Search results for: host transcriptome and drug repurposing

Authors: Mukta Singh, Ratan Kumar Saha, Himadri Saha, Paramveer Singh

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The present study evaluated the effect of sub-lethal doses of antifungal drug miconazole nitrate (MCZ) on immunological responses including immune-related gene expression and its role as a prophylactic drug against S. parasitica in Labeo rohita fingerlings. Fish were fed with sub lethal doses of MCZ i.e., T1- 6.30 mg MCZ kgBW⁻¹, T2- 12.61 mg MCZ kgBW⁻¹ and T3- 25.22 mg MCZ kgBW⁻¹ and sampling was done at different time intervals for 240 h. Immunological parameters viz. lysozyme activity, oxygen radical production and plasma anti-protease activity showed significant enhancement (p < 0.05) in fish fed with T2 and T3 doses. Significant reduction in plasma protein content was observed in all the dietary groups as compared to control. Expression of immune-relevant genes like TLR-22 and β2-M showed significantly higher expression at six h and 24 h of sampling in both liver and head-kidney. However, these genes showed a down-regulation after 120 h of sampling in both the tissues. Preventive efficacy study showed that single dose of MCZ provides protection against oomycetes up to the fourth day of infection. Significantly higher mortality was observed in control diet-fed fish as compared to fish fed with MCZ medicated diet. Thus, from the study, it can be concluded that the MCZ can act as a potent antifungal agent for preventing oomycetes infection as well as to enhance the immune response.

Keywords: antifungal, immune gene, immunological, miconazole nitrate, prophylactic

Procedia PDF Downloads 232

Authors: Rita Ghosh, Joykrishna Dey

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PEG-based amphiphiles are of tremendous importance for its widespread applications in pharmaceutics, household purposes, and drug delivery. Previously, a number of single PEG-tailed amphiphiles having significant applications have been reported from our group. Therefore, it was of immense interest to explore the properties and application potential of PEG-based double tailed amphiphiles. Herein, for the first time, two novel double PEG-tailed amphiphiles having different PEG chain lengths have been developed. The self-assembly behavior of the newly developed amphiphiles in aqueous buffer (pH 7.0) was thoroughly investigated at 25 oC by a number of techniques including, 1H-NMR, and steady-state and time-dependent fluorescence spectroscopy, dynamic light scattering, transmission electron microscopy, atomic force microscopy, and isothermal titration calorimetry. Despite having two polar PEG chains both molecules were found to have strong tendency to self-assemble in aqueous buffered solution above a very low concentration. Surprisingly, the amphiphiles were shown to form stable vesicles spontaneously at room temperature without any external stimuli. The results of calorimetric measurements showed that the vesicle formation is driven by the hydrophobic effect (positive entropy change) of the system, which is associated with the helix-to-random coil transition of the PEG chain. The spectroscopic data confirmed that the bilayer membrane of the vesicles is constituted by the PEG chains of the amphiphilic molecule. Interestingly, the vesicles were also found to exhibit structural transitions upon addition of salts in solution. These properties of the vesicles enable them as potential candidate for drug delivery.

Keywords: double-tailed amphiphiles, fluorescence, microscopy, PEG, vesicles

Procedia PDF Downloads 108

Authors: E. C. Mattos, V. S. M. G. Daros, R. Dal Col, A. L. Nascimento

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The aim of this study is to present the results of a retrospective survey on the foreign matter found in foods analyzed at the Adolfo Lutz Institute, from July 2001 to July 2015. All the analyses were conducted according to the official methods described on Association of Official Agricultural Chemists (AOAC) for the micro analytical procedures and Food and Drug Administration (FDA) for the macro analytical procedures. The results showed flours, cereals and derivatives such as baking and pasta products were the types of food where foreign matters were found more frequently followed by condiments and teas. Fragments of stored grains insects, its larvae, nets, excrement, dead mites and rodent excrement were the most foreign matter found in food. Besides, foreign matters that can cause a physical risk to the consumer’s health such as metal, stones, glass, wood were found but rarely. Miscellaneous (shell, sand, dirt and seeds) were also reported. There are a lot of extraneous materials that are considered unavoidable since are something inherent to the product itself, such as insect fragments in grains. In contrast, there are avoidable extraneous materials that are less tolerated because it is preventable with the Good Manufacturing Practice. The conclusion of this work is that although most extraneous materials found in food are considered unavoidable it is necessary to keep the Good Manufacturing Practice throughout the food processing as well as maintaining a constant surveillance of the production process in order to avoid accidents that may lead to occurrence of these extraneous materials in food.

Keywords: extraneous materials, food contamination, foreign matter, surveillance

Procedia PDF Downloads 343

Authors: Amelia R. Anshar, Dini Kurnia, Muh A. Bahar

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Nowadays, there are so many incidences had been reported in pet animals regarding drug overdose caused by incorrect doses of a non-steroidal anti-inflammatory drug (NSAID), for instance, meloxicam. As supporting treatment, the avocado is used in traditional medicine to treat or prevent some health cases. The study was aimed at providing the basis for the antioxidant activity of avocado puree in animal medicine. Experimental animals used in this study were 24 male rats that were randomly divided into 4 groups (n=6). Control Group I got 1 ml CMC 1% and control II got meloxicam 30 mg/kgBB and 1 ml CMC 1%. Treatment group I got meloxicam 30 mg/kgBB and avocado 5 g/kgBB/day and treatment II got meloxicam 30 mg/kgBB and avocado 10 g/kgBB/day. The study was conducted over 8 days, then the level of Blood Urea Nitrogen and creatinine of the white rats were examined in 1st day and 8th day. The results were analyzed by ANOVA Two Way With Replication, then followed by T-test (α = 0,05) if there were a difference. Comparison test among the four groups after treatment with avocado using Anova Two Way With Replication test showed that there were significant differences between the mean of the four groups either decreased levels of Blood Urea Nitrogen and creatinine with p < 0,05. Treatment group I and II received treatment showed remarkable (p < 0,05) decreases ini Blood Urea Nitrogen level by 27,17 mg/dl and 17,83 mg/dl respectively. There was also significant decrease in the values of creatinine in Treatment group I and treatment group II by 0,983 mg/dl and 0,713 mg/dl respectively. The conclusion of this study was that avocado decreases level of Blood Urea Nitrogen and creatinine in white rats which are exposed to toxic doses of meloxicam.

Keywords: avocado, blood urea nitrogen, creatinine, meloxicam

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Authors: Debatosh Das, Moxian Chen, Jianhua Zhang, Caroline Gutjahr

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Arbuscular mycorrhiza (AM) is a mutualistic symbiosis between plant roots and Glomeromycotina fungi, which is activated under low but inhibited by high phosphate. The effect of phosphate on AM development has been observed for many years, but mechanisms regulating it under contrasting phosphate levels remain unknown. Based on previous observations that promoters of several AM functional genes contain PHR binding motifs, we hypothesized that PHR2, a master regulator of phosphate starvation response in rice, was recruited to regulate AM symbiosis development. We observed a drastic reduction in root colonization and significant AM transcriptome modulation in phr2. PHR2 targets genes required for root colonization and AM signaling. The role of PHR2 in improving root colonization, mycorrhizal phosphate uptake, and growth response was confirmed in field soil. In conclusion, rice PHR2, which is considered a master regulator of phosphate starvation responses, acts as a positive regulator of AM symbiosis between Glomeromycotina fungi and rice roots. PHR2 directly targets the transcription of plant strigolactone and AM genes involved in the establishment of this symbiosis. Our work facilitates an understanding of ways to enhance AMF propagule populations introduced in field soils (as a biofertilizer) in order to restore the natural plant-AMF networks disrupted by modern agricultural practices. We show that PHR2 is required for AM-mediated improvement of rice yield in low phosphate paddy field soil. Thus, our work contributes knowledge for rational application of AM in sustainable agriculture. Our data provide important insights into the regulation of AM by the plant phosphate status, which has a broad significance in agriculture and terrestrial ecosystems.

