Search results for: drug interactions

Authors: Emílie Kučerová, Tereza Veverková, Marina Morozovová, Eva Kudová, Jitka Viktorová

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The blood-brain barrier (BBB) is a key element regulating the transport of substances between the blood and the central nervous system (CNS). The BBB protects the CNS from potentially harmful substances and maintains a suitable environment for nervous activity in the CNS, but at the same time, it represents a significant obstacle to the entry of drugs into the CNS. Pharmacoresistant epilepsy is a form of epilepsy that cannot be suppressed using two (or more) appropriately chosen antiepileptic drugs. In many cases, pharmacoresistant epilepsy is characterized by an increased concentration of efflux pumps on the luminal sides of the endothelial cells that form the BBB and an increased number of drug-metabolizing enzymes in the BBB cells, thereby preventing the effective transport of antiepileptic drugs into the CNS. Currently, a number of scientific groups are focusing on the preparation and improvement of BBB models in vitro in order to study cell interactions or transport mechanisms. However, in pathological conditions such as pharmacoresistant epilepsy, there are changes in BBB structure, and current BBB models are insufficient for related research. Our goal is to develop a suitable BBB model for pharmacoresistant epilepsy in vitro and use it to test the transfer of potential antiepileptic drugs. This model is created by co-culturing immortalized human cerebral microvascular endothelial cells, human vascular pericytes and immortalized human astrocytes. The BBB in vitro is cultivated in the form of a 2D transwell model and the integrity of the barrier is verified by measuring transendothelial electrical resistance (TEER). From the current results, a contact cell arrangement with the cultivation of endothelial cells on the upper side of the insert and the co-cultivation of astrocytes and pericytes on the lower side of the insert is selected as the most promising for BBB model cultivation. The pharmacoresistance of the BBB model is achieved by long-term cultivation of endothelial cells in an increasing concentration of selected antiepileptic drugs, which should lead to increased production of efflux pumps and drug-metabolizing enzymes. The pharmacoresistant BBB model in vitro will be further used for the screening of substances that could act both as antiepileptics and at the same time as inhibitors of efflux pumps in endothelial cells. This project was supported by the Technology Agency of the Czech Republic (TACR), Personalized Medicine: Translational research towards biomedical applications, No. TN02000109 and by the Academy of Sciences of the Czech Republic (AS CR) – grant RVO 61388963.

Keywords: antiepileptic drugs, blood-brain barrier, efflux transporters, pharmacoresistance

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

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

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

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

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

Keywords: schizophrenia, antipsychotic, cortisol, HPA

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Authors: Leandra Prempeh, Emily Malugen

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

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

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Authors: Maryam Beiranvand

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Multi-drug resistance in various microorganisms has increased globally in many healthcare facilities. Less effective antimicrobial activity of drug therapies for infection control becomes trouble. Since 1980, no new type of antimicrobial drug has been identified, even though combinations of antibiotic drugs have been discovered almost every decade. Between 1981 and 2006, over 70% of novel pharmaceuticals and chemical agents came from natural sources. Microorganisms have yielded almost 22,000 natural compounds. The identification of antimicrobial components from endophytes bacteria could help overcome the threat posed by multi-drug resistant strains. The project aims to analyze and identify antimicrobial peptides isolated from entophytic bacteria and their activity against multidrug-resistant Gram-negative bacteria in South Korea. Endophytic Paenibacillus polymyxa. 4G3 isolated from the plant, Gynura procumbery exhibited considerable antimicrobial activity against Methicillin-resistant Staphylococcus aureus, and Escherichia coli. The Rapid Annotations using Subsystems Technology showed that the total size of the draft genome was 5,739,603bp, containing 5178 genes with 45.8% G+C content. Genome annotation using antiSMASH version 6.0.0 was performed, which predicted the most common types of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS). In this study, diethyl aminoethyl cellulose (DEAEC) resin was used as the first step in purifying for unknown peptides, and then the target protein was identified using hydrophilic and hydrophobic solutions, optimal pH, and step-by-step tests for antimicrobial activity. This crude was subjected to C18 chromatography and elution with 0, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% methanol, respectively. Only the fraction eluted with 20% -60% methanol demonstrated good antimicrobial activity against MDR E. coli. The concentration of the active fragment was measured by the Brad-ford test, and Protein A280 - Thermo Fisher Scientific at the end by examining the SDS PAGE Resolving Gel, 10% Acrylamide and purity were confirmed. Our study showed that, based on the combined results of the analysis and purification. P polymyxa. 4G3 has a high potential exists for producing novel functions of polymyxin E and bacitracin against bacterial pathogens.

Keywords: endophytic bacteria, antimicrobial activity, antimicrobial peptide, whole genome sequencing analysis, multi -drug resistance gram negative bacteria

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Authors: Sarah Crawford, Gerry Lesley

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

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

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Authors: Thomas Chinwe Urama, Patrick Oseloka Ezepue, Peters Chimezie Nnanwa

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This paper investigates the universal financial dynamics in two dominant stock markets in Sub-Saharan Africa, through an in-depth analysis of the cross-correlation matrix of price returns in Nigerian Stock Market (NSM) and Johannesburg Stock Exchange (JSE), for the period 2009 to 2013. The strength of correlations between stocks is known to be higher in JSE than that of the NSM. Particularly important for modelling Nigerian derivatives in the future, the interactions of other stocks with the oil sector are weak, whereas the banking sector has strong positive interactions with the other sectors in the stock exchange. For the JSE, it is the oil sector and beverages that have greater sectorial correlations, instead of the banks which have the weaker correlation with other sectors in the stock exchange.

