Search results for: drug loading

Authors: Kazunari Ozaki, Mitsuru Kageyama, Kenki Miyazawa, Yoshio Nakamura

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Background: Kampo (Japanese Traditional medicine) is a medicine traditionally practiced in Japan, based on ancient Chinese medicine. Most Kampo doctors have used decoction of crude drug pieces for treatment. 93% of the Kampo drugs sold in Japan are Kampo products nowadays. Of all Kampo products, 81% of them are Kampo extract formulations for prescription, which is prepared in powdered or granulated form from medicinal crude drug extracts mixed with appropriate excipient. Physicians with medical license for Western medicine prescribe these Kampo extract formulations for prescription in Japan. Objectives: Our study aims at presenting a brief history of Kampo extract formulations for prescription in Japan. Methods: Systematic searches for relevant studies were conducted using not only printed journals but also electronic journals from the bibliographic databases, such as PubMed/Medline, Ichushi-Web, and university/institutional websites, as well as search engines, such as Google and Google Scholar. Results: The first commercialization of Kampo extract formulations for general use (or OTC (over-the-counter) Kampo extract formulation) was achieved after 1957. The number of drugs has been subsequentially increased, reaching 148 Kampo extract formulation for prescription currently. Conclusion: We provide a history of Kampo extract formulations for prescription in Japan. The originality of this research is that it analyzes the background history of Kampo in parallel with relevant transitions in the government and insurance systems.

Keywords: health insurance system, history, Kampo, Kampo extract formulation for prescription, OTC Kampo extract formulation, pattern corresponding prescription (Ho-sho-so-tai) system

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Authors: Yakui Bai, Chen Sun, Ke Wang

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An experimental investigation of environmental effect on fatigue behavior in SA508 Gr.3 Cl.2 Steam Generator Forging CAP1400 nuclear power plant has been carried out. In order to simulate actual loading condition, a range of strain amplitude was applied in different low cycle fatigue (LCF) tests. The current American Society of Mechanical Engineers (ASME) design fatigue code does not take full account of the interactions of environmental, loading, and material's factors. A range of strain amplitude was applied in different low cycle fatigue (LCF) tests at a strain rate of 0.01%s⁻¹. A design fatigue model was constructed by taking environmentally assisted fatigue effects into account, and the corresponding design curves were given for the convenience of engineering applications. The corrosion fatigue experiment was performed in a strain control mode in 320℃ borated and lithiated water environment to evaluate the effects of a mixed environment on fatigue life. Stress corrosion cracking (SCC) in steam generator large forging in primary water of pressurized water reactor was also observed. In addition, it is found that the CF life of SA508 Gr.3 Cl.2 decreases with increasing temperature in the water environment. The relationship between the reciprocal of temperature and the logarithm of fatigue life was found to be linear. Through experiments and subsequent analysis, the mechanisms of reduced low cycle fatigue life have been investigated for steam generator forging.

Keywords: failure behavior, low alloy steel, steam generator forging, stress corrosion cracking

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Authors: Yong Jae Yu, Jae-Yeol Cho

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In the design of structural concrete for impact loading, design or model codes often employ a dynamic increase factor (DIF) to impose dynamic effect on static response. Dynamic increase factors that are obtained from laboratory material test results and that are commonly given as a function of strain rate only are quite different from each other depending on the design concept of design codes like ACI 349M-06, fib Model Code 2010 and ACI 370R-14. Because the dynamic increase factors currently adopted in the codes are too simple and limited to consider a variety of strength of materials, their application in practical design is questionable. In this study, the dynamic increase factors used in the three codes were validated through the finite element analysis of reinforced concrete slab elements which were tested and reported by other researcher. The test was intended to simulate a wall element of the containment building in nuclear power plants that is assumed to be subject to impact scenario that the Pentagon experienced on September 11, 2001. The finite element analysis was performed using the ABAQAUS 6.10 and the plasticity models were employed for the concrete, reinforcement. The dynamic increase factors given in the three codes were applied to the stress-strain curves of the materials. To estimate the dynamic increase factors, strain rate was adopted as a parameter. Comparison of the test and analysis was done with regard to perforation depth, maximum deflection, and surface crack area of the slab. Consequently, it was found that DIF has so great an effect on the behavior of the reinforced concrete structures that selection of DIF should be very careful. The result implies that DIF should be provided in design codes in more delicate format considering various influence factors.

Keywords: impact, strain rate, DIF, slab elements

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Authors: Maha Al-Ali, Selvakannan Periasamy, Rajarathinam Parthasarathy

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Drying temperature is an important factor impacting the physicochemical properties of the dried materials, particularly the pharmaceutical powders. Drying of pharmaceuticals by using microwave radiation is very limited, and the available information about the interaction between the electromagnetic radiations and the pharmaceutical material is still scarce. Therefore, microwave drying process is employed in this work to dry the wet (moisturised) granules of the formulated naproxen-sodium drug. This study aims to investigate the influences of the microwave radiation temperatures on the moisture removal, the crystalline structure, the size and morphology of the dried naproxen-sodium particles, and identify any potential changes in the chemical groups of the drug. In this work, newly formulated naproxen-sodium is prepared and moisturized by wet granulation process and hence dried by using microwave radiation at different temperatures. Moisture analyzer, Fourier-transform infrared spectroscopy, powder X-ray diffraction, and scanning electron microscope are used to characterise the non-moisturised powder (reference powder), the moisturised granules, and the dried particles. The results show that microwave drying of naproxen-sodium at high drying temperature is more efficient than that at low temperatures in terms of the moisture removal. Although there is no significant change in the chemical structure of the dried particles, the particle size, crystallinity and morphology are relatively changed with changing of heating temperature.

Keywords: heating temperature, microwave drying, naproxen-sodium, particle size

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Authors: Ziyad S. Haidar

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Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ghada S. Ellithy, John. W. Murphy, Maureen K. Corcoran

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Erosion rate of soils during a levee or dam overtopping event is a major component in risk assessment evaluation of breach time and downstream consequences. The mechanism and evolution of dam or levee breach caused by overtopping erosion is a complicated process and difficult to measure during overflow due to accessibility and quickly changing conditions. In this paper, the results of a flume erosion tests are presented and discussed. The tests are conducted on a coarse-grained material with a median grain size D50 of 5 mm in a 1-m (3-ft) wide flume under varying flow rates. Each test is performed by compacting the soil mix r to its near optimum moisture and dry density as determined from standard Proctor test in a box embedded in the flume floor. The box measures 0.45 m wide x 1.2 m long x 0.25 m deep. The material is tested several times at varying hydraulic loading to determine the erosion rate after equal time intervals. The water depth, velocity are measured at each hydraulic loading, and the acting bed shear is calculated. A shallow water lidar (SWL) system was utilized to record the progress of soil erodibility and water depth along the scanned profiles of the tested box. SWL is a non-contact system that transmits laser pulses from above the water and records the time-delay between top and bottom reflections. Results from the SWL scans are compared with before and after manual measurements to determine the erosion rate of the soil mix and other erosion parameters.

