Search results for: in-utero drug exposure

Authors: Papon Thamvasupong, Kwanchanok Viravaidya-Pasuwat

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Osteoarthritis affects a lot of people worldwide. Local injection of glucosamine is one of the alternative treatment methods to replenish the natural lubrication of cartilage. However, multiple injections can potentially lead to possible bacterial infection. Therefore, a drug delivery system is desired to reduce the frequencies of injections. A hydrogel is one of the delivery systems that can control the release of drugs. Thermo-reversible hydrogels can be beneficial to the drug delivery system especially in the local injection route because this formulation can change from liquid to gel after getting into human body. Once the gel is in the body, it will slowly release the drug in a controlled manner. In this study, various formulations of Pluronic-based hydrogels were synthesized for the controlled release of glucosamine. One of the challenges of the Pluronic controlled release system is its fast dissolution rate. To overcome this problem, alginate and calcium sulfate (CaSO₄) were added to the polymer solution. The characteristics of the hydrogels were investigated including the gelation temperature, gelation time, hydrogel dissolution and glucosamine release mechanism. Finally, a mathematical model of glucosamine release from Pluronic-alginate-hyaluronic acid hydrogel was developed. Our results have shown that crosslinking Pluronic gel with alginate did not significantly extend the dissolution rate of the gel. Moreover, the gel dissolution profiles and the glucosamine release mechanisms were best described using the zeroth-order kinetic model, indicating that the release of glucosamine was primarily governed by the gel dissolution.

Keywords: controlled release, drug delivery system, glucosamine, pluronic, thermoreversible hydrogel

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Authors: Abhay Asthana, Shally Toshkhani, Gyati Shilakari

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The present research was aimed to develop a biodegradable dermal patch formulation for wound healing in a novel, sustained and systematic manner. The goal is to reduce the frequency of dressings with improved drug delivery and thereby enhance therapeutic performance. In present study optimized formulation was designed using component polymers and excipients (e.g. Hydroxypropyl methyl cellulose, Ethylcellulose, and Gelatin) to impart significant folding endurance, elasticity and strength. Gelatin was used to get a mixture using ethylene glycol. Chitosan dissolved in suitable medium was mixed with stirring to gelatin mixture. With continued stirring to the mixture Curcumin was added in optimized ratio to get homogeneous dispersion. Polymers were dispersed with stirring in final formulation. The mixture was sonicated casted to get the film form. All steps were carried out under under strict aseptic conditions. The final formulation was a thin uniformly smooth textured film with dark brown-yellow color. The film was found to have folding endurance was around 20 to 21 times without a crack in an optimized formulation at RT (23C). The drug content was in range 96 to 102% and it passed the content uniform test. The final moisture content of the optimized formulation film was NMT 9.0%. The films passed stability study conducted at refrigerated conditions (4±0.2C) and at room temperature (23 ± 2C) for 30 days. Further, the drug content and texture remained undisturbed with stability study conducted at RT 23±2C for 45 and 90 days. Percentage cumulative drug release was found to be 80% in 12 h and matched the biodegradation rate as drug release with correlation factor R2 > 0.9. The film based formulation developed shows promising results in terms of stability and release profiles.

Keywords: biodegradable, patch, bioactive, polymer

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Authors: Sema Şenoğlu, Sevgi Karakuş

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Hydrazone scaffold is important to design new drug groups and is found to possess numerous uses in pharmaceutical chemistry. Besides, hydrazone derivatives are also known for biological activities such as anticancer, antimicrobial, antiviral, and antifungal. Hydrazone derivatives are promising anticancer agents because they inhibit cancer proliferation and induce apoptosis. Human carbonic anhydrase IX has a high potential to be an antiproliferative drug target, and targeting this protein is also important for obtaining potential anticancer inhibitors. The protein construct was retrieved as a PDB file from the RCSB protein database. This binding interaction of proteins and ligands was performed using Discovery Studio Visualizer. In vitro inhibitory activity of hydrazone derivatives was tested against enzyme carbonic anhydrase IX on the PyRx programme. Most of these molecules showed remarkable human carbonic anhydrase IX inhibitory activity compared to the acetazolamide. As a result, these compounds appear to be a potential target in drug design against human carbonic anhydrase IX.

Keywords: cancer, carbonic anhydrase IX enzyme, docking, hydrazone

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Authors: Junie B. Billones, Maria Constancia O. Carrillo, Voltaire G. Organo, Stephani Joy Y. Macalino, Inno A. Emnacen, Jamie Bernadette A. Sy

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One of the major interferences in the Philippines’ tuberculosis control program is the widespread prevalence of Mtb strains that are resistant to known drugs, such as the MDR-TB (Multi Drug Resistant Tuberculosis) and XDR-TB (Extensively Drug Resistant Tuberculosis). Therefore, there is a pressing need to search for novel Mtb drug targets in order to be able to combat these drug resistant strains. The enzyme 7,8-diaminopelargonic acid aminotransferase enzyme, or more commonly known as BioA, is one such ideal target, as it is known that humans do not possess this enzyme. BioA primarily plays a key role in Mtb’s lipid biosynthesis pathway; more specifically in the synthesis of the enzyme cofactor biotin. In this study, structure-based pharmacophore screening, docking, and ADMET evaluation of compounds obtained from the DrugBank chemical database were performed against the MtbBioA enzyme. Results of the screening, docking, ADMET, and TOPKAT calculations revealed that out of the 6,516 compounds in the library, only 7 compounds indicated more favorable binding energies as compared to the enzyme’s known inhibitor, amiclenomycin (ACM), as well as good solubility and toxicity properties. Moreover, out of these 7 compounds, Molecule 6 exhibited the best solubility and toxicity properties. In the future, these lead compounds may then be subjected to bioactivity assays in vitro or in vivo for further evaluation of its therapeutic efficacy.

