Search results for: antibacterial drug

Authors: Donna M. Morrison, Lambert Chester, Coretta A. N. Samuels, David R. Ledoux

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A survey was conducted in the five rice-growing regions in Guyana to determine the presence of aflatoxins in multiple fractions of rice in June/October 2015 growing season. The fractions were paddy, steamed paddy, cargo rice, white rice and parboiled rice. Samples were analyzed by High Performance Liquid Chromatography. A subset of the samples was further analyzed by enzyme-linked immunosorbent assay (ELISA) for concurrence. All analyses were conducted at the University of Missouri, USA. Of the 186 samples tested, 16 had aflatoxin concentrations greater than 20 ppb the recommended limit for aflatoxins in food according to the United States Food and Drug Administration. An additional three samples had aflatoxin B₁ concentrations greater than the European Union Commission maximum levels for aflatoxin B₁ in rice at 5 µg/kg and total aflatoxins (B₁, B₂, G₁ and G₂) at 10 µg/kg. The survey indicates that there is no widespread aflatoxin problem in rice in Guyana. The incidence of aflatoxins appears to be localized.

Keywords: aflatoxin, enzyme-linked immunosorbent assay (ELISA), high-performance liquid chromatography (HPLC), rice fractions

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Authors: Jyh-Cheng Chen, Tai-Jing Wang, Yun-Wei Lin

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Astaxanthin has been demonstrated to exhibit a wide range of beneficial effects including anti-inflammatory and anti-cancer properties. However, the molecular mechanism of astaxanthin-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Rad51 plays a central role in homologous recombination and high levels of Rad51 expression are observed in chemo- or radioresistant carcinomas. In this study, astaxanthin treatment inhibited cell viability and proliferation of two NSCLC cells, A549 and H1703. Treatment with astaxanthin decreased Rad51 expression and phospho-AKT protein level in a time and dose-dependent manner. Furthermore, expression of constitutively active AKT (AKT-CA) vector significantly rescued the decreased Rad51 protein and mRNA levels in astaxanthin-treated NSCLC cells. Combined treatment with PI3K inhibitors (LY294002 or wortmannin) and astaxanthin further decreased the Rad51 expression in NSCLC cells. Knockdown of Rad51 enhanced astaxanthin-induced cytotoxicity and growth inhibition in NSCLC cells. These findings may have implications for the rational design of future drug regimens incorporating astaxanthin for the treatment of NSCLC.

Keywords: astaxanthin, cytotoxicity, AKT, non-small cell lung cancer, PI3K

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Authors: Laxman H. Surwase, Lalit V. Sonawane, Bhagwat N. Poul

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A simple stability indicating high performance liquid chromatographic method has been developed for the simultaneous determination of Levosalbutamol Sulphate and Ipratropium Bromide in bulk and pharmaceutical dosage form using reverse phase Zorbax Eclipse Plus C8 column (250mm×4.6mm), with mobile phase phosphate buffer (0.05M KH2PO4): acetonitrile (55:45v/v) pH 3.5 adjusted with ortho-phosphoric acid, the flow rate was 1.0 mL/min and the detection was carried at 212 nm. The retention times of Levosalbutamol Sulphate and Ipratropium Bromide were 2.2007 and 2.6611 min respectively. The correlation coefficient of Levosalbutamol Sulphate and Ipratropium Bromide was found to be 0.997 and 0.998.Calibration plots were linear over the concentration ranges 10-100µg/mL for both Levosalbutamol Sulphate and Ipratropium Bromide. The LOD and LOQ of Levosalbutamol Sulphate were 2.520µg/mL and 7.638µg/mL while for Ipratropium Bromide was 1.201µg/mL and 3.640 µg/mL. The accuracy of the proposed method was determined by recovery studies and found to be 100.15% for Levosalbutamol Sulphate and 100.19% for Ipratropium Bromide respectively. The method was validated for accuracy, linearity, sensitivity, precision, robustness, system suitability. The proposed method could be utilized for routine analysis of Levosalbutamol Sulphate and Ipratropium Bromide in bulk and pharmaceutical capsule dosage form.