Keywords: coarse-grained materials, erosion rate, LIDAR system, soil erosion

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Authors: Orathai Srithongtham, Ubonsri Thabuddha

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The youth with HIV positive is not difference from the general youth in term of sexual needs. Sexual health is crucial the most to support the youth with HIV positive to be sexual well-being. This study aims to elucidate the sexual health on protection from STDs (Sexual Transmitted Diseases) and HIV transmission and to explain sexual risk behavior of the youth with HIV positive. The target group was the youth with HIV positive about 23 cases from two provinces in northeastern part of Thailand. Qualitative method was applied for collecting data by in-depth interview. Content analysis was use for data analysis. The youth with HIV positive was protection from STDs and HIV transmission by using the condom during sexual activity. The reason to deny the condom use were ashamed, condom is not a part of life, no have fit size, and the youth fear to stigmatized as a mental disorder and fear to stigmatized as going to fuck someone. The youth who trust with nurse in clinic was dare to request the condom by face. Sexual activity without condom use is sexual risk behavior. The major causes were couple trust and the sexual enjoyment first and sexual active competition with friend without condom use. The concern on HIV was the boyfriend or girlfriend not accepts the HIV positive people, worry about the HIV transmutation, and finally not compliance to ARV drug. The youth with HIV positive was lacking of the knowledge on sexual health on the issues of access to condom and the concern to keep on relationship with the boyfriend or girlfriend. This concern issues was led to the non-adherence of ARV drug and HIV distribution. To provide the sexual health service is more essential to the youth with HIV positive.

Keywords: sexual health, sexual risk behavior, youth, HIV

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Authors: Jannes Quer, Amir Niknejad, Marcus Weber

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Computational Drug Design is often based on Molecular Dynamics simulations of molecular systems. Molecular Dynamics can be used to simulate, e.g., the binding and unbinding event of a small drug-like molecule with regard to the active site of an enzyme or a receptor. However, the time-scale of the overall binding event is many orders of magnitude longer than the time-scale of simulation. Thus, there is a need to speed-up molecular simulations. In order to speed up simulations, the molecular dynamics trajectories have to be ”steared” out of local minimizers of the potential energy surface – the so-called metastabilities – of the molecular system. Increasing the kinetic energy (temperature) is one possibility to accelerate simulated processes. However, with temperature the entropy of the molecular system increases, too. But this kind ”stearing” is not directed enough to stear the molecule out of the minimum toward the saddle point. In this article, we give a new mathematical idea, how a potential energy surface can be changed in such a way, that entropy is kept under control while the trajectories are still steared out of the metastabilities. In order to compute the unsteared transition behaviour based on a steared simulation, we propose to use extrapolation methods. In the end we mathematically show, that our method accelerates the simulations along the direction, in which the curvature of the potential energy surface changes the most, i.e., from local minimizers towards saddle points.

Keywords: extrapolation, Eyring-Kramers, metastability, multilevel sampling

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Authors: Kittitara Chunlakittiphan, Patompong Satapornpong

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Introduction: The variation of genetics affects how our body responds to pharmaceuticals elucidates the correlation between long-term use of medical cannabis and adverse drug reactions (ADRs). Medical cannabis is regarded as the treatment for chronic pain, cancer pain, acute pain, psychological disorders, multiple sclerosis and migraine management. However, previous studies have shown that delta-9-Tetrahydrocannabinol (THC), an ingredient found in cannabis, was the cause of ADRs in CB1 receptors found in humans. Previous research suggests that distributions of the cannabinoid type 1 (CB1) receptor gene and pharmacogenetic markers, which vary amongst different populations, might affect incidences of ADRs. Although there is an evident need to investigate the level of the CB1 receptor gene (rs806365), studies on the distribution of CB1-pharmacogenetics markers in Thai patients are limited. Objective: Therefore, the aim of this study is to investigate the distribution of the rs806365 polymorphism in Thai patients who have been treated with medical cannabis. Materials and Methods: We enrolled 31 Thai patients with THC-induced ADRs and 34 THC-tolerant controls to take part in this study. All patients with THC-induced ADRs were accessed through a review of medical records by physicians. EDTA blood of 3ml was collected to obtain the CNR1 gene (rs806365) and genotyping of this gene was conducted using the real-time PCR ViiA7 (ABI, Foster City, CA, USA) following the manufacturer’s instruction. Results: The sample consisted of 65 patients (40/61.54%) were females and (25/38.46%) were males, with an age range of 19-87 years, who have been treated with medical cannabis. In this study, the most common THC-induced ADRs were dry mouth and/or dry throat, tachycardia, nausea, and arrhythmia. Across the whole sample, we found that 52.31% of Thai patients carried a heterozygous variant (rs806365, CT allele). Moreover, the number of rs806365 (CC, homozygous variant) carriers totaled seventeen people (26.15%) amongst the subjects of Thai patients treated with medical cannabis. Furthermore, 17 out of 22 patients (77.27%) who experienced severe ADRs: Tachycardia and/or arrhythmia, carried an abnormal rs806365 gene (CT and CC alleles). Conclusions: The results propose that the rs806365 gene is widely distributed amongst the Thai population and there is a link between this gene and vulnerability to developing THC-induced ADRs after being treated with medical cannabis. Therefore, it is necessary to screen for the rs806365 gene before using medical cannabis to treat a patient.