Keywords: 7, 8-diaminopelargonic acid aminotransferase, BioA, pharmacophore, molecular docking, ADMET, TOPKAT

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Authors: Wessam H. Abd-Elsalam, Mona M. Saber, Samar M. Abouelatta

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Non-steroidal anti-inflammatory drugs (NSAIDs) are considered a double edged sword in inflammatory bowel diseases (IBDs). Some studies reported their advantageous effect in decreasing inflammation, and other studies reported that their use is associated with colitis aggravation. This study aimed to use specifically formulated trehalose-based nano-carriers that targets the colon in an attempt to alleviate inflammation caused by NSAIDs. L-α-phosphatidylcholine (PL), trehalose, and transcutol were used to prepare the trehalosomes (THs), which were also loaded with Tenoxicam(TXM) as a model NSAID. To optimize the formulation variables, a full 23 factorial design, using Design-Expert® software, was performed. The optimized formulation composed of trehalose: PL at a weight ratio of 1:1, 377.72 mg transcutol, and sonicated for 4 min, possessed a spherical shape with a size of 268.61 nm and EE% of 97.83% and released 70.22% of its drug content over 24 h. The superior protective action of TXM loaded THs compared to TXM suspension and drug-free THs was shown by the inhibition of the inflammatory biomarkers, namely; IL-1ß, IL-6, and TNF-alpha levels, as well as oxidative stress markers, measured as GSH and MDA. Improved histopathology of the colonic tissue in male New Zealand rabbits also confirmed the superiority of the TXM loaded THs compared to the unformulated drug or the drug free nano-carriers. Our findings highlight the prosperous role of THs in colon targeting and its anti-inflammatory characteristics in guarding against possible NSAIDs-driven exacerbation of colitis.

Keywords: inflammatory bowel disease, trehalose, trehalosomes, colon targeting

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Authors: Rudra Vaghela, P. K. Kulkarni

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The aim of the present research was to develop oral Amphotericin B (AmB) nanocrystals (Nc) grafted with suitable ligand in order to enhance drug transport across the intestinal epithelial barrier and subsequently, active uptake by macrophages. AmB Nc were prepared by liquid anti-solvent precipitation technique (LAS). Poloxamer 188 was used to stabilize the prepared AmB Nc and grafted with mannose for actively targeting M cells in Peyer’s patches. To prevent shedding of the stabilizer and ligand, N,N’-Dicyclohexylcarbodiimide (DCC) was used as a cross-linker. The prepared AmB Nc were characterized for particle size, PDI, zeta potential, X-ray diffraction (XRD) and surface morphology using scanning electron microscope (SEM) and evaluated for drug content, in vitro drug release and cell uptake studies using caco-2 cells. The particle size of stabilized AmB Nc grafted with WGA was in the range of 287-417 nm with negative zeta potential between -18 to -25 mV. XRD studies revealed crystalline nature of AmB Nc. SEM studies revealed that ungrafted AmB Nc were irregular in shape with rough surface whereas, grafted AmB Nc were found to be rod-shaped with smooth surface. In vitro drug release of AmB Nc was found to be 86% at the end of one hour. Cellular studies revealed higher invasion and uptake of AmB Nc towards caco-2 cell membrane when compared to ungrafted AmB Nc. Our findings emphasize scope on developing oral delivery system for passively targeting M cells in Peyer’s patches.

Keywords: leishmaniasis, amphotericin b nanocrystals, macrophage targeting, LAS technique

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Authors: Anam Naveed, Asma Andleeb, Mehreen Sirshar

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In the article, Image processing techniques have been applied on cardiac images for enhancing the image quality. Two types of methodologies considers for survey, invasive techniques and non-invasive techniques. Different image processes for improvement of cardiac image quality and reduce the amount of radiation exposure for invasive techniques are explored. Different image processing algorithms for enhancing the noninvasive cardiac image qualities are described. Beside these two methodologies, third methodology has applied on live streaming of heart rate on ECG window for extracting necessary information, removing noise and enhancing quality. Sensitivity analyses have been carried out to investigate the impacts of cardiac images for diagnosis of cardiac arteries disease and how the enhancement on images will help the cardiologist to diagnoses disease. The paper evaluates strengths and weaknesses of different techniques applied for improved the image quality and draw a conclusion. Some specific limitations must be considered for whole survey, like the patient heart beat must be 70-75 beats/minute while doing the angiography, similarly patient weight and exposure radiation amount has some limitation.

Keywords: cardiac images, CT angiography, critical analysis, exposure radiation, invasive techniques, invasive techniques, non-invasive techniques

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Authors: Dolly Gadhiya, Jayvadan Patel, Mihir Raval

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Lercanidipine hydrochloride is a calcium channel blockers used for treating angina pectoris and hypertension. Lercanidipine is a BCS Class II drug having poor aqueous solubility. Absolute bioavailability of Lercanidipine is very low and the main reason ascribed for this is poor aqueous solubility of the drug. Design and formulatation of nanocrystals by media milling method was main focus of this study. In this present study preliminary optimization was carried out with one factor at a time (OFAT) approach. For this different parameters like size of milling beads, amount of zirconium beads, types of stabilizer, concentrations of stabilizer, concentrations of drug, stirring speeds and milling time were optimized on the basis of particle size, polydispersity index and zeta potential. From the OFAT model different levels for above parameters selected for Plackett - Burman Design (PBD). Plackett-Burman design having 13 runs involving 6 independent variables was carried out at higher and lower level. Based on statistical analysis of PBD it was found that concentration of stabilizer, concentration of drug and stirring speed have significant impact on particle size, PDI, zeta potential value and saturation solubility. These experimental designs for preparation of nanocrystals were applied successfully which shows increase in aqueous solubility and dissolution rate of Lercanidipine hydrochloride.

