Search results for: drug induced premature chromosome condensation

Authors: Jay Ananth

Abstract:

The drug discovery process currently requires numerous years of clinical testing as well as money just for a single drug to earn FDA approval. For drugs that even make it this far in the process, there is a very slim chance of receiving FDA approval, resulting in detrimental hurdles to drug accessibility. To minimize these inefficiencies, numerous studies have implemented computational methods, although few computational investigations have focused on a crucial feature of drugs: lipophilicity. Lipophilicity is a physical attribute of a compound that measures its solubility in lipids and is a determinant of drug efficacy. This project leverages Artificial Intelligence to predict the impact of a drug’s lipophilicity on its performance by accounting for factors such as binding affinity and toxicity. The model predicted lipophilicity and binding affinity in the validation set with very high R² scores of 0.921 and 0.788, respectively, while also being applicable to a variety of target receptors. The results expressed a strong positive correlation between lipophilicity and both binding affinity and toxicity. The model helps in both drug development and discovery, providing every pharmaceutical company with recommended lipophilicity levels for drug candidates as well as a rapid assessment of early-stage drugs prior to any testing, eliminating significant amounts of time and resources currently restricting drug accessibility.

Keywords: drug discovery, lipophilicity, ligand-receptor interactions, machine learning, drug development

Procedia PDF Downloads 77

Authors: Bryony Davies

Abstract:

Many cell and tissue culture practices ignore the effects of gravity on cell biology, and little is known about how cell components may move in response to gravitational forces. Starfish oocytes provide an excellent model for interrogating the movement of cell components due to their unusually large size, ease of handling, and high transparency. Chromosomes from starfish oocytes can be visualised by microinjection of the histone-H2B-mCherry plasmid into the oocytes. The movement of the chromosomes can then be tracked by live-cell fluorescence microscopy. The results from experiments using these methods suggest that there is a replicable downward movement of centrally located chromosomes at a median velocity of 0.39 μm/min. Chromosomes nearer the nuclear boundary showed more restricted movement. Chromosome density and shape could also be altered by microinjection of restriction enzymes, primarily Alu1, before imaging. This was found to alter the speed of chromosome movement, with chromosomes from Alu1-injected nuclei showing a median downward velocity of 0.60 μm/min. Overall, these results suggest that there is a non-negligible movement of chromosomes in response to gravitational forces and that this movement can be altered by enzyme activity. Future directions based on these results could interrogate if this observed downward movement extends to other cell components and to other cell types. Additionally, it may be important to understand whether gravitational orientation and vertical positioning of cell components alter cell behaviour. The findings here may have implications for current cell culture practices, which do not replicate cell orientations or external forces experienced in vivo. It is possible that a failure to account for gravitational forces in 2D cell culture alters experimental results and the accuracy of conclusions drawn from them. Understanding possible behavioural changes in cells due to the effects of gravity would therefore be beneficial.

Keywords: starfish, oocytes, live-cell imaging, microinjection, chromosome dynamics

Procedia PDF Downloads 74

Authors: Zellagui Redouane, Bellaouar Ahmed, Lachi Mohammed

Abstract:

The railway axles are the essential parts in the bogie of train, and its failure creates a big problem in the railway transport; during the work of this parts we noticed a premature deterioration. The aim has been presented a predictive model allowing the identification of the probable causes that are the cause of these premature deterioration. The results are employed for predicting fatigue crack growth in the railway axle, Also we want to present the variation value of stress intensity factor in different positions of elliptical crack tip. The modeling of axle in performed by the SOLID WORKS software and imported into ANSYS.

Keywords: crack growth, static load, railway axle, lifetime

Procedia PDF Downloads 329

Authors: Firas Rashad Al-Samarai

Abstract:

