9%) indicating that GCC are more drug resistant than the parental cells. All this indicates that the giant cell formation and its ability to obtain drug resistance is an expanding field in cancer research.

Keywords: ANOVA, cisplatin, doxorubicin, drug resistance, giant cancer cells, NK/Ly lymphoma, paclitaxel, vinblastine

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Authors: Morteza Keshavarz

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In this work, using density functional theory (DFT) thermodynamic stability and quantum molecular descriptors of cyclophoshphamide (an anticancer drug)-functionalized zigzag (8,0) CNT, armchair (4,4) CNT and nanocone complexes in water, for two attachment namely the sidewall and tip, is considered. Calculation of the total electronic energy (Et) and binding energy (Eb) of all complexes indicates that the most thermodynamic stability belongs to the sidewall-attachment of cyclophosphamide into functional nanocone. On the other hand, results from chemical hardness show that drug-functionalized zigzag (8,0) and armchair (4,4) complexes in the tip-attachment configuration possess the smallest and greatest chemical hardness, respectively. By computing the solvation energy, it is found that the solution of the drug and all complexes are spontaneous in water. Furthermore, chirality, type of nanovector (nanotube or nanocone), or attachment configuration have no effects on solvation energy of complexes.

Keywords: carbon nanotube, drug delivery, cyclophosphamide drug, density functional theory (DFT)

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Authors: John Hang Leung, Shyh-Yau Wang, Hei-Tung Yip, Fion, Ho Tsung-chin, Agnes LF Chan

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Objectives: Platinum-resistant ovarian cancer has a short overall survival of 9–12 months and limited treatment options. The combination of immunotherapy and targeted therapy appears to be a promising treatment option for patients with ovarian cancer, particularly to patients with platinum-resistant recurrent ovarian cancer (PRrOC). However, there are no direct head-to-head clinical trials comparing their efficacy and toxicity. We, therefore, used a network to directly and indirectly compare seven newer immunotherapies or targeted therapies combined with chemotherapy in platinum-resistant relapsed ovarian cancer, including antibody-drug conjugates, PD-1 (Programmed death-1) and PD-L1 (Programmed death-ligand 1), PARP (Poly ADP-ribose polymerase) inhibitors, TKIs (Tyrosine kinase inhibitors), and antiangiogenic agents. Methods: We searched PubMed (Public/Publisher MEDLINE), EMBASE (Excerpta Medica Database), and the Cochrane Library electronic databases for phase II and III trials involving PRrOC patients treated with immunotherapy or targeted therapy plus chemotherapy. The quality of included trials was assessed using the GRADE method. The primary outcomes compared were progression-free survival, the secondary outcomes were overall survival and safety. Results: Seven randomized controlled trials involving a total of 2058 PRrOC patients were included in this analysis. Bevacizumab plus chemotherapy showed statistically significant differences in PFS (Progression-free survival) but not OS (Overall survival) for all interested targets and immunotherapy regimens; however, according to the heatmap analysis, bevacizumab plus chemotherapy had a statistically significant risk of ≥grade 3 SAEs (Severe adverse effects), particularly hematological severe adverse events (neutropenia, anemia, leukopenia, and thrombocytopenia). Conclusions: Bevacizumab plus chemotherapy resulted in better PFS as compared with all interested regimens for the treatment of PRrOC. However, statistical differences in SAEs as bevacizumab plus chemotherapy is associated with a greater risk for hematological SAE.

Keywords: platinum-resistant recurrent ovarian cancer, network meta-analysis, immune checkpoint inhibitors, target therapy, antiangiogenic agents

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Authors: S. Ataei, F. Sarrafzadeh Javadi, K. Gilani, E. Moazeni

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Drug delivery systems using colloidal particulate carriers such as niosomes or liposomes have distinct advantages over conventional dosage forms because the particles can act as drug-containing reservoirs. These carriers play an increasingly important role in drug delivery. Niosomes are vesicular delivery systems which result from the self-assembly of hydrated surfactant. Niosomes are now widely studied as an attractive to liposomes because they alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids and high cost. The encapsulation of drugs in niosomes can decrease drug toxicity, increase the stability of drug and increase the penetrability of drug in the location of application, and may reduce the dose and systemic side effect. Nowadays, Niosomes are used by the pharmaceutical industry in manufacturing skin medications, eye medication, in cosmetic formulas and these vesicular systems can be used to deliver aspiratory drugs. One way of improving dispersion in the water phase and solubility of the hydrophobic drug is to formulate in into niosomes. Itraconazole (ITZ) was chosen as a model hydrophobic drug. This drug is water insoluble (solubility ~ 1 ng/ml at neutral pH), is a broad-spectrum triazole antifungal agent and is used to treat various fungal disease. This study aims to investigate the capability of forming itraconazole niosomes with Spans, Tweens, Brijs as non-ionic surfactants. To this end, various formulations of niosomes have been studied with regard to parameters such as the degree of containment and particle size.