Keywords: Lercanidipine hydrochloride, nanocrystals, OFAT, Plackett Burman

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Authors: Ana Caroline Ibrahim Lino, Denise Bomtempo Birche de Carvalho

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The background of this research is the international process of control and monitoring of illicit psychoactive substances that has commenced in the early 20th century. This process was intensified with the UN Single Convention on Narcotic Drugs of 1961 and had its culmination in the 1970s with the "War on drugs", a doctrine undertaken by the United States of America. Since then, the phenomenon of drug prohibition has been pushing debates around alternatives of public policies to confront their consequences at a global level and in the specific context of Latin America. Previous research has answered the following key questions: a) With what characteristics and models has the international illicit drug control system consolidated in Latin America with the creation of the Organization of American States (OAS) and the Inter-American Drug Abuse Control Commission (CICAD)? b) What drug policies and programs were determined as guidelines for the member states by the OAS and CICAD? The present paper mainly addresses the analysis of the drug strategies developed by the OAS/CICAD for the Americas from 2004 to 2016. The primary sources have been extracted from the OAS/CICAD documents and reports, listed on the Internet sites of these organizations. Secondary sources refer to bibliographic research on the subject with the following descriptors: illicit drugs, public policies, international organizations, OAS, CICAD, and reducing the demand and supply of illicit drugs. The "content analysis" technique was used to organize the collected material and to choose the axes of analysis. The results show that the policies, strategies, and action plans for Latin America had been focused on anti-drug actions since the creation of the Commission until 2010. The discourses and policies to reduce drug demand and supply were of great importance for solving the problem. However, the real focus was on eliminating the substances by controlling the production, marketing, and distribution of illicit drugs. Little attention was given to the users and their families. The research is of great relevance to the Social Work. The guidelines and parameters of the Social Worker's profession are in line with the need for social, ethical, and political strengthening of any dimension that guarantees the rights of users of psychoactive substances. In addition, it contributed to the understanding of the political, economic, social, and cultural factors that structure the prohibitionism, whose matrix anchors the deprivation of rights and violence.

Keywords: illicit drug policies, international organizations, latin America, prohibitionism, reduce the demand and supply of illicit drugs

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Authors: Jacky Bhagat, Baban S Ingole

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In this study, in vivo experiments were carried out to investigate the effects of a toxic polycyclic aromatic hydrocarbon (PAH), benzo(k)fluoranthene (B[k]F), on marine gastropod, Morula granulata collected from Goa, west coast of India. Snails were exposed to different concentrations of B(k)F (1, 10, 25 and 50 µg/L) for 96 h. The genotoxic effects were evaluated by measuring DNA strand breaks using alkaline comet assay and oxidative stress were measured with the help of battery of biomarkers such as superoxide dismutase (SOD) catalase (CAT), glutathione-s-transferase (GST), and lipid peroxidation (LPO). Concentration-dependent increase in percentage tail DNA (TDNA) was observed in snails exposed to B(k)F. Exposure concentrations above 1 µg/L of B(k)F, showed significant increase in SOD activity and LPO value in snails. After 96 h, SOD activity were found to be doubled for 50 µg/L of B(k)F with reference to control. Significant increase in CAT and GST activity was observed at all exposure conditions at the end of the exposure time. Our study showed that B(k)F induces oxidative stress in snails which further lead to genotoxic damage.

Keywords: benzo(k)fluoranthene, comet assay, gastropod, oxidative stress

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Authors: Meng-Ying Chiu, Yu-Fang Huang, Pei-Wei Wang, Yi-Ru Wang, Yi-Shuan Shao, Mei-Lien Chen

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Background: Organophosphate pesticides (OPs) are the most heavily used pesticides in agriculture in Taiwan. Therefore, they are commonly detected in general public including pregnant women and children. These compounds are proven endocrine disrupters that may affect the neural development in humans. The aim of this study is to assess the OPs exposure of children in 2 years of age and to examine the association between the exposure concentrations and neurodevelopmental effects in children. Methods: In a prospective cohort of 280 mother-child pairs, urine samples of prenatal and postnatal were collected from each participant and analyzed for metabolites of OPs by using gas chromatography-mass spectrometry. Six analytes were measured including dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP), and diethyldithiophosphate (DEDTP). This study created a combined concentration measure for dimethyl compounds (DMs) consisting of the three dimethyl metabolites (DMP, DMTP, and DMDTP), for diethyl compounds (DEs) consisting of the three diethyl metabolites (DEP, DETP, and DEDTP) and six dialkyl phosphate (DAPs). The Bayley Scales of Infant and Toddler Development (Bayley-III) was used to assess children's cognitive behavior at 2 years old. The association between OPs exposure and Bayley-III scale score was determined by using the Mann-Whitney U test. Results: The measurements of urine samples are still on-going. This preliminary data are the report of 56 children aged 2 from the cohort. The detection rates for DMP, DMTP, DMDTP, DEP, DETP, and DEDTP are 80.4%, 69.6%, 64.3%, 64.3%, 62.5%, and 75%, respectively. After adjusting the creatinine concentrations of urine, the median (nmol/g creatinine) of urinary DMP, DMTP, DMDTP, DEP, DETP, DEDTP, DMs, DEs, and DAPs are 153.14, 53.32, 52.13, 19.24, 141.65, 192.17, 308.8, 311.6, and 702.11, respectively. The concentrations of urine are considerably higher than that in other countries. Children’s cognitive behavior was used three scales for Bayley-III, including cognitive, language and motor. In Mann-Whitney U test, the higher levels of DEs had significantly lower motor score (p=0.037), but no significant association was found between the OPs exposure levels and the score of either cognitive or language. Conclusion: The limited sample size suggests that Taipei children are commonly exposed to OPs and OPs exposure might affect the cognitive behavior of young children. This report will present more data to verify the results. The predictors of OPs concentrations, such as dietary pattern will also be included.

