Search results for: drug toxicity

Authors: Sara Assi, Berthe Hayar, Claudio Pisano, Nadine Darwiche, Walid Saad

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Nanomedicine, the application of nanotechnology to medicine, is an emerging discipline that has gained significant attention in recent years. Current breakthroughs in nanomedicine have paved the way to develop effective drug delivery systems that can be used to target cancer. The use of nanotechnology provides effective drug delivery, enhanced stability, bioavailability, and permeability, thereby minimizing drug dosage and toxicity. As such, the use of nanoparticle (NP) formulations in drug delivery has been applied in various cancer models and have shown to improve the ability of drugs to reach specific targeted sites in a controlled manner. Cancer is one of the major causes of death worldwide; in particular, colorectal cancer (CRC) is the third most common type of cancer diagnosed amongst men and women and the second leading cause of cancer related deaths, highlighting the need for novel therapies. Retinoids, consisting of natural and synthetic derivatives, are a class of chemical compounds that have shown promise in preclinical and clinical cancer settings. However, retinoids are limited by their toxicity and resistance to treatment. To overcome this resistance, various synthetic retinoids have been developed, including the adamantyl retinoid ST1926, which is a potent anti-cancer agent. However, due to its limited bioavailability, the development of ST1926 has been restricted in phase I clinical trials. We have previously investigated the preclinical efficacy of ST1926 in CRC models. ST1926 displayed potent inhibitory and apoptotic effects in CRC cell lines by inducing early DNA damage and apoptosis. ST1926 significantly reduced the tumor doubling time and tumor burden in a xenograft CRC model. Therefore, we developed ST1926-NPs and assessed their efficacy in CRC models. ST1926-NPs were produced using Flash NanoPrecipitation with the amphiphilic diblock copolymer polystyrene-b-ethylene oxide and cholesterol as a co-stabilizer. ST1926 was formulated into NPs with a drug to polymer mass ratio of 1:2, providing a stable formulation for one week. The contin ST1926-NP diameter was 100 nm, with a polydispersity index of 0.245. Using the MTT cell viability assay, ST1926-NP exhibited potent anti-growth activities as naked ST1926 in HCT116 cells, at pharmacologically achievable concentrations. Future studies will be performed to study the anti-tumor activities and mechanism of action of ST1926-NPs in a xenograft mouse model and to detect the compound and its glucuroconjugated form in the plasma of mice. Ultimately, our studies will support the use of ST1926-NP formulations in enhancing the stability and bioavailability of ST1926 in CRC.

Keywords: nanoparticles, drug delivery, colorectal cancer, retinoids

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Authors: Ainoa Guinart, Maria Korpidou, Daniel Doellerer, Cornelia Palivan, Ben L. Feringa

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Stimuli responsive systems arise from the need to meet unsolved needs of current molecular drugs. Our study presents the design of a delivery system with high spatiotemporal control and tuneable release profiles. We study the incorporation of a hydrophobic synthetic molecular motor into PDMS-b-PMOXA block copolymer vesicles to create a self-assembled system. We prove their successful incorporation and selective activation by low powered visible light (λ 430 nm, 6.9 mW). We trigger the release of a fluorescent dye with high release efficiencies over sequential cycles (up to 75%) with the ability to turn on and off the release behaviour on demand by light irradiation. Low concentrations of photo-responsive units are proven to trigger release down to 1 mol% of molecular motor. Finally, we test our system in relevant physiological conditions using a lung cancer cell line and the encapsulation of an approved drug. Similar levels of cell viability are observed compared to the free-given drugshowing the potential of our platform to deliver functional drugs on demand with the same efficiency and lower toxicity.

Keywords: molecular motor, polymer, drug delivery, light-responsive, cancer, selfassembly

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Authors: Nishank Raisinghani

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Efficiently predicting drug response remains a challenge in the realm of drug discovery. To address this issue, we propose four model architectures that combine graphical representation with varying positions of multiheaded self-attention mechanisms. By leveraging two types of multi-omics data, transcriptomics and genomics, we create a comprehensive representation of target cells and enable drug response prediction in precision medicine. A majority of our architectures utilize multiple transformer models, one with a graph attention mechanism and the other with a multiheaded self-attention mechanism, to generate latent representations of both drug and omics data, respectively. Our model architectures apply an attention mechanism to both drug and multiomics data, with the goal of procuring more comprehensive latent representations. The latent representations are then concatenated and input into a fully connected network to predict the IC-50 score, a measure of cell drug response. We experiment with all four of these architectures and extract results from all of them. Our study greatly contributes to the future of drug discovery and precision medicine by looking to optimize the time and accuracy of drug response prediction.

Keywords: drug discovery, transformers, graph neural networks, multiomics

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Authors: Reza Ferdousi, Reza Safdari, Yadollah Omidi

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Drug-drug interactions (DDIs) are main cause of the adverse drug reactions and nature of the functional and molecular complexity of drugs behavior in human body make them hard to prevent and treat. With the aid of new technologies derived from mathematical and computational science the DDIs problems can be addressed with minimum cost and efforts. Market basket analysis is known as powerful method to identify co-occurrence of thing to discover patterns and frequency of the elements. In this research, we used market basket analysis to identify important bio-elements in DDIs occurrence. For this, we collected all known DDIs from DrugBank. The obtained data were analyzed by market basket analysis method. We investigated all drug-enzyme, drug-carrier, drug-transporter and drug-target associations. To determine the importance of the extracted bio-elements, extracted rules were evaluated in terms of confidence and support. Market basket analysis of the over 45,000 known DDIs reveals more than 300 important rules that can be used to identify DDIs, CYP 450 family were the most frequent shared bio-elements. We applied extracted rules over 2,000,000 unknown drug pairs that lead to discovery of more than 200,000 potential DDIs. Analysis of the underlying reason behind the DDI phenomena can help to predict and prevent DDI occurrence. Ranking of the extracted rules based on strangeness of them can be a supportive tool to predict the outcome of an unknown DDI.