Keywords: random matrix theory, cross-correlations, emerging markets, option pricing, eigenvalues eigenvectors, inverse participation ratios and implied volatility

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Authors: Sudhir Kumar, V. R. Sinha

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

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

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

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

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

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Authors: Ilham Zaidi, P. Sankara Sarma, Quazi Taufique Ahmed, V. Raman Kutty, Khalid Umer Khayyam, Gurpreet Singh, Abhishek Royal

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Introduction: Tuberculosis is a global public health emergency, but it is particularly acute in India, which has the world's highest tuberculosis burden. Due to overpopulation, lack of sanitation, malnutrition, low living standards, and poor socioeconomic status, among other factors, it is India's most common infectious disease. The long period of treatment is one of the main reasons for considering it as a public health emergency. Consequently, there is an increase in patient noncompliance, which leads to treatment failure, adverse treatment outcomes, and deaths. This could lead to the growth of anti-TB drug resistance. According to the WHO, approximately 558 thousand new cases of Multi-Drug Resistance Tuberculosis were diagnosed worldwide, with 8.5 percent developed Extensively Drug Resistance Tuberculosis. Methodology: This study is a program-based cross-sectional descriptive survey of adult tuberculosis patients enrolled in the Delhi-based Revised National Tuberculosis Program. The study setting was 27 NTEP districts of Delhi. (N=65,893) and Sample size- was 200; the sampling method which is used in the study was the systemic random sampling method. Results: Most of the demographic factors (age, gender, residence, and family type) were not significantly associated with adherence; marital status was found statistically significant with the treatment compliance. Hesitation while telling people about the disease and motivation to strictly follow drug schedule by healthcare workers were other factors where a significant association with drug adherence was observed. The study findings also suggest that provision of food, minimal financial and other moral support from family, counseling, discussion and politeness by healthcare providers might also facilitate adherence. Discussion and Conclusions: For TB treatment, adherence, age, sex, socioeconomic status, types of accommodations, malnutrition, and personal hygiene should all be considered; similar results were observed in previous studies. In the care of TB patients, DOTS services, health workers, and family support play a significant role. According to the country's National Strategic Plan, the Indian government has set a goal of eliminating tuberculosis by 2025 and patients' compliance with TB care and treatment adherence is very crucial to achieve this aim. A cohort study will be able to give a better understanding of factors associated with adherence since this study may have missed some defaulters who were absconding and could not be reached. Important Terms: RNTCP, NTEP, DOTS, DS-TB, DR-TB, RR-TB, MDR-TB, XDR-TB, Treatment failure, Treatment relapse, Treatment adherence.

Keywords: treatment adherence, treatment relapse, treatment failure, drug resistance tuberculosis

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Authors: Shazia Mannan, Zunera Khalid, Hammad-Ul-Mubeen

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Wingless type Mouse mammary tumor virus (MMTV) Integration site-10B (Wnt10B) is an important member of the Wnt protein family that functions as cellular messenger in paracrine manner. Aberrant Wnt10B activity is the cause of several abnormalities including cancers of breast, cervix, liver, gastric tract, esophagus, pancreas as well as physiological problems like obesity, and osteoporosis. The objective of this study was to determine the possible inhibitors against aberrant expression of Wnt10B in order to prevent and treat the physiological disorders associated with it. Wnt10B3D structure was predicted by using comparative modeling and then analyzed by PROCHECK, Verify3D, and Errat. The model having 84.54% quality value was selected and acylated to satisfy the hydrophobic nature of Wnt10B. For search of inhibitors, virtual screening was performed on Natural Products (NP) database. The compounds were filtered and ligand-based screening was performed using the antagonist for mouse Wnt-3A. This resulted in a library of 272 unique compounds having most potent drug like activities for Wnt-4. Out of the 271 molecules analyzed three small molecules ZINC35442871, ZINC85876388, and ZINC00754234 having activity against Wnt4 abbarent expression were found common through docking experiment of Wnt10B. It is concluded that the three molecules ZINC35442871, ZINC85876388, and ZINC00754234 can be considered as lead compounds for performing further drug designing experiments against aberrant Wnt expressions.