Keywords: biomonitoring, children, neurodevelopment, organophosphate pesticides exposure

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Authors: Begum Rokeya, Rahelee Zinnat, Fatema Jebunnesa, Israt Ara Hossain, A. Rahman

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Background and Aims: Arsenic in drinking water is a global environmental health problem, and the exposure may increase dyslipidemia and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of lipid metabolism, atherosclerosis formation, arsenic exposure and impact in pregnancy is still unclear. Recent epidemiological evidences indicate close association between inorganic arsenic exposure via drinking water and Dyslipidemia. However, the exact mechanism of this arsenic-mediated increase in atherosclerosis risk factors remains enigmatic. We explore the association of the effect of arsenic on serum lipid profile in pregnant subjects. Methods: A total 200 pregnant mother screened in this study from arsenic exposed area. Our study group included 100 exposed subjects were cases and 100 Non exposed healthy pregnant were controls requited by a cross-sectional study. Clinical and anthropometric measurements were done by standard techniques. Lipidemic status was assessed by enzymatic endpoint method. Urinary As was measured by inductively coupled plasma-mass spectrometry and adjusted with specific gravity and Arsenic exposure was assessed by the level of urinary arsenic level > 100 μg/L was categorized as arsenic exposed and < 100 μg/L were categorized as non-exposed. Multivariate logistic regression and Student’s t - test was used for statistical analysis. Results: Systolic and diastolic blood pressure both were significantly higher in the Arsenic exposed pregnant subjects compared to the Non-exposed group (p<0.001). Arsenic exposed subjects had 2 times higher chance of developing hypertensive pregnancy (Odds Ratio 2.2). In parallel to the findings in Ar exposed subjects showed significantly higher proportion of triglyceride and total cholesterol and low density of lipo protein when compare to non- arsenic exposed pregnant subjects. Significant correlation of urinary arsenic level was also found with SBP, DBP, TG, T chol and serum LDL-Cholesterol. On multivariate logistic regression showed urinary arsenic had a positive association with DBP, SBP, Triglyceride and LDL-c. Conclusion: In conclusion, arsenic exposure may induce dyslipidemia like atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element.

Keywords: Arsenic Exposure, Dyslipidemia, Gestational Diabetes Mellitus, Serum lipid profile

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Authors: M. Naveed Yasin, Robert Brooke, Andrew Chan, Geoffrey I. N. Waterhouse, Drew Evans, Darren Svirskis, Ilva D. Rupenthal

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Poly(3,4-ethylenedioxythiophene) (PEDOT) is a robust conducting polymer (CP) exhibiting high conductivity and environmental stability. It can be synthesized by either chemical, electrochemical or vapour phase polymerization (VPP). Dexamethasone sodium phosphate (dexP) is an anionic drug molecule which has previously been loaded onto PEDOT as a dopant via electrochemical polymerisation; however this technique requires conductive surfaces from which polymerization is initiated. On the other hand, VPP produces highly organized biocompatible CP structures while polymerization can be achieved onto a range of surfaces with a relatively straight forward scale-up process. Following VPP of PEDOT, dexP can be loaded and subsequently released via ion-exchange. This study aimed at preparing and characterising both non-porous and porous VPP PEDOT structures including examining drug loading and release via ion-exchange. Porous PEDOT structures were prepared by first depositing a sacrificial polystyrene (PS) colloidal template on a substrate, heat curing this deposition and then spin coating it with the oxidant solution (iron tosylate) at 1500 rpm for 20 sec. VPP of both porous and non-porous PEDOT was achieved by exposing to monomer vapours in a vacuum oven at 40 mbar and 40 °C for 3 hrs. Non-porous structures were prepared similarly on the same substrate but without any sacrificial template. Surface morphology, compositions and behaviour were then characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM), x-ray photoelectron spectroscopy (XPS) and cyclic voltammetry (CV) respectively. Drug loading was achieved by 50 CV cycles in a 0.1 M dexP aqueous solution. For drug release, each sample was exposed to 20 mL of phosphate buffer saline (PBS) placed in a water bath operating at 37 °C and 100 rpm. Film was stimulated (continuous pulse of ± 1 V at 0.5 Hz for 17 mins) while immersed into PBS. Samples were collected at 1, 2, 6, 23, 24, 26 and 27 hrs and were analysed for dexP by high performance liquid chromatography (HPLC Agilent 1200 series). AFM and SEM revealed the honey comb nature of prepared porous structures. XPS data showed the elemental composition of the dexP loaded film surface, which related well with that of PEDOT and also showed that one dexP molecule was present per almost three EDOT monomer units. The reproducible electroactive nature was shown by several cycles of reduction and oxidation via CV. Drug release revealed success in drug loading via ion-exchange, with stimulated porous and non-porous structures exhibiting a proof of concept burst release upon application of an electrical stimulus. A similar drug release pattern was observed for porous and non-porous structures without any significant statistical difference, possibly due to the thin nature of these structures. To our knowledge, this is the first report to explore the potential of VPP prepared PEDOT for stimuli-responsive drug delivery via ion-exchange. The produced porous structures were ordered and highly porous as indicated by AFM and SEM. These porous structures exhibited good electroactivity as shown by CV. Future work will investigate porous structures as nano-reservoirs to increase drug loading while sealing these structures to minimize spontaneous drug leakage.

Keywords: PEDOT for ion-exchange drug delivery, stimuli-responsive drug delivery, template based porous PEDOT structures, vapour phase polymerization of PEDOT

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Authors: Meenu Mehta, Munish Garg

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The use of oral anticancer drugs from AYUSH system of medicine is widely increased among the society due to their low cost, enhanced efficacy, increased patient preference, lack of inconveniences related to infusion and they provide an opportunity to develop chronic treatment regimens. However, oral delivery of these drugs usually laid down by the limited bioavailability of the drug, which is associated with a wide variation. As most of the cytotoxic agents have a narrow therapeutic window and are dosed at or near the maximum tolerated dose, a wide variability in the bioavailability can negatively affect treatment result. It is estimated that 40% of active substances are poorly soluble in water. The improvement of bio-availability of drugs with such properties presents one of the greatest challenges in drug formulations. There are several techniques reported in literature. Among all these Self Emulsifying Drug Delivery System (SEDDS) has gained more attention due to enhanced oral bio-availability enabling a reduction in dose. Thus, SEDDS anticancer drugs will have the increased bioavailability and efficacy. These dosage form will provide societal benefit in a cost-effective manner as compared to other oral dosage forms. Present study reflects on the formulation strategies as SEDDS for oral anticancer agents of AYUSH system for enhanced bioavailability with proven efficacy by cancer cell lines.