Keywords: drug-drug interaction, market basket analysis, rule discovery, important bio-elements

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Authors: Arpa Petchsomrit, Namfa Sermkaew, Ruedeekorn Wiwattanapatapee

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Oil entrapped floating alginate beads of curcumin were developed and characterized. Cremophor EL, Cremophor RH and Tween 80 were utilized to improve the solubility of the drug. The oil-loaded floating gel beads prepared by emulsion gelation method contained sodium alginate, mineral oil and surfactant. The drug content and % encapsulation declined as the ratio of surfactant was increased. The release of curcumin from 1% alginate beads was significantly more than for the 2% alginate beads. The drug released from the beads containing 25% of tween 80 was about 70% while a higher drug release was observed with the beads containing Cremophor EL or Cremohor RH (approximately 90%). The developed floating beads of curcumin powder with surfactant provided a superior drug release than those without surfactant. Floating beads based on oil entrapment containing the drug solubilized in surfactants is a new delivery system to enhance the dissolution of poorly soluble drugs.

Keywords: alginate, curcumin, floating drug delivery, oil entrapped bead

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Authors: Burcu Doymus, Fatma N. Kok, Sakip Onder

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Titanium and titanium-based materials are commonly used to replace or regenerate the injured or lost tissues because of accidents or illnesses. Hospital infections and strong bond formation at the implant-tissue interface are directly affecting the success of the implantation as weak bonding with the native tissue and hospital infections lead to revision surgery. The purpose of the presented study is to modify the surface of the titanium substrates with nano/microspheres for local drug delivery and to prevent hospital infections. Firstly, titanium surfaces were silanized with APTES (3-Triethoxysilylpropylamine) following the negatively charged oxide layer formation. Then characterization studies using Scanning Electron Microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) were done on the modified surfaces. Secondly, microspheres/nanospheres were prepared with chitosan that is a natural polymer and having valuable properties such as non-toxicity, high biocompatibility, low allergen city and biodegradability for biomedical applications. Antibiotic (ciprofloxacin) loaded micro/nanospheres have been fabricated using emulsion cross-linking method and have been immobilized onto the titanium surfaces with different immobilization techniques such as covalent bond and entrapment. Optimization studies on size and drug loading capacities of micro/nanospheres were conducted before the immobilization process. Light microscopy and SEM were used to visualize and measure the size of the produced micro/nanospheres. Loaded and released drug amounts were determined by using UV- spectrophotometer at 278 nm. Finally, SEM analysis and drug release studies on the micro/nanospheres coated Ti surfaces were done. As a conclusion, it was shown that micro/nanospheres were immobilized onto the surfaces successfully and drug release from these surfaces was in a controlled manner. Moreover, the density of the micro/nanospheres after the drug release studies was higher on the surfaces where the entrapment technique was used for immobilization. Acknowledgement: This work is financially supported by The Scientific and Technological Research Council Of Turkey (Project # 217M220)

Keywords: chitosan, controlled drug release, nanosphere, nosocomial infections, titanium

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Authors: Syeda Hira, Muhammad Gulfraz

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Background: Liver diseases cause serious health issues. Plants contain active compounds that significantly help in the treatment of various diseases. Ficus carica is traditionally used for the treatment of liver diseases. The purpose of the present study was the isolation and identification of active components from F.carica leaves which are responsible for hepatoprotective activity. Methods: The study was designed to identify the most active hepatoprotective sub-fraction from ethyl acetate fraction of Ficus carica by in vitro study and evaluation of its in vivo hepatoprotective effect in animal models. Ethyl acetate fraction was subjected to column, and a total of eight sub-fractions were obtained. In vitro, the hepatoprotective effect of all sub-fractions was determined on HepG2 cell lines. Toxicity was induced by CCl₄ (Carbon tetrachloride), and silymarin was used as a positive control. On the basis of the results, the most active sub-fraction was subjected to LC-MS and FT-IR analysis for the identification of bioactive compounds. In vivo, the hepatoprotective effect was determined in mice. Toxicity was induced by CCl₄; at the end of the experiment, biochemical parameters such as ALT, AST, ALP, bilirubin, and total protein were estimated in serum. Histopathology of liver tissues was also done. Results: Sub-fraction FVI exhibited significant (P<0.05) hepatoprotective activity as compared to other sub-fractions, which was almost similar to the standard drug silymarin. Six known bioactive compounds were identified from this sub-fraction after LC-MS analysis. In vivo, the hepatoprotective activity of sub-fraction FVI was evaluated in CCl₄-induced toxicated mice. Administration of CCl₄ significantly increased level of ALT (Alanine transaminase), AST (Aspartate aminotransferase), ALP (Alkaline phosphatase), and bilirubin and decreased the total protein. Treatment with sub-fraction FVI significantly (p<0.05) reversed the level of these biomarkers toward normal at both doses of 25 mg/kg and 50 mg/kg. Conclusion: Our findings confirmed the hepatoprotective effect of ethyl acetate fraction of F.carica. It could be a good candidate for the development of a natural hepatoprotective drug; pre-clinical investigation on ethyl acetate fraction is recommended.