Introduction: Benign prostatic hyperplasia (BPH) is a common condition as men get older. An enlarged prostate gland can cause uncomfortable urinary symptoms, such as blocking the flow of urine out of the bladder. It can also cause bladder, urinary tract, or kidney problems. Objective: to evaluate the efficacy and interaction of tamsulosin with finasteride treatment on induced benign prostate hyperplasia (BPH) in mice. Methods: BPH was induced by subcutaneous injection of testosterone propionate (20 mg/kg) for 30 days. Eighty-five mice were divided into five groups. The first group (G1): twenty-five mice induced BPH treated with tamsulosin orally and divided into five equal subgroups with doses (0.017, 0.052, 0.087, 0. 123, and 0.158) mg/kg, the second group (G2): twenty-five mice induced BPH treated with finasteride orally and divided into five equal subgroups with doses (0.175, 0.527, 0.878, 1.23, and 1.580) mg/kg. the third group (G3): twenty-five mice induced BPH treated with a combination of tamsulosin with finasteride orally, and divided into five equal subgroups with doses (0.0085, 0.0875), (0.026, 0.2635), (0.0435, 0.439) , (0.0615, 0.615) and ( 0.079 , 0.790 ) mg/kg respectively. Fourth group (G4): five mice induced BPH and treated distilled water. Fifth group (G5): five mice were not inducing BPH and without any treatment. Results: The results showed a gradual significant increase in prostate weight % and prostate index % Inhibitions until reached saturation in the last two doses of tamsulosin, finasteride, and combination groups, the maximum effective dose of tamsulosin and finasteride were (0.156) and (1.495) mg/kg respectively. Moreover, the effective dose of the combination (tamsulosin and finasteride) was estimated (0.06876, 0.6876) mg/kg, respectively, as well as the type of interaction was synergism and the value of the combination index was 0.046. Conclusions: We concluded that the combination of tamsulosin with finasteride showed a synergistic effect in BPH treatment by minimizing the side effect of each drug as s result of decreasing the dose of each one.

Keywords: Tamsulosin, Finasteride, combination, BPH

Procedia PDF Downloads 51

Authors: Yasmin Begum Mohammed

Abstract:

Ketorolac tromethamine (KTM) is a non-steroidal anti-inflammatory drug with a potent analgesic and anti-inflammatory activity due to prostaglandin related inhibitory effect of drug. It is a non-selective cyclo-oxygenase inhibitor. The drug is currently used orally and intramuscularly in multiple divided doses, clinically for the management arthritis, cancer pain, post-surgical pain, and in the treatment of migraine pain. KTM has short biological half-life of 4 to 6 hours, which necessitates frequent dosing to retain the action. The frequent occurrence of gastrointestinal bleeding, perforation, peptic ulceration, and renal failure lead to the development of other drug delivery strategies for the appropriate delivery of KTM. The ideal solution would be to target the drug only to the cells or tissues affected by the disease. Drug targeting could be achieved effectively by liposomes that are biocompatible and biodegradable. The aim of the study was to develop a parenteral liposome formulation of KTM with improved efficacy while reducing side effects by targeting the inflammation due to arthritis. PEG-anchored (stealth) and non-PEG-anchored liposomes were prepared by thin film hydration technique followed by extrusion cycle and characterized for in vitro and in vivo. Stealth liposomes (SLs) exhibited increase in percent encapsulation efficiency (94%) and 52% percent of drug retention during release studies in 24 h with good stability for a period of 1 month at -20°C and 4°C. SLs showed about maximum 55% of edema inhibition with significant analgesic effect. SLs produced marked differences over those of non-SL formulations with an increase in area under plasma concentration time curve, t₁/₂, mean residence time, and reduced clearance. 0.3% of the drug was detected in arthritic induced paw with significantly reduced drug localization in liver, spleen, and kidney for SLs when compared to other conventional liposomes. Thus SLs help to increase the therapeutic efficacy of KTM by increasing the targeting potential at the inflammatory region.

Keywords: biodistribution, ketorolac tromethamine, stealth liposomes, thin film hydration technique

Procedia PDF Downloads 273

Authors: Nishank Raisinghani

Abstract:

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

Procedia PDF Downloads 115

Authors: Reza Ferdousi, Reza Safdari, Yadollah Omidi

Abstract:

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

Procedia PDF Downloads 289

Authors: Arpa Petchsomrit, Namfa Sermkaew, Ruedeekorn Wiwattanapatapee

Abstract:

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

Procedia PDF Downloads 364

Authors: Hind O. Osman, Tilal Elsaman, Bashir A. Yousef, Esraa Elhadi, Aimun A. E. Ahmed, Eyman Mohamed Eltayib, Malik Suliman Mohamed, Magdi Awadalla Mohamed

Abstract:

Epilepsy is the most common neurological condition and cause of substantial morbidity and mortality. In the present study, the molecular hybridization tool was adopted to obtain six Schiff bases of isatin and adamantane-1-carbohydrazide (18–23). Then, their anticonvulsant activity was evaluated using a pentylenetetrazole- (PTZ-) induced seizure model using phenobarbitone as a positive control. Our findings showed that compounds 18–23 provided significant protection against PTZ-induced seizure, and maximum activities were associated with compound 23. Moreover, all investigated compounds increased the latency of induced convulsion and reduced the duration of epilepsy, with compound 23 being the best. Interestingly, most of the synthesized molecules showed a reduction in neurological symptoms and severity of the seizure. Molecular docking studies suggest GABA-A receptor as a potential target, and in silico ADME screening revealed that the pharmaceutical properties of compound 23 are within the specified limit. Thus, compound 23 was identified as a promising candidate that warrants further drug discovery processes.