Keywords: levosalbutamol sulphate, ipratropium bromide, RP-HPLC, phosphate buffer, acetonitrile

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Authors: Milica Z. Karadzic, Lidija R. Jevric, Sanja Podunavac-Kuzmanovic, Strahinja Z. Kovacevic, Anamarija I. Mandic, Katarina Penov-Gasi, Andrea R. Nikolic, Aleksandar M. Okljesa

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In this study, a set of 29 newly synthesized steroid derivatives were investigated using reversed-phase high-performance liquid chromatography (RP-HPLC) as a first step in preselection of drug candidates. This analysis presents an experimental determination of chromatographic lipophilicity, and it was conducted to obtain physicochemical characterization of these molecules. As the most widely used bonded phases in RP-HPLC, octadecyl (C18) and octyl (C8) were used. Binary mixtures of water and acetonitrile or methanol were used as mobile phases. Obtained results were expressed as retention factor values logk and they were correlated with logP values. The results showed that both columns provide good estimations of the chromatographic lipophilicity of the molecules included in this study. This analysis was conducted in order to characterize newly synthesized steroid derivatives for further investigation regarding their antiproliferative and antimicrobial activity. This article is based upon work from COST Action (CM1306), supported by COST (European Cooperation in Science and Technology).

Keywords: antiproliferative activity, chromatographic lipophilicity, liquid chromatography, steroids

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Authors: Jaomai Tungsiripat, Patompong Satapornpong

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Allopurinol have been used to treat diseases that relating with the reduction of uric acid and be a treatment preventing the severity of, including gout, chronic kidney disease, chronic heart failure, and diabetes mellitus (type 2). However, allopurinol metabolites can cause a severe cutaneous adverse reaction (SCARs) consist of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome(SJS)/Toxic Epidermal Necrolysis (TEN). Previous studies, we found only HLA-B*58:01 allele has a strongly association with allopurinol-induced SCARs in many populations: Han Chinese [P value = 4.7 x 10−24], European [P value <10−6], and Thai [P value <0.001].However, there was no update the frequency of HLA-B alleles and pharmacogenetics markers distribution in healthy Thais and support for screening before the initiation of treatment. The aim of this study was to investigate the prevalence of HLA-B*58:01 allele associated with allopurinol-induced SCARs in healthy Thai population. A retrospective study of 260 individual healthy subjects who living in Thailand. HLA-B were genotyped using sequence-specific oligonucleotides (PCR-SSOs).In this study, we identified the prevalence of HLA-B alleles consist ofHLA-B*46:01 (12.69%), HLA-B*15:02 (8.85%), HLA-B*13:01 (6.35%), HLA-B*40:01 (6.35%), HLA-B*38:02 (5.00%), HLA-B*51:01 (5.00%), HLA-B*58:01 (4.81%), HLA-B*44:03 (4.62%), HLA-B*18:01 (3.85%) and HLA-B*15:25 (3.08%). Therefore, the distribution of HLA-B*58:01 will support the clinical implementation and screening usage of allopurinol in Thai population.

Keywords: allopurinol, HLA-B*58: 01, Thai population, SCARs

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Authors: Sandeep Pandey, Nimra Habib, Ranjana Singh, Abbas Ali Mahdi

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Leukemia is a malignancy of blood that mainly affects children and young adults; while advancement in the early diagnosis will have the potential to improve the outcome of diseases. A wide range of disease including leukemia shows inflammatory signals in their pathogenesis. In a pilot study conducted in our laboratory, 52 people were screened, of which 26 had leukemia and 26 were free from any kind of malignancy. We performed the estimation of the inflammatory cytokine Interleukin-8 and it was found significantly raised in all the leukemia patients concerning healthy volunteers who participated in the study. Flow cytometry had been performed for the confirmation of leukemia and further genomic, and proteomic, analyses of the sample revealed that IL-8 levels showed a positive correlation in patients with leukemia. The results had shown constitutive secretion of interleukin-8 by leukemia cells. So, our finding demonstrated that IL-8 is considered to have a role in the pathogenesis of leukemia, and quantification of IL-8 levels in leukemia conditions might be more useful and feasible in the clinical setting for the prediction of drug responses where it may represent a putative target for innovative diagnostic toward effective therapeutic approaches. However, further research explorations in this area are needed that include a greater number of patients with all different forms of leukemia, and estimating their IL-8 levels may hold the key for the additional predictive values on the recurrence of leukemia and its prognosis.