Keywords: Ficus carica, hepatoprotective, CCl₄, bioactive compounds, liver markers

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Authors: Farah El Mohtadi, Richard d'Arcy, Nicola Tirelli

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Since 40 years, poly (ethylene glycol) (PEG) has been the gold standard in biomaterials and drug delivery, because of its combination of chemical and biological inertness. However, the possibility of its breakdown under oxidative conditions and the demonstrated development of anti-PEG antibodies highlight the necessity to develop carriers based on materials with increased stability in a challenging biological environment. Here, we describe the synthesis of polysulfide via anionic ring-opening polymerization. In vitro, the synthesized polymer was characterized by low toxicity and a level of complement activation (in human plasma) and macrophage uptake slightly lower than PEG and poly (2‐methyl-2‐oxazoline) (PMOX), of a similar size. Importantly, and differently from PEG, on activated macrophages, the synthesized polymer showed a strong and dose-dependent ROS scavenging activity, which resulted in the corresponding reduction of cytokine production. Therefore, the results from these studies show that polysulfide is highly biocompatible and are potential candidates to be used as an alternative to PEG for various applications in nanomedicine.

Keywords: PEG, low toxicity, ROS scavenging, biocompatible

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Authors: Romasa Qasim, G. M. Sayedur Rahman, Nahid Hasan, M. Shazzad Hosain

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Millions of people worldwide suffer from Hepatitis C, one of the fatal diseases. Interferon (IFN) and ribavirin are the available treatments for patients with Hepatitis C, but these treatments have their own side-effects. Our research focused on the development of an orally taken small molecule drug targeting the proteins in Hepatitis C Virus (HCV), which has lesser side effects. Our current study aims to the Pharmacophore based drug development of a specific small molecule anti-viral drug for Hepatitis C Virus (HCV). Drug designing using lab experimentation is not only costly but also it takes a lot of time to conduct such experimentation. Instead in this in silico study, we have used computer-aided techniques to propose a Pharmacophore-based anti-viral drug specific for the protein domains of the polyprotein present in the Hepatitis C Virus. This study has used homology modeling and ab initio modeling for protein 3D structure generation followed by pocket identification in the proteins. Drug-able ligands for the pockets were designed using de novo drug design method. For ligand design, pocket geometry is taken into account. Out of several generated ligands, a new Pharmacophore is proposed, specific for each of the protein domains of HCV.

Keywords: pharmacophore-based drug design, anti-viral drug, in-silico drug design, Hepatitis C virus (HCV)

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Authors: M. Helen

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Chemical graph serves as a convenient model for any real or abstract chemical system. Dendrimers are novel three dimensional hyper branched globular nanopolymeric architectures. Drug delivery scientists are especially enthusiastic about possible utility of dendrimers as drug delivery tool. Dendrimers like poly L lysine (PLL), poly-propylene imine (PPI) and poly-amidoamine (PAMAM), etc., are used as gene carrier in drug delivery system because of their chemical characteristics. These characteristics of chemical compounds are analysed using topological indices (invariants under graph isomorphism) such as Wiener index, Zagreb index, etc., Prof. V. R. Kulli motivated by the application of Zagreb indices in finding the total π energy and derived Gourava indices which is an improved version over Zagreb indices. In this paper, we study the structure of PLL-Dendrimer that has the following applications: reduction in toxicity, colon delivery, and topical delivery. Also, we determine first and second Gourava indices, first and second hyper Gourava indices, product and sum connectivity Gourava indices for PLL-Dendrimer. Gourava Indices have found applications in Quantitative Structure-Property Relationship (QSPR)/ Quantitative Structure-Activity Relationship (QSAR) studies.

Keywords: connectivity Gourava indices, dendrimer, Gourava indices, hyper GouravaG indices

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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: Sanjay Singh, Parameswara Rao Vuddanda

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The aim of the present study is study the factual benefit of nano size and surface coating of p-gp efflux inhibitor on enhancement of bioavailability of Berberine chloride (BBR); a p-gp substrate. In addition, 28 days sub acute oral toxicity study was also conducted to assess the toxicity of the formulation on chronic administration. BBR loaded polymeric nanoparticles (BBR-NP) were prepared by nanoprecipitation method. BBR NP were surface coated (BBR-SCNP) with the 1 % w/v of vitamin E TPGS. For bioavailability study, total five groups (n=6) of rat were treated as follows first; pure BBR, second; physical mixture of BBR, carrier and vitamin E TPGS, third; BBR-NP, fourth; BBR-SCNP and fifth; BBR and verapamil (widely used p-gp inhibitor). Blood was withdrawn at pre-set timing points in 24 hrs study and drug was quantified by HPLC method. In oral chronic toxicity study, total four groups (n=6) were treated as follows first (control); water, second; pure BBR, third; BBR surface coated nanoparticles and fourth; placebo BBR surface coated nanoparticles. Biochemical levels of liver (AST, ALP and ALT) and kidney (serum urea and creatinine) along with their histopathological studies were also examined (0-28 days). The AUC of BBR-SCNP was significantly 3.5 folds higher compared to all other groups. The AUC of BBR-NP was 3.23 and 1.52 folds higher compared to BBR solution and BBR with verapamil group, respectively. The physical mixture treated group showed slightly higher AUC than BBR solution treated group but significantly low compared to other groups. It indicates that encapsulation of BBR in nanosize form can circumvent P-gp efflux effect. BBR-NP showed pharmacokinetic parameters (Cmax and AUC) which are near to BBR-SCNP. However, the difference in values of T1/2 and clearance indicate that surface coating with vitamin E TPGS not only avoids the P-gp efflux at its absorption site (intestine) but also at organs which are responsible for metabolism and excretion (kidney and liver). It may be the reason for observed decrease in clearance of BBR-SCNP. No toxicity signs were observed either in biochemical or histopathological examination of liver and kidney during toxicity studies. The results indicate that administration of BBR in surface coated nanoformulation would be beneficial for enhancement of its bioavailability and longer retention in systemic circulation. Further, sub acute oral dose toxicity studies for 28 days such as evaluation of intestine, liver and kidney histopathology and biochemical estimations indicated that BBR-SCNP developed were safe for long use.