Keywords: rs806365, THC-induced adverse drug reactions, CB1 receptor, Thai population

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Authors: Nabil Omar, Farah Jibril, Oraib Amjad

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Purpose: Trabecatine is a is a potent marine-derived antineoplastic drug which binds to the minor groove of the DNA, bending DNA towards the major groove resulting in a changed conformation that interferes with several DNA transcription factors, repair pathways and cell proliferation. Trabectedin was approved by the European Medicines Agency (EMA; London, UK) for the treatment of adult patients with advanced stage soft tissue sarcomas in whom treatment with anthracyclines and ifosfamide has failed, or for those who are not candidates for these therapies. The recommended dosing regimen is 1.5 mg/m2 IV over 24 hours every 3 weeks. The purpose of this study was to comprehensively review available data on the safety and efficacy of trabectedin used as indicated for patients at a Tertiary Cancer Center at Qatar. Methods: A medication administration report generated in the electronic health record identified all patients who received trabectedin between November 1, 2015 and November 1, 2017. This retrospective chart review evaluated the indication of trabectedin use, compliance to administration protocol and the recommended monitoring parameters, number of patients improved on the drug and continued treatment, number of patients discontinued treatment due to side-effects and the reported side effects. Progress and discharged notes were utilized to report experienced side effects during trabectedin therapy. A total of 3 patients were reviewed. Results: Total of 2 out of 3 patients who received trabectedin were receiving it for non-FDA and non-EMA, approved indications; metastatic rhabdomyosarcoma and ovarian cancer stage IV with poor prognosis. And only one patient received it as indicated for leiomyosarcoma of left ureter with metastases to liver, lungs and bone. None of the patients has continued the therapy due to development of serious side effects. One patient had stopped the medication after one cycle due to disease progression and transient hepatic toxicity, the other one had disease progression and developed 12 % reduction in LVEF after 12 cycles of trabectedin, and the third patient deceased, had disease progression on trabectedin after the 10th cycle that was received through peripheral line which resulted in developing extravasation and left arm cellulitis requiring debridement. Regarding monitoring parameters, at baseline the three patients had ECHO, and Creatine Phosphokinase (CPK) but it was not monitored during treatment as recommended. Conclusion: Utilizing this medication as indicated with performing the appropriate monitoring parameters as recommended can benefit patients who are receiving it. It is important to reinforce the intravenous administration via central intravenous line, the re-assessment of left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan at 2- to 3-month intervals thereafter until therapy is discontinued, and CPK and LFTs levels prior to each administration of trabectedin.

Keywords: trabectedin, drug-use evaluation, safety, effectiveness, adverse drug reaction, monitoring

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Authors: Jake Tempo, Taylor Smithurst, Jen Leah, Skye Waddingham, Amanda Catlin, Richard Cetti

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Introduction: Percutaneous nephrolithotomy (PCNL) is the gold-standard procedure for removing large or complex renal stones. Many operating positions can be used, and the debate over the ideal position continues. PCNL can be a long procedure during which patients can sustain pressure injuries. These injuries are often underreported in the literature. Interface pressure mapping records the pressure loading between a surface and the patient. High pressures with prolonged loading result in ischaemia, muscle deformation, and reperfusion which can cause skin breakdown and muscular injury. We compared the peak pressure indexes of common PCNL positions to identify positions which may be at high risk of pressure injuries. We hope the data can be used to adapt high-risk positions so that the PPI can be lessened by either adapting the positions or by using adjuncts to lower PPI. Materials and Methods: We placed a 23-year-old male subject in fourteen different PCNL positions while performing interface pressure mapping. The subject was 179 cm with a weight of 63.3 kg, BMI 19.8kg/m². Results: Supine positions had a higher mean PPI (119mmHg (41-137)) compared to prone positions (64mmHg (32-89)) (p=0.046 two tailed t-test). The supine flexed position with a bolster under the flank produced the highest PPI (194mmHg), and this was at the sacrum. Peak pressure indexes >100mmHg were recorded in eight PCNL positions. Conclusion: Supine PCNL positions produce higher PPI than prone PCNL positions. Our study shows where ‘at risk’ bony prominences are for each PCNL position. Surgeons must ensure these areas are protected during prolonged operations.

Keywords: PCNL, pressure ulcer, interface pressure mapping, surgery

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Authors: Auni Idi Muhire

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Background: Prior to April 2012, resuscitations were often ineffective resulting in poor patient outcomes. An initiative was implemented at Rwanda Military Hospital (RMH) to review root causes and plan strategies to improve patient outcomes. An interdisciplinary committee was developed to review this problem. Purpose: Analyze the frequency, obstacles, and outcome of patient resuscitation following cardiac and/or respiratory arrest. Methods: A form was developed to allow recording of all actions taken during resuscitation including response times, staff present, and equipment and medications used. Results:-The patient population requiring the most resuscitation effort are the intensive care patients, most frequently the neonatal the intensive care patients (42.8%) -Despite having trained staff representatives, not all resuscitations follow protocol -Lack of compliance with drug administration guidelines was noted, particularly in initiating use of drugs despite the drug being available (59%). Lesson Learned: Basic Life Support training for interdisciplinary staff resulted in more effective response to cardiac and/or respiratory arrest at RMH. Obstacles to effective resuscitation included number of staff, knowledge and skill level of staff, availability of appropriate equipment and medications, staff communication, and patient Do not Attempt Resuscitation (DNR) status.

Keywords: resuscitation, case analysis of knowledge versus practice, intensive care, critical care

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Authors: Wei Jun, Liao Hualin, Wang Huajian, Chen Jingkai, Liang Hongjun, Liu Chuanfu

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Kuqa Piedmont is rich in oil and gas resources and has great development potential in Tarim Basin, China. However, there is a huge thick gravel layer developed with high content, wide distribution and variation in size of gravel, leading to the condition of strong heterogeneity. So that, the drill string is in a state of severe vibration and the drill bit is worn seriously while drilling, which greatly reduces the rock-breaking efficiency, and there is a complex load state of impact and three-dimensional in-situ stress acting on the rock in the bottom hole. The dynamic mechanical properties and the influencing factors of conglomerate, the main component of gravel layer, are the basis of engineering design and efficient rock breaking method and theoretical research. Limited by the previously experimental technique, there are few works published yet about conglomerate, especially rare in dynamic load. Based on this, a kind of 3D SHPB system, three-dimensional prestress, can be applied to simulate the in-situ stress characteristics, is adopted for the dynamic test of the conglomerate. The results show that the dynamic strength is higher than its static strength obviously, and while the three-dimensional prestress is 0 and the loading strain rate is 81.25~228.42 s-1, the true triaxial equivalent strength is 167.17~199.87 MPa, and the strong growth factor of dynamic and static is 1.61~1.92. And the higher the impact velocity, the greater the loading strain rate, the higher the dynamic strength and the greater the failure strain, which all increase linearly. There is a critical prestress in the impact direction and its vertical direction. In the impact direction, while the prestress is less than the critical one, the dynamic strength and the loading strain rate increase linearly; otherwise, the strength decreases slightly and the strain rate decreases rapidly. In the vertical direction of impact load, the strength increases and the strain rate decreases linearly before the critical prestress, after that, oppositely. The dynamic strength of the conglomerate can be reduced properly by reducing the amplitude of impact load so that the service life of rock-breaking tools can be prolonged while drilling in the stratum rich in gravel. The research has important reference significance for the speed-increasing technology and theoretical research while drilling in gravel layer.