Keywords: Wnt10B inhibitors, comparative computational studies, proto-oncogene, molecular docking

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Authors: Rosa Tsegaye Aga, Xuan Jiang, Pavel Vazquez Faci, Siqing Liu, Simon Rayner, Endalkachew Alemu, Markos Abebe

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Tuberculosis (TB) is a major cause of disease globally. In most cases, TB is treatable and curable, but only with the proper treatment. There is a time when drug-resistant TB occurs when bacteria become resistant to the drugs that are used to treat TB. Current strategies to identify drug-resistant TB bacteria are laboratory-based, and it takes a longer time to identify the drug-resistant bacteria and treat the patient accordingly. But machine learning (ML) and data science approaches can offer new approaches to the problem. In this study, we propose to develop an ML-based model to predict the antibiotic resistance phenotypes of TB isolates in minutes and give the right treatment to the patient immediately. The study has been using the whole genome sequence (WGS) of TB isolates as training data that have been extracted from the NCBI repository and contain different countries’ samples to build the ML models. The reason that different countries’ samples have been included is to generalize the large group of TB isolates from different regions in the world. This supports the model to train different behaviors of the TB bacteria and makes the model robust. The model training has been considering three pieces of information that have been extracted from the WGS data to train the model. These are all variants that have been found within the candidate genes (F1), predetermined resistance-associated variants (F2), and only resistance-associated gene information for the particular drug. Two major datasets have been constructed using these three information. F1 and F2 information have been considered as two independent datasets, and the third information is used as a class to label the two datasets. Five machine learning algorithms have been considered to train the model. These are Support Vector Machine (SVM), Random forest (RF), Logistic regression (LR), Gradient Boosting, and Ada boost algorithms. The models have been trained on the datasets F1, F2, and F1F2 that is the F1 and the F2 dataset merged. Additionally, an ensemble approach has been used to train the model. The ensemble approach has been considered to run F1 and F2 datasets on gradient boosting algorithm and use the output as one dataset that is called F1F2 ensemble dataset and train a model using this dataset on the five algorithms. As the experiment shows, the ensemble approach model that has been trained on the Gradient Boosting algorithm outperformed the rest of the models. In conclusion, this study suggests the ensemble approach, that is, the RF + Gradient boosting model, to predict the antibiotic resistance phenotypes of TB isolates by outperforming the rest of the models.

Keywords: machine learning, MTB, WGS, drug resistant TB

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Authors: Mostafa Sefidgar, Sohrab Zendehboudi, Hossein Bazmara, Madjid Soltani

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Based on findings from clinical applications, most drug treatments fail to eliminate malignant tumors completely even though drug delivery through systemic administration may inhibit their growth. Therefore, better understanding of tumor formation is crucial in developing more effective therapeutics. For this purpose, nowadays, solid tumor modeling and simulation results are used to predict how therapeutic drugs are transported to tumor cells by blood flow through capillaries and tissues. A solid tumor is investigated as a porous media for fluid flow simulation. Most of the studies use Darcy model for porous media. In Darcy model, the fluid friction is neglected and a few simplified assumptions are implemented. In this study, the effect of these assumptions is studied by considering Brinkman model. A multi scale mathematical method which calculates fluid flow to a solid tumor is used in this study to investigate how neglecting fluid friction affects the solid tumor simulation. In this work, the mathematical model in our previous studies is developed by considering two model of momentum equation for porous media: Darcy and Brinkman. The mathematical method involves processes such as fluid flow through solid tumor as porous media, extravasation of blood flow from vessels, blood flow through vessels and solute diffusion, convective transport in extracellular matrix. The sprouting angiogenesis model is used for generating capillary network and then fluid flow governing equations are implemented to calculate blood flow through the tumor-induced capillary network. Finally, the two models of porous media are used for modeling fluid flow in normal and tumor tissues in three different shapes of tumors. Simulations of interstitial fluid transport in a solid tumor demonstrate that the simplifications used in Darcy model affect the interstitial velocity and Brinkman model predicts a lower value for interstitial velocity than the values that Darcy model does.

Keywords: solid tumor, porous media, Darcy model, Brinkman model, drug delivery

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Authors: Shohel Ahmed, Md. Abdul Alim, Sumaiya Rahman

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Optimal control can be helpful to test and compare different vaccination strategies of a certain disease. The mathematical model of HIV we consider here is a set of ordinary differential equations (ODEs) describing the interactions of CD4+T cells of the immune system with the human immunodeficiency virus (HIV). As an early treatment setting, we investigate an optimal chemotherapy strategy where control represents the percentage of effect the chemotherapy has on the system. The aim is to obtain a new optimal chemotherapeutic strategy where an isoperimetric constraint on the chemotherapy supply plays a crucial role. We outline the steps in formulating an optimal control problem, derive optimality conditions and demonstrate numerical results of an optimal control for the model. Numerical results illustrate how such a constraint alters the optimal vaccination schedule and its effect on cell-virus interactions.