Keywords: biofertilizer, phosphate, mycorrhiza, rice, sustainable, symbiosis

Procedia PDF Downloads 117

Authors: Sunita Gakkhar, Arti Mishra

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In this paper, a nonlinear host vector model has been proposed and analyzed for the two strain dengue dynamics incorporating ADE effect. The model considers that the asymptomatic infected people are more responsible for secondary infection than that of symptomatic ones and differentiates between them. The existence conditions are obtained for various equilibrium points. Basic reproduction number has been computed and analyzed to explore the effect of secondary infection enhancement parameter on dengue infection. Stability analyses of various equilibrium states have been performed. Numerical simulation has been done for the stability of endemic state.

Keywords: dengue, ade, stability, threshold, asymptomatic, infection

Procedia PDF Downloads 414

Authors: Chi Wu, Dean Wu, Wen-Te Liu, Cheng-Yu Tsai, Shin-Mei Hsu, Yin-Tzu Lin, Ru-Yin Yang

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Background: The results of previous studies compared the benefits and risks of receiving insomnia medication. However, the effects between hypnotic drugs used and enhancement of sleep quality were still unclear. Objective: The aim of this study is to establish a prediction model for hypnotic drugs' dosage used for insomnia subjects and associated the relationship between sleep stage ratio change and drug types. Methodologies: According to American Academy of Sleep Medicine (AASM) guideline, sleep stages were classified and transformed to hypnogram via the polysomnography (PSG) in a hospital in New Taipei City (Taiwan). The subjects with diagnosis for insomnia without receiving hypnotic drugs treatment were be set as the comparison group. Conversely, hypnotic drugs dosage within the past three months was obtained from the clinical registration for each subject. Furthermore, the collecting subjects were divided into two groups for training and testing. After training convolution neuron network (CNN) to predict types of hypnotics used and dosages are taken, the test group was used to evaluate the accuracy of classification. Results: We recruited 76 subjects in this study, who had been done PSG for transforming hypnogram from their sleep stages. The accuracy of dosages obtained from confusion matrix on the test group by CNN is 81.94%, and accuracy of hypnotic drug types used is 74.22%. Moreover, the subjects with high ratio of wake stage were correctly classified as requiring medical treatment. Conclusion: CNN with hypnogram was potentially used for adjusting the dosage of hypnotic drugs and providing subjects to pre-screening the types of hypnotic drugs taken.

Keywords: convolution neuron network, hypnotic drugs, insomnia, polysomnography

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Authors: Emel Bayraktar, Gulengun Turk

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Introduction and Objective: Safe administration of medicines is one of the main responsibilities of nurses. Intramuscular drug administration is among the most common methods used by nurses among all drug applications. This study was carried out in order to determine determine the effect of education given on injection in ventrogluteal area on the level of knowledge of nurses on this subject. Methods: The sample of the study consisted of 20 nurses who agreed to participate in the study between 01 October and 31 December 2019. The research is a pretest-posttest comparative, quasi-experimental type pilot study. The nurses were given a 4-hour training prepared on injection into the ventrogluteal area. The training consisted of two hours of theoretical and two hours of laboratory practice. Before the training and 4 weeks after the training, a questionnaire form containing questions about their knowledge and practices regarding the injection of the ventrogluteal region was applied to the nurses. Results: The average age of the nurses is 26.55 ± 7.60, 35% (n = 7) of them are undergraduate and 30% (n = 6) of them work in intensive care units. Before the training, 35% (n = 7) of the nurses stated that the most frequently used intramuscular injection site was the ventrogluteal area, and 75% (n = 15) stated that the safest area was the rectus femoris muscle. After the training, 55% (n = 11) of the nurses stated that they most frequently used the ventrogluteal area and 100% (n = 20) of them stated that the ventrogluteal area was the safest area. The average score the nurses got from the premises before the training is 14.15 ± 6.63 (min = 0, max = 20), the total score is 184. The average score obtained after the training was determined as 18.69 ± 2.35 (min = 12, max = 20), and the total score was 243. Conclusion: As a result of the research, it was determined that the training given on the injection of ventrogluteal area increased the knowledge level of the nurses. It is recommended to organize in-service trainings for all nurses on the injection of ventrogluteal area.

Keywords: safe injection, knowledge level, nurse, intramuscular injection, ventrogluteal area

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Authors: Michio Kurosu

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Alterations in glycosylation not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Identification of cell type-specific glycoconjugates (tumor markers) has led to the discovery of new assay systems for certain cancers via immunodetection reagents. N- and O-linked glycans are the most abundant forms of glycoproteins. Recent studies of cancer immunotherapy are based on the immunogenicity of truncated O-glycan chains (e.g., Tn, sTn, T, and sLea/x). The prevalence of N-linked glycan changes in the development of tumor cells is known; however, therapeutic antibodies against N-glycans have not yet been developed. This is due to the lack of specificity of N-linked glycans between normal/healthy and cancer cells. Abnormal branching of N-linked glycans has been observed, particularly in solid cancer cells. While the discovery of drug-like glycosyltransferase inhibitors that block the biosynthesis of specific branching has a very low likelihood of success, altered glycosylation levels can be exploited by suppressing N-glycan biosynthesis through the inhibition of dolichyl-phosphate N-acetylglucosaminephosphotransferase1 (DPAGT1) activity. Inhibition of DPAGT1 function leads to changes of O-glycosylation on proteins associated with mitochondria and zinc finger binding proteins (indirect effects). On the basis of dynamic crosstalk between DPAGT1 and Snail/Slung/ZEB1 (a family of transcription factors that promote the repression of the adhesion molecules), we have developed pharmacologically acceptable selective DPAGT1 inhibitors. Tunicamycin kills a wide range of cancer and healthy cells in a non-selective manner. In sharp contrast, our DPAGT1 inhibitors display strong cytostatic effects against 16 solid cancers, which require the overexpression of DPAGT1 in their progression but do not affect the cell viability of healthy cells. The identified DPAGT1 inhibitors possess impressive anti-metastatic ability in various solid cancer cell lines and induce their mitochondrial structural changes, resulting in apoptosis. A prototype DPAGT1 inhibitor, APPB has already been proven to shrink solid tumors (e.g., pancreatic cancers, triple-negative breast cancers) in vivo while suppressing metastases and has strong synergistic effects when combined with current cytotoxic drugs (e.g., paclitaxel). At this conference, our discovery of selective DPAGT1 inhibitors with drug-like properties and proof-of-pharmaceutical concept studies of a novel DPAGT1 inhibitor are presented.