Keywords: physicochemical, non-ionic surfactant vesicles, itraconazole

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Authors: Ahilya Singh, Brad Carte, Ramesh Subramani, William Aalbersberg

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A total of 37 actinomycete strains were purified from 25 Solomon Islands marine sediments using four different types of isolation media. Among them, 54% of the strains had obligate requirement of seawater for growth. The ethyl acetate extract of 100 ml fermentation product of each strain was screened for antimicrobial activity against multidrug resistant human pathogens and cytotoxic activity against brine shrimps. A total of 67% of the ethyl acetate extracts showed antimicrobial and/or cytotoxic activities. A strain F-1915 was selected for isolation and evaluation of bioactive compound(s) based on its bioactive properties and chemical profile analysis using the LC-MS. The strain F-1915 was identified to have 96% sequence similarity to Streptomyces violaceusniger on the basis of 16S rDNA sequences using BLAST analysis. The 16S rDNA revealed that the strain F-1915 is a new member of MAR4 clade of actinomycetes. The MAR4 clade is an interesting clade of actinomycetes known for the production of pharmaceutically important hybrid isoprenoid compounds. The ethyl acetate extract of the fermentation product of this strain was purified by silica gel column chromatography and afforded the isolation of one bioactive pure compound. Based on the 1D and 2D NMR spectral data of compound 1 it was identified as a new mono-brominated phenazinone, Marinophenazimycin A, a structure which has already been studied by external collaborators at Scripps Institution of Oceanography but is yet to be published. Compound 1 displayed significant antimicrobial activity against drug resistant human pathogens. The minimum inhibitory concentration (MIC) of compound 1 was against Methicillin Resistant Staphylococcus aureus (MRSA) was about 1.9 μg/ml and MIC recorded against Amphotericin Resistant Candida albicans (ARCA) was about 0.24 μg/ml. The bioactivity of compound 1 against ARCA was found to be better than the standard antifungal agent amphotericin B. Compound 1 however did not show any cytotoxic activity against brine shrimps.

Keywords: actinomycetes, antimicrobial activity, brominated phenazine, MAR4 clade, marine natural products, multidrug resistent, 1D and 2D NMR

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Authors: Sunit Kumar Sahoo, Prakash Chandra Senapati

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The main drawback to design drug delivery systems with BCS class II drugs is their low bioavailabilty due to their inherent low permeability characteristics. So the present investigation aspire to develop a self-nanoemulsifying drug delivery system (SNEDDS) of BCS class II anti HIV drug efavirenz (EFZ) using mixtures of non-ionic surfactant mixtures with the main objective to improve the oral bioavailability of said drug. Results obtained from solubility studies of EFZ in various expients utilized for construction of the pseudo ternary phase diagram containing surfactant mixtures. Surfactants in 1:1 combination are used with different co-surfactants in different ratio to delineate the area of monophasic region of the pseudo ternary phase diagram. The formulations which offered positive results in different thermodynamic stability studies were considered for percentage transmittance and turbidity analysis. The various characterization studies like the TEM analysis of post diluted SNEDDS formulations r confirmed the size in nanometric range (below 50 nm) and FT-IR studies confirmed the intactness of the drug the in the preconcentrate. The in vitro dissolution profile of SNEDDS showed that 80% drug was released within 30 min in case of optimized SNEDDS while it was approximately 18.3 % in the case of plain drug powder.. The Pharmacokinetic study using rat model revealed a 2.63 fold increase in AUC (0-∞) in comparison to plain EFZ suspension. The designed delivery system illustrated the confidence in creating a formulation of EFZ with enhanced bioavailability for better HIV treatment.