Keywords: bioavailability, berberine nanoparticles, p-gp efflux inhibitor, nanoprecipitation method

Procedia PDF Downloads 386

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

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

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

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Authors: V. Balamuralidhara

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The aim of the present work was to develop Paclitaxel loaded polyacrylamide grafted guar gum nanoparticles as pH responsive nanoparticle systems for targeting colon. The pH sensitive nanoparticles were prepared by modified ionotropic gelation technique. The prepared nanoparticles showed mean diameters in the range of 264±0.676 nm to 726±0.671nm, and a negative net charge 10.8 mV to 35.4mV. Fourier Transformed Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) studies suggested that there was no chemical interaction between drug and polymers. The encapsulation efficiency of the drug was found to be 40.92% to 48.14%. The suitability of the polyacrylamide grafted guar gum ERN’s for the release of Paclitaxel was studied by in vitro release at pH 1.2 and 7.4. It was observed that, there was no significant amount of drug release at gastric pH and 97.63% of drug release at pH 7.4 was obtained for optimized formulation F3 at the end of 12 hrs. In vivo drug targeting performance for the prepared optimized formulation (F3) and pure drug Paclitaxel was evaluated by HPLC. It was observed that the polyacrylamide grafted guar gum can be used to prepare nanoparticles for targeting the drug to the colon. The release performance was greatly affected by the materials used in ERN’s preparation, which allows maximum release at colon’s pH. It may be concluded that polyacrylamide grafted guar gum nanoparticles loaded with paclitaxel have desirable release responsive to specific pH. Hence it is a unique approach for colonic delivery of drug having appropriate site specificity and feasibility and controlled release of drug.

Keywords: colon targeting, polyacrylamide grafted guar gum nanoparticles, paclitaxel, nanoparticles

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Authors: Afaf Benhouda, Mouloud Yahia, Hachani Khadraoui, Asma Meddour, Souhila Benbia, Abdelmoudjib Ghecham, Djahida Benhouda

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Umbilicus rupestris (UR) is an herbal medicine traditionally applied against the ignitions of the skin. The present paper aimed to study the acute and subacute toxicity with orally administered methanolic leaves extract of Umbilicus rupestris L (URMeOH). In acute toxicity tests, four groups of rats (n = 6/group/female) were orally treated with doses of 500, 1000, 1500 and 2000 mg/kg, and general behaviour, adverse effects, and mortality were recorded for up to 14 days. In subacute toxicity study, rats received URAMeOH by gavage at the doses of 100, 200 mg/kg/day (n = 6/group) for 28 days, and biochemical, hematological, and histopathological changes in tissues (liver, kidney) were determined. URMeOH did not produce any hazardous symptoms or death and in the acute toxicity test. Subacute treatment with URMeOH did not show any change in body weight, and hematological and biochemical profiles. In addition, no change was observed either in macroscopic or microscopic aspects of vital organs in rats. Our result showed that Umbilicus rupestris extract could be safe for human use.

Keywords: acute toxicity, biochemical parameters, hematological parameters, Umbilicus rupestris, subacute toxicity

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Authors: B. Medani Amna, M. A. Elbadwi Samia, E. Amin Ahmed

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Variable plants present in nature are used by simple rural and urban people, researchers and drug manufacturers for medicinal purposes. Garad is one of the most commonly used in Sudan for both treatment and prophylaxis of infections in the respiratory, urinogenital tracts and the skin. Water exctracts from Acacia nilotica bods were used in this very experiment to test for their toxicity to Nubian goats at two dose rates under proper experimental conditions. The clinical, pathological, haematological and biological changes in Nubian goats given daily oral doses of 1 and 5 g/kg body weight of Acacia nilotica to two groups of test goats. The goats of the control group were undosed with Acacia nilotica.Other than the dose co-related mortality rates, the clinical signs were observed to be salivation, staggered gait, intermittent loss of voice and low appetite. On histopathological testing, the main lesions were hepatic centrolobular necrosis and fatty changes associated with the significant changes in GGT and ALP are indicating hepatic dysfunction.Renal malfunction is indicated by haemorrhages in addition to the change in the urea concentration. The congested, haemorrhagic, emphysematous, edematous and cyanotic lungs may contribute to the development of dyspnea. Acacia nilotica poisoning may lead to an immunosuppression pointed out by the lymphocyte infiltration. On evaluation of the above results, Acacia nilotica was considered toxic to Nubian goats at the above mentioned doses. Future work for Acacia nilotica was forwarded and practical implications of the result were highlighted.