Keywords: huge thick gravel layer, conglomerate, 3D SHPB, dynamic strength, the deformation characteristics, prestress

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Authors: F. Pires, V. Geraldo, O. N. Oliveira Jr., M. Raposo

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Catechins are powerful antioxidants which have attractive properties useful for tumor therapy. Considering their antioxidant activity, these molecules can act as a scavenger of the reactive oxygen species (ROS), alleviating the damage of cell membrane induced by oxidative stress. The complexity and dynamic nature of the cell membrane compromise the analysis of the biophysical interactions between drug and cell membrane and restricts the transport or uptake of the drug by intracellular targets. To avoid the cell membrane complexity, we used biomimetic systems as liposomes and Langmuir monolayers to study the interaction between catechin and membranes at the molecular level. Liposomes were formed after the dispersion of anionic 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)(sodium salt) (DPPG) phospholipids in an aqueous solution, which mimic the arrangement of lipids in natural cell membranes and allows the entrapment of catechins. Langmuir monolayers were formed after dropping amphiphilic molecules, DPPG phospholipids, dissolved in an organic solvent onto the water surface. In this work, we mixed epigallocatechin-3-gallate (EGCG) with DPPG liposomes and exposed them to ultra-violet radiation in order to evaluate the antioxidant potential of these molecules against oxidative stress induced by radiation. The presence of EGCG in the mixture decreased the rate of lipid peroxidation, proving that EGCG protects membranes through the quenching of the reactive oxygen species. Considering the high amount of hydroxyl groups (OH groups) on structure of EGCG, a possible mechanism to these molecules interact with membrane is through hydrogen bonding. We also investigated the effect of EGCG at various concentrations on DPPG Langmuir monolayers. The surface pressure isotherms and infrared reflection-absorption spectroscopy (PM-IRRAS) results corroborate with absorbance results preformed on liposome-model, showing that EGCG interacts with polar heads of the monolayers. This study elucidates the physiological action of EGCG which can be incorporated in lipid membrane. These results are also relevant for the improvement of the current protocols used to incorporate catechins in drug delivery systems.

Keywords: catechins, lipid membrane, anticancer agent, molecular interactions

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Authors: Dagmara Malina, Katarzyna Bialik-Wąs, Klaudia Pluta

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The growing significance of transdermal systems, in which skin is a route for systemic drug delivery, has generated a considerable amount of data which has resulted in a deeper understanding of the mechanisms of transport across the skin in the context of the controlled and prolonged release of active substances. One of such solutions may be the use of carrier systems based on intelligent polymers with different physicochemical properties. In these systems, active substances, e.g. drugs, can be conjugated (attached), immobilized, or encapsulated in a polymer matrix that is sensitive to specific environmental conditions (e.g. pH or temperature changes). Intelligent polymers can be divided according to their sensitivity to specific environmental stimuli such as temperature, pH, light, electric, magnetic, sound, or electromagnetic fields. Materials & methods—The first stage of the presented research concerned the synthesis of pH-sensitive polymeric carriers by a radical polymerization reaction. Then, the selected active substance (hydrocortisone) was introduced into polymeric carriers. In a further stage, bio-hybrid sodium alginate/poly(vinyl alcohol) – SA/PVA-based hydrogel matrices modified with various carrier-drug systems were prepared with the chemical cross-linking method. The conducted research included the assessment of physicochemical properties of obtained materials i.e. degree of hydrogel swelling and degradation studies as a function of pH in distilled water and phosphate-buffered saline (PBS) at 37°C in time. The gel fraction represents the insoluble gel fraction as a result of inter-molecule cross-linking formation was also measured. Additionally, the chemical structure of obtained hydrogels was confirmed using FT-IR spectroscopic technique. The dynamic light scattering (DLS) technique was used for the analysis of the average particle size of polymer-carriers and carrier-drug systems. The nanocarriers morphology was observed using SEM microscopy. Results & Discussion—The analysis of the encapsulated polymeric carriers showed that it was possible to obtain the time-stable empty pH-sensitive carrier with an average size 479 nm and the encapsulated system containing hydrocortisone with an average 543 nm, which was introduced into hydrogel structure. Bio-hybrid hydrogel matrices are stable materials, and the presence of an additional component: pH-sensitive carrier – hydrocortisone system, does not reduce the degree of cross-linking of the matrix nor its swelling ability. Moreover, the results of swelling tests indicate that systems containing higher concentrations of the drug have a slightly higher sorption capacity in each of the media used. All analyzed materials show stable and statically changing swelling values in simulated body fluids - there is no sudden fluid uptake and no rapid release from the material. The analysis of FT-IR spectra confirms the chemical structure of the obtained bio-hybrid hydrogel matrices. In the case of modifications with a pH-sensitive carrier, a much more intense band can be observed in the 3200-3500 cm⁻¹ range, which most likely originates from the strong hydrogen interactions that occur between individual components.

Keywords: hydrogels, polymer nanocarriers, sodium alginate/poly(vinyl alcohol) matrices, wound dressings.

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Authors: Aniket Kumar, Jacob Peedicayil

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Major depressive disorder (MDD) is a common and important psychiatric disorder. Several clinical features of MDD suggest an epigenetic basis for its pathogenesis. Since epigenetics (heritable changes in gene expression not involving changes in DNA sequence) may underlie the pathogenesis of MDD, epigenetic drugs such as DNA methyltransferase inhibitors (DNMTi) and histone deactylase inhibitors (HDACi) may be useful for treating MDD. The available literature indexed in Pubmed on preclinical drug trials of epigenetic drugs for the treatment of MDD was investigated. The search terms we used were ‘depression’ or ‘depressive’ and ‘HDACi’ or ‘DNMTi’. Among epigenetic drugs, it was found that there were 3 preclinical trials using HDACi and 3 using DNMTi for the treatment of MDD. All the trials were conducted on rodents (mice or rats). The animal models of depression that were used were: learned helplessness-induced animal model, forced swim test, open field test, and the tail suspension test. One study used a genetic rat model of depression (the Flinders Sensitive Line). The HDACi that were tested were: sodium butyrate, compound 60 (Cpd-60), and valproic acid. The DNMTi that were tested were: 5-azacytidine and decitabine. Among the three preclinical trials using HDACi, all showed an antidepressant effect in animal models of depression. Among the 3 preclinical trials using DNMTi also, all showed an antidepressant effect in animal models of depression. Thus, epigenetic drugs, namely, HDACi and DNMTi, may prove to be useful in the treatment of MDD and merit further investigation for the treatment of this disorder.