Keywords: DPAGT1 inhibitors, anti-metastatic drugs, natural product based drug designs, cytostatic effects

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Authors: Sidong Zhao, Xingping Wang

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Recently, the government of China has provided strong support the developments of overseas industrial parks. The global distribution of China overseas industrial parks has gradually moved from the 'sparks of fire' to the 'prairie fires.' The support and distribution have promoted developing overseas industrial parks to a strategy of constructing a China's new open economic system and a typical representative of the 'Chinese wisdom' and the 'China's plans' that China has contributed to the globalization of the new era under the initiative of the Belt and Road. As the industrial parks are the basis of 'work/employment', a basic function of a city (Athens Constitution), planning for developments of industrial parks has become a long-term focus of urban planning. Based on the research of the planning and the analysis of the present developments of some typical China overseas industrial parks, we found some interesting rules: First, large numbers of the China overseas industrial parks are located in less developed countries. These industrial parks have become significant drives of the developments of the host cities and even the regions in those countries, especially in investment, employment and paid tax fee for the local, etc. so, the planning and development of overseas industrial parks have received extensive attention. Second, there are some problems in the small part of the overseas Park, such as the planning of the park not following the planning of the host city and lack of implementation of the park planning, etc. These problems have led to the difficulties of the implementation of the planning and the sustainable developments of the parks. Third, a unique pattern of space development has been formed. in the dimension of the patterns of regional spatial distribution, there are five characteristics - along with the coast, along the river, along with the main traffic lines and hubs, along with the central urban area and along the connections of regions economic. In the dimension of the spatial relationships between the industrial park and the city, there is a growing and evolving trend as 'separation – integration - union'. In the dimension of spatial mode of the industrial parks, there are different patterns of development, such as a specialized industrial park, complex industrial park, characteristic town and new urban area of industry, etc. From the perspective of the trends of the developments and spatial modes, in the future, the planning of China overseas industrial parks should emphasize the idea of 'building a city based on the industrial park'. In other words, it's making the developments of China overseas industrial parks move from 'driven by policy' to 'driven by the functions of the city', accelerating forming the system of China overseas industrial parks and integrating the industrial parks and the cities.

Keywords: overseas industrial park, spatial mode, planning, China

Procedia PDF Downloads 182

Authors: Yihenew Simegniew Birhan, Hsieh Chih Tsai

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The recent advancements in synthetic chemistry and nanotechnology fostered the development of different nanocarriers for enhanced intracellular delivery of pharmaceutical agents to tumor cells. Polymeric micelles (PMs), characterized by small size, appreciable drug loading capacity (DLC), better accumulation in tumor tissue via enhanced permeability and retention (EPR) effect, and the ability to avoid detection and subsequent clearance by the mononuclear phagocyte (MNP) system, are convenient to improve the poor solubility, slow absorption and non-selective biodistribution of payloads embedded in their hydrophobic cores and hence, enhance the therapeutic efficacy of chemotherapeutic agents. Recently, redox-responsive polymeric micelles have gained significant attention for the delivery and controlled release of anticancer drugs in tumor cells. In this study, we synthesized redox-responsive diselenide bond containing amphiphilic polymer, Bi(mPEG-PLGA)-Se₂ from mPEG-PLGA, and 3,3'-diselanediyldipropanoic acid (DSeDPA) using DCC/DMAP as coupling agents. The successful synthesis of the copolymers was verified by different spectroscopic techniques. Above the critical micelle concentration, the amphiphilic copolymer, Bi(mPEG-PLGA)-Se₂, self-assembled into stable micelles. The DLS data indicated that the hydrodynamic diameter of the micelles (123.9 ± 0.85 nm) was suitable for extravasation into the tumor cells through the EPR effect. The drug loading content (DLC) and encapsulation efficiency (EE) of DOX-loaded micelles were found to be 6.61 wt% and 54.9%, respectively. The DOX-loaded micelles showed initial burst release accompanied by sustained release trend where 73.94% and 69.54% of encapsulated DOX was released upon treatment with 6mM GSH and 0.1% H₂O₂, respectively. The biocompatible nature of Bi(mPEG-PLGA)-Se₂ copolymer was confirmed by the cell viability study. In addition, the DOX-loaded micelles exhibited significant inhibition against HeLa cells (44.46%), at a maximum dose of 7.5 µg/mL. The fluorescent microscope images of HeLa cells treated with 3 µg/mL (equivalent DOX concentration) revealed efficient internalization and accumulation of DOX-loaded Bi(mPEG-PLGA)-Se₂ micelles in the cytosol of cancer cells. In conclusion, the intelligent, biocompatible, and the redox stimuli-responsive behavior of Bi(mPEG-PLGA)-Se₂ copolymer marked the potential applications of diselenide-linked mPEG-PLGA micelles for the delivery and on-demand release of chemotherapeutic agents in cancer cells.

Keywords: anticancer drug delivery, diselenide bond, polymeric micelles, redox-responsive

Procedia PDF Downloads 99

Authors: Tivani Phosa Mashamba-Thompson, Mahmoud E. S. Soliman

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To date, the cause of neurodegeneration is not well understood and diseases that stem from neurodegeneration currently have no known cures. Cathepsin B (CB) enzyme is known to be involved in the production of peptide neurotransmitters and toxic peptides in neurodegenerative diseases (NDs). CA-074Me is a membrane-permeable irreversible selective cathepsin B (CB) inhibitor as confirmed by in vivo studies. Due to the lack of the crystal structure, the binding mode of CA-074Me with the human CB at molecular level has not been previously reported. The main aim of this study is to gain an insight into the binding mode of CB CA-074Me to human CB using various computational tools. Herein, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition analysis were employed to accomplish the aim of the study. Another objective was to identify novel CB inhibitors based on the structure of CA-074Me using fragment based drug design using scaffold hoping drug design approach. Results showed that two of the designed ligands (hit 1 and hit 2) were found to have better binding affinities than the prototype inhibitor, CA-074Me, by ~2-3 kcal/mol. Per-residue energy decomposition showed that amino acid residues Cys29, Gly196, His197 and Val174 contributed the most towards the binding. The Van der Waals binding forces were found to be the major component of the binding interactions. The findings of this study should assist medicinal chemist towards the design of potential irreversible CB inhibitors.

Keywords: cathepsin B, scaffold hopping, docking, molecular dynamics, binding-free energy, neurodegerative diseases

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Authors: Jignasha Derasari, Patel Krishna M, Modi Jignasa G.