Keywords: isatin and adamantane, anticonvulsant activity, PTZ-induced seizure, molecular docking

Procedia PDF Downloads 179

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

Abstract:

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)

Procedia PDF Downloads 240

Authors: Wisam H. Benamer, Ehab A. Elfallah, Mohamed A. Elshaari, Farag A. Elshaari

Abstract:

A challenge for laboratories is to provide bacterial identification and antibiotic sensitivity results within a short time. Hence, advancement in the required technology is desirable to improve timing, accuracy and quality. Even with the current advances in methods used for both phenotypic and genotypic identification of bacteria the need is there to develop method(s) that enhance the outcome of bacteriology laboratories in accuracy and time. The hypothesis introduced here is based on the assumption that the chromosome of any bacteria contains unique sequences that can be used for its identification and typing. The outcome of a pilot study designed to test this hypothesis is reported in this manuscript. Methods: The complete chromosome sequences of several bacterial species were downloaded to use as search targets for unique sequences. Visual basic and SQL server (2014) were used to generate a complete set of 18-base long primers, a process started with reverse translation of randomly chosen 6 amino acids to limit the number of the generated primers. In addition, the software used to scan the downloaded chromosomes using the generated primers for similarities was designed, and the resulting hits were classified according to the number of similar chromosomal sequences, i.e., unique or otherwise. Results: All primers that had identical/similar sequences in the selected genome sequence(s) were classified according to the number of hits in the chromosomes search. Those that were identical to a single site on a single bacterial chromosome were referred to as unique. On the other hand, most generated primers sequences were identical to multiple sites on a single or multiple chromosomes. Following scanning, the generated primers were classified based on ability to differentiate between medically important bacterial and the initial results looks promising. Conclusion: A simple strategy that started by generating primers was introduced; the primers were used to screen bacterial genomes for match. Primer(s) that were uniquely identical to specific DNA sequence on a specific bacterial chromosome were selected. The identified unique sequence can be used in different molecular diagnostic techniques, possibly to identify bacteria. In addition, a single primer that can identify multiple sites in a single chromosome can be exploited for region or genome identification. Although genomes sequences draft of isolates of organism DNA enable high throughput primer design using alignment strategy, and this enhances diagnostic performance in comparison to traditional molecular assays. In this method the generated primers can be used to identify an organism before the draft sequence is completed. In addition, the generated primers can be used to build a bank for easy access of the primers that can be used to identify bacteria.

Keywords: bacteria chromosome, bacterial identification, sequence, primer generation

Procedia PDF Downloads 167

Authors: Pear-Rarin Leelakunakorn, Patompong Satapornpong

Abstract:

Introduction: Dapsone is an anti-inflammatory and antibiotic drug that was widely used for the treatment of leprosy, acne fulminans, and dermatitis herpetiformis (DH). However, dapsone is the main cause that triggers severe cutaneous adverse reactions (SCARs), with a possibility of 0.4 to 3.6% of patients after initiating treatment. In fact, the mortality rate of dapsone-induced SCARs is approximately 9.9%. In previous studies, HLA-B*13:01 was strongly associated with dapsone-induced SCARs in Han Chinese, Thais, and Koreans. Nevertheless, the distribution of HLA-B*13:01 marker in each population might differ. Moreover, there were found that the association between HLA-C*03:04 and dapsone hypersensitivity syndrome in Han Chinese leprosy patients by OR = 9.00 and p-value = 2.23×10⁻¹⁹. Objective: The aim of this study was to investigate the distribution of HLA-C* 03:04 in Thailand's healthy population. Method: A total of 350 participants were HLA-C genotyping used sequence-specific oligonucleotides (PCR-SSOs). This study was approved by the Ethics Committee of Rangsit University Result : The most frequency of HLA -C alleles in Thais, consist of HLA -C* 01:02 (17.00 %), -C*08:01 (11.00%) , -C*07:02 (10.70%) , -C* 03:04 ( 9.10%) , -C* 03:02 (8.00%) , -C* 07:01 (6.30%), -C* 07:04 (4.60%), -C* 04:01 (4.40%) ,-C* 12:02 ( 4.30% ) ,and -C* 04:03(3.90%). Interestingly, HLA -C* 03:04 allele was similar to the distribution among Thais and other populations such as Eastern Europe (6.09%), Vietnam (7.42% ), East Croatia (2.25%), and Han Chinese (11.70%). Conclusion: Consequently, HLA-C*03:04 might serve as a pharmacogenetic marker for screening prior to initiation therapy with dapsone for prevention of dapsone-induced SCARs in Thai population.