Keywords: anticancer agents, AYUSH system, bioavailability, SEDDS

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Authors: Malay K. Das, Bhupen Kalita

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The poor oral bioavailability of resveratrol (RSV) due to presystemic metabolism can be avoided via dermal route of administration. The hydrophilic-lipophilic nature of resveratrol-phospholipid complex (RSVPs) favors the delivery of resveratrol via the skin. The RSVPs embedded polymeric patch with moderate adhesiveness was developed for dermal application for sustained anti-inflammatory effect. The prepared patches were evaluated for various physicochemical properties, surface morphology by SEM, TEM, and compatibility of patch components by FT-IR and DSC studies. The dermal flux of the optimized patch formulation was found to be at 4.28 ± 0.48 mg/cm2/24 h. The analysis of skin extract after permeation study revealed the presence of resveratrol, which confirmed the localization of RSVPs in the skin. The stability of RSVPs in the polymeric patch and the physiologic environment was confirmed by FE-SEM studies on the patches after drug release and skin permeation studies. The RSVPs particles released from the polymer matrix maintaining the structural integrity and permeate the keratinized horney layer of skin. The optimized patch formulation showed sustained anti-inflammatory effect (84.10% inhibition of inflammation at 24 h) in carrageenan-induced rat paw edema model compared to marketed diclofenac sodium gel (39.58% inhibition of inflammation at 24 h). The CLSM study confirmed the localization of RSVPs for a longer period, thus enabling drug targeting to the dermis for sustained anti-inflammatory effect. Histological studies with phase contrast trinocular microscope suggested no alteration of skin integrity and no evidence of the presence of inflammatory cells after exposure to the permeants. The patch was found to be safe for skin application as evaluated by Draize method for skin irritation scoring in a rabbit model. These results suggest the therapeutic efficacy of the developed patch in both acute and chronic inflammatory diseases.

Keywords: resveratrol-phospholipid complex, skin delivery, sustained anti-inflammatory effect, inflammatory diseases, dermal patch

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Authors: Yi-Shuan ShaoShao, Yen-An Tsai, Chia-Huang Chang, Kai-Wei Liao, Ming-Song Tsai, Mei-Lien Chen

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Organophosphate pesticides (OPs) is an environmental hormone with proven endocrine-disrupting effects that may affect the growth and development in human. A large amount of organophosphate pesticides (OPs) is used throughout Taiwan, and human may be exposed through dietary intake or residential use. During pregnancy, OPs can be transferred to the blood stream reaching the fetus through the placenta. The aim of this study was to explore the association between maternal OPs exposure levels and fetal developments and birth outcomes. A birth cohort was follow-up. Maternal urine sample were collected at the first, second, and third gestational trimester. Fetal growth characteristics were measured by ultrasonic scan and birth outcomes were assessed by pediatrician. Urinary metabolite of organophosphate pesticides were assessed using gas chromatography-mass spectrometry. The analytes included dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphates (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP), and diethyldithiophosphate (DEDTP). We found that all of urine samples in each trimester were detected at least one metabolite for dialkyl phosphate (DAP). The detection rate range of OP urinary metabolites were from the lowest 22% DEDTP to the highest 100% DMP and DMTP. And to compared geometric means (GM) of urinary metabolites with three trimesters, that third trimester had the highest concentration for DMPs, DEPs, and DAPs in pregnant women were 368.01, 169.85 and 543.75 nmol/g creatinine, respectively. We observed that DAPs concentration in first and second trimester were significantly negative association with head circumference. DMPs in first trimester was significantly negative association with thoracic circumference (p=0.05) by spearman correlation. Our results support associations with prenatal OPs exposure with fetal head circumference and thoracic circumference. It provided that maternal OPs exposure might affect birth outcomes. Thus, prenatal exposure to OPs and health risk worthy of attention and concern.

Keywords: DAPs, birth outcomes, organophosphate pesticides, prenatal

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Authors: S. Mohamed, D. Gonzalez, C. Sayada, P. Halfon

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Drug resistance mutations are routinely detected using standard Sanger sequencing, which does not detect minor variants with a frequency below 20%. The impact of detecting minor variants generated by ultra-deep sequencing (UDS) on HIV drug-resistance (DR) interpretations has not yet been studied. Fifty HIV-1 patients who experienced virological failure were included in this retrospective study. The HIV-1 UDS protocol allowed the detection and quantification of HIV-1 protease and reverse transcriptase variants related to genotypes A, B, C, E, F, and G. DeepChek®-HIV simplified DR interpretation software was used to compare Sanger sequencing and UDS. The total time required for the UDS protocol was found to be approximately three times longer than Sanger sequencing with equivalent reagent costs. UDS detected all of the mutations found by population sequencing and identified additional resistance variants in all patients. An analysis of DR revealed a total of 643 and 224 clinically relevant mutations by UDS and Sanger sequencing, respectively. Three resistance mutations with > 20% prevalence were detected solely by UDS: A98S (23%), E138A (21%) and V179I (25%). A significant difference in the DR interpretations for 19 antiretroviral drugs was observed between the UDS and Sanger sequencing methods. Y181C and T215Y were the most frequent mutations associated with interpretation differences. A combination of UDS and DeepChek® software for the interpretation of DR results would help clinicians provide suitable treatments. A cut-off of 1% allowed a better characterisation of the viral population by identifying additional resistance mutations and improving the DR interpretation.

Keywords: HIV-1, ultra-deep sequencing, Sanger sequencing, drug resistance

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Authors: Prakriti Diwan, S. Saraf

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The present study involves preparation and evaluation of microparticles of diclofenac sodium. The microparticles were prepared by the emulsion solvent evaporation techniques using ethylcellulose polymer. Four different batches of microspheres were prepared by varying the concentration of polymer from 50% to 80% w/w. The microspheres were characterized for drug content, percentage yield and encapsulation efficiency, particle size analysis and surface morphology. Microsphere prepared with high drug content produces higher percentage yield and encapsulation efficiency values. It was observed the increase in concentration of the polymer, increases the mean particle size of the microspheres. The effect of polymer concentration on the in vitro release of diclofenac from the microspheres was also studied. The production microparticles yield showed 98.74%, mean particle size 956.32µm and loading efficiency 97.15%. The results were found that microparticles prepared had slower release than microparticles (p>0.05). Therefore, it may be concluded that drug loaded microparticles are suitable delivery systems for diclofenac sodium.