Keywords: Acaia nilotica, toxicity data, Nubian goats, Garad

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Authors: Shasline Gedeon, Tiffany W. Ardley, Ying Wang, Nathan J. Gesmundo, Katarina A. Sarris, Ana L. Aguirre

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Drug discovery and delivery involve drug targeting, an approach that helps find a drug against a chosen target through high throughput screening and other methods by way of identifying the physical properties of the potential lead compound. Physical properties of potential drug candidates have been an imperative focus since the unveiling of Lipinski's Rule of 5 for oral drugs. Throughout a compound's journey from discovery, clinical phase trials, then becoming a classified drug on the market, the desirable properties are optimized while minimizing/eliminating toxicity and undesirable properties. In the pharmaceutical industry, the ability to generate molecules in parallel with maximum efficiency is a substantial factor achieved through sp²-sp² carbon coupling reactions, e.g., Suzuki Coupling reactions. These reaction types allow for the increase of aromatic fragments onto a compound. More recent literature has found benefits to decreasing aromaticity, calling for more sp³-sp² carbon coupling reactions instead. The objective of this project is to provide a comparison between various sp³-sp² carbon coupling methods and reaction conditions, collecting data on production of the desired product. There were four different coupling methods being tested amongst three cores and 4-5 installation groups per method; each method ran under three distinct reaction conditions. The tested methods include the Photoredox Decarboxylative Coupling, the Photoredox Potassium Alkyl Trifluoroborate (BF3K) Coupling, the Photoredox Cross-Electrophile (PCE) Coupling, and the Weix Cross-Electrophile (WCE) Coupling. The results concluded that the Decarboxylative method was very difficult in yielding product despite the several literature conditions chosen. The BF3K and PCE methods produced competitive results. Amongst the two Cross-Electrophile coupling methods, the Photoredox method surpassed the Weix method on numerous accounts. The results will be used to build future libraries.

Keywords: drug discovery, high throughput chemistry, photoredox chemistry, sp³-sp² carbon coupling methods

Procedia PDF Downloads 139

Authors: K. K. Balavenkatraman, B. Bertschi, K. Bigot, A. Grevot, A. Doelemeyer, S. D. Chibout, A. Wolf, F. Pognan, N. Manevski, O. Kretz, P. Swart, K. Litherland, J. Ashton-Chess, B. Ling, R. Wettstein, D. J. Schaefer

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Skin toxicity is poorly detected during preclinical studies, and drug-induced side effects in humans such as rashes, hyperplasia or more serious events like bullous pemphigus or toxic epidermal necrolysis represent an important hurdle for clinical development. In vitro keratinocyte-based epidermal skin models are suitable for the detection of chemical-induced irritancy, but do not recapitulate the biological complexity of full skin and fail to detect potential serious side-effects. Normal healthy skin explants may represent a valuable complementary tool, having the advantage of retaining the full skin architecture and the resident immune cell diversity. This study investigated several conditions for the maintenance of good morphological structure after several days of culture and the retention of phase II metabolism for 24 hours in skin explants in vitro. Human skin samples were collected with informed consent from patients undergoing plastic surgery and immediately transferred and processed in our laboratory by removing the underlying dermal fat. Punch biopsies of 4 mm diameter were cultured in an air-liquid interface using transwell filters. Different cultural conditions such as the effect of calcium, temperature and cultivation media were tested for a period of 14 days and explants were histologically examined after Hematoxylin and Eosin staining. Our results demonstrated that the use of Williams E Medium at 32°C maintained the physiological integrity of the skin for approximately one week. Upon prolonged incubation, the upper layers of the epidermis become thickened and some dead cells are present. Interestingly, these effects were prevented by addition of EGFR inhibitors such as Afatinib or Erlotinib. Phase II metabolism of the skin such as glucuronidation (4-methyl umbeliferone), sulfation (minoxidil), N-acetyltransferase (p-toluidene), catechol methylation (2,3-dehydroxy naphthalene), and glutathione conjugation (chlorodinitro benzene) were analyzed by using LCMS. Our results demonstrated that the human skin explants possess metabolic activity for a period of at least 24 hours for all the substrates tested. A time course for glucuronidation with 4-methyl umbeliferone was performed and a linear correlation was obtained over a period of 24 hours. Longer-term culture studies will indicate the possible evolution of such metabolic activities. In summary, these results demonstrate that human skin explants maintain a normal structure for several days in vitro and are metabolically active for at least the first 24 hours. Hence, with further characterisation, this model may be suitable for the study of drug-induced toxicity.

Keywords: human skin explant, phase II metabolism, epidermal growth factor receptor, toxicity

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Authors: M. Rahimnejad, B. Vahidi, B. Ebrahimi Hoseinzadeh, F. Yazdian, P. Motamed Fath, R. Jamjah

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In this study, we developed and simulated nano-drug delivery systems efficacy in compare to free drug prescription. Computational models can be utilized to accelerate experimental steps and control the experiments high cost. Molecular dynamics simulation (MDS), in particular NAMD was utilized to better understand the anti-cancer drug interaction with cell membrane model. Paclitaxel (PTX) and dipalmitoylphosphatidylcholine (DPPC) were selected for the drug molecule and as a natural phospholipid nanocarrier, respectively. This work focused on two important interaction parameters between molecules in terms of center of mass (COM) and van der Waals interaction energy. Furthermore, we compared the simulation results of the PTX interaction with the cell membrane and the interaction of DPPC as a nanocarrier loaded by the drug with the cell membrane. The molecular dynamic analysis resulted in low energy between the nanocarrier and the cell membrane as well as significant decrease of COM amount in the nanocarrier and the cell membrane system during the interaction. Thus, the drug vehicle showed notably better interaction with the cell membrane in compared to free drug interaction with the cell membrane.