Keywords: DNA methylation, drug discovery, epigenetics, major depressive disorder

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Authors: Ravisinh Solanki, Ravi Patel, Chhaganbhai Patel

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Purpose: The purpose of this study is to develop a methodology for the risk assessment and evaluation of nitrosamine impurities in Glipizide antidiabetic formulations. Nitroso compounds, including nitrosamines, have emerged as significant concerns in drug products, as highlighted by the ICH M7 guidelines. This study aims to identify known and potential sources of nitrosamine impurities that may contaminate Glipizide formulations and assess their presence. By determining observed or predicted levels of these impurities and comparing them with regulatory guidance, this research will contribute to ensuring the safety and quality of combination antidiabetic drug products on the market. Factors contributing to the presence of genotoxic nitrosamine contaminants in glipizide medications, such as secondary and tertiary amines, and nitroso group-complex forming molecules, will be investigated. Additionally, conditions necessary for nitrosamine formation, including the presence of nitrosating agents, and acidic environments, will be examined to enhance understanding and mitigation strategies. Method: The methodology for the study involves the implementation of the N-Nitroso Acid Precursor (NAP) test, as recommended by the WHO in 1978 and detailed in the 1980 International Agency for Research on Cancer monograph. Individual glass vials containing equivalent to 10mM quantities of Glipizide is prepared. These compounds are dissolved in an acidic environment and supplemented with 40 mM NaNO2. The resulting solutions are maintained at a temperature of 37°C for a duration of 4 hours. For the analysis of the samples, an HPLC method is employed for fit-for-purpose separation. LC resolution is achieved using a step gradient on an Agilent Eclipse Plus C18 column (4.6 X 100 mm, 3.5µ). Mobile phases A and B consist of 0.1% v/v formic acid in water and acetonitrile, respectively, following a gradient mode program. The flow rate is set at 0.6 mL/min, and the column compartment temperature is maintained at 35°C. Detection is performed using a PDA detector within the wavelength range of 190-400 nm. To determine the exact mass of formed nitrosamine drug substance related impurities (NDSRIs), the HPLC method is transferred to LC-TQ-MS/MS with the same mobile phase composition and gradient program. The injection volume is set at 5 µL, and MS analysis is conducted in Electrospray Ionization (ESI) mode within the mass range of 100−1000 Daltons. Results: The samples of NAP test were prepared according to the protocol. The samples were analyzed using HPLC and LC-TQ-MS/MS identify possible NDSRIs generated in different formulations of glipizide. It was found that the NAP test generated a various NDSRIs. The new finding, which has not been reported yet, discovered contamination of Glipizide. These NDSRIs are categorised based on the predicted carcinogenic potency and recommended its acceptable intact in medicines. The analytical method was found specific and reproducible.

Keywords: NDSRI, nitrosamine impurities, antidiabetic, glipizide, LC-MS/MS

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Authors: Emma R. Arakelova, Stepan G. Grigoryan, Flora G. Arsenyan, Nelli S. Babayan, Ruzanna M. Grigoryan, Natalia K. Sarkisyan

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Novel nanosize zinc oxide composites of doxorubicin obtained by deposition of 180 nm thick zinc oxide film on the drug surface using DC-magnetron sputtering of a zinc target in the form of gels (PEO+Dox+ZnO and Starch+NaCMC+Dox+ZnO) were studied for drug delivery applications. The cancer specificity was revealed both in in vitro and in vivo models. The cytotoxicity of the test compounds was analyzed against human cancer (HeLa) and normal (MRC5) cell lines using MTT colorimetric cell viability assay. IC50 values were determined and compared to reveal the cancer specificity of the test samples. The mechanistic study of the most active compound was investigated using Flow cytometry analyzing of the DNA content after PI (propidium iodide) staining. Data were analyzed with Tree Star FlowJo software using cell cycle analysis Dean-Jett-Fox module. The in vivo anticancer activity estimation experiments were carried out on mice with inoculated ascitic Ehrlich’s carcinoma at intraperitoneal introduction of doxorubicin and its zinc oxide compositions. It was shown that the nanosize zinc oxide film deposition on the drug surface leads to the selective anticancer activity of composites at the cellular level with the range of selectivity index (SI) from 4 (Starch+NaCMC+Dox+ZnO) to 200 (PEO(gel)+Dox+ZnO) which is higher than that of free Dox (SI = 56). The significant increase in vivo antitumor activity (by a factor of 2-2.5) and decrease of general toxicity of zinc oxide compositions of doxorubicin in the form of the above mentioned gels compared to free doxorubicin were shown on the model of inoculated Ehrlich's ascitic carcinoma. Mechanistic studies of anticancer activity revealed the cytostatic effect based on the high level of DNA biosynthesis inhibition at considerable low concentrations of zinc oxide compositions of doxorubicin. The results of studies in vitro and in vivo behavior of PEO+Dox+ZnO and Starch+NaCMC+Dox+ZnO composites confirm the high potential of the nanosize zinc oxide composites as a vector delivery system for future application in cancer chemotherapy.

Keywords: anticancer activity, cancer specificity, doxorubicin, zinc oxide

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Authors: Deepak Mohan, Sushma Sharma, Mohammad Asif

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Diclofenac sodium being one of the most common non-steroidal anti-inflammatory drugs is normally used as painkiller and to reduce inflammation. The drug is known to alter the enzymatic activities of acid and alkaline phosphatase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminases. The drug also results in change in the concentration of proteins and lipids in the body. The present study is an attempt to study different biochemical changes electrophoretically due to administration of different doses of diclofenac (4mg/kg/body weight and 14mg/kg/body weight) on liver and testes of mice from 7-28 days of investigation. Homogenization of the tissue was done, supernatant separated was loaded in the gel and native polyacrylamide gel electrophoresis was conducted. Diclofenac administration resulted in alterations of all these biochemical parameters which were observed in native polyacrylamide gel electrophoretic studies. The severe degenerative changes as observed during later stages of the experiment showed correlation with increase or decrease in the activities of all the enzymes studied in the present investigation. Image analysis of gel in liver showed a decline of 7.4 and 5.3 % in low and high dose group after 7 days whereas a decline of 9.6 and 7.5% was registered after 28 days of investigation. Similar analysis for testis also showed an appreciable decline in the activity of alkaline phosphatase after 28 days. Gel analysis of serum was also performed to find a correlation in the enzymatic activities between the tissue and blood.