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Chemical stability of pharmaceutical molecules is a matter of great concern as it affects the safety and efficacy of the drug product.Stability testing data provides the basis to understand how the quality of a drug substance and drug product changes with time under the influence of various environmental factors. Besides this, it also helps in selecting proper formulation and package as well as providing proper storage conditions and shelf life, which is essential for regulatory documentation. The ICH guideline states that stress testing is intended to identify the likely degradation products which further help in determination of the intrinsic stability of the molecule and establishing degradation pathways, and to validate the stability indicating procedures. A simple, accurate and precise stability indicating RP- HPLC method was developed and validated for simultaneous estimation of Amiloride Hydrochloride and Furosemide in tablet dosage form. Separation was achieved on an Phenomenexluna ODS C18 (250 mm × 4.6 mm i.d., 5 µm particle size) by using a mobile phase consisting of Ortho phosphoric acid: Acetonitrile (50:50 %v/v) at a flow rate of 1.0 ml/min (pH 3.5 adjusted with 0.1 % TEA in Water) isocratic pump mode, Injection volume 20 µl and wavelength of detection was kept at 283 nm. Retention time for Amiloride Hydrochloride and Furosemide was 1.810 min and 4.269 min respectively. Linearity of the proposed method was obtained in the range of 40-60 µg/ml and 320-480 µg/ml and Correlation coefficient was 0.999 and 0.998 for Amiloride hydrochloride and Furosemide, respectively. Forced degradation study was carried out on combined dosage form with various stress conditions like hydrolysis (acid and base hydrolysis), oxidative and thermal conditions as per ICH guideline Q2 (R1). The RP- HPLC method has shown an adequate separation for Amiloride hydrochloride and Furosemide from its degradation products. Proposed method was validated as per ICH guidelines for specificity, linearity, accuracy; precision and robustness for estimation of Amiloride hydrochloride and Furosemide in commercially available tablet dosage form and results were found to be satisfactory and significant. The developed and validated stability indicating RP-HPLC method can be used successfully for marketed formulations. Forced degradation studies help in generating degradants in much shorter span of time, mostly a few weeks can be used to develop the stability indicating method which can be applied later for the analysis of samples generated from accelerated and long term stability studies. Further, kinetic study was also performed for different forced degradation parameters of the same combination, which help in determining order of reaction.

Keywords: amiloride hydrochloride, furosemide, kinetic study, stability indicating RP-HPLC method validation

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Authors: Keshari Shrestha, Philip Vatterott

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Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially fatal drug-related syndrome. DRESS classically presents with a diffuse maculopapular rash, fevers, and eosinophilia more than three weeks after drug exposure. DRESS can present with multi-organ involvement, with liver damage being the most common and severe. Pulmonary involvement is a less common manifestation and is associated with poor clinical outcomes. Chest imaging is often nonspecific, and symptoms can range from mild cough to acute respiratory distress syndrome (ARDS) . This is a case of a 49-year-old female with a history of recent clostridium difficile colitis status post treatment with oral vancomycin who presented with rash, acute liver and kidney failure, as well as diffuse nodular alveolar lung opacities concerning for DRESS syndrome with multi-organ involvement. Clinical Course: This patient initially presented to an outside hospital with clostridium difficile colitis, acute liver injury, and acute kidney injury. She developed a desquamating maculopapular rash in the setting of recent oral vancomycin, meloxicam, and furosemide initiation. She was hospitalized on two additional occasions with worsening altered mental status, liver injury, and acute kidney injury and was initiated on intermittent hemodialysis. Notably, she was found to have systemic eosinophilia (4100 cells/microliter) several weeks prior. She was transferred to this institution for further management where she was found to have encephalopathy, jaundice, lower extremity edema, and diffuse bilateral rhonchorous breath sounds on pulmonary examination. The patient was started on methylprednisolone for suspected DRESS syndrome. She underwent an evaluation for alternative causes of her organ failure. Her workup included a negative infectious, autoimmune, metabolic, toxic, and malignant work-up. Abdominal computed tomography (CT) and ultrasound were remarkable for evidence of hepatic steatosis and possible cirrhotic morphology. Additionally, a chest CT demonstrated diffuse and symmetric nodular alveolar lung opacities with peripheral sparing not consistent with acute respiratory distress syndrome or edema. Ultimately, her condition continued to decline, and she required intubation on several occasions. On hospital day 25 she succumbed to distributive shock in the setting of probable sepsis and multi-organ failure. Discussion: DRESS syndrome occurs in 1 in 1,000 to 10,000 patients with a mortality rate of around 10%. Anti-convulsant, anti-bacterial, anti-viral, and sulfonamide drugs are the most common drugs implicated in the development of DRESS syndrome; however, the list of offending agents is extensive . The diagnosis of DRESS syndrome is made after excluding other causes of disease such as infectious and autoimmune etiologies. The RegiSCAR scoring system is used to diagnose DRESS syndrome with 2-3 points indicating possible disease, 4-5 probable disease, and >5 definite disease. This patient scored a 7 on the RegiSCAR scale for eosinophilia, rash, organ involvement, and exclusion of other causes (infectious and autoimmune). While the pharmacologic trigger in this case is unknown, it is speculated to be caused by vancomycin, meloxicam, or furosemide due to the favorable timeline of initiation. Despite aggressive treatment, DRESS syndrome can often be fatal. Because of this, early diagnosis and treatment of patients with suspected DRESS syndrome is imperative.

Keywords: drug reaction with eosinophilia and systemic symptoms, multi-organ failure, pulmonary involvement, renal failure

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Authors: Jaya Mathew

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Many organizations are faced with the challenge of how to analyze and build Machine Learning models using their sensitive telemetry data. In this paper, we discuss how users can leverage the power of R without having to move their big data around as well as a cloud based solution for organizations willing to host their data in the cloud. By using ScaleR technology to benefit from parallelization and remote computing or R Services on premise or in the cloud, users can leverage the power of R at scale without having to move their data around.

Keywords: predictive maintenance, machine learning, big data, cloud based, on premise solution, R

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Authors: Zsanett Bahor, Cristina Nunes-Fonseca, Gillian L. Currie, Emily S. Sena, Lindsay D.G. Thomson, Malcolm R. Macleod

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Psychosis is ranked as the third most disabling medical condition in the world by the World Health Organization. Despite a substantial amount of research in recent years, available treatments are not universally effective and have a wide range of adverse side effects. Since many clinical drug candidates are identified through in vivo modelling, a deeper understanding of these models, and their strengths and limitations, might help us understand reasons for difficulties in psychosis drug development. To provide an unbiased summary of the preclinical psychosis literature we performed a systematic electronic search of PubMed for publications modelling a psychotic disorder in vivo, identifying 14,721 relevant studies. Double screening of 11,000 publications from this dataset so far established 2403 animal studies of psychosis, with the most common model being schizophrenia (95%). 61% of these models are induced using pharmacological agents. For all the models only 56% of publications test a therapeutic treatment. We propose a systematic review of these studies to assess the prevalence of reporting of measures to reduce risk of bias, and a meta-analysis to assess the internal and external validity of these animal models. Our findings are likely to be relevant to future preclinical studies of psychosis as this generation of strong empirical evidence has the potential to identify weaknesses, areas for improvement and make suggestions on refinement of experimental design. Such a detailed understanding of the data which inform what we think we know will help improve the current attrition rate between bench and bedside in psychosis research.