Keywords: anti-cancer drug, center of mass, interaction energy, molecular dynamics simulation, nanocarrier

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Authors: D. R. Rama Brahma Reddy, A. Vijaya Sarada Reddy

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Nanoparticles represent a promising drug delivery system of controlled and targeted drug release. They are specially designed to release the drug in the vicinity of target tissue. The aim of this study was to prepare and evaluate polymethacrylic acid nanoparticles containing Zidovudine in different drug to polymer ratio by nanoprecipitation method. SEM indicated that nanoparticles have a discrete spherical structure without aggregation. The average particle size was found to be 120 ± 0.02 - 420 ± 0.05 nm. The particle size of the nanoparticles was gradually increased with increase in the proportion of polymethacrylic acid polymer. The drug content of the nanoparticles was increasing on increasing polymer concentration up to a particular concentration. No appreciable difference was observed in the extent of degradation of product during 60 days in which, nanoparticles were stored at various temperatures. FT-IR studies indicated that there was no chemical interaction between drug and polymer and stability of drug. The in-vitro release behavior from all the drug loaded batches was found to be zero order and provided sustained release over a period of 24 h. The developed formulation overcome and alleviates the drawbacks and limitations of Zidovudine sustained release formulations and could possibility be advantageous in terms of increased bio availability of Zidovudine.

Keywords: nanoparticles, zidovudine, biodegradable, polymethacrylic acid

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Authors: Inês N. Peça , A. Bicho, Rui Gardner, M. Margarida Cardoso

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Inorganic/organic nanocomplexes offer tremendous scope for future biomedical applications, including imaging, disease diagnosis and drug delivery. The combination of Fe3O4 with biocompatible polymers to produce smart drug delivery systems for use in pharmaceutical formulation present a powerful tool to target anti-cancer drugs to specific tumor sites through the application of an external magnetic field. In the present study, we focused on the evaluation of the effect of the magnetic field application time on the rate of drug release from iron oxide polymeric nanoparticles. Doxorubicin, an anticancer drug, was selected as the model drug loaded into the nanoparticles. Nanoparticles composed of poly(d-lactide-co-glycolide (PLGA), a biocompatible polymer already approved by FDA, containing iron oxide nanoparticles (MNP) for magnetic targeting and doxorubicin (DOX) were synthesized by the o/w solvent extraction/evaporation method and characterized by scanning electron microscopy (SEM), by dynamic light scattering (DLS), by inductively coupled plasma-atomic emission spectrometry and by Fourier transformed infrared spectroscopy. The produced particles yielded smooth surfaces and spherical shapes exhibiting a size between 400 and 600 nm. The effect of the magnetic doxorubicin loaded PLGA nanoparticles produced on cell viability was investigated in mammalian CHO cell cultures. The results showed that unloaded magnetic PLGA nanoparticles were nontoxic while the magnetic particles without polymeric coating show a high level of toxicity. Concerning the therapeutic activity doxorubicin loaded magnetic particles cause a remarkable enhancement of the cell inhibition rates compared to their non-magnetic counterpart. In vitro drug release studies performed under a non-permanent magnetic field show that the application time and the on/off cycle duration have a great influence with respect to the final amount and to the rate of drug release. In order to determine the mechanism of drug release, the data obtained from the release curves were fitted to the semi-empirical equation of the the Korsmeyer-Peppas model that may be used to describe the Fickian and non-Fickian release behaviour. Doxorubicin release mechanism has shown to be governed mainly by Fickian diffusion. The results obtained show that the rate of drug release from the produced magnetic nanoparticles can be modulated through the magnetic field time application.

Keywords: drug delivery, magnetic nanoparticles, PLGA nanoparticles, controlled release rate

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Authors: Gagan Dhawan

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Mycobacterium tuberculosis was described as ‘captain of death’ with an inherent property of multiple drug resistance majorly caused by the competent mechanism of efflux pumps. In this study, various open source tools combining chemo-informatics with bioinformatics were used for efficient in-silico drug designing. The efflux pump, Rv1218c, belonging to the ABC transporter superfamily, which is predicted to be a tetronasin-transporter in M. tuberculosis was targeted. Recent studies have shown that Rv1218c forms a complex with two more efflux pumps (Rv1219c and Rv1217c) to provide multidrug resistance to the bacterium. The 3D structure of the protein was modeled (as the structure was unavailable in the previously collected databases on this gene). The TMHMM analysis of this protein in TubercuList has shown that this protein is present in the outer membrane of the bacterium. Virtual screening of compounds from various publically available chemical libraries was performed on the M. tuberculosis protein using various open source tools. These ligands were further assessed where various physicochemical properties were evaluated and analyzed. On comparison of different physicochemical properties, toxicity and docking, the ligand 2-(hydroxymethyl)-6-[4, 5, 6-trihydroxy-2-(hydroxymethyl) tetrahydropyran-3-yl] oxy-tetrahydropyran-3, 4, 5-triol was found to be best suited for further studies.