Keywords: diclofenac, inflammation, polyacrylamide, phosphatase

Procedia PDF Downloads 152

Authors: Eun Mi Ryu, Ah Young An, Ji Yeon Kang, Yeong Soo Shin, Hee Sun Kim

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As the number of fire incidents has been increased, fire incidents significantly damage economy and human lives. Especially when high strength reinforced concrete is exposed to high temperature due to a fire, deterioration occurs such as loss in strength and elastic modulus, cracking, and spalling of the concrete. Therefore, it is important to understand risk of structural safety in building structures by studying structural behaviors and rehabilitation of fire damaged high strength concrete structures. This paper aims at investigating rehabilitation effect on fire damaged high strength concrete beams using experimental and analytical methods. In the experiments, flexural specimens with high strength concrete are exposed to high temperatures according to ISO 834 standard time temperature curve. After heated, the fire damaged reinforced concrete (RC) beams having different cover thicknesses and fire exposure time periods are rehabilitated by removing damaged part of cover thickness and filling polymeric mortar into the removed part. From four-point loading test, results show that maximum loads of the rehabilitated RC beams are 1.8~20.9% higher than those of the non-fire damaged RC beam. On the other hand, ductility ratios of the rehabilitated RC beams are decreased than that of the non-fire damaged RC beam. In addition, structural analyses are performed using ABAQUS 6.10-3 with same conditions as experiments to provide accurate predictions on structural and mechanical behaviors of rehabilitated RC beams. For the rehabilitated RC beam models, integrated temperature–structural analyses are performed in advance to obtain geometries of the fire damaged RC beams. After spalled and damaged parts are removed, rehabilitated part is added to the damaged model with material properties of polymeric mortar. Three dimensional continuum brick elements are used for both temperature and structural analyses. The same loading and boundary conditions as experiments are implemented to the rehabilitated beam models and nonlinear geometrical analyses are performed. Structural analytical results show good rehabilitation effects, when the result predicted from the rehabilitated models are compared to structural behaviors of the non-damaged RC beams. In this study, fire damaged high strength concrete beams are rehabilitated using polymeric mortar. From four point loading tests, it is found that such rehabilitation is able to make the structural performance of fire damaged beams similar to non-damaged RC beams. The predictions from the finite element models show good agreements with the experimental results and the modeling approaches can be used to investigate applicability of various rehabilitation methods for further study.

Keywords: fire, high strength concrete, rehabilitation, reinforced concrete beam

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Authors: Shabnum Shaheen, Nida Haroon, Farah Khan, Sumera Javad, Mehreen Jalal, Samina Sarwar

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Coffee Senna is pharmaceutically very important and used for multiple health disorders such as gastric pains, indigestion, snakebites, asthma and fever, tuberculosis and menstrual problems. However, its immense medicinal value and great demand lead to adulteration issue which could be injurious for users. Some times its adulterant Seena weed (Senna occidentalis L.) is used as its substitute which definitely not as effective as Coffee Senna. Hence, the present study was undertaken to provide some tools for systematic and pharmaceutical authentication of a shrubby plant Coffee Senna (Cassia occidentalis Linn.). These parameters included macro and micro morphological characters, anatomical and palynomorph characterization, solubility, fluorescence and phytochemical analysis. By the application of these parameters acquired results revealed that, these two plants are distinct from each other. The Coffee Seena was found to be an annual shrub with trilobed pollen, diacytic, paracytic and anisocytic stomata whereas the Seena weed stands out as an annual or perennial herb with spheroidal and circular pollen and paracytic type of stomata. The powdered drug of Coffee seena is dark grayish green whereas the powdered drug of Seena weed is light green in color. These findings are constructive in authentic identification of these plants.

Keywords: coffee senna, Senna weed, taxonomic evaluation, pharmaceutical markers

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Authors: Roy Y. C. Huang, J. S. Kuang, Hamdolah Behnam

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Beam-column connections play an important role in the reinforced concrete moment resisting frame (RCMRF), which is one of the most commonly used structural systems around the world. The premature failure of such connections would severely limit the seismic performance and increase the vulnerability of RCMRF. In the past decades, researchers primarily focused on investigating the structural behaviour and failure mechanisms of conventional beam-column joints, the beam width of which is either smaller than or equal to the column width, while studies in wide beam-column joints were scarce. This paper presents the preliminary experimental results of two full-scale exterior wide beam-column connections, which are mainly designed and detailed according to ACI 318-14 and ACI 352R-02, under reversed cyclic loading. The ratios of the design shear force to the nominal shear strength of these specimens are 1.0 and 1.7, respectively, so as to probe into differences of the joint shear strength between experimental results and predictions by design codes of practice. Flexural failure dominated in the specimen with ratio of 1.0 in which full-width plastic hinges were observed, while both beam hinges and post-peak joint shear failure occurred for the other specimen. No sign of premature joint shear failure was found which is inconsistent with ACI codes’ prediction. Finally, a modification of current codes of practice is provided to accurately predict the joint shear strength in wide beam-column joint.

Keywords: joint shear strength, reversed cyclic loading, seismic vulnerability, wide beam-column joints

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Authors: Esmaeil Asadzadeh, Mehtab Alam

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Well documented records of the past failures of the structures reveals that the progressive collapse of structures is one of the major reasons for dramatic human loss and economical consequences. Progressive collapse is the failure mechanism in which the structure fails gradually due to the sudden removal of the structural elements. The sudden removal of some structural elements results in the excessive redistributed loads on the others. This sudden removal may be caused by any sudden loading resulted from local explosion, impact loading and terrorist attacks. Hyperbolic thin walled concrete shell structures being an important part of nuclear and thermal power plants are always prone to such terrorist attacks. In concrete structures, the gradual failure would take place by generation of initial cracks and its propagation in the supporting columns along with the tower shell leading to the collapse of the entire structure. In this study the mechanism of progressive collapse for such high raised towers would be simulated employing the finite element method. The aim of this study would be providing clear conceptual step-by-step descriptions of various procedures for progressive collapse analysis using commercially available finite element structural analysis software’s, with the aim that the explanations would be clear enough that they will be readily understandable and will be used by practicing engineers. The study would be carried out in the following procedures: 1. Provide explanations of modeling, simulation and analysis procedures including input screen snapshots; 2. Interpretation of the results and discussions; 3. Conclusions and recommendations.