Keywords: diclofenac sodium, emulsion solvent evaporation, ethylcellulose, microparticles

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Authors: Majid Farsadrooh, Mehran Feizi-Dehnayebi

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Serum albumin is the most abundant protein that is present in the circulatory system of a wide variety of organisms. Although it is a significant macromolecule, it can contribute to osmotic blood pressure and also, plays a superior role in drug disposition and efficiency. Molecular docking simulation can improve in silico drug design and discovery procedures to propound a lead compound and develop it from the discovery step to the clinic. In this study, the molecular docking simulation was applied to select a lead molecule through an investigation of the interaction of the two anticancer drugs (Alitretinoin and Abemaciclib) with Human Serum Albumin (HSA). Then, a series of new compounds (a-e) were suggested using lead molecule modification. Density functional theory (DFT) including MEP map and HOMO-LUMO analysis were used for the newly proposed compounds to predict the reactivity zones on the molecules, stability, and chemical reactivity. DFT calculation illustrated that these new compounds were stable. The estimated binding free energy (ΔG) values for a-e compounds were obtained as -5.78, -5.81, -5.95, -5,98, and -6.11 kcal/mol, respectively. Finally, the pharmaceutical properties and toxicity of these new compounds were estimated through OSIRIS DataWarrior software. The results indicated no risk of tumorigenic, irritant, or reproductive effects and mutagenicity for compounds d and e. As a result, compounds d and e, could be selected for further study as potential therapeutic candidates. Moreover, employing molecular docking simulation with the prediction of pharmaceutical properties helps to discover new potential drug compounds.

Keywords: drug design, anticancer, computational studies, DFT analysis

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Authors: Luiz Drude de Lacerda, Kevin Luiz Cordeiro Ferrer do Carmo, Victor Lacerda Moura, Rayone Wesley Santos de Oliveira, Moisés Fernandes Bezerra

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Fish is a food source well recognized for its health benefits. However, the consumption of fish, especially carnivorous species, is the main path of human exposure to Hg, a widely distributed pollutant on the planet and that accumulates along food chains. Studies on the impacts on public health by fish intake show existing toxic risks even when at low concentrations. This study quantifies, for the first time, the concentrations of Hg in muscle tissue of the nine most commercialized fish species in the fish market of São Luís (MA) in north Brazil and estimates the consequent human exposure through consumption. Concentrations varied according to trophic level, with the highest found in the larger carnivorous species; the Yellow hake (Cynoscion acoupa) (296.4 ± 241.2 ng/g w.w) and the Atlantic croaker (Micropogonias undulatus) (262.8 ± 89.1 ng/g w.w.), whereas the lowest concentrations were recorded in iliophagous Mullets (Mugil curema) (20.5 ± 9.6 ng/g w.w.). Significant correlations were observed between Hg concentrations and individual length in only two species: the Flaming catfish (Bagre marinus) and the Atlantic bumper (Chloroscombrus crysurus). Given the relatively uniform size of individuals of the other species and/or the small number of samples, this relationship was not found for the other species. The estimated risk coefficients, despite the relatively low concentrations of Hg, suggest that yellow hake and Whitemouth croaker (Micropogonias furnieri), fish most consumed by the local population, present some risk to human health (> 1) HQ and THQ, depending on the frequency of their consumption.

Keywords: contamination, fish, human exposure, risk assessment

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Authors: Alaa I. Arafa, Hemdan O. A. Said. Marwa A. M. Ali

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This paper investigates and evaluates experimentally the structural behavior of high strength concrete (HSC) beams under fire and compares it with that of Normal strength concrete (NSC) beams. The main investigated parameters are: concrete compressive strength (300 or 600 kg/cm²); the concrete cover thickness (3 or 5 cm); the degree of temperature (room temperature or 600 ^oC); the type of cooling (air or water); and the fire exposure time (3 or 5 hours). Test results showed that the concrete compressive strength decreases significantly as the exposure time to fire increases.

Keywords: experimental, fire, high strength concrete beams, monotonic loading

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Authors: Afolabi O.J, Simon-Oke I.A., Oniya M.O., Okaka C.E.

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River blindness is a skin, and an eye disease caused by Onchocerca volvulus and vectored by a female hematophagous blackfly. The study aims to evaluate the distribution of the clinical signs of river blindness and the efficacy of ivermectin in the treatment of river blindness in Idogun. Observational studies in epidemiology that involve the use of a structured questionnaire to obtain useful epidemiological information from the respondents, physical assessment via palpation from head to ankle was used to assess clinical signs from the respondents and skin snip test was used to evaluate the prevalence of the disease. The efficacy of the drug was evaluated and expressed in percentages. One hundred and ninety-two (192) out of the 384 respondents examined, showed various signs of river blindness. However, it was only 108 (28.1%) respondents with the clinical signs that demonstrated Onchocerca volvulus microfilariae in their skin snips. The clinical signs observed among the respondents include skin depigmentation such as dermatitis, leopard skin, papules, pruritus and self-inflicted injury, while ocular symptoms include cataract, ocular lesion and partial blindness. Among these clinical signs, papules, and pruritus were the most dominant in the community. The prevalence of the clinical signs was observed to vary significantly among the age groups and gender (P<0.05). The efficacy of the drug after 6 and 12 months of treatments shows that the drug is more effective at age groups 10-50 years than the age groups 51-90 years. Ivermectin is observed to be efficacious in the treatment of the disease. However, to achieve eradication of the disease, the drug may be administered at 0.15mg/kg twice a year.

Keywords: riverblindness, clinical signs, ivermectin, Idogun

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Authors: Hasan Basri Jumin

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The in vitro flowering of orange jessamine plantlets derived from protoplast was affected by the manipulation of plant growth regulators, sugar and light conditions. MT basal medium containing 5% sucrose and supplemented with 0.001 mg 1-1 indole-acetic-acid was found to be a suitable medium for development of globular somatic embryos derived from protoplasts to form heart-shaped somatic embryos with cotyledon-like structures. The highest percentage (85 %) of flowering was achieved with plantlet on half-strength MT basal medium containing 5% sucrose and 0.001 mg1-1 indole-acetic-acid in light. Exposure to darkness for more than 3 weeks followed by re-exposure to light reduced flowering. Flowering required a 10-day exposure to indole-acetic-acid. Photoperiod with 18 h and 79.4 µmol m-2 s-1 light intensity promoted in vitro flowering in high frequencies. The sucrose treatment affected the flower bud size distribution. Flower buds originating from plantlet derived from protoplasts developed into normal flowers.