Keywords: T-ALL, IL-8, leukemia pathogenesis, cancer therapeutics

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Authors: T. A. Ajiboye

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This study examines the effects of health education programme on knowledge and prevention of cerebrovascular disease among hypertensive patients in University College Hospital, Ibadan. A quasi-experimental design was adopted for the study. 100 hypertensive patients were conveniently selected from general outpatient department in UCH. Data generated were analyzed using ANOVA at 0.05 alpha levels. The findings of the study revealed that health education programme significantly influenced both the knowledge of hypertensive patients (F=22.70; DF=1/99; p < .05) and their attitude (F=10.377; DF=1/99; p < .05) on cerebrovascular disease. Findings also discovered that health education programme significantly reduce the complication of hypertension to cerebrovascular disease (F= 16.41; DF=7/286; p < 0.05) among the hypertensive patients at UCH. Based on the findings, it is recommended that hypertensive patients should relieve themselves from stress, engage themselves on regular exercises, compliance with drug and diet regimes coupled with keeping up of regular appointment. Government should design health information that will center on hypertension and cerebrovascular disease so as to keep health and community development problems to the barest minimum. Finally, there should be provision of social amenities and recreational centers, as this will prevents hypertension problems.

Keywords: cerebrovascular disease, effectiveness, health education, hypertension, knowledge, prevention

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Authors: Daniel C. Bonzo

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Practical considerations lead to the use of unit of analysis within subjects, e.g., bleeding episodes or treatment-related adverse events, in rare disease settings. This is coupled with data augmentation techniques such as extrapolation to enlarge the subject base. In general, one can think about extrapolation of data as extending information and conclusions from one estimand to another estimand. This approach induces hierarchichal clustered data with varying cluster sizes. Extrapolation of clinical trial data is being accepted increasingly by regulatory agencies as a means of generating data in diverse situations during drug development process. Under certain circumstances, data can be extrapolated to a different population, a different but related indication, and different but similar product. We consider here the problem of estimation (point and interval) using a mixed-models approach under an extrapolation. It is proposed that estimators (point and interval) be constructed using weighting schemes for the clusters, e.g., equally weighted and with weights proportional to cluster size. Simulated data generated under varying scenarios are then used to evaluate the performance of this approach. In conclusion, the evaluation result showed that the approach is a useful means for improving statistical inference in rare disease settings and thus aids not only signal detection but risk-benefit evaluation as well.

Keywords: clustered data, estimand, extrapolation, mixed model

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Authors: Hae Dun Kim, Joo Hyun Jang, Geu Rim Seo, Kyung Soo Ra, Hyung Joo Suh

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Lactuca sativa (lettuce) has been known for its medical property to relieve anxiety and nervous. This study was implemented to investigate sleep-promoting effects of the lettuce alcohol extract (LAE). Caffeine is widely used psychoactive substance known to induced wakefulness and insomnia to its consumers. In the present study, the sedative-hypnotic activity of the LAE was studied using the method of pentobarbital-induced sleep in the mouse model. The LAE was administrated to mice 30 min before the pentobarbital injection. The LAE prolonged the pentobarbital-induced sleep duration and decreased sleep latency. The effects of LAE were comparable to those of induced by diazepam. Another study was performed to examine whether LAE ameliorates caffeine-induced sleep disturbance in mice. Additionally, caffeine (10 mg/kg, p.o) delayed sleep onset and reduced sleep duration of mice. Conversely, LAE treatment (80 or 160 mg/kg, p.o), especially at 160 mg/kg, normalized the sleep disturbance induced by caffeine. LAE supplementation can counter the sleep disturbance induced by caffeine. These results suggest that LAE possess significant sedative-hypnotic activity, which supports the popular use of lettuce for treatment of insomnia and provide the basis for new drug discovery. Furthermore, these results demonstrate that the lettuce extract may be preferable for the treatment of insomnia.