Keywords: chemotherapy of HIV, optimal control involving ODEs, optimality conditions, Pontryagin’s maximum principle

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Authors: X. Li, J. Sundquist, C. Sjöstedt, M. Winkleby, K. S. Kendler, K. Sundquist

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Aims: This study examines the association between the incidence of drug abuse (DA) and linking (communal) social capital, a theoretical concept describing the amount of trust between individuals and societal institutions. Methods: We present results from an 8-year population-based cohort study that followed all residents in Sweden, aged 15-44, from 2003 through 2010, for a total of 1,700,896 men and 1,642,798 women. Social capital was conceptualized as the proportion of people in a geographically defined neighborhood who voted in local government elections. Multilevel logistic regression was used to estimate odds ratios (ORs) and between-neighborhood variance. Results: We found robust associations between linking social capital (scored as a three level variable) and DA in men and women. For men, the OR for DA in the crude model was 2.11 [95% confidence interval (CI) 2.02-2.21] for those living in areas with the lowest vs. highest level of social capital. After accounting for neighborhood-level deprivation, the OR fell to 1.59 (1.51-1-68), indicating that neighborhood deprivation lies in the pathway between linking social capital and DA. The ORs remained significant after accounting for age, sex, family income, marital status, country of birth, education level, and region of residence, and after further accounting for comorbidities and family history of comorbidities and family history of DA. For women, the OR decreased from 2.15 (2.03-2.27) in the crude model to 1.31 (1.22-1.40) in the final model, adjusted for multiple neighborhood-level and individual-level variables. Conclusions: Our study suggests that low linking social capital may have important independent effects on DA.

Keywords: drug abuse, social linking capital, environment, family

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Authors: Catherine Peyrols Wu

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Intercultural interactions are becoming increasingly common in organizations and life. These interactions are often the stage of miscommunication and conflict. In management research, these problems are commonly attributed to cultural differences in values and interactional norms. As a result, the notion that intercultural competence can minimize these challenges is widely accepted. Cultural differences, however, are not the only source of a challenge during intercultural interactions. The need to rely on a lingua franca – or common language between people who have different mother tongues – is another important one. In theory, a lingua franca can improve communication and ease coordination. In practice however, disparities in people’s ability and confidence to communicate in the language can exacerbate tensions and generate inefficiencies. In this study, we draw on power theory to develop a model of disparities in language competence and conflict in a multicultural work context. Specifically, we hypothesized that differences in language competence between interaction partners would be positively related to conflict such that people would report greater conflict with partners who have more dissimilar levels of language competence and lesser conflict with partners with more similar levels of language competence. Furthermore, we proposed that cultural intelligence (CQ) an intercultural competence that denotes an individual’s capability to be effective in intercultural situations, would weaken the relationship between disparities in language competence and conflict such that people would report less conflict with partners who have more dissimilar levels of language competence when the interaction partner has high CQ and more conflict when the partner has low CQ. We tested this model with a sample of 135 undergraduate students working in multicultural teams for 13 weeks. We used a round-robin design to examine conflict in 646 dyads nested within 21 teams. Results of analyses using social relations modeling provided support for our hypotheses. Specifically, we found that in intercultural dyads with large disparities in language competence, partners with the lowest level of language competence would report higher levels of interpersonal conflict. However, this relationship disappeared when the partner with higher language competence was also high in CQ. These findings suggest that communication in a lingua franca can be a source of conflict in intercultural collaboration when partners differ in their level of language competence and that CQ can alleviate these effects during collaboration with partners who have relatively lower levels of language competence. Theoretically, this study underscores the benefits of CQ as a complement to language competence for intercultural effectiveness. Practically, these results further attest to the benefits of investing resources to develop language competence and CQ in employees engaged in multicultural work.

Keywords: cultural intelligence, intercultural interactions, language competence, multicultural teamwork

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Authors: Magno Enrique Mendoza Meza

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This paper deals with the comparison of three control techniques: the hysteresis on-off control (HyOOC), the hybrid on-off control (HOOC) and the simple Structured Treatment Interruptions (sSTI). These techniques are applied to the mathematical model developed by Kirschner and Webb. To compare these techniques we use a cost functional that minimize the wild-type virus population and the mutant virus population, but the main objective is to minimize the systemic cost of treatment and maximize levels of healthy CD4+ T cells. HyOOC, HOOC, and sSTI are applied to the drug therapies using a reverse transcriptase and protease inhibitors; simulations show that these controls maintain the uninfected cells in a small, bounded neighborhood of a pre-specified level. The controller HyOOC and HOOC are designed by appropriate choice of virtual equilibrium points.

Keywords: virus dynamics, on-off control, hysteresis, multi-drug therapies

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Authors: Clara Franch de la Cal, Christopher J Morris, Michael McArthur

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Cystic fibrosis (CF) is an autosomal recessive genetic disorder characterized by abnormal transport of chloride and sodium across the lung epithelium, leading to thick and viscous secretions. Within which CF patients suffer from repeated bacterial pulmonary infections, with Pseudomonas aeru-ginosa (PA) eliciting the greatest inflammatory response, causing an irreversible loss of lung func-tion that determines morbidity and mortality. The cell wall of PA is a permeability barrier to many antibacterials and the rise of Mutli-Drug Resistant strains (MDR) is eroding the efficacy of the few remaining clinical options. In addition when PA infection becomes established it forms an antibi-otic-resistant biofilm, embedded in which are slow growing cells that are refractive to drug treat-ment. Making the development of new antibacterials a major challenge. This work describes the development of new type of nanoparticulate oligonucleotide antibacterial capable of tackling PA infections, including MDR strains. It is being developed to both block growth and prevent biofilm formation. These oligonucleotide therapeutics, Transcription Factor Decoys (TFD), act on novel genomic targets by capturing key regulatory proteins to block essential bacterial genes and defeat infection. They have been successfully transfected into a wide range of pathogenic bacteria, both in vitro and in vivo, using a proprietary delivery technology. The surfactant used self-assembles with TFD to form a nanoparticle stable in biological fluids, which protects the TFD from degradation and preferentially transfects prokaryotic membranes. Key challenges are to adapt the nanoparticle so it is active against PA in the context of biofilms and to formulate it for administration by inhalation. This would allow the drug to be delivered to the respiratory tract, thereby achieving drug concentrations sufficient to eradicate the pathogenic organisms at the site of infection.