Keywords: drug resistance, efflux pump, molecular docking, virtual screening

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Authors: Stanely Nsubuga

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Background In Uganda, injection drug use is a growing but less studied problem. Preventing the transition to injection drug use may help prevent blood-borne viral transmission, but little is known about when and how people transition to injection drug use. A greater understanding of this transition process may aid in the country’s efforts to prevent the continued growth of injection drug use, HIV, and hepatitis C Virus (HCV) infection among people who inject drugs (PWID). Methods Using a rapid situation assessment framework, we conducted semi-structured interviews among 125 PWID (102 males and 23 females)—recruited through outreach and snow-ball sampling. Participants were interviewed about their experiences on when and how they transitioned into injection drug use and these issues were also discussed in 12 focus groups held with the participants. Results All the study participants started their drug use career with non-injecting forms including chewing, smoking, and sniffing before transitioning to injecting. Transitioning was generally described as a peer-driven and socially learnt behavior. The participants’ social networks and accessibility to injectable drugs on the market and among close friends influenced the time lag between first regular drug use and first injecting—which took an average of 4.5 years. By the age of 24, at least 81.6% (95.7% for females and 78.4% for males) had transitioned into injecting. Over 84.8% shared injecting equipment during their first injection, 47.2% started injecting because a close friend was already injecting, 26.4% desired to achieve a greater “high” (26.4%) which could reflect drug-tolerance, and 12% out of curiosity.

Keywords: People who Use Drugs, transition, injection drug use, Uganda

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Authors: Owonikoko Abayomi Dele

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Epilepsy is an unresolved disease that needs urgent attention. It is a brain disorder that affects over sixty-five (65) million people around the globe. Despite the availability of commercial anti-epileptic drugs, the war against this unmet condition is yet to be resolved. Most epilepsy patients are resistant to available anti-epileptic medications thus the need for affordable novel therapy against epilepsy is a necessity. Numerous phytochemicals have been reported for their potency, efficacy and safety as therapeutic agents against many diseases. This study investigated 99 isolated phytochemicals from Chasmanthera dependens and Carissa edulis against carbonic anhydrase (ii) drug target. The absorption, distribution, metabolism, excretion and toxicity (ADMET) of the isolated compounds were examined using admet SAR-2 web server while Swiss ADME was used to analyze the oral bioavailability, drug-likeness and lead-likeness properties of the selected leads. PASS web server was used to predict the biological activities of selected leads while other important physicochemical properties and interactions of the selected leads with the active site of the target after successful molecular docking simulation with the pyrx virtual screening tool were also examined. The results of these study identified seven lead compounds; C49- alpha-carissanol (-7.6 kcal/mol), C13- Catechin (-7.4 kcal/mol), C45- Salicin (-7.4 kcal/mol), C6- Bisnorargemonine (-7.3 kcal/mol), C36- Pallidine (-7.1 kcal/mol), S4- Lacosamide (-7.1 kcal/mol), and S7- Acetazolamide (-6.4 kcal/mol) for CA II (3HS4 receptor). These leads compounds are probable inhibitors of this drug target due to the observed good binding affinities and favourable interactions with the active site of the drug target, excellent ADMET profiles, PASS Properties, drug-likeness, lead-likeness and oral bioavailability properties. The identified leads have better binding energies as compared to the binding energies of the two standards. Thus, seven identified lead compounds can be developed further towards the development of new anti-epileptic medications.

Keywords: drug-likeness, phytochemicals, carbonic anhydrases, metalloeazymes, active site, ADMET

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Authors: Sarah Nasr, Maha M. A. Nasra, Ossama Y. Abdallah

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The present work aimed to prepare Silymarin loaded MCM-41 type mesoporous silica nanoparticles (MSNs) and to assess the system’s solubility enhancement ability on the pharmacodynamic performance of Silymarin as a hepatoprotective agent. MSNs prepared by soft-templating technique, were loaded with Silymarin, characterized for particle size, zeta potential, surface properties, DSC and XRPD. DSC and specific surface area data confirmed deposition of Silymarin in an amorphous state in MSNs’ pores. In-vitro drug dissolution testing displayed enhanced dissolution rate of Silymarin upon loading on MSNs. High dose Acetaminophen was then used to inflict hepatic injury upon albino male Wistar rats simultaneously receiving either free Silymarin, Silymarin loaded MSNs or blank MSNs. Plasma AST, ALT, albumin and total protein and liver homogenate content of TBARs or LDH as measures of antioxidant drug action were assessed for all animal groups. Results showed a significant superiority of Silymarin loaded MSNs to free drug in almost all parameters. Meanwhile prolonged administration of blank MSNs had no evident toxicity on rats.

Keywords: mesoporous silica nanoparticles, safety, solubility enhancement, silymarin

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Authors: Maryam Hamedanlou, Shahla Hajializadeh

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The transdermal drug delivery system is one of the types of novel drug delivery system that the drug is absorbed into the skin. The major considerations for designing and producing transdermal patch are small size, suitable drug release and good adhering. In this study, drug-in-adhesive transdermal patch contained non-steroidal anti-inflammatory ketoprofen is prepared. Also, the effect of non-woven fabric and plastic backing layers on adhesion properties is assessed. The results of the test, demonstrated the use of plastic backing layer increases tack and peel rather than non-woven fabric type. The balance tack with plastic backing layer patch is 6.7 (N/mm2), and the fabric one is 3.8 (N/mm2), and their peel is 9.2 (N/25mm) and 8.3 (N/25mm) by arrangement.