Keywords: caffeine, Lactuca sativa, sleep duration, sleep latency

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Authors: M. Krishna

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The study was intended to identify if scalp cooling therapy is effective on preventing chemotherapy-induced hair loss among cancer patients. Critical literature of non-randomized controlled trials was used to investigate whether scalp cooling therapy is effective on preventing chemotherapy-induced alopecia. The review identified that scalp cooling therapy is effective on preventing chemotherapy-induced alopecia. Most of the patients receiving chemotherapy experience alopecia. It is also perceived as the worst effect of chemotherapy. This may be severe and lead the patients to withdraw the chemo treatment. The image disturbance caused by alopecia will make the patient depressed and will lead to declined immunity. With the knowledge on effectiveness of scalp cooling therapy on preventing chemotherapy-induced alopecia, patient undergoing chemotherapy will not be hesitant to undergo the treatment. Patients are recommended to go through scalp cooling therapy every chemo cycle and the proper therapy duration is 30 minutes before, during chemo. The suggested duration of the scalp cooling therapy is 45-90 minutes for an effective and positive outcome. This finding is excluding other factors of alopecia such as menopause, therapeutic drugs, poor hair density, liver function problems, and drug regimes.

Keywords: alopecia, cancer, chemotherapy, scalp cooling therapy

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Authors: Mir Hussain Nawaz, Lyudmila Nedyalkova, Haizhong Zhu, Wael M. Rabeh

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In this study, we aim to biochemically and structurally characterize the interactions of human HK2 with the mitochondria in addition to the role of its N-terminal domain in catalysis and stability of the full-length enzyme. Here, we solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn α-helix. Different from the inactive N-terminal domains of isozymes 1 and 3, the N- domain of HK2 not only capable to catalyze a reaction but it is responsible for the thermodynamic stabilizes of the full-length enzyme. Deletion of first α-helix of the N-domain that binds to the mitochondria altered the stability and catalytic activity of the full-length HK2. In addition, we found the linker helix between the N- and C-terminal domains to play an important role in controlling the catalytic activity of the N-terminal domain. HK2 is a major step in the regulation of glucose metabolism in cancer making it an ideal target for the development of new anticancer therapeutics. Characterizing the structural and molecular mechanisms of human HK2 and its role in cancer metabolism will accelerate the design and development of new cancer therapeutics that are safe and cancer specific.

Keywords: cancer metabolism, enzymology, drug discovery, protein stability

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Authors: Watchawin Ekphinitphithaya, Patompong Satapornpong

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Introduction: Carbamazepine (CBZ) is one of the most prescribed antiepileptic drugs (AEDs) by neurologists and non-neurologist worldwide. CBZ is usually prescribed along with other drugs, leading to the possibility of severe cutaneous adverse drug reactions (SCARs). The HLA-B*15:02 is strongly associated with CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations, while HLA-A*31:01 allele has been reported to be associated with CBZ-induced SCARs in European population and Japanese. Objective: The aim of this study is to investigate the distribution of pharmacogenetics HLA-A*31:01 marker in a healthy Thai population associated with Carbamazepine-induced SCARs. Materials and Methods: Prospective study, 350 unrelated healthy Thais were recruited in this study. Human leukocyte antigen-A alleles were genotyped using PCR-sequence specific oligonucleotides (PCR-SSOs). Results: The frequency of HLA-A alleles were HLA-A*11:01 (190 alleles, 27.14%), HLA-A*24:02 (82 alleles, 11.71%), HLA-A*02:03 (80 alleles, 11.43%), HLA-A*33:03 (76 alleles, 10.86%), HLA-A*02:07 (58 alleles, 8.29%), HLA-A*02:01 (35 alleles, 5.00%), HLA-A*24:07 (29 alleles, 4.14%), HLA-A*02:06 – HLA-A*30:01 (15 alleles, 2.14%), and HLA-A*01:01 (14 alleles, 2.00%). Particularly, the number of HLA-A*31:01 alleles was 6 of 700 (0.86%) in the healthy Thai population. Many research presented varying distributions of HLA-A*31:01 in Asians, including 2% of Han Chinese, 9% of Japanese and 5% of Koreans. In addition, this allele was found approximately 2-5% in the Caucasian population. Conclusions: Thus, the pharmacogenetics database is vital to support in many populations, especially in Thais, for screening HLA-A*31:01 allele to avoid CBZ-induced SCARs before initiating treatments in each population.