Keywords: efavirenz, self-nanoemulsifying, surfactant mixture, bioavailability

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Authors: R. H. Bustos, L. Martinez, J. García, F. Suárez

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MRP1 (Multi-drug resistance associated protein 1) and MRP2 (Multi-drug resistance associated protein 2) are two proteins belonging to the transporters of ABC (ATP-Binding Cassette). These transporter proteins are involved in the efflux of several biological drugs and xenobiotic and also in multiple physiological, pathological and pharmacological processes. Evidence has been found that there is a correlation among different polymorphisms found and their clinical implication in the resistance to antiepileptic, chemotherapy and anti-infectious drugs. In our study, exonic regions of MRP1/ABCC1 y MRP2/ABCC2 were studied in the Colombian population, specifically in the region of the central Savannah (Cundinamarca) to determinate SNP (Single Nucleotide Polymorphisms) and determinate its allele frequency and its genomics frequency. Results showed that for our population, SNP are found that have been previously reported for MRP1/ABCC1 (rs200647436, rs200624910, rs150214567) as well as for MRP2/ABCC2 (rs2273697, rs3740066, rs142573385, rs17216212). In addition, 13 new SNP were identified. Evidences show an important clinic correlation for polymorphisms rs3740066 and rs2273697. The study object population displays genetic variability as compared to the one reported in other populations.

Keywords: ATP-binding cassette (ABCC), Colombian population, multidrug-resistance protein (MRP), pharmacogenetic, single nucleotide polymorphism (SNP)

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Authors: Recep Kesli, Gulşah Asik, Cengiz Demir, Onur Turkyilmaz

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Objective: Acinetobacter baumannii (A. baumannii) can cause health-care associated infections, such as bacteremia, urinary tract and wound infections, endocarditis, meningitis, and pneumonia, particularly in intensive care unit patients. In this study, we aimed to evaluate A. baumannii production in sputum and bronchoalveolar lavage and susceptibilities for antibiotics in a 24 months period. Methods: Between October 2013 and September 2015, Acinetobacter baumannii isolated from respiratory tract speciments were evaluated retrospectively. The strains were isolated from the different intensive care units patients. A. baumannii strains were identified by both the conventional methods and aoutomated identification system -VITEK 2 (bio-Merieux, Marcy l’etoile, France). Antibiotic resistance testing was performed by Kirby-Bauer disc diffusion method according to CLSI criteria. Results: All the ninety isolates included in the study were from respiratory tract specimens. While of all the isolated 90 Acinetobacter baumannii strains were found to be resistant (100%), against ceftriaxone, ceftazidime, ciprofloxacin and piperacillin/ tazobactam, resistance rates against other tested antibiotics found as follows; meropenem 77, 86%, imipenem 75, 83%, trimethoprim-sulfamethoxazole (TMP-STX) 69, 76,6%, gentamicin 51, 56,6% and amikacin 48, 53,3%. Colistin was found as the most effective antibiotic against Acinetobacter baumannii, and there were not found any resistant (0%) strain against colistin. Conclusion: This study demonstrated that the no resistance was found in Acinetobacter baumannii against to colistin. High rates of resistance to carbapenems (imipenem and meropenem) and other tested antibiotics (ceftiaxone, ceftazidime, ciprofloxacine, piperacilline-tazobactam, TMP-STX gentamicin and amikacin) also have remarkable resistance rates. There was a significant relationship between demographic features of patients such as age, undergoing mechanical ventilation, length of hospital stay with resistance rates. High resistance rates against antibiotics require implementation of the infection control program and rational use of antibiotics. In the present study, while there were not found colistin resistance, panresistance were found against to ceftriaxone, ceftazidime, ciprofloxacin and piperacillin/ tazobactam.

Keywords: acinetobacter baumannii, antibiotic resistance, multi drug resistance, intensive care unit

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Authors: P. Chihomvu, P. Stegmann, M. Pillay

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Pollution of the Klip River has caused microorganisms inhabiting it to develop protective survival mechanisms. This study isolated and characterized the heavy metal resistant bacteria in the Klip River. Water and sediment samples were collected from six sites along the course of the river. The pH, turbidity, salinity, temperature and dissolved oxygen were measured in-situ. The concentrations of six heavy metals (Cd, Cu, Fe, Ni, Pb, and Zn) of the water samples were determined by atomic absorption spectroscopy. Biochemical and antibiotic profiles of the isolates were assessed using the API 20E® and Kirby Bauer Method. Growth studies were carried out using spectrophotometric methods. The isolates were identified using 16SrDNA sequencing. The uppermost part of the Klip River with the lowest pH had the highest levels of heavy metals. Turbidity, salinity and specific conductivity increased measurably at Site 4 (Henley on Klip Weir). MIC tests showed that 16 isolates exhibited high iron and lead resistance. Antibiotic susceptibility tests revealed that the isolates exhibited multi-tolerances to drugs such as tetracycline, ampicillin, and amoxicillin.

Keywords: Klip River, heavy metals, resistance, 16SrDNA

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