Keywords: HLA-C*03:04, SCARs, thai population, allele frequency

Procedia PDF Downloads 102

Authors: V. Balamuralidhara

Abstract:

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

Procedia PDF Downloads 319

Authors: Asher John Mohan, Krishna K. L.

Abstract:

Objectives: (1) To assess the extent of memory impairment induced by Phenytoin (PHT) at normal and reduced dose on temporal lobe epileptic mice. (2) To evaluate the protective effect of Levetiracetam (LEV) on aggravation of memory impairment in temporal lobe epileptic mice by PHT. Materials and Methods: Albino mice of either sex (n=36) were used for the study for a period of 64 days. Convulsions were induced by intraperitoneal administration of pilocarpine 280 mg/kg on every 6th day. Radial arm maze (RAM) was employed to evaluate the memory impairment activity on every 7th day. The anticonvulsant and memory impairment activity were assessed in PHT normal and reduced doses both alone and in combination with LEV. RAM error scores and convulsive scores were the parameters considered for this study. Brain acetylcholine esterase and glutamate were determined along with histopathological studies of frontal cortex. Results: Administration of PHT for 64 days on mice has shown aggravation of memory impairment activity on temporal lobe epileptic mice. Although the reduction in PHT dose was found to decrease the degree of memory impairment the same decreased the anticonvulsant potency. The combination with LEV not only brought about the correction of impaired memory but also replaced the loss of potency due to the reduction of the dose of the antiepileptic drug employed. These findings were confirmed with enzyme and neurotransmitter levels in addition to histopathological studies. Conclusion: This study thus builds a foundation in combining a nootropic anticonvulsant with an antiepileptic drug to curb the adverse effect of memory impairment associated with temporal lobe epilepsy. However further extensive research is a must for the practical incorporation of this approach into disease therapy.

Keywords: anti-epileptic drug, Phenytoin, memory impairment, Pilocarpine

Procedia PDF Downloads 292

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

Abstract:

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

Procedia PDF Downloads 310

Authors: Kumaran Narayanan, Pei-Sheng Liew

Abstract:

This paper adapts the bacteriophage N15 protelomerase enzyme to assemble linear chromosomes as vectors for gene expression in human cells. Phage N15 has the unique ability to replicate as a linear plasmid with telomeres in E. coli during its prophage stage of life-cycle. The virus-encoded protelomerase enzyme cuts its circular genome and caps its ends to form hairpin telomeres, resulting in a linear human-chromosome-like structure in E. coli. In mammalian cells, however, no enzyme with TelN-like activities has been found. In this work, we show for the first-time transfer of the protelomerase from phage into human and mouse cells and demonstrate recapitulation of its activity in these hosts. The function of this enzyme is assayed by demonstrating cleavage of its target DNA, followed by detecting telomere formation based on its resistance to recBCD enzyme digestion. We show protelomerase expression persists for at least 60 days, which indicates limited silencing of its expression. Next, we show that an intact human β-globin gene delivered on this linear chromosome accurately retains its expression in the human cellular environment for at least 60 hours, demonstrating its stability and potential as a vector. These results demonstrate that the N15 protelomerse is able to function in mammalian cells to cut and heal DNA to create telomeres, which provides a new tool for creating novel structures by DNA resolution in these hosts.

Keywords: chromosome, beta-globin, DNA, gene expression, linear vector

Procedia PDF Downloads 168

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

Abstract:

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

Procedia PDF Downloads 591

Authors: R. K. Purohit

Abstract:

Ionizing radiation induces cellular damage through direct ionization of DNA and other cellular targets and indirectly via reactive oxygen species which may include effects from epigenetic changes. So there is a need of hour is to search for an ideal radioprotector which could minimize the deleterious and damaging effects caused by ionizing radiation. Radioprotectors are agents which reduce the radiation effects on cell when applied prior to exposure of radiation. The aim of this study was to access the efficacy of Emblica officinalis in reducing radiation and lead induced changes in mice liver. For the present experiment, healthy male Swiss albino mice (6-8 weeks) were selected and maintained under standard conditions of temperature and light. Fruit extract of Emblica was fed orally at the dose of 0.01 ml/animal/day. The animal were divided into seven groups according to the treatment i.e. lead acetate solution as drinking water (group-II) or exposed to 3.5 or 7.0 Gy gamma radiation (group-III) or combined treatment of radiation and lead acetate (group-IV). The animals of experimental groups were administered Emblica extract seven days prior to radiation or lead acetate treatment (group V, VI and VII) respectively. The animals from all the groups were sacrificed by cervical dislocation at each post-treatment intervals of 1, 2, 4, 7, 14 and 28 days. After sacrificing the animals pieces of liver were taken out and some of them were kept at -20°C for different biochemical parameters. The histopathological changes included cytoplasmic degranulation, vacuolation, hyperaemia, pycnotic and crenated nuclei. The changes observed in the control groups were compared with the respective experimental groups. An increase in the value of total proteins, glycogen, acid phosphtase, alkaline phosphatase activity and RNA was observed up to day-14 in the non drug treated group and day 7 in the Emblica treated groups, thereafter value declined up to day-28 without reaching to normal. The value of cholesterol and DNA showed a decreasing trend up to day -14 in non drug treated groups and day-7 in drug treated groups, thereafter value elevated up to day-28. The biochemical parameters were observed in the form of increase or decrease in the values. The changes were found dose dependent. After combined treatment of radiation and lead acetate synergistic effect were observed. The liver of Emblica treated animals exhibited less severe damage as compared to non-drug treated animals at all the corresponding intervals. An early and fast recovery was also noticed in Emblica pretreated animals. Thus, it appears that Emblica is potent enough to check lead and radiation induced heptic lesion in Swiss albino mice.

Keywords: radiation, lead , emblica, mice, liver

Procedia PDF Downloads 296

Authors: Elizabeth McLean, Katrina Skewes-McFerran, Grace Thompson

Abstract:

Scholarship highlights the need to further examine and better understand and foster the process of becoming a parent to a premature baby in the neonatal context to support the critical development of the parent-infant relationship. Music therapy research documents significant benefits of music therapy on neonatal physiological and neurodevelopmental function, reduced maternal anxiety and validating parents’ relationship with their premature baby, yet limited studies examine the role of music in supporting parental identity. This was a multi-site study, exploring parents’ musical engagement with their hospitalised baby and parental identity in a NU. In-depth interviews with nine parents of a premature baby across varying time points in their NU journey took place. Data collection and analysis was influenced by Constructive Grounded Theory methodology. Findings in the form of a substantive grounded theory illuminated the contribution of parents’ musical engagement on their sense of parental identity in the NU. Specifically, the significance of their baby’s level and type of response during musical interactions in influencing parents’ capacity to engage in musical dialogue with their baby emerged. Specific conditions that acted as both barriers and fosters in parents’ musical engagement across a high- risk pregnancy and NU admission also emerged. Recommendations for future research into the role of music and music therapy in supporting parental coping and transition to parenthood during a high-risk pregnancy and birth and beyond the NU will be discussed.

Keywords: grounded theory, musical engagement, music therapy, parental identity

Procedia PDF Downloads 158

Authors: Titus A. Beu

Abstract:

Many modern gene-delivery protocols rely on condensed complexes of DNA with polycations to introduce the genetic payload into cells by endocytosis. In particular, polyethyleneimine (PEI) stands out by a high buffering capacity (enabling the efficient condensation of DNA) and relatively simple fabrication. Realistic computational studies can offer essential insights into the formation process of DNA-PEI polyplexes, providing hints on efficient designs and engineering routes. We present comprehensive computational investigations of solvated PEI and DNA-PEI polyplexes involving calculations at three levels: ab initio, all-atom (AA), and coarse-grained (CG) molecular mechanics. In the first stage, we developed a rigorous AA CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field (FF) for PEI on the basis of accurate ab initio calculations on protonated model pentamers. We validated this atomistic FF by matching the results of extensive molecular dynamics (MD) simulations of structural and dynamical properties of PEI with experimental data. In a second stage, we developed a CG MARTINI FF for PEI by Boltzmann inversion techniques from bead-based probability distributions obtained from AA simulations and ensuring an optimal match between the AA and CG structural and dynamical properties. In a third stage, we combined the developed CG FF for PEI with the standard MARTINI FF for DNA and performed comprehensive CG simulations of DNA-PEI complex formation and condensation. Various technical aspects which are crucial for the realistic modeling of DNA-PEI polyplexes, such as options of treating electrostatics and the relevance of polarizable water models, are discussed in detail. Massive CG simulations (with up to 500 000 beads) shed light on the mechanism and provide time scales for DNA polyplex formation independence of PEI chain size and protonation pattern. The DNA-PEI condensation mechanism is shown to primarily rely on the formation of DNA bundles, rather than by changes of the DNA-strand curvature. The gained insights are expected to be of significant help for designing effective gene-delivery applications.

Keywords: DNA condensation, gene-delivery, polyethylene-imine, molecular dynamics.