Keywords: antibacterials, transcriptional factor decoys (TFDs), pseudomonas aeruginosa

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Authors: Katharigatta N. Venugopala, Melendhran Pillay, Bander E. Al-Dhubiab

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Tuberculosis (TB) infection is caused mainly by Mycobacterium tuberculosis (MTB) and it is one of the most threatening and wide spread infectious diseases in the world. Benzothiazole derivatives are found to have diverse chemical reactivity and broad spectrum of pharmacological activity. Some of the important pharmacological activities shown by the benzothiazole analogues are antitumor, anti-inflammatory, antimicrobial, anti-tubercular, anti-leishmanial, anticonvulsant and anti-HIV properties. Keeping all these facts in mind in the present investigation it was envisaged to synthesize a series of novel {2-(benzo[d]-thiazol-2-yl-methoxy)-substitutedaryl}-(substitutedaryl)-methanones (4a-f) and characterize by IR, NMR (1H and 13C), HRMS and single crystal x-ray studies. The title compounds are investigated for in vitro anti-tubercular activity against two TB strains such as H37Rv (ATCC 25177) and MDR-MTB (multi drug resistant MTB resistant to Isoniazid, Rifampicin and Ethambutol) by agar diffusion method. Among the synthesized compounds in the series, test compound {2-(benzo[d]thiazol-2-yl-methoxy)-5-fluorophenyl}-(4-chlorophenyl)-methanone (2c) was found to exhibit significant activity with MICs of 1 µg/mL and 2 µg/mL against H37Rv and MDR-MTB, respectively when compared to standard drugs. Single crystal x-ray studies was used to study intra and intermolecular interactions, including polymorphism behavior of the test compounds, but none of the compounds exhibited polymorphism behavior.

Keywords: benzothiazole analogues, characterization, crystallography, anti-TB activity

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Authors: Jiji Jose, R. Narayanacharyulu, Molly Mathew, Jisha Prems

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Introduction: Lercanidipine hydrochloride (LD), an effective calcium channel blocker, widely used for the treatment of chronic stable angina and hypertension seems to be potential transdermal therapeutic system candidate, mainly due to its low oral bio availability, short half life and high first-pass metabolism. Objective: To develop transdermal therapeutic systems for LD and to evaluate its in vivo performance in rabbits. Methodology: Transdermal patches of LD were formulated using the polymer blend of eudragit RL100 (ERL) and polyvinyl pyrolidone (PVP) by casting method Propylene glycol (PG) and tween 80 were used as plasticizer and permeation enhancer respectively. The pharmaco kinetic parameters of LD after the administration of transdermal patches was compared with that of oral administration. The study was carried out in a two way crossover design in male New Zealand albino rabbits. Results: The formulation with ERL: PVP ratio 1:4 with 15% w/w PG as plasticizer and 4% w/w tween 80 as permeation enhancer showed the best drug release results. The pharmacokinetic parameters such as Cmax, tmax, mean residence time (MRT) and area under the curve (AUC 0-∞) were significantly different following transdermal administration compared to oral administration. The terminal half life of transdermally administered LD was found to similar that of oral administration. A sustained drug release over a period of 24 hrs was observed after transdermal administration. Conclusion: The fabricated transdermal delivery system have the potential to provide controlled and extended drug release, better bio availability and thus, this may improve the patient compliance.

Keywords: transdermal therapeutic system, lercanidipine hydrochloride, eudragit, skinpermeation

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Authors: Sahil Anand, John Luetke, Nikhil Venkatesh, Dorothy Wong

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Trust plays an important role in building and sustaining long-term relationships between people. In this paper, we present a robot that communicates using nonverbal behaviors such as facial expressions and body movements. Our study reports on an experiment in which participants were asked to team up with the robot to perform specific tasks. We varied the expressivity of the robot and measured the effects on trust, quality of interactions as well as on the praising and punishing behavior of the participant towards the robot. We found that participants developed a stronger affinity towards the expressive robot, but did not show any significant differences in the level of trust. When the same robot made mistakes, participants unconsciously punished it with lesser intensity compared to the neutral robot. The results emphasize the role of expressive behaviors on participant’s perception of the robot and also on the quality of interactions between humans and robots.