Keywords: animal models, psychosis, systematic review, schizophrenia

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Authors: Christopher R. Triggle, Hong Ding, Khaled Machaca, Gnanapragasam Arunachalam

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The antidiabetic drug, metformin, has been in clinical use for over 50 years and remains the first choice drug for the treatment of type two diabetes. In addition to its effectiveness as an oral anti-hyperglycaemic drug metformin also possesses vasculoprotective effects that are assumed to be secondary to its ability to reduce insulin resistance and control glycated hemoglobin levels; however, recent data from our laboratory indicate that metformin also has direct vasoprotective effects that are mediated, at least in part, via the anti-ageing gene, SIRT1. Diabetes is a major risk factor for the development of cardiovascular disease (CVD) and it is also well established that tobacco use further enhances the risk of CVD; however, it is not known whether treatment with metformin can offset the negative effects of diabetes and tobacco use on cardiac function. The current study was therefore designed to investigate 1: the effects of hyperglycaemia (HG) either alone or in the presence of elevated fatty acids (palmitate) and nicotine on the protein expression levels of the deacetylase sirtuin 1 (the protein product of SIRT1), anti-apoptotic Bcl-2, pro-apoptotic BIM and the pro-apoptotic, tumour suppressor protein, acetylated p53 in cardiomyocytes. 2: the ability of metformin to prevent the detrimental effects of HG, palmitate and nicotine on cardiomyocyte survival. Cell culture protocols were designed using a rat cardiomyocyte cell line, H9c2, either under normal glycaemic (NG) conditions of 5.5mM glucose, or hyperglycaemic conditions (HG) of 25mM glucose with, or without, added palmitate (250μM) or nicotine (1.0mM) for 24h. Immuno-blotting was used to detect the expression of sirtuin 1, Bcl-2, BIM, acetylated (Ac)-p53, p53 with β-actin used as the reference protein. Exposure to HG, palmitate, or nicotine alone significantly reduced expression of sirtuin1, Bcl-2 and raised the expression levels of acetylated p53 and BIM; however, the combination of HG, palmitate and nicotine had a synergistic effect to significantly suppress the expression levels of sirtuin 1 and Bcl-2, but further enhanced the expression of Ac-p53, and BIM. The inclusion of 1000μM, but not 50μM, metformin in the H9c2 cell culture protocol prevented the effects of HG, palmitate and nicotine on the pro-apoptotic pathways. Collectively these data indicate that metformin, in addition to its anti-hyperglycaemic and vasculoprotective properties, also has direct cardioprotective actions that offset the negative effects of hyerglycaemia, elevated free fatty acids and nicotine on cardiac cell survival. These data are of particular significance for the treatment of patients with diabetes who are also smokers as the inclusion of metformin in their therapeutic treatment plan should help reduce cardiac-related morbidity and mortality.

Keywords: apoptosis, cardiac muscle, diabetes, metformin, nicotine

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Authors: Parthiban Srinivasan

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With recent advances in computational power and access to enough data in biosciences, artificial intelligence methods are increasingly being used in drug discovery research. These methods are essentially a series of advanced statistics based exercises that review the past to indicate the likely future. Our goal is to develop a model that accurately predicts biological activity and toxicity parameters for novel compounds. We have compiled a robust library of over 150,000 chemical compounds with different pharmacological properties from literature and public domain databases. The compounds are stored in simplified molecular-input line-entry system (SMILES), a commonly used text encoding for organic molecules. We utilize an automated process to generate an array of numerical descriptors (features) for each molecule. Redundant and irrelevant descriptors are eliminated iteratively. Our prediction engine is based on a portfolio of machine learning algorithms. We found Random Forest algorithm to be a better choice for this analysis. We captured non-linear relationship in the data and formed a prediction model with reasonable accuracy by averaging across a large number of randomized decision trees. Our next step is to apply deep neural network (DNN) algorithm to predict the biological activity and toxicity properties. We expect the DNN algorithm to give better results and improve the accuracy of the prediction. This presentation will review all these prominent machine learning and deep learning methods, our implementation protocols and discuss these techniques for their usefulness in biomedical and health informatics.

Keywords: deep learning, drug discovery, health informatics, machine learning, toxicity prediction

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Authors: Susmita Goswami, Joyeeta Mitra, Indu Gaur, Neha Bhadauria, Shilpi Shilpi, Prabir K. Paul

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'Malbhog’, an indigenous banana variety, much prized for its flavour and delicacy suffers production losses due to Fusarium oxysporum f.sp. cubense. The pathogen enters young plants through feeder roots causing wilting of plants ultimately leading to death of plants. The pathogen spreads rapidly to other plants in the field. In eastern part of India, this variety escapes the onslaught of the pathogen when either co-cultivated or rotated with Amorphophallus campanulatus (yam). The present study provides an insight into the physiological aspect of the biocontrol by yam. In vitro application of sterile aqueous extract of yam tuber (100gm/100ml distilled water and its 1:10 and 1:100 dilutions) were mixed with PDA media which was substantially inoculated with spores of Fusarium oxysporum f.sp. cubense. The extract could significantly reduce germination of pathogen spores. Banana variety susceptible to Fusarium sp was raised in soil rite under aseptic conditions. Spores of the pathogen (106 spores/ml) were inoculated into the soil rite. The plants were spread with aqueous extract of yam. The control plants were treated with sterilized distilled water. The activity of phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO) and peroxidase (POX) were estimated in leaves and roots at interval of 24 hours for 5 days after treatment. The incidence of wilt disease was recorded after two weeks. The results demonstrated that yam extract could induce significant activity of PAL, PPO and POX along with accumulation of phenols in both roots and leaves of banana plants. However, significantly high activity of enzymes and phenol accumulation was observed in roots. The disease incidence was significantly low in yam treated plants. The results clearly demonstrated the control of the pathogen due to induction of defense mechanism in the host by the extract. The observed control of the pathogen in the field could possibly be due to induction of such defense responses in host by exudates leached into the soil from yam tubers. Yam extract could be a potential source of environment-friendly biocide against Panama wilt of banana.

Keywords: Amorphophallus campanulatus, banana, Fusarium oxysporum f.sp. cubense, phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), peroxidase (POX)

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Authors: Ramandeep Kaur, Makula Ajitha

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Fluvastatin has been reported for increasing bone mineral density in osteoporosis since last decade. Systemically administered drug undergoes extensive hepatic first-pass metabolism, thus very small amount of drug reaches the bone tissue which is highly insignificant. The present study aims to deliver fluvastatin in the form of nanoemulsion (NE) gel directly to the bone tissue through transdermal route thereby bypassing hepatic first pass metabolism. The NE formulation consisted of isopropyl myristate as oil, tween 80 as surfactant, transcutol as co-surfactant and water as the aqueous phase. Pseudoternary phase diagrams were constructed using aqueous titration method and NE’s obtained were subjected to thermodynamic-kinetic stability studies. The stable NE formulations were evaluated for their droplet size, zeta potential, and transmission electron microscopy (TEM). The nano-sized formulations were incorporated into 0.5% carbopol 934 gel matrix. Ex-vivo permeation behaviour of selected formulations through rat skin was investigated and compared with the conventional formulations (suspension and emulsion). Further, in-vivo pharmacokinetic study was carried using male Wistar rats. The optimized NE formulations mean droplet size was 11.66±3.2 nm with polydispersity index of 0.117. Permeation flux of NE gel formulations was found significantly higher than the conventional formulations i.e. suspension and emulsion. In vivo pharmacokinetic study showed significant increase in bioavailability (1.25 fold) of fluvastatin than oral formulation. Thus, it can be concluded that NE gel was successfully developed for transdermal delivery of fluvastatin for the treatment of osteoporosis.