Keywords: progressive collapse, cooling towers, finite element analysis, crack generation, reinforced concrete

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Authors: Shenghong Huang, Weirong Wang, Xisheng Luo, Xinzhu Li, Xinwen Zhao

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Understanding of material mixing induced by Richtmyer-Meshkov instability (RMI) at extreme shock compressing conditions (high energy density environment: P >> 100GPa, T >> 10000k) is of great significance in engineering and science, such as inertial confinement fusion(ICF), supersonic combustion, etc. Turbulent mixing induced by RMI is a kind of complex fluid dynamics, which is closely related with hydrodynamic conditions, thermodynamic states, material physical properties such as compressibility, strength, surface tension and viscosity, etc. as well as initial perturbation on interface. For phenomena in ordinary thermodynamic conditions (low energy density environment), many investigations have been conducted and many progresses have been reported, while for mixing in extreme thermodynamic conditions, the evolution may be very different due to ionization as well as large difference of material physical properties, which is full of scientific problems and academic interests. In this investigation, the first principle based molecular dynamic method is applied to study metal Lithium and gas Hydrogen (Li-H2) interface mixing in micro/meso scale regime at different shock compressing loading speed ranging from 3 km/s to 30 km/s. It's found that, 1) Different from low-speed shock compressing cases, in high-speed shock compresing (>9km/s) cases, a strong acceleration of metal/gas interface after strong shock compression is observed numerically, leading to a strong phase inverse and spike growing with a relative larger linear rate. And more specially, the spike growing rate is observed to be increased with shock loading speed, presenting large discrepancy with available empirical RMI models; 2) Ionization is happened in shock font zone at high-speed loading cases(>9km/s). An additional local electric field induced by the inhomogeneous diffusion of electrons and nuclei after shock font is observed to occur near the metal/gas interface, leading to a large acceleration of nuclei in this zone; 3) In conclusion, the work of additional electric field contributes to a mechanism of RMI in micro/meso scale regime at extreme shock compressing conditions, i.e., a Rayleigh-Taylor instability(RTI) is induced by additional electric field during RMI mixing process and thus a larger linear growing rate of interface spike.

Keywords: ionization, micro/meso scale, material mixing, shock

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Authors: Shirin Jalili, Sadegh Hasannia, Hadi Shirzad, Afshin Khara

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Morphine is one of the most medicinally important analgesics and narcotics. Structurally, it is classified as an alkaloid because of the presence of nitrogen. Its structure is similar to that of codeine, thebaine, and heroin. An immunoassay to accurately discriminate between these analogous alkaloids would be highly beneficial. A key factor for such an assay is specificity with high sensitivity, which is totally dependent on the antibody employed. However, most antibodies against haptens are polyclonal serum antibodies that exhibit significant cross-reactivities with closely related compounds. The camel-derived single-chain antibody fragments (VHH) are the smallest molecules with antigen-binding capacity, possessing unique properties compared to other conventional antibodies. In this study, a library containing the VHH genes of a camel immunized with with morphine conjugated BSA following phage display technology was generated. By screening the camel-derived variable region of the heavy chain cDNA phage display library with the ability to bind the desired hapten, we obtained some nanobodies that recognize this hapten. Phage display expression of the Nbs from this library and pannings against this hapten resulted in a clear enrichment of four distinct Nb-displaying phages with specificity for morphine that could be a potential target site for the development of new strategies for the development of a biosensor for detecting illicit drug.

Keywords: phage display, nanobody, Morphine-3, glucuronide, ELISA, biosensor

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Authors: P. Selva, B. Lorraina, J. Alexis, A. Seror, A. Longuet, C. Mary, F. Denard

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Over the past four decades, the fatigue behavior of nickel-based alloys has been widely studied. However, in recent years, significant advances in the fabrication process leading to grain size reduction have been made in order to improve fatigue properties of aircraft turbine discs. Indeed, a change in particle size affects the initiation mode of fatigue cracks as well as the fatigue life of the material. The present study aims to investigate the fatigue behavior of a newly developed nickel-based superalloy under biaxial-planar loading. Low Cycle Fatigue (LCF) tests are performed at different stress ratios so as to study the influence of the multiaxial stress state on the fatigue life of the material. Full-field displacement and strain measurements as well as crack initiation detection are obtained using Digital Image Correlation (DIC) techniques. The aim of this presentation is first to provide an in-depth description of both the experimental set-up and protocol: the multiaxial testing machine, the specific design of the cruciform specimen and performances of the DIC code are introduced. Second, results for sixteen specimens related to different load ratios are presented. Crack detection, strain amplitude and number of cycles to crack initiation vs. triaxial stress ratio for each loading case are given. Third, from fractographic investigations by scanning electron microscopy it is found that the mechanism of fatigue crack initiation does not depend on the triaxial stress ratio and that most fatigue cracks initiate from subsurface carbides.

Keywords: cruciform specimen, multiaxial fatigue, nickel-based superalloy

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Authors: Neeraj Kumar, J. P. Narayan

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The effects of multiple Structure-Soil-Structure Interactions (SSSI) on the seismic wave-field is generally disregarded by earthquake engineers, particularly the surface waves which cause more damage to buildings. Closely built high rise buildings exchange substantial seismic energy with each other and act as a full-coupled dynamic system. In this paper, SSI effects on the building responses and the free field motion due to a small city consisting 25- homogenous buildings blocks of 10-storey are quantified. The rocking and translational behavior of building under Rayleigh wave loading is studied for different dimensions of the building. The obtained dynamic parameters of buildings revealed a reduction in building roof drift with an increase in number of buildings ahead of the considered building. The strain developed by vertical component of Rayleigh may cause tension in structural components of building. A matching of fundamental frequency of building for the horizontal component of Rayleigh wave with that for vertically incident SV-wave is obtained. Further, the fundamental frequency of building for the vertical vibration is approximately twice to that for horizontal vibration. The city insulation has caused a reduction of amplitude of Rayleigh wave up to 19.3% and 21.6% in the horizontal and vertical components, respectively just outside the city. Further, the insulating effect of city was very large at fundamental frequency of buildings for both the horizontal and vertical components. Therefore, it is recommended to consider the insulating effects of city falling in the path of Rayleigh wave propagation in seismic hazard assessment for an area.