Keywords: transdermal drug delivery system, single layer patch of ketoprofen, plastic layer, fabric backing layer

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Authors: Yong Ren, Yaping Zhang

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A numerical model has been developed to investigate the thermally triggered release kinetics for drug delivery using phase change material as shell of microcapsules. Biocompatible material n-Eicosane is used as demonstration. PCM shell of microcapsule will remain in solid form after the drug is taken, so the drug will be encapsulated by the shell, and will not be released until the target body part of lesion is exposed to external heat source, which will thermally trigger the release kinetics, leading to solid-to-liquid phase change. The findings can lead to better understanding on the key effects influencing the phase change process for drug delivery applications. The facile approach to release drug from core/shell structure of microcapsule can be well integrated with organic solvent free fabrication of microcapsules, using double emulsion as template in microfluidic aqueous two phase system.

Keywords: phase change material, drug release kinetics, double emulsion, microfluidics

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Authors: Shiva Rezaei, Seyed Jalal Hosseinimehr, Abbasali Karimpour Malekshah, Mansooreh Mirzaei, Fereshteh Talebpour Amiri, Mehryar Zargari

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Objective(s): Cyclophosphamide (CP), as an antineoplastic drug, is widely used in cancer patients, and liver toxicity is one of its complications. Sinapic acid (SA), as a natural phenylpropanoid, has antioxidant, anti-inflammatory, and anti-cancer properties. Materials and Methods: The purpose of the current study was to determine the protective effect of SA versus CP-induced liver toxicity. In this research, BALB/c mice were treated with SA (5 and 10 mg/kg) orally for one week, and CP (200 mg/kg) was injected on day 3 of the study. Oxidative stress markers, serum liver-specific enzymes, histopathological features, caspase-3, and nuclear factor kappa-B cells were then checked. Results: CP induced hepatotoxicity in mice and showed structural changes in liver tissue. CP significantly increased liver enzymes and lipid peroxidation and decreased glutathione. The immunoreactivity of caspase-3 and nuclear factor kappa-B cells was significantly increased. Administration of SA significantly maintained histochemical parameters and liver function enzymes in mice treated with CP. Immunohistochemical examination showed SA reduced apoptosis and inflammation. Conclusion: The data confirmed that SA with anti-apoptotic, anti-oxidative, and anti-inflammatory activities was able to preserve CP-induced liver injury in mice.

Keywords: apoptosis, cyclophosphamide, liver injury, inflammation, oxidative stress, sinapic acid

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Authors: Lali Khurtsia, Vano Tsertsvadze

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Georgian drug policy is directed to reduce the supply of drugs. Retrospective analysis has shown that law enforcement activities have been followed by the expulsion of particular injecting drugs. The demand remains unchanged and drugs are substituted by the hand-made, even more dangerous homemade drugs entered the market. To find out expected new trends on the Georgian drug market, qualitative study was conducted with Georgian drug users to determine drug supply routes. It turned out that drug suppliers and consumers for safety reasons and to protect their anonymity, use Skype to make deals. IT in illegal drug trade is even more sophisticated in the worldwide. Trading with Bitcoins in the Darknet ensures high confidentiality of money transactions and the safe circulation of drugs. In 2014 largest Bitcoin mining enterprise in the world was built in Georgia. We argue that the use of Bitcoins and Darknet by Georgian drug consumers and suppliers will be an incentive to response adequately to the government's policy of restricting supply in order to satisfy market demand for drugs.

Keywords: bitcoin, darknet, drugs, policy

Procedia PDF Downloads 435

Authors: Ade O. Oyewole, Sunday O. Okoh, Ruth O. Ishola, Adenike D. Odusote, Chima C. Igwe, Gloria N. Elemo, Anthony I. Okoh

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Azadirachta indica (Neem tree) also referred to as an all-purpose tree is used in a wide range of medical preparations in tropical and subtropical countries for prevention and management of various livestock, crops products and human diseases. In Nigeria however, the potentials of this plant have not been fully exploited thus it causes an environmental nuisance during the fruiting season. With a rise in the demand for herbal personal care products globally extracts from different parts of the neem plant were used as the bio-active ingredients in the formulation of personal care products. In this study, formulated neem soap, body cream, lotion, toothpaste and shampoo are analyzed to determine their antibacterial, antifungal, and toxicity properties. The efficacies of these products for management of infectious diseases, both oral and dermal, were also investigated in vitro. Oil from the neem seeds obtained using a mechanical press and acetone extracts of both the neem bark and leaves obtained by the maceration method were used in the formulation and production of the neem personal care products. The antimicrobial and toxicity properties of these products were investigated by agar diffusion, and haemolytic methods respectively. The five neem products (NPs) exhibited strong antibacterial activities against four multi–drug resistant pathogenic and three none pathogenic bacterial strains (Escherichia coli (180), Listeria ivanovii, Staphylococcus aureus, Enterobacter cloacae, Vibro spp., Streptococcus uberis, Mycobacterium smegmatis), except the neem lotion with insignificant activity against E. coli and S. aureus. The minimum inhibitory concentration (MIC) range was between 0.20-0.40 mg/ mL. The 5 NPs demonstrated moderate activity against three clinical dermatophytes isolates (Tinea corporis, Tinea capitis, and Tinea cruiz) as well as one fungal strain (Candida albican) with the MIC ranging between 0.30 - 0.50 mg/ mL and 0.550 mg/mL respectively. The soap and shampoo were the most active against test bacteria and fungi. The haemolytic analysis results on the 5 NPs indicated none toxicity at 0.50 mg/ mL in sheep red blood cells (SRBC).

Keywords: antimicrobial, Azadirachta indica, multi–drug resistant pathogenic bacteria, personal care products

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