Procedia PDF Downloads 96

Authors: Jia-Ling Ho, Xiu-Ru Zhang, Zwe-Ling Kong

Abstract:

Diabetes mellitus (DM) is a major health problem that affects patients’ life quality throughout the world due to its many complications. It characterized by chronic hyperglycemia with oxidative stress, which impaired male reproductive function. Fibroblast growth factor 21 (FGF21) is a metabolic regulator that is required for normal spermatogenesis and protects against diabetes-induced germ cell apoptosis. Echinacea purpurea ethanol extract (EE), which contain phenolic acid and isobutylamide, had been proven to have antidiabetic property. Silica-chitosan nanoparticles (Nano-CS) has drug delivery and controlled release properties. This study aims to investigate whether silica-chitosan nanoparticles encapsulated EE (Nano-EE) had more ameliorating male infertility by analyzing the effect of testicular FGF21. The Nano-EE was characterized before used to treatment the diabetic rat model. Male Sprague-Dawley (SD) rats were obtained and divided into seven groups. A group was no induced Streptozotocin (STZ), marked as normal group. Diabetic rats were induced into diabetes by STZ (33 mg/kg). A diabetic group was no treatment with sample (diabetic control group), and other groups were treatment by Nano-CS (465 mg/kg), Nano-EE (93, 279, 465 mg/kg), and metformin (Met) (200 mg/kg) used as reference drug for 7 weeks. Our results indicated that the average nanoparticle size and zeta potential of Nano-EE were 2630 nm and -21.3 mV, respectively. The encapsulation ratio of Nano-EE was about 70%. It also confirmed the antioxidative activity was unchanged by comparing the DPPH and ABTS scavenging of Nano-EE and EE. In vivo test, Nano-EE can improve the STZ induced hyperglycemia, insulin resistance, and plasma FGF21 levels. Nano-EE has increased sperm motility, mitochondria membrane potential (MMP), plasma testosterone level, and reduction of abnormal sperm, nitric oxide (NO), superoxide production as well as reactive oxygen species (ROS). In addition, in plasma antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) was increased whereas pro-inflammatory cytokines TNF-α, and IL-1β were decreased. Further, in testis, protein content of FGF21, PGC-1α, and SIRT1 were improved. Nano-EE might improve diabetes-induced down-regulation of testicular FGF21 and SIRT1/PGC-1α signaling hence maintain spermatogenesis.

Keywords: diabetes mellitus, Echinacea purpurea, reproductive dysfunction, silica-chitosan nanoparticles

Procedia PDF Downloads 163

Authors: Stanely Nsubuga

Abstract:

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

Procedia PDF Downloads 101

Authors: Oleg Reva, Ilya Korotetskiy, Marina Lankina, Murat Kulmanov, Aleksandr Ilin

Abstract:

Molecular docking approaches are widely used for design of new antibiotics and modeling of antibacterial activities of numerous ligands which bind specifically to active centers of indispensable enzymes and/or key signaling proteins of pathogens. Widespread drug resistance among pathogenic microorganisms calls for development of new antibiotics specifically targeting important metabolic and information pathways. A generally recognized problem is that almost all molecular targets have been identified already and it is getting more and more difficult to design innovative antibacterial compounds to combat the drug resistance. A promising way to overcome the drug resistance problem is an induction of reversion of drug resistance by supplementary medicines to improve the efficacy of the conventional antibiotics. In contrast to well established computer-based drug design, modeling of drug resistance reversion still is in its infancy. In this work, we proposed an approach to identification of compensatory genetic variants reducing the fitness cost associated with the acquisition of drug resistance by pathogenic bacteria. The approach was based on an analysis of the population genetic of Mycobacterium tuberculosis and on results of experimental modeling of the drug resistance reversion induced by a new anti-tuberculosis drug FS-1. The latter drug is an iodine-containing nanomolecular complex that passed clinical trials and was admitted as a new medicine against MDR-TB in Kazakhstan. Isolates of M. tuberculosis obtained on different stages of the clinical trials and also from laboratory animals infected with MDR-TB strain were characterized by antibiotic resistance, and their genomes were sequenced by the paired-end Illumina HiSeq 2000 technology. A steady increase in sensitivity to conventional anti-tuberculosis antibiotics in series of isolated treated with FS-1 was registered despite the fact that the canonical drug resistance mutations identified in the genomes of these isolates remained intact. It was hypothesized that the drug resistance phenotype in M. tuberculosis requires an adjustment of activities of many genes to compensate the fitness cost of the drug resistance mutations. FS-1 cased an aggravation of the fitness cost and removal of the drug-resistant variants of M. tuberculosis from the population. This process caused a significant increase in genetic heterogeneity of the Mtb population that was not observed in the positive and negative controls (infected laboratory animals left untreated and treated solely with the antibiotics). A large-scale search for linkage disequilibrium associations between the drug resistance mutations and genetic variants in other genomic loci allowed identification of target proteins, which could be influenced by supplementary drugs to increase the fitness cost of the drug resistance and deprive the drug-resistant bacterial variants of their competitiveness in the population. The approach will be used to improve the efficacy of FS-1 and also for computer-based design of new drugs to combat drug-resistant infections.