Keywords: human-robot interaction, nonverbal communication, relationships, social robot, trust

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Authors: Wei-Ju Huang, Hung-Pin Hsu

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[Background] In congestive heart failure (CHF), it has always been the principle of clinical treatment to control the water retention mechanism in the body to prevent excessive fluid retention. Early control of sympathetic nerves, Renin-Angiotensin-Aldosterone system (RAA system, RAAS), or strengthening of Atrial Natriuretic Peptide (ANP) was the point. In RAA system, related hormones, such as angiotensin, or enzymes in the pathway, such as ACE-I, can be used with corresponding inhibitors to reduce water content.[Aim] In recent years, clinical studies have pointed out that if different mechanisms are combined, the control effect seems to be better. For example, recent studies showed that ENTRESTO, a combination of Sacubitril and Valsartan, is a good new drug for CHF. Sacubitril is a prodrug. After activation, it can inhibit neprilysin and act as a neprilysin inhibitor (ARNI) to reduce the breakdown of natriuretic peptides(ANP). Valsartan is a kind of angiotensin receptor blocker (ARB), both of which are used to treat heart failure at the same time, have excellent curative effects.[Materials and Methods] Considering the side effects of this drug, coughing and a few cases of diarrhea were observed. However, the effect of this drug on the patient's intestinal tract has not been confirmed. On the other hand, studies have pointed out that ANP supplement can improve the CHF and increase the inhibitory effect on cancer cells. Therefore, the purpose of this study is to use a special microbial detection method to prove that whether oral drugs have an effect on microorganisms.The experimental method uses Nissui Compact Dry to observe the situation in different types of microorganisms. After the drug is dissolved in water, it is implanted in a petri dish, and the presence of different microorganisms is detected through different antibody reactions to confirm whether the drug has some toxicology in the gut.[Results and Discussion]From the above experimental results, it can be known that among the effects of Sacubitril and Valsartan on the basic microbial flora of the human body, low doses had no significant effect on Escherichia coli or intestinal bacteria. If Sacubitril or Valsartan with a high concentration of 3mg/ml is used alone or under the stimulation of a high concentration of the two drugs, it has a significant inhibitory effect on Escherichia coli. However, in terms of the effect on intestinal bacteria, high concentration of Sacubitril has a more significant inhibitory effect on intestinal bacteria, while high concentration of Valsartan has a less significant inhibitory effect on intestinal bacteria. The inhibitory effect of the combination of the two drugs on intestinal bacteria is also less significant.[Conclusion]The results of this study can be used as a further reference for the possible side effects of the clinical use of Sacubitril and Valsartan on the intestinal tract of patients,

Keywords: sacubitril, valsartan, entresto, congestive heart failure (CHF)

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Authors: Aakanchha Jain, D. V. Kohli

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Cubosomes are nanoparticles but instead of the solid particles, cubosomes are self-assembled liquid crystalline particles of certain surfactant with proper ratio of water with a microstructure that provides unique properties of practical interest. Cubosomes encapsulating Fluconazole were prepared by emulsification method and characterized for particle size, entrapment efficiency. The cubosomes prepared were 257.2±2.94 nm in size with drug entrapment efficiency of 66.2±2.69%. The optimized formulation characterized for shape and surface morphology by TEM and SEM analysis. SEM photograph showed the smooth surface of optimized cubosomes and TEM photograph revealed square somewhat circular intact shapes of cubosomes. MIC was determined by XTT based method and antifungal activity was determined in vitro. The cumulative percentage of Fnz from cubosomes permeated via dialysis membrane (MWCO 12-14 KD) showed a percent cumulative drug release of 76.86% while Fnz solution showed release up to 91.04% in 24 hours in PBS (pH 6.5)(p < 0.005).

Keywords: Candids albicans, cubosomes, fluconazole, topical delivery

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Authors: Sunil K. Jena, Sanjaya K. Samal, Mahesh Chand, Abhay T. Sangamwar

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Tamoxifen (TMX) and its analogues are approved as a first line therapy for the treatment of estrogen receptor-positive tumors. However, clinical development of TMX has been hampered by its low bioavailability and severe hepatotoxicity. Herein, we attempt to design a new drug delivery vehicle that could enhance the pharmacokinetic performance of TMX. Initially, high-molecular weight carboxymethyl chitosan was hydrolyzed to low-molecular weight carboxymethyl chitosan (LMW CMC) with hydrogen peroxide under the catalysis of phosphotungstic acid. Amphiphilic block copolymers of LMW CMC were synthesized via amidation reaction between the carboxyl group of α-tocopherol succinate (TS) and an amine group of LMW CMC. These amphiphilic block copolymers were self-assembled to nanosize core-shell-structural micelles in the aqueous medium. The critical micelle concentration (CMC) decreased with the increasing substitution of TS on LMW CMC, which ranged from 1.58 × 10-6 to 7.94 × 10-8 g/mL. Maximum TMX loading up to 8.08 ± 0.98% was achieved with Cmc-TS4.5 (TMX/Cmc-TS4.5 with 1:8 weight ratio). Both blank and TMX-loaded polymeric micelles (TMX-PM) of Cmc-TS4.5 exhibits spherical shape with the particle size below 200 nm. TMX-PM has been found to be stable in the gastrointestinal conditions and released only 44.5% of the total drug content by the first 72 h in simulated gastric fluid (SGF), pH 1.2. However, the presence of pepsin does not significantly increased the TMX release in SGF, pH 1.2, released only about 46.2% by the first 72 h suggesting its inability to cleave the peptide bond. In contrast, the release of TMX from TMX-PM4.5 in SIF, pH 6.8 (without pancreatin) was slow and sustained, released only about 10.43% of the total drug content within the first 30 min and nearly about 12.41% by the first 72 h. The presence of pancreatin in SIF, pH 6.8 led to an improvement in drug release. About 28.09% of incorporated TMX was released in the presence of pancreatin in 72 h. A cytotoxicity study demonstrated that TMX-PM exhibited time-delayed cytotoxicity in human MCF-7 breast cancer cells. Pharmacokinetic studies on Sprague-Dawley rats revealed a remarkable increase in oral bioavailability (1.87-fold) with significant (p < 0.0001) enhancement in AUC0-72 h, t1/2 and MRT of TMX-PM4.5 than that of TMX-suspension. Thus, the results suggested that CMC-TS micelles are a promising carrier for TMX delivery.