Keywords: Carbamazepine, HLA-A*31:01, Thai population, pharmacogenetics

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Authors: Mochammad Indra Permana, Andhiani Sharfina Arnellya, Dika Pramita Destiani, Budhi Prihartanto

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Cardiovascular disease is the cause of the highest mortality rates in the world. The number of cardiovascular disease patients is increasing every year. Data obtained from World Health Organization (WHO) that 17,5 million people died from this disease. The condition of cardiovascular diseases such as atrial fibrillation, myocardial infarction, venous thromboembolism, and several other conditions need anticoagulant therapy. Results of the anticoagulant therapy are measured not only by the effectiveness of International Normalized Ratio (INR) value but also by the quality of life of the patients. The purpose of this study was to determine the quality of life of patients on oral anticoagulant therapy in outpatient cardiac department Dr. Hasan Sadikin central general hospital, Bandung, Indonesia. This is a cross-sectional study with collecting data from the quality of life questionnaire and medical record of the patients. The results of this study showed that 28 patients (46,7%) had a good quality of life, 30 patients (50%) had a moderate quality of life, and 2 patients (3,3%) had a poor quality of life with no significant differences in quality of life based on age, gender, diagnosis, and duration of drug use.

Keywords: anticoagulant, cardiovascular diseases, INR, quality of life

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Authors: Claire Williams

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Randomised controlled Trials (RCTs) of efficacy are still perceived as the gold standard for the generation of evidence, and whilst advances in data collection methods are well developed, this progress has not been matched for the reporting of adverse events (AEs). Assessment and reporting of AEs in clinical trials are fraught with human error and inefficiency and are extremely time and resource intensive. Recent research conducted into the quality of reporting of AEs during clinical trials concluded it is substandard and reporting is inconsistent. Investigators commonly send reports to sponsors who are incorrectly categorised and lacking in critical information, which can complicate the detection of valid safety signals. In our presentation, we will describe an electronic data capture system, which has been designed to support clinical trial processes by reducing the resource burden on investigators, improving overall trial efficiencies, and making trials safer for patients. This proprietary technology was developed using expertise proven in the delivery of the world’s first prospective, phase 3b real-world trial, ‘The Salford Lung Study, ’ which enabled robust safety monitoring and reporting processes to be accomplished by the remote monitoring of patients’ EHRs. This technology enables safety alerts that are pre-defined by the protocol to be detected from the data extracted directly from the patients EHR. Based on study-specific criteria, which are created from the standard definition of a serious adverse event (SAE) and the safety profile of the medicinal product, the system alerts the investigator or study team to the safety alert. Each safety alert will require a clinical review by the investigator or delegate; examples of the types of alerts include hospital admission, death, hepatotoxicity, neutropenia, and acute renal failure. This is achieved in near real-time; safety alerts can be reviewed along with any additional information available to determine whether they meet the protocol-defined criteria for reporting or withdrawal. This active surveillance technology helps reduce the resource burden of the more traditional methods of AE detection for the investigators and study teams and can help eliminate reporting bias. Integration of multiple healthcare data sources enables much more complete and accurate safety data to be collected as part of a trial and can also provide an opportunity to evaluate a drug’s safety profile long-term, in post-trial follow-up. By utilising this robust and proven method for safety monitoring and reporting, a much higher risk of patient cohorts can be enrolled into trials, thus promoting inclusivity and diversity. Broadening eligibility criteria and adopting more inclusive recruitment practices in the later stages of drug development will increase the ability to understand the medicinal products risk-benefit profile across the patient population that is likely to use the product in clinical practice. Furthermore, this ground-breaking approach to AE detection not only provides sponsors with better-quality safety data for their products, but it reduces the resource burden on the investigator and study teams. With the data taken directly from the source, trial costs are reduced, with minimal data validation required and near real-time reporting enables safety concerns and signals to be detected more quickly than in a traditional RCT.