Keywords: complete genome sequencing, computational modeling, drug resistance reversion, Mycobacterium tuberculosis

Procedia PDF Downloads 239

Authors: Florin G. Borcan, Ramona C. Albulescu, Adela Chirita-Emandi

Abstract:

pH-responsive drug delivery systems are gaining more importance because these systems deliver the drug at a specific time in regards to pathophysiological necessity, resulting in improved patient therapeutic efficacy and compliance. Polyurethane materials are well-known for industrial applications (elastomers and foams used in different insulations and automotive), but they are versatile biocompatible materials with many applications in medicine, as artificial skin for the premature neonate, membrane in the hybrid artificial pancreas, prosthetic heart valves, etc. This study aimed to obtain the physico-chemical characterization of a drug delivery system based on polyurethane microparticles. The synthesis is based on a polyaddition reaction between an aqueous phase (mixture of polyethylene-glycol M=200, 1,4-butanediol and Tween® 20) and an organic phase (lysin-diisocyanate in acetone) combined with simultaneous emulsification. Different active agents (omeprazole, amoxicillin, metoclopramide) were used to verify the release profile of the macromolecular particles in different pH mediums. Zetasizer measurements were performed using an instrument based on two modules: a Vasco size analyzer and a Wallis Zeta potential analyzer (Cordouan Technol., France) in samples that were kept in various solutions with different pH and the maximum absorbance in UV-Vis spectra were collected on a UVi Line 9,400 Spectrophotometer (SI Analytics, Germany). The results of this investigation have revealed that these particles are proper for a prolonged release in gastric medium where they can assure an almost constant concentration of the active agents for 1-2 weeks, while they can be disassembled faster in a medium with neutral pHs, such as the intestinal fluid.

Keywords: lysin-diisocyanate, nanostructures, polyurethane, Zetasizer

Procedia PDF Downloads 163

Authors: Yuri S. Djikaev

Abstract:

A large subset of aqueous aerosols can be initially (immediately upon formation) coated with various organic amphiphilic compounds whereof the hydrophilic moieties are attached to the aqueous aerosol core while the hydrophobic moieties are exposed to the air thus forming a hydrophobic coating thereupon. We study the thermodynamics of water condensation on such an aerosol whereof the hydrophobic organic coating is being concomitantly processed by chemical reactions with atmospheric reactive species. Such processing (chemical aging) enables the initially inert aerosol to serve as a nucleating center for water condensation. The most probable pathway of such aging involves atmospheric hydroxyl radicals that abstract hydrogen atoms from hydrophobic moieties of surface organics (first step), the resulting radicals being quickly oxidized by ubiquitous atmospheric oxygen molecules to produce surface-bound peroxyl radicals (second step). Taking these two reactions into account, we derive an expression for the free energy of formation of an aqueous droplet on an organic-coated aerosol. The model is illustrated by numerical calculations. The results suggest that the formation of aqueous cloud droplets on such aerosols is most likely to occur via Kohler activation rather than via nucleation. The model allows one to determine the threshold parameters necessary for their Kohler activation. Numerical results also corroborate previous suggestions that one can neglect some details of aerosol chemical composition in investigating aerosol effects on climate.

Keywords: aqueous aerosols, organic coating, chemical aging, cloud condensation nuclei, Kohler activation, cloud droplets

Procedia PDF Downloads 366

Authors: Maryam Hamedanlou, Shahla Hajializadeh

Abstract:

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

Procedia PDF Downloads 227

Authors: Fariha Qureshi, Mohammad Tahir

Abstract:

Epidemiological evidences indicated that arsenic contamination in drinking water increased the incidence of spontaneous abortion, stillbirth and premature babies in pregnant women. This study was designed to investigate the protective role of vitamin C&E against sodium arsenate induced fetal toxicity in albino mice. Twenty-four pregnant albino mice of BALB/c strain were randomly divided into 4 groups having 6 animals in each. Group A1 served as control and was injected with 0.1ml/kg/day distilled water I/P for 18 days. Groups A2,A3 & A4 received single I/P injection of sodium arsenate 35mg/kg on 8th gestational day, whereas groups A3 and A4 were also given Vitamin C and E by I/P injection, 9 mg/kg/day and 15 mg/kg/day respectively, starting from 8th GD and continued for the rest of the pregnancy period. The early implantation sites, fetal resorptions, weight of live fetuses and crown rump length were recorded. Gross morphological examination was carried out for malformations. Fetal kidneys were extracted for histological and micrometric analysis. Group A2 exhibited an increased incidence of abortion, fetal resorptions, significant decrease in number of litter and fetal weight; the difference of means was statistically significant among the groups (p<0.000). In group A2 fetal kidneys presented glomerulonephritis with acute tubular necrotic changes and interstitial fibrosis. Groups A3&A4 showed statistically significant improvement in these parameters. The results revealed the antioxidant potential of Vitamin C and E in protecting against arsenic induced fetal toxicity in mice.

Keywords: fetal toxicity, fetal resorptions, interstitial fibrosis, tocopherol

Procedia PDF Downloads 239

Authors: Alsu F. Saifitdinova, Alexey S. Komissarov, Svetlana A. Galkina, Elena I. Koshel, Maria M. Kulak, Stephen J. O'Brien, Elena R. Gaginskaya

Abstract:

The mystery of sex determination is one of the most ancient and still not solved until the end so far. In many species, sex determination is genetic and often accompanied by the presence of dimorphic sex chromosomes in the karyotype. Genomic sequencing gave the information about the gene content of sex chromosomes which allowed to reveal their origin from ordinary autosomes and to trace their evolutionary history. Female-specific W chromosome in birds as well as mammalian male-specific Y chromosome is characterized by the degeneration of gene content and the accumulation of repetitive DNA. Tandem repeats complicate the analysis of genomic data. Despite the best efforts chicken W chromosome assembly includes only 1.2 Mb from expected 55 Mb. Supplementing the information on the sex chromosome composition not only helps to complete the assembly of genomes but also moves us in the direction of understanding of the sex-determination systems evolution. A whole-genome survey to the assembly Gallus_gallus WASHUC 2.60 was applied for repeats search in assembled genome and performed search and assembly of high copy number repeats in unassembled reads of SRR867748 short reads datasets. For cytogenetic analysis conventional methods of fluorescent in situ hybridization was used for previously cloned W specific satellites and specifically designed directly labeled synthetic oligonucleotide DNA probe was used for bioinformatically identified repetitive sequence. Hybridization was performed with mitotic chicken chromosomes and manually isolated giant meiotic lampbrush chromosomes from growing oocytes. A novel chicken W specific satellite (GGAAA)n which is not co-localizes with any previously described classes of W specific repeats was identified and mapped with high resolution. In the composition of autosomes this repeat units was found as a part of upstream regions of gonad specific protein coding sequences. These findings may contribute to the understanding of the role of tandem repeats in sex specific differentiation regulation in birds and sex chromosome evolution. This work was supported by the postdoctoral fellowships from St. Petersburg State University (#1.50.1623.2013 and #1.50.1043.2014), the grant for Leading Scientific Schools (#3553.2014.4) and the grant from Russian foundation for basic researches (#15-04-05684). The equipment and software of Research Resource Center “Chromas” and Theodosius Dobzhansky Center for Genome Bioinformatics of Saint Petersburg State University were used.

Keywords: birds, lampbrush chromosomes, sex chromosomes, tandem repeats

Procedia PDF Downloads 363

Authors: Yong Ren, Yaping Zhang

Abstract:

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

Procedia PDF Downloads 331

Authors: Sourabh Jain, Vikas Jain, Dharmendar Kumar

Abstract:

The present study investigated the antidiabetic potential of Cedrus deodara heart wood aqueous extract. Aqueous extract of Cedrus deodara was found to reduce blood sugar level in alloxan induced diabetic rats. Reduction in blood sugar could be seen from 5th day after continuous administration of the extract and on 21st day sugar levels were found to be reduced by 40.20%. Oxidative stress produced by alloxan was found to be significantly lowered by the administration of Cedrus deodara aqueous extract (500 mg/kg). This was evident from a significant decrease in lipid per oxidation level in liver induced by alloxan. The level of Glutathione, Catalase, Superoxide dismutase and Glutathione-S-Transferase in liver, kidney and pancreas tissue were found to be increased significantly after drug administration. The results obtained in the present study suggest that the Cedrus deodara aqueous extract effectively and significantly reduced the oxidative stress induced by alloxan and produced a reduction in blood sugar level.

Keywords: Cedrus deodara, heartwood, antioxidant, anti-diabetic, anti-inflammatory

Procedia PDF Downloads 357