Keywords: fluvastatin, nanoemulsion gel, osteoporosis, transdermal

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Authors: Michal Kielbik, Izabela Szulc-Kielbik, Anna Brzostek, Jaroslaw Dziadek, Magdalena Klink

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The goal of many research groups in the world is to find new components that are important for survival of mycobacteria in the host cells. Mycobacterium tuberculosis (Mtb) possesses a number of enzymes degrading cholesterol that are considered to be an important factor for its survival and persistence in host macrophages. One of them - cholesterol oxidase (ChoD), although not being essential for cholesterol degradation, is discussed as a virulence compound, however its involvement in macrophages’ response to Mtb is still not sufficiently determined. The recognition of tubercle bacilli antigens by pathogen recognition receptors is crucial for the initiation of the host innate immune response. An important receptor that has been implicated in the recognition and/or uptake of Mtb is Toll-like receptor type 2 (TLR2). Engagement of TLR2 results in the activation and phosphorylation of intracellular signaling proteins including IRAK-1 and -4, TRAF-6, which in turn leads to the activation of target kinases and transcription factors responsible for bactericidal and pro-inflammatory response of macrophages. The aim of these studies was a detailed clarification of the role of Mtb cholesterol oxidase as a virulence factor affecting the TLR2 signaling pathway in human macrophages. As human macrophages the THP-1 differentiated cells were applied. The virulent wild-type Mtb strain (H37Rv), its mutant lacking a functional copy of gene encoding cholesterol oxidase (∆choD), as well as complimented strain (∆choD–choD) were used. We tested the impact of Mtb strains on the expression of TLR2-depended signaling proteins (mRNA level, cytosolic level and phosphorylation status). The cytokine and bactericidal response of THP-1 derived macrophages infected with Mtb strains in relation to TLR2 signaling pathway dependence was also determined. We found that during the 24-hours of infection process the wild-type and complemented Mtb significantly reduced the cytosolic level and phosphorylation status of IRAK-4 and TRAF-6 proteins in macrophages, that was not observed in the case of ΔchoD mutant. Decreasement of TLR2-dependent signaling proteins, induced by wild-type Mtb, was not dependent on the activity of proteasome. Blocking of TLR2 expression, before infection, effectively prevented the induced by wild-type strain reduction of cytosolic level and phosphorylation of IRAK-4. None of the strains affected the surface expression of TLR2. The mRNA level of IRAK-4 and TRAF-6 genes were significantly increased in macrophages 24 hours post-infection with either of tested strains. However, the impact of wild-type Mtb strain on both examined genes was significantly stronger than its ΔchoD mutant. We also found that wild-type strain stimulated macrophages to release high amount of immunosuppressive IL-10, accompanied by low amount of pro-inflammatory IL-8 and bactericidal nitric oxide in comparison to mutant lacking cholesterol oxidase. The influence of wild-type Mtb on this type of macrophages' response strongly dependent on fully active IRAK-1 and IRAK-4 signaling proteins. In conclusion, Mtb using cholesterol oxidase causes the over-activation of TLR2 signaling proteins leading to the reduction of their cytosolic level and activity resulting in the modulation of macrophages response to allow its intracellular survival. Supported by grant: 2014/15/B/NZ6/01565, National Science Center, Poland

Keywords: Mycobacterium tuberculosis, cholesterol oxidase, macrophages, TLR2-dependent signaling pathway

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Authors: Famurewa Olumide Joseph, Akinsulore Adesanmi

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The current study investigated aggressive behaviour and its association with substance use disorder among senior secondary school students in Ilesha, Nigeria. Participants were three hundred and seventy-five (375) comprising (212) females and (163) males of senior secondary school students in Ilesa East and Ilesa West; who were randomly selected among the population of students from the schools. The mean age of the respondents was 14.61 years (S.D = 1.16), with 311 (82.9%) between 14 – 16 years. Female respondents were 212 (56.5%), while male respondents were 163 (43.5%). A cross sectional design was adopted. Three instruments were used for data collection. Buss Perry Aggression Questionnaire, Alcohol Use Disorder Identification Test (AUDIT) and Drug Abuse Screening Test (DAST). It was hypothesized that aggressive behaviour will be associated with substance use disorder among senior secondary school students in Ilesa East and Ilesa West. The result indicated that the overall prevalence of substance use disorder was 16.0%. Chi-Square test exploring the association between aggressive behaviour and substance use disorder shows that there is a significant association between aggressive behaviour and substance use disorder (χ2 =8.55, p =0.014). Results also showed that emotional problem (χ2 (2) =13.0; p = 0.001) was statistically significant while current medications intake (χ2 (2) =2.03; p =0.362) and overall wellbeing (χ2 (4) =2.49; p =0.646) were not statistically significant. There is an inverse association between prosocial behaviour and aggressive behaviour (r= -0.037, p>0.05). This indicates that as the level of prosocial behaviour increases, the level of aggressive behaviour among respondents decreases. However, alcohol use had no correlation with aggressive behaviour (r=0.070, p>0.05). Among the implications stated is that factors such as emotional symptoms, conduct problems, hyperactivity, peer problem and drug use contributed to the prevalence of aggressive behaviour among students. Suggestions for further studies were equally made.

Keywords: aggressive behaviour, alcohol, prevalence, students, substance use disorder (SUD)

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Authors: Nancy M. El-Baz, Laila Ziko, Rania Siam, Wael Mamdouh

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Cancer is one of the most devastating diseases, and has over than 10 million new cases annually worldwide. Despite the effectiveness of chemotherapeutic agents, their systemic toxicity and non-selective anticancer actions represent the main obstacles facing cancer curability. Due to the effective enhanced permeability and retention (EPR) effect of nanomaterials, nanoparticles (NPs) have been used as drug nanocarriers providing targeted cancer drug delivery systems. In addition, several inorganic nanoparticles such as silver (AgNPs) nanoparticles demonstrated a potent anticancer activity against different cancers. The present study aimed at formulating core-shell inorganic NPs-based combinatorial therapy based on combining the anticancer activity of AgNPs along with doxorubicin (DOX) and evaluating their cytotoxicity on MCF-7 breast cancer cells. These inorganic NPs-based combinatorial therapies were designed to (i) Target and kill cancer cells with high selectivity, (ii) Have an improved efficacy/toxicity balance, and (iii) Have an enhanced therapeutic index when compared to the original non-modified DOX with much lower dosage The in-vitro cytotoxicity studies demonstrated that the NPs-based combinatorial therapy achieved the same efficacy of non-modified DOX on breast cancer cell line, but with 96% reduced dose. Such reduction in DOX dose revealed that the combination between DOX and NPs possess a synergic anticancer activity against breast cancer. We believe that this is the first report on a synergic anticancer effect at very low dose of DOX against MCF-7 cells. Future studies on NPs-based combinatorial therapy may aid in formulating novel and significantly more effective cancer therapeutics.