Keywords: more comprehensive and accurate safety data, near real-time safety alerts, reduced resource burden, safer trials

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Authors: Loredana Elena Nita, Maria Bercea, Aurica P. Chiriac, Iordana Neamtu

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The paper is devoted to the behavior of gels based on poly(itaconic anhydride-co-3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane) copolymers, with different ratio between the comonomers, and hyaluronic acid (HA). The gel formation was investigated by small-amplitude oscillatory shear measurements following the viscoelastic behavior as a function of gel composition, temperature and shear conditions. Hyaluronic acid was investigated in the same conditions and its rheological behavior is typical to viscous fluids. In the case of the copolymers, the ratio between the two comonomers influences the viscoelastic behavior, a higher content of itaconic anhydride favoring the gel formation. Also, the sol-gel transition was evaluated according to Winter-Chambon criterion that identifies the gelation point when the viscoelastic moduli (G’ and G”) behave similarly as a function of oscillation frequency. From rheological measurements, an optimum composition was evidenced for which the system presents a typical gel-like behavior at 37 °C: the elastic modulus is higher than the viscous modulus and they are not dependent on the oscillation frequency. The formation of the 3D macroporous network was also evidenced by FTIR spectra, SEM microscopy and chemical imaging. These hydrogels present a high potential as drug delivery systems.

Keywords: copolymer, viscoelasticity, gelation, 3D network

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Authors: Huayang Yu, Nicola Ingram, David C. Green, Paul D. Thornton

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The dual stimuli-controlled release of doxorubicin from gel-embedded nanoparticles is reported. Non-cytotoxic polymer nanoparticles are formed from poly(ethylene glycol)-b-poly(benzyl glutamate) that, uniquely, contain a central ester link. This connection renders the nanoparticles pH-responsive, enabling extensive doxorubicin release in acidic solutions (pH 6.5), but not in solutions of physiological pH (pH 7.4). Doxorubicin loaded nanoparticles were found to be stable for at least 31 days and lethal against the three breast cancer cell lines tested. Furthermore, doxorubicin-loaded nanoparticles could be incorporated within a thermoresponsive poly(2-hydroxypropyl methacrylate) gel depot, which forms immediately upon injection of poly(2-hydroxypropyl methacrylate) into aqueous solution. The combination of the poly(2-hydroxypropyl methacrylate) gel and poly(ethylene glycol)-b-poly(benzyl glutamate) nanoparticles yields an injectable doxorubicin delivery system that facilities near-complete drug release when maintained at elevated temperatures (37 °C) in acidic solution (pH 6.5). In contrast, negligible payload release occurs when the material is stored at room temperature in a non-acidic solution (pH 7.4). The system has great potential as a vehicle for the prolonged, site-specific release of chemotherapeutics.

Keywords: biodegradable, nanoparticle, polymer, thermoresponsive

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Authors: Y. Ruchi, A. Prerna, S. Deepshikha

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Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”. It is a neurodegenerative disease associated with degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord characterized by distal muscle weakness, atrophy, normal sensation, pyramidal signs and progressive muscular paralysis reflecting. ALS2 is a juvenile autosomal recessive disorder, slowly progressive, that maps to chromosome 2q33 and is associated with mutations in the alsin gene, a putative GTPase regulator. In this paper we have done homology modeling of alsin2 protein using multiple templates (3KCI_A, 4LIM_A, 402W_A, 4D9S_A, and 4DNV_A) designed using the Prime program in Schrödinger software. Further modeled structure is used to identify effective binding sites on the basis of structural and physical properties using sitemap program in Schrödinger software, structural and function analysis is done by using Prosite and ExPASy server that gives insight into conserved domains and motifs that can be used for protein classification. This paper summarizes the structural, functional and binding site property of alsin2 protein. These binding sites can be potential drug target sites and can be used for docking studies.