Keywords: structure-soil-structure interactions, Rayleigh wave propagation, finite difference simulation, dynamic response of buildings

Procedia PDF Downloads 215

Authors: Zahid Manzoor, Shaukat Hussain Munawar, Zahid Iqbal, Imran Ahmad Khan, Abdul Aziz, Hafiz Muhammad Qasim

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The present study was aimed to investigate the pharmacokinetics behavior and optimal dosage regimen of danofloxacin in 8 adult healthy buffaloes of local breed (Nili Ravi) following single intravenous administration at the dose of 2.5 mg/kg body weight. Plasma drug concentrations at various time intervals were measured by HPLC method. In vitro plasma protein binding was determined employing the ultrafiltration technique. The distribution and elimination of danofloxacin was rapid, as indicated by the values (Mean±SD) of distribution half-life (t1/2α = 0.25±0.09 hours) and elimination half life (t1/2β = 3.26±0.43 hours), respectively. Volume of distribution at steady state (Vss) was 1.14±0.12 L/kg, displaying its extensive distribution into various body fluids and tissues. The high value of AUC (9.80±2.14 µg/ml.hr) reflected the vast area of the body covered by drug concentration. The mean residence time was noted to be 4.78±0.52 hours. On the basis of pharmacokinetic parameters, a suitable intravenous regimen for danofloxacin in adult buffaloes would be 6.5 mg/kg to be repeated after 12 hours intervals. The present study is the foremost pharmacokinetic study of danofloxacin in the local species which would provide the valueable contribution in the local manufacturing of danofloxacin in Pakistan in future.

Keywords: danofloxacin, pharmacokinetics, plasma protein binding, buffaloes, dosage regimen

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Authors: Samia A. El-Fiky, F. A. Abou-Zaid, Ibrahim M. Farag, Naira M. Efiky

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Clomipramine hydrochloride is one of the most used tricyclic antidepressant drug in Egypt. This drug contains in its chemical structure on two benzene rings. Benzene is considered to be toxic and clastogenic agent. So, the present study was designed to assess the genotoxic effect of Clomipramine hydrochloride on somatic and germ cells in mice. Three dose levels 0.195 (Low), 0.26 (Medium), and 0.65 (High) mg/kg.b.wt. were used. Seven groups of male mice were utilized in this work. The first group was employed as a control. In the remaining six groups, each of the above doses was orally administrated for two groups, one of them was treated for 5 days and the other group was given the same dose for 30 days. At the end of experiments, the animals were sacrificed for cytogenetic and sperm examination as well as histopathological investigations by using hematoxylin and eosin stains (H and E stains) and electron microscope. Concerning the sperm studies, these studies were confined to 5 days treatment with different dose levels. Moreover, the ultrastructural investigation by electron microscope was restricted to 30 days treatment with drug doses. The results of the dose dependent effect of Clomipramine showed that the treatment with three different doses induced increases of frequencies of chromosome aberrations in bone marrow and spermatocyte cells as compared to control. In addition, mitotic and meiotic activities of somatic and germ cells were declined. The treatments with medium or high doses were more effective for inducing significant increases of chromosome aberrations and significant decreases of cell divisions than treatment with low dose. The effect of high dose was more pronounced for causing such genetic deleterious in respect to effect of medium dose. Moreover, the results of the time dependent effect of Clomipramine observed that the treatment with different dose levels for 30 days led to significant increases of genetic aberrations than treatment for 5 days. Sperm examinations revealed that the treatment with Clomipramine at different dose levels caused significant increase of sperm shape abnormalities and significant decrease in sperm count as compared to control. The adverse effects on sperm shape and count were more obviousness by using the treatments with medium or high doses than those found in treatment with low dose. The group of mice treated with high dose had the highest rate of sperm shape abnormalities and the lowest proportion of sperm count as compared to mice received medium dose. In histopathological investigation, hematoxylin and eosin stains showed that, the using of low dose of Clomipramine for 5 or 30 days caused a little pathological changes in liver tissue. However, using medium and high doses for 5 or 30 days induced severe damages than that observed in mice treated with low dose. The treatment with high dose for 30 days gave the worst results of pathological changes in hepatic cells. Moreover, ultrastructure examination revealed, the mice treated with low dose of Clomipramine had little differences in liver histological architecture as compared to control group. These differences were confined to cytoplasmic inclusions. Whereas, prominent pathological changes in nuclei as well as dilated of rough Endoplasmic Reticulum (rER) were observed in mice treated with medium or high doses of Clomipramine drug. In conclusion, the present study adds evidence that treatments with medium or high doses of Clomipramine have genotoxic effects on somatic and germ cells of mice, as unwanted side effects. However, the using of low dose (especially for short time, 5 days) can be utilized as a therapeutic dose, where it caused relatively similar proportions of genetic, sperm, and histopathological changes as those found in normal control.

Keywords: clomipramine, mice, chromosome aberrations, sperm abnormalities, histopathology

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Authors: Vincent Iacobellis, Kamran Behdinan

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A finite element cohesive zone model is used to predict the temperature dependent material properties of a polyimide matrix composite with unidirectional carbon fiber arrangement. The cohesive zone parameters have been obtained from previous research involving an atomistic-to-continuum multiscale simulation of the fiber-matrix interface using the bridging cell multiscale method. The goal of the research was to both investigate the effect of temperature change on the composite behavior with respect to transverse loading as well as the validate the use of cohesive parameters obtained from atomistic-to-continuum multiscale modeling to predict fiber-matrix interfacial cracking. From the multiscale model cohesive zone parameters (i.e. maximum traction and energy of separation) were obtained by modeling the interface between the coarse-grained polyimide matrix and graphite based carbon fiber. The cohesive parameters from this simulation were used in a cohesive zone model of the composite microstructure in order to predict the properties of the macroscale composite with respect to changes in temperature ranging from 21 ˚C to 316 ˚C. Good agreement was found between the microscale RUC model and experimental results for stress-strain response, stiffness, and material strength at low and high temperatures. Examination of the deformation of the composite through localized crack initiation at the fiber-matrix interface also agreed with experimental observations of similar phenomena. Overall, the cohesive zone model was shown to be both effective at modeling the composite properties with respect to transverse loading as well as validated the use of cohesive zone parameters obtained from the multiscale simulation.

Keywords: cohesive zone model, fiber-matrix interface, microscale damage, multiscale modeling

Procedia PDF Downloads 487