Keywords: nanoparticles-based combinatorial therapy, silver nanoparticles, doxorubicin, breast cancer

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Authors: Milijana N. Miljkovic, Viktorija M. Dragojevic-Simic, Nemanja K. Rancic, Vesna M. Jacevic, Snezana B. Djordjevic, Momir M. Mikov, Aleksandra M. Kovacevic

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Itraconazole (ITZ) is a weak base and extremely lipophilic compound, with water solubility as a rate-limiting step in its absorption from the gastrointestinal tract. Its absolute bioavailability, about 55%, is maximal when its oral formulation, capsules, are taken immediately after a full meal. Peak plasma concentrations (Cmax) are reached within 2 to 5 hrs after their administration. ITZ undergoes extensive hepatic metabolism by human CYP3A4 isoenzyme and more than 30 different metabolites have been identified. One of the main ones is hydroxyitraconazole (HITZ), in which plasma concentrations are almost twice higher than those of ITZ. Gender differences in drug PK (Pharmacokinetics) have already been recognized, but variations in metabolism are believed to be their major cause. The aim of the study was to investigate the influence of gender on ITZ PK parameters after administration of oral capsule formulation, following 100 mg single dosing in healthy adult volunteers under fed conditions. The single-center, open-label PK study was performed. PK analyses included PK parameters obtained after a single 100 mg dose administration of itraconazole capsules to 48 females and 66 males. Blood samples were collected at pre-dose and up to 72.0 h after administration (1.0, 2.0, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 9.0, 12.0, 24.0, 36.0 and 72.0 hrs). The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxyitraconazole, were Cmax, AUClast, and AUCtot. Plasma concentrations of ITZ and HITZ were determined using a validated liquid chromatographic method with mass spectrometric detection, while pharmacokinetic parameters were estimated using non-compartmental methods. The pharmacokinetic analyses were performed using Kinetica software version 5.0. The mean value of ITZ Cmaxmen was 74.79 ng/ml, and Cmaxwomen was 51.291 ng/ml (independent samples test; p = 0.005). Hydroxyitraconazole had a mean value of Cmaxmen 106.37 ng/ml, and the mean value Cmaxwomen was 70.05 ng/ml. Women had, on average, lower AUClast and Cmax than men. AUClastmen for ITZ was 736.02 ng/mL*h and AUClastwomen was 566.62 ng/mL*h, while AUClastmen for HITZ was 1154.80 was ng/mL*h and AUClastwomen for HITZ was 708.12 ng/mL*h (independent samples test; p = 0.033). The mean values of ITZ AUCtotmen were 884.73 ng/mL*h and AUCtotwomen was 685.10 ng/mL*h. AUCtotmen for HITZ was 1290.41 ng/mL*h, while AUCtotwomen for HIZT was 788.60 ng/mL*h (p < 0.001). The results could point out to lower oral bioavailability of ITZ in women, since values of Cmax, AUClast, and AUCtot of both ITZ and HITZ were significantly lower in women than in men, respectively. The reason may be higher expression and activity of CYP3A4 in women than in men, but there also may be differences in other PK parameters. High variability of both ITZ and HITZ concentrations in both genders confirmed that ITZ is a highly variable drug. Further examinations of its PK are needed to justify strategies for therapeutic drug monitoring in patients treated by this antifungal agent.

Keywords: itraconazole, gender, hydroxyitraconazole, pharmacokinetics

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Authors: Mostafa Mabrouk, Basma E. Abdel-Ghany, Mona Moaness, Bothaina M. Abdel-Hady, Hanan H. Beherei

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Tissue engineering became a promising field for bone repair and regenerative medicine in which cultured cells, scaffolds and osteogenic inductive signals are used to regenerate tissues. The annual cost of treating bone defects in Egypt has been estimated to be many billions, while enormous costs are spent on imported bone grafts for bone injuries, tumors, and other pathologies associated with defective fracture healing. The current study is aimed at developing a more strategic approach in order to speed-up recovery after bone damage. This will reduce the risk of fatal surgical complications and improve the quality of life of people affected with such fractures. 3D scaffolds loaded with cheap nano-particles that possess an osteogenic effect were prepared by nano-electrospinning. The Microstructure and morphology characterizations of the 3D scaffolds were monitored using scanning electron microscopy (SEM). The physicochemical characterization was investigated using X-ray diffractometry (XRD) and infrared spectroscopy (IR). The Physicomechanical properties of the 3D scaffold were determined by a universal testing machine. The in vitro bioactivity of the 3D scaffold was assessed in simulated body fluid (SBF). The bone-bonding ability of novel 3D scaffolds was also evaluated. The obtained nanofibrous scaffolds demonstrated promising microstructure, physicochemical and physicomechanical features appropriate for enhanced bone regeneration. Therefore, the utilized nanomaterials loaded with the drug are greatly recommended as cheap alternatives to growth factors.

Keywords: bone regeneration, cheap scaffolds, nanomaterials, active molecules

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Authors: Abbas Jafarizad, Duygu Ekinci

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In this work targeted drug delivery is proposed to decrease adverse effect of drugs with concomitant reduces in consumption and treatment outgoings. Nanoparticles (NPs) can be prepared from a variety of materials such as lipid, biodegradable polymer that prevent the drugs cytotoxicity in healthy cells, etc. One of the most important drugs used in chemotherapy is mitoxantrone (MTX) which prevents cell proliferation by inhibition of topoisomerase II and DNA repair; however, it is not selective and has some serious side effects. In this study, mentioned aim is achieved by using several nanocarriers like magnetite (Fe3O4) and their composites with magnetic graphene oxide (Fe3O4@GO). Also, cytotoxic potential of Fe3O4, Fe3O4-MTX, and Fe3O4@GO-MTX nanocomposite were evaluated on mesenchymal stem cells (MSCs). In this study, we reported the synthesis of monodisperse Fe3O4 NPs and Fe3O4@GO nanocomposite and their structures were investigated by using field emission scanning electron microscope (FESEM), Fourier transform infrared (FTIR) spectra, atomic force microscopy (AFM), Brauneur Emmet Teller (BET) isotherm and contact angle studies. Moreover, we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cytotoxic effects of MTX, Fe3O4 NPs, Fe3O4-MTX and Fe3O4@GO-MTX nanocomposite on MSCs. The in-vitro MTT results indicated that all concentrations of MTX and Fe3O4@GO-MTX nanocomposites showed cytotoxic effects while all concentrations of Fe3O4 NPs and Fe3O4-MTX NPs did not show any cytotoxic effect on stem cells. The results from this study indicated that using Fe3O4 NPs as anticancer drug delivery systems could be a trustworthy method for cancer treatment. But for reaching excellent and accurate results, further investigation is necessary.

Keywords: mitoxantrone, magnetite, magnetic graphene oxide, MTT assay, mesenchymal stem cells

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Authors: Nashed Atef Nashed Farag

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Introduction: Reporting adverse events following vaccination remains a challenge. WHO has mandated pharmacovigilance centers around the world to submit Adverse Events Following Immunization (AEFI) reports from different countries to a large electronic database of adverse drug event data called Vigibase. Despite sufficient information about AEFIs on Vigibase, they are not available to the general public. However, the WHO has an alternative website called VigiAccess, an open-access website that serves as an archive for reported adverse reactions and AEFIs. The aim of the study was to establish a reporting model for a number of commonly used vaccines in the VigiAccess system. Methods: On February 5, 2018, VigiAccess comprehensively searched for ESSI reports on the measles vaccine, oral polio vaccine (OPV), yellow fever vaccine, pneumococcal vaccine, rotavirus vaccine, meningococcal vaccine, tetanus vaccine, and tuberculosis vaccine (BCG). These are reports from all pharmacovigilance centers around the world since they joined the WHO Drug Monitoring Program. Results: After an extensive search, VigiAccess found 9,062 AEFIs from the measles vaccine, 185,829 AEFIs from the OPV vaccine, 24,577 AEFIs from the yellow fever vaccine, 317,208 AEFIs from the pneumococcal vaccine, 73,513 AEFIs from the rotavirus vaccine, and 145,447 AEFIs from meningococcal cal vaccine, 22,781 EI FI vaccines against tetanus and 35,556 BCG vaccines against AEFI. Conclusion: The study found that among the eight vaccines examined, pneumococcal vaccines were associated with the highest number of AEFIs, while measles vaccines were associated with the fewest AEFIs.