Keywords: ALS, binding site, homology modeling, neuronal degeneration

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Authors: R. Reshma srilakshmi, S. Shalini, P. Yogeeswari, D. Sriram

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Lysine aminotransferase is a crucial enzyme for dormancy in M. tuberculosis. It is involved in persistence and antibiotic resistance. In present work, we attempted to develop benzthiazole derivatives as lysine aminotransferase inhibitors. In our attempts, we also unexpectedly arrived at an interesting compound 21 (E)-4-(5-(2-(benzo[d]thiazol-2-yl)-2-cyanovinyl)thiophen-2-yl)benzoic acid which even though has moderate activity against persistent phase of mycobacterium, it has significant potency against active phase. In the entire series compound 22 (E)-4-(5-(2-(benzo[d]thiazol-2-yl)-2-cyanovinyl)thiophen-2-yl)isophthalic acid emerged as potent molecule with LAT IC50 of 2.62 µM. It has a significant log reduction of 2.9 and 2.3 fold against nutrient starved and biofilm forming mycobacteria. It was found to be inactive in MABA assay and M.marinum induced zebra fish model. It is also devoid of cytotoxicity. Compound 22 was also found to possess bactericidal effect which is independent of concentration and time. It was found to be effective in combination with Rifampicin in 3D granuloma model. The results are very encouraging as the hit molecule shows activity against active as well as persistent forms of tuberculosis. The identified hit needs further more pharmacokinetic and dynamic screening for development as new drug candidate.

Keywords: benzothiazole, latent tuberculosis, LAT, nutrient starvation

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Authors: Ankur Chaudhuri, Sibani Sen Chakraborty

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In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

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Authors: Mabroka Omar Sherehe

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Despite the great efficacy of isoniazid (INH) and rifampicine (RIF) combination in the treatment of tuberculosis, hepatotoxicity is the most common serious complication. The potential protective effect of simvastatin (sim) against combination-induced hepatotoxicity was investigated in the present study. The administration of INH-RIF combination (50mg/kg each for 14 days) resulted in a significant increased activities of serum alanine and aspartate aminotransferases, such effects were further supported by histopathological studies. INH-RIF combination produced a significant increase in liver lipid, decreased SOD and CAT, and a significant depletion of GSH level. Additionally, treatment with INH-RIF combination resulted in a significant increase in liver MPO activity. The lipid-lowering drug, Sim demonstrated in the current study an evident antioxidant action, such effect was mediated via decreasing the elevated MDA, MPO, and restoring liver CAT activity. Additionally, Sim restored liver NO level to near basal value Furthermore, one cannot rule out the lipid-lowering effect of Sim that would probably add to its beneficial hepatoprotective antioxidant activity, where Sim decreased the elevated cholesterol, TGs and LDL cholesterol level and increased the serum HDL cholesterol level.

Keywords: isoniazid, rifampicine, oxidative stress, nitric oxide

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Authors: Naira Sahakyan, Margarit Petrosyan, Armen Trchounian

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One of the tasks in contemporary biotechnology, pharmacology and other fields of human activities is to obtain biologically active substances from plants. They are very essential in the treatment of many diseases due to their actually high therapeutic value without visible side effects. However, sometimes the possibility of obtaining the metabolites is limited due to the reduction of wild-growing plants. That is why the plant cell cultures are of great interest as alternative sources of biologically active substances. Besides, during the monitored cultivation, it is possible to obtain substances that are not synthesized by plants in nature. Isolated culture of Ajuga genevensis with high growth activity and ability of regeneration was obtained using MS nutrient medium. The agar-diffusion method showed that aqueous extracts of callus culture revealed high antimicrobial activity towards various gram-positive (Bacillus subtilis A1WT; B. mesentericus WDCM 1873; Staphylococcus aureus WDCM 5233; Staph. citreus WT) and gram-negative (Escherichia coli WKPM M-17; Salmonella typhimurium TA 100) microorganisms. The broth dilution method revealed that the minimal and half maximal inhibitory concentration values against E. coli corresponded to the 70 μg/mL and 140 μg/mL concentration of the extract respectively. According to the photochemiluminescent analysis, callus tissue extracts of leaf and root origin showed higher antioxidant activity than the same quantity of A. genevensis intact plant extract. A. genevensis intact plant and callus culture extracts showed no cytotoxic effect on K-562 suspension cell line of human chronic myeloid leukemia. The GC-MS analysis showed deep differences between the qualitative and quantitative composition of callus culture and intact plant extracts. Hexacosane (11.17%); n-hexadecanoic acid (9.33%); and 2-methoxy-4-vinylphenol (4.28%) were the main components of intact plant extracts. 10-Methylnonadecane (57.0%); methoxyacetic acid, 2-tetradecyl ester (17.75%) and 1-Bromopentadecane (14.55%) were the main components of A. genevensis callus culture extracts. Obtained data indicate that callus culture of A. genevensis can be used as an alternative source of biologically active substances.