Keywords: indole-acetc-acid, light-intensity, Murraya-paniculata, photoperiod, plantlet, Zeatin

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Authors: Robin L. Rohrer

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Introduction: Pre-natal or early childhood exposure to the medical radiation used in diagnosis or treatment is an identified risk for childhood cancers but can be difficult to document. The author developed a family questionnaire/interview form to identify possible exposures. Aims: This retrospective study examines pre-natal and early childhood medical radiation exposure in a cohort of children diagnosed with a solid tumor including brain tumors from 1985-2015 at the Children’s Hospital of Pittsburgh (CHP). The hospital is a tri-state regional referral center which treats about 150-180 new cases of cancer in children per year. About 70% are diagnosed with a solid tumor. Methods: Each consented family so far (approximately 50% of the cohort) has been interviewed in person or by the phone call. Medical staff and psycho- social staff referred patient families for the interview with the author. Results: Among the families interviewed to date at least one medical radiation exposure has been identified (pre-conception, pre-natal or early childhood) in over 70% of diagnosed children. These exposures have included pre-conception sinus or chest CT or X-ray in either parent, sinus CT or X-ray in the mother or diagnostic radiation of chest or abdomen in children. Conclusions: Exposures to medical radiation for a child later diagnosed with cancer may occur at several critical junctures. These exposures may well contribute to a ‘perfect storm’ in the still elusive causes of childhood cancer. The author plans to expand the study from 1975 to present to hopefully further document these junctures.

Keywords: pediatric, solid tumors, medical radiation, cancer

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Authors: Minwuyelet Maru, Solomon Habtemariam, Endalamaw Gadissa, Abraham Aseffa

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Background: Tuberculosis is a major public health problem in Ethiopia. The burden of TB is aggravated by emergence and expansion of drug resistant tuberculosis and different lineages of Mycobacterium tuberculosis (M. tuberculosis) have been reported in many parts of the country. Describing strains of Mycobacterial isolates and drug susceptibility pattern is necessary. Method: Sputum samples were collected from smear positive pulmonary TB patients age >= 7 years between October 1, 2012 to September 30, 2013 and Mycobacterial strains isolated on Loweensten Jensen (LJ) media. Each strain was characterized by deletion typing and Spoligotyping. Drug sensitivity testing was determined with the indirect proportion method using Middle brook 7H10 media and association to determine possible risk factors to drug resistance was done. Result: A total of 144 smear positive pulmonary tuberculosis patients were enrolled. The age of participants ranged from 7 to 78 with mean age of 29.22 (±10.77) years. In this study 82.2% (n=97) of the isolates were sensitive to the four first line anti-tuberculosis drugs and resistance to any of the four drugs tested was 17.8% (n=21). A high frequency of any resistance was observed in isoniazid, 13.6%, (n=16) followed by streptomycin, 11.8% (n=14). No significant association of isoniazid resistance with HIV, sex and history of previous TB treatment was observed but there was significant association with age, high between 31-35 years of age (p=0.01). Majority, 89.9% (n=128) of participants were new cases and only 11.1% (n=16) had history of previous TB treatment. No MDR-TB from new cases and 2 MDRTB (13.3%) was isolated from re-treatment cases which was significantly associated with previous TB treatment (p<0.01). Thirty two different types of spoligotype patterns were identified and 74.1% were grouped in to 13 clusters. The dominant strains were SIT 25, 18.1% (n=21), SIT 53, 17.2% (n=20) and SIT 149, 8.6% (n=10). Lineage 4 is the predominant lineage followed by lineage 3 and lineage 7 comprising 65.5% (n=76), 28.4% (n=33) and 6% (n=7) respectively. Majority of strains from lineage 3 and 4 were SIT 25 (63.6%) and SIT 53 (26.3%) whereas SIT 343 was the dominant strain from lineage 7 (71.4%). Conclusion: Wide spread of lineage 3 and lineage 4 of the modern lineage and high number of strain cluster indicates high ongoing transmission. The high proportion resistance to any of the first line anti-tuberculosis drugs may be a potential source in the emergence of MDR-TB. Wide spread of SIT 25 and SIT 53 having a tendency of ease transmission and presence of higher resistance of isoniazid in working and mobile age group, 31-35 years of age may increase risk of drug resistant strains transmission.

Keywords: tuberculosis, drug susceptibility, strain diversity, lineage, Ethiopia, spoligotyping

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Authors: Eskinder Desta Shumuye, Jun Zhao, Zike Wang

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This paper summarizes the results of experimental studies carried out at Zhengzhou University, School of Mechanics and Engineering Science, research laboratory, on the performance of concrete produced by combining Ordinary Portland Cement (OPC) with Ground-Granulated Blast Furnace Slag (GGBS). Concrete specimens cast with OPC and various percentage of GGBS (0%, 30%, 50%, and 70%) were subjected to high temperature exposure and extensive experimental test reproducing basic freeze-thaw cycle and a chloride-ion attack to determine their combined effects within the concrete samples. From the experimental studies, comparisons were made on the physical, mechanical, and microstructural properties in compassion with ordinary Portland cement concrete (OPC). Further, durability of GGBS cement concrete, such as exposure to accelerated carbonation, chloride ion attack, and freeze-thaw action in compassion with various percentage of GGBS and ordinary Portland cement concrete of similar mixture composition was analyzed. The microstructure, mineralogical composition, and pore size distribution of concrete specimens were determined via Scanning Electron Microscopy (SEM) analysis and X-Ray Diffraction (XRD). The result demonstrated that when the exposure temperature increases from 200 ºC to 400 ºC, the residual compressive strength was fluctuating for all concrete group, and compressive strength and chloride ion exposure of the concrete decreased with the increasing of slag content. The SEM and EDS results showed an increase in carbonation rate with increasing in slag content.