Keywords: carboxymethyl chitosan, d-α-tocopherol succinate, pharmacokinetic, polymeric micelles, tamoxifen

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Authors: Mehrnaz Mostafavi

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Lung cancer is one of the most harmful forms of cancer. The long-term survival rate of lung cancer patients treated by conventional modalities such as surgical resection, radiation, and chemotherapy remains far from satisfactory. Systemic drug delivery is rarely successful because only a limited amount of the chemotherapeutic drug targets lung tumor sites, even when administered at a high dose. Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest.Multimodal or combination therapy represents a promising new method to fight disease. Therefore, a combination of different therapeutic strategies may be the best alternative to improve treatment outcomes for lung cancer. Photothermal therapy was proposed as a novel approach to treatment. In this work, photothermal therapy with gold nanoparticles and near infrared laser (NIR) irradiation was investigated.Four types of small (<100nm), NIR absorbing gold nanoparticles (nanospheres, nanorods) were synthesized using wet chemical methods and characterized by transmission electron microscopy, dynamic light scattering and UV-vis spectroscopy. Their synthesis and properties were evaluated, to determine their feasibility as a photothermal agent for clinical applications. In vitro cellular uptake studies of the nanoparticles into lung cancer cell lines was measured using light scattering microscopy.Small gold nanorods had good photothermal properties and the greatest cellular uptake, and were used in photothermal studies. Under 4W laser irradiation, an increase in temperature of 10°C and decrease in cell viability of up to 80% were obtained.

Keywords: photothermal, therapy, cancer, gold nanorods

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Authors: Vandana T. Gawande, Kailash G. Bothara, Chandani O. Satija

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The present research work was aimed to determine stability of cefprozil monohydrate (CEFZ) as per various stress degradation conditions recommended by International Conference on Harmonization (ICH) guideline Q1A (R2). Forced degradation studies were carried out for hydrolytic, oxidative, photolytic and thermal stress conditions. The drug was found susceptible for degradation under all stress conditions. Separation was carried out by using High Performance Thin Layer Chromatographic System (HPTLC). Aluminum plates pre-coated with silica gel 60F254 were used as the stationary phase. The mobile phase consisted of ethyl acetate: acetone: methanol: water: glacial acetic acid (7.5:2.5:2.5:1.5:0.5v/v). Densitometric analysis was carried out at 280 nm. The system was found to give compact spot for cefprozil monohydrate (0.45 Rf). The linear regression analysis data showed good linear relationship in the concentration range 200-5.000 ng/band for cefprozil monohydrate. Percent recovery for the drug was found to be in the range of 98.78-101.24. Method was found to be reproducible with % relative standard deviation (%RSD) for intra- and inter-day precision to be < 1.5% over the said concentration range. The method was validated for precision, accuracy, specificity and robustness. The method has been successfully applied in the analysis of drug in tablet dosage form. Three unknown degradation products formed under various stress conditions were isolated by preparative HPTLC and characterized by mass spectroscopic studies.

Keywords: cefprozil monohydrate, degradation products, HPTLC, stress study, stability indicating method

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Authors: Khaled Alshammari

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Ciprofloxacin (CIP) is a common antibiotic drug used as a strudy electron donor that interacts with dynamic π -acceptors such as 2,3-dinitrosalsylic acid (HDNS) and Tetracyanoethylene (TCNE) for synthesizing a new model of charge transfer (CT) complexes. The synthesized complexes were identified using diverse analytical methods such as UV–vis spectra, photometric titration measurements, FT-IR, HNMR Spectroscopy, and thermogravimetric analysis techniques (TGA/DTA). The stoichiometries for all the formed complexes were found to be a 1:1 M ratio between the reactants. The characteristic spectroscopic properties such as transition dipole moment (µ), oscillator strength (f), formation constant (KCT), ionization potential (ID), standard free energy (∆G), and energy of interaction (ECT) for the CT-complexes were collected. The developed CT complexes were tested for their toxicity on main organs, antimicrobial activity, antioxidant activity, and biofilm formation.