Keywords: surgical approach, anatomical approach, decompression, axillary nerve, quadrangular space adverse events following immunization, cameroon, COVID-19 vaccines, nOPV, ODK vaccines, adverse reactions, VigiAccess, adverse event reporting

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Authors: Adela Diepoltova, Klara Konecna, Ondrej Jandourek, Petr Nachtigal

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A loss of control over antibiotic-resistant pathogens has become a global issue due to severe and often untreatable infections. This state is reflected in complicated treatment, health costs, and higher mortality. All these factors emphasize the urgent need for the discovery and development of new anti-infectives. One of the most common pathogens mentioned in the phenomenon of antibiotic resistance are bacteria of the genus Staphylococcus. These bacterial agents have developed several mechanisms against the effect of antibiotics. One of them is biofilm formation. In staphylococci, biofilms are associated with infections such as endocarditis, osteomyelitis, catheter-related bloodstream infections, etc. To author's best knowledge, no validated and standardized methodology evaluating candidate compound activity against staphylococcal biofilms exists. However, a variety of protocols for in vitro drug activity testing has been suggested, yet there are often fundamental differences. Based on our experience, a key methodological step that leads to credible results is to form a robust biofilm with appropriate attributes such as firm adherence to the substrate, a complex arrangement in layers, and the presence of extracellular polysaccharide matrix. At first, for the purpose of drug antibiofilm activity evaluation, the focus was put on various conditions (supplementation of cultivation media by human plasma/fetal bovine serum, shaking mode, the density of initial inoculum) that should lead to reproducible and robust in vitro staphylococcal biofilm formation in microtiter plate model. Three model staphylococcal reference strains were included in the study: Staphylococcus aureus (ATCC 29213), methicillin-resistant Staphylococcus aureus (ATCC 43300), and Staphylococcus epidermidis (ATCC 35983). The total biofilm biomass was quantified using the Christensen method with crystal violet, and results obtained from at least three independent experiments were statistically processed. Attention was also paid to the viability of the biofilm-forming staphylococcal cells and the presence of extracellular polysaccharide matrix. The conditions that led to robust biofilm biomass formation with attributes for biofilms mentioned above were then applied by introducing an alternative method analogous to the commercially available test system, the Calgary Biofilm Device. In this test system, biofilms are formed on pegs that are incorporated into the lid of the microtiter plate. This system provides several advantages (in situ detection and quantification of biofilm microbial cells that have retained their viability after drug exposure). Based on our preliminary studies, it was found that the attention to the peg surface and substrate on which the bacterial biofilms are formed should also be paid to. Therefore, further steps leading to the optimization were introduced. The surface of pegs was coated by human plasma, fetal bovine serum, and L-polylysine. Subsequently, the willingness of bacteria to adhere and form biofilm was monitored. In conclusion, suitable conditions were revealed, leading to the formation of reproducible, robust staphylococcal biofilms in vitro for the microtiter model and the system analogous to the Calgary biofilm device, as well. The robustness and typical slime texture could be detected visually. Likewise, an analysis by confocal laser scanning microscopy revealed a complex three-dimensional arrangement of biofilm forming organisms surrounded by an extracellular polysaccharide matrix.

Keywords: anti-biofilm drug activity screening, in vitro biofilm formation, microtiter plate model, the Calgary biofilm device, staphylococcal infections, substrate modification, surface coating

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Authors: Kobauri Sophio, Kantaria Tengiz, Tugushi David, Puiggali Jordi, Katsarava Ramaz

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Biodegradable biomaterials (BB) are of high interest for numerous applications in modern medicine as resorbable surgical materials and drug delivery systems. This kind of materials can be cleared from the body after the fulfillment of their function that excludes a surgical intervention for their removal. One of the most promising BBare amino acids based biodegradable poly(ester amide)s (PEAs) which are composed of naturally occurring (α-amino acids) and non-toxic building blocks such as fatty diols and dicarboxylic acids. Key bis-nucleophilic monomers for synthesizing the PEAs are diamine-diesters-di-p-toluenesulfonic acid salts of bis-(α-amino acid)-alkylenediesters (TAADs) which form the PEAs after step-growth polymerization (polycondensation) with bis-electrophilic counter-partners - activated diesters of dicarboxylic acids. The PEAs combine all advantages of the 'parent polymers' – polyesters (PEs) and polyamides (PAs): Ability of biodegradation (PEs), a high affinity with tissues and a wide range of desired mechanical properties (PAs). The scopes of applications of thePEAs can substantially be expanded by their functionalization, e.g. through the incorporation of hydrophobic fragments into the polymeric backbones. Hydrophobically modified PEAs can form non-covalent adducts with various compounds that make them attractive as drug carriers. For hydrophobic modification of the PEAs, we selected so-called 'Azlactone Method' based on the application of p-phenylene-bis-oxazolinons (bis-azlactones, BALs) as active bis-electrophilic monomers in step-growth polymerization with TAADs. Interaction of BALs with TAADs resulted in the PEAs with low MWs (Mw2,800-19,600 Da) and poor material properties. The high-molecular-weight PEAs (Mw up to 100,000) with desirable material properties were synthesized after replacement of a part of BALs with activated diester - di-p-nitrophenylsebacate, or a part of TAAD with alkylenediamine – 1,6-hexamethylenediamine. The new hydrophobically modified PEAs were characterized by FTIR, NMR, GPC, and DSC. It was shown that after the hydrophobic modification the PEAs retain the biodegradability (in vitro study catalyzed by α-chymptrypsin and lipase), and are of interest for constructing resorbable surgical and pharmaceutical devices including drug delivering containers such as microspheres. The new PEAs are insoluble in hydrophobic organic solvents such as chloroform or dichloromethane (swell only) that allowed elaborating a new technology of fabricating microspheres.

Keywords: amino acids, biodegradable polymers, bis-azlactones, microspheres

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Authors: Veronika Lesáková, Silvia Slezáková, František Štěpánek

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Additive manufacturing technologies producing drug dosage forms aimed at personalized medicine applications are promising strategies with several advantages over the conventional production methods. One of the emerging technologies is 3D printing which reduces manufacturing steps and thus allows a significant drop in expenses. A decrease in material consumption is also a highly impactful benefit as the tested drugs are frequently expensive substances. In addition, 3D printed dosage forms enable increased patient compliance and prevent misdosing as the dosage forms are carefully designed according to the patient’s needs. The incorporation of multiple drugs into a single dosage form further increases the degree of personalization. Our research focuses on the development of 3D printed tablets incorporating multiple drugs (candesartan, losartan) and thermoplastic polymers (e.g., KlucelTM HPC EF). The filaments, an essential feed material for 3D printing,wereproduced via hot-melt extrusion. Subsequently, the extruded filaments of various formulations were 3D printed into tablets using an FDM 3D printer. Then, we have assessed the influence of the internal structure of 3D printed tablets and formulation on dissolution behaviour by obtaining the dissolution profiles of drugs present in the 3D printed tablets. In conclusion, we have developed tablets containing multiple drugs providing modified release profiles. The 3D printing experiments demonstrate the high tunability of 3D printing as each tablet compartment is constructed with a different formulation. Overall, the results suggest that the 3D printing technology is a promising manufacturing approach to dual tablet preparation for personalized medicine.

Keywords: 3D printing, drug delivery, hot-melt extrusion, dissolution kinetics

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