Keywords: Ajuga genevensis, antibacterial activity, antioxidant activity, callus cultures

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Authors: Megan E. Davies

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As substance use become an increasing prevalent occurrence amongst young people, prevention programs designed specifically for children and adolescents are required to protect against associated cognitive, psychological, and behavioural issues. Further, young people from marginalized backgrounds would highly benefit from culturally adapted substance use prevention programs. The first and second phase of the Life Skills Training (LST) program, the Maskwacis Life Skills Training (MLST) program, the Bii-Zin-Da-De-Da (BZDDD; “Listening to One Another”), and a culturally sensitive smoking prevention program, all of which have been adapted to Canadian Indigenous cultures and are applied within the school and family settings, are discussed. Additionally, comorbid disorders, at-risk personality types, and motivating factors associated with substance use amongst Canadian children and adolescents, specifically Indigenous youth, are explored through the application of a biopsychosocial model. Requital efforts being made in Canada towards Indigenous communities are described within a historical context, and substance use prevention programs targeting Indigenous children and adolescents are compared. Through this lens, suggestions are presented for future research on preventative interventions directed towards substance use within minority groups.

Keywords: early intervention, cultural appropriateness, life skills training, smoking prevention, drug and alcohol prevention

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Authors: Farzad Khajavi

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Studies about the interaction between active pharmaceutical ingredients (API) and excipients are so important in the pre-formulation stage of development of all dosage forms. Analytical techniques such as differential scanning calorimetry (DSC), Thermal gravimetry (TG), and Furrier transform infrared spectroscopy (FTIR) are commonly used tools for investigating regarding compatibility and incompatibility of APIs with excipients. Sometimes the interpretation of data obtained from these techniques is difficult because of severe overlapping of API spectrum with excipients in their mixtures. Principal component analysis (PCA) as a powerful factor analytical method is used in these situations to resolve data matrices acquired from these analytical techniques. Binary mixtures of API and interested excipients are considered and produced. Peaks of FTIR, DSC, or TG of pure API and excipient and their mixtures at different mole ratios will construct the rows of the data matrix. By applying PCA on the data matrix, the number of principal components (PCs) is determined so that it contains the total variance of the data matrix. By plotting PCs or factors obtained from the score of the matrix in two-dimensional spaces if the pure API and its mixture with the excipient at the high amount of API and the 1:1mixture form a separate cluster and the other cluster comprise of the pure excipient and its blend with the API at the high amount of excipient. This confirms the existence of compatibility between API and the interested excipient. Otherwise, the incompatibility will overcome a mixture of API and excipient.

Keywords: API, compatibility, DSC, TG, interactions

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Authors: M. Dahiru, O. I. Enabulele

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The research wish to investigate the occurrence of multidrug- resistant Acinetobacter, in carrot and estimate the role of carrot in its transmission, in a rapidly growing urban population. Thus, 50 carrot samples were collected from Jakara wastewater irrigation farms and analyzed on MacConkey agar and screened by Microbact 24E (Oxoid) and susceptibility of isolates tested against 10 commonly used antibiotics. Acinetobacter baumannii and A. lwoffii were isolated in 22.00% and 16% of samples respectively. Resistance to ceporex and penicillin of 36.36% and 27.27% in A. baumannii, and sensitivity to ofloxacin, pefloxacin, gentimycin and co-trimoxazole, were observed. However, for A. lwoffii apart from 37.50% resistance to ceporex, it was also resistant to all other drugs tested. There was a similarity in the resistant shown by A. baumannii and A. lwoffii to fluoroquinolones drugs and β- lactame drugs families in addition to between sulfonamide and animoglycoside demonstrated by A. lwoffii. Interestingly, when resistant similarities to different antibiotics were compared for A. baumannii and A. lwoffii as a whole, significant correlation was observed at P < 0.05 to CPX to NA (46.2%), and SXT to AU (52.6%) respectively, and high multi drug resistance (MDR) of 27.27% and 62.50% by