Keywords: biological, biofilm, toxicity, thermal analysis, charge transfer, spectroscopy

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Authors: Carol Yue-En Ong, Angelina Hui-Min Tan, Quan Liu, Paul Chi-Lui Ho

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A public general hospital in Singapore has recently implemented an automated unit-dose machine in their inpatient dispensary, Swisslog, with the objective of reducing human error and improving patient safety. However, a concern in stability arises as tablets are removed from their original packaging (bottled loose tablets/capsules) and are repackaged into individual, clear plastic wrappers as unit doses in the system. Drugs that are light-sensitive and hygroscopic would be more susceptible to degradation as the wrapper does not offer full protection. Hence, this study was carried out to study the stability of haloperidol tablets and phenytoin capsules that are light-sensitive and hygroscopic respectively. Validated HPLC-UV assays were first established for quantification of these two compounds. The medications involved were put in the Swisslog and sampled every week for one month. The collected data was analysed and showed no degradation over time. This study also explored an alternative approach for drug stability determination-Raman spectroscopy. The advantage of Raman spectroscopy is its high time efficiency and non-destructive nature. The results suggest that drug degradation can indeed be detected using Raman microscopy, but further research is needed to establish this approach for quantification or qualification of compounds. NanoRam®, a portable Raman spectrocope was also used alongside Raman microscopy but was unsuccessful in detecting degradation in this study.

Keywords: drug stability, haloperidol, HPLC, phenytoin, raman spectroscopy, Swisslog

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Authors: Nabil A. Albaser

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Background: There is a serious problem with adverse drug reactions (ADRs) everywhere, including Yemen. Since it helps with the detection, assessment, reporting and prevention of ADRs, pharmacovigilance (PV) is an essential part of the healthcare system. The unbiased reporting of ADRs remains the foundation of PV. Students majoring in healthcare should acquire the knowledge and skills necessary to conduct PV in a range of clinical settings. The primary objective of this study was to evaluate the understanding and attitudes of final-year Pharmacy, Nursing, and Midwifery students at Al-Razi University in Sana'a, Yemen, regarding PV and ADRs reporting. Methods: The study followed descriptive cross-sectional approach. A validated, self-administered questionnaire with three parts—demographic information, knowledge, and perceptions of Pharmacovigilance was online distributed to final-year Pharmacy, Nursing, and Midwifery students. The questionnaire was given to 175 students; 122 of them responded with a percentage (69.7%). Results: The majority of respondents were male (79.5%). More than the tow-third of the students, 68.9%, were beyond the age of 23. Although the majority of students, 80%, heard about the terms of ADRs and PV, but only 50% and 57.4% of the respondents, respectively, could define the both terms correctly. However, only 11.48 % of them, nevertheless, took a PV course. More than a half of them (56.6%) had a positive perceptions towards pharmacovigilance and ADR reporting and had a moderate degree of knowledge (68.9%). Conclusion: The study demonstrated that the participants lacked sufficient knowledge of pharmacovigilance and ADR reporting. They showed a moderate level of understanding of reporting ADRs as well as a favorable opinion of dealing with and reporting ADRs. Yemen's health care curriculum should include lessons on pharmacovigilance.

Keywords: adverse drug reaction reporting, pharmacovigilance, yemen, knowlegde

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Authors: M. R. Vijayakumar, K. Priyanka, Ramoji Kosuru, Lakshmi, Sanjay Singh

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Trans resveratrol (RES) is a non-flavonoid poly-phenolic compound proved for its therapeutic and preventive effect against various types of cancer. However, the practical application of RES in cancer treatment is limited because of its higher dose (up to 7.5 g/day in humans), low biological half life, rapid metabolism and faster elimination in mammals. PEGylated core-shell type lipid polymer hybrid nanoparticles are the novel drug delivery systems for long circulation and improved anti cancer effect of its therapeutic payloads. Therefore, the main objective of this study is to extend the biological half life (long circulation) and improve the therapeutic efficacy of RES through core shell type of nanoparticles. D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), a novel surfactant is applied for the preparation of PEGylated lipid polymer hybrid nanoparticles. The prepared nanoparticles were evaluated by various state of the art techniques such as dynamic light scattering (DLS) technique for particle size and zeta potential, TEM for shape, differential scanning calorimetry (DSC) for interaction analysis and XRD for crystalline changes of drug. Entrapment efficiency and invitro drug release were determined by ultracentrifugation method and dialysis bag method, respectively. Cancer cell viability studies were performed by MTT assay, respectively. Pharmacokinetic studies after i.v administration were performed in sprague dawley rats. The prepared NPs were found to be spherical in shape with smooth surfaces. Particle size and zeta potential of prepared NPs were found to be in the range of 179.2±7.45 to 266.8±9.61 nm and -0.63 to -48.35 mV, respectively. DSC revealed absence of potential interaction. XRD study revealed presence of amorphous form in nanoparticles. Entrapment efficiency was found to be 83.7 % and drug release was found to be in controlled manner. MTT assay showed low MEC and pharmacokinetic studies showed higher AUC of nanoformulaition than its pristine drug. All these studies revealed that the RES loaded PEG modified core-shell type lipid polymer hybrid nanoparticles can be an alternative tool for chemopreventive and therapeutic application of RES in cancer.

Keywords: trans resveratrol, cancer nanotechnology, long circulating nanoparticles, bioavailability enhancement, core shell nanoparticles, lipid polymer hybrid nanoparticles

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