Keywords: accelerated carbonation, chloride-ion, concrete, ground-granulated blast furnace slag, GGBS, high-temperature

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Authors: Sheraz Gul

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The requirements for progressing a compound to clinical trials is well established and relies on the results from in-vitro and in-vivo animal tests to indicate that it is likely to be safe and efficacious when testing in humans. The typical data package required will include demonstrating compound safety, toxicity, bioavailability, pharmacodynamics (potential effects of the compound on body systems) and pharmacokinetics (how the compound is potentially absorbed, distributed, metabolised and eliminated after dosing in humans). If the desired criteria are met and the compound meets the clinical Candidate criteria and is deemed worthy of further development, a submission to regulatory bodies such as the US Food & Drug Administration for an exploratory Investigational New Drug Study can be made. The purpose of this study is to collect data to establish that the compound will not expose humans to unreasonable risks when used in limited, early-stage clinical studies in patients or normal volunteer subjects (Phase I). These studies are also designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on their effectiveness. In order to reach the above goals, we have developed a pre-clinical high throughput Absorption, Distribution, Metabolism and Excretion–Toxicity (ADME–Toxicity) panel of assays to identify compounds that are likely to meet the Lead and Candidate compound acceptance criteria. This panel includes solubility studies in a range of biological fluids, cell viability studies in cancer and primary cell-lines, mitochondrial toxicity, off-target effects (across the kinase, protease, histone deacetylase, phosphodiesterase and GPCR protein families), CYP450 inhibition (5 different CYP450 enzymes), CYP450 induction, cardio-toxicity (hERG) and gene-toxicity. This panel of assays has been applied to multiple compound series developed in a number of projects delivering Lead and clinical Candidates and examples from these will be presented.

Keywords: absorption, distribution, metabolism and excretion–toxicity , drug discovery, food and drug administration , pharmacodynamics

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Authors: Ji-Chan Jang

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Tuberculosis is still major health problem because there is an increase of multidrug-resistant and extensively drug-resistant forms of the disease. Therefore, the most urgent clinical need is to discover potent agents and develop novel drug combination capable of reducing the duration of MDR and XDR tuberculosis therapy. Three reference strains H37Rv, CDC1551, W-Beijing GC1237 and six clinical isolates of MDRTB were tested to daptomycin in the range of 0.013 to 256 mg/L. Daptomycin is resistant to all tested M. tuberculosis strains not only laboratory strains but also clinical MDR strains that were isolated at different source. Daptomycin will not be an antibiotic of choice for treating infection of Gram positive atypical slowly growing M. tuberculosis.

Keywords: tuberculosis, daptomycin, resistance, Mycobacterium tuberculosis

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Authors: Cao Yuping, Li Longfei, Zhao Xingfu, Zhang Yalin

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Purpose: This study examined the effects of exposure to domestic physical violence (DPV) on children’s behavior in a community sample. Method: Ninety-three 12-16 year-old adolescents exposed to DPV were matched with 54 adolescents with no exposure to DPV based on age, gender, family composition and parental age and education level. Participation included assessment with the Childhood Trauma Questionnaire (CTQ-SF) and Child Behavior Checklist (CBCL) by the adolescents and their parents respectively. Results: CBCL total score and anxiety/depression, social interaction problems, attention problems, delinquency, aggression and externalizing scores were significantly higher in adolescents exposed to DPV than those in controls (all ps<0.05).The CBCL total score and scores of anxiety/depression, social interaction problems, attention problems, delinquency, aggression and externalizing behaviors of boys were significantly higher in the research group than in the controls (all ps<0.05). Delinquency scores in abused adolescents were significantly higher than in DPV witnessed (p<0.05), but no other scores of CBCL were significant different. Different subtypes of behavioral problems were associated with different types of abuse. Conclusions: DPV exposure is associated with adverse behaviors in children, especially among boys. Children witness DPV alone have similar behavioral scores as the abused children. We recommend that both abused and DPV witness adolescents in Chinese communities need treatment to mitigate the effects on maladjusted behaviors.

Keywords: domestic violence, child, behavior, community, China

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Authors: Elsayed A. M. Shokr, A. Alhazemi, T. Naser, Talal A. Zuhair, Adel A. Zuhair, Ahmed N. Alshamary, Thamer A. Alanazi, Hosam A. Alanazi

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The main threats to human health from heavy metals are associated with exposure to Pb, Cd, Cu, Mo, Zn, Ni, Mn Co and Cr. is mainly via intake of drinking water being the most important source in most populations. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. Heavy metals have been used by humans for thousands of years. Although several adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and is even increasing in some parts of the world, in particular in less developed countries, though emissions have declined in most developed countries over the last 100 years. A strong relationship between contaminated drinking water with heavy metals from some of the stations of water shopping in Hail, KSA and chronic diseases such as renal failure, liver cirrhosis, and chronic anemia has been identified in this study. These diseases are apparently related to contaminant drinking water with heavy metals such as Pb, Cd, Cu, Mo, Zn, Ni, Mn Co and Cr. Renal failure is related to contaminate drinking water with lead and cadmium, liver cirrhosis to copper and molybdenum, and chronic anemia to copper and cadmium. Recent data indicate that adverse health effects of cadmium exposure may occur at lower exposure levels than previously anticipated, primarily in the form of kidney damage but possibly also bone effects and fractures. The general population is primarily exposed to mercury via drinking water being a major source of methyl mercury exposure, and dental amalgam. During the last century lead, cadmium, zinc, iron and arsenic is mainly via intake of drinking water being the most important source in most populations. Long-term exposure to lead, cadmium, zinc, iron and arsenic in drinking-water is mainly related to primarily in the form of kidney damage. Studies of these diseases suggest that abnormal incidence in specific areas is related to toxic materials in the groundwater and thereby led to the contamination of drinking water in these areas.

Keywords: heavy metals, liver functions, kidney functions and chronic renal failure, hail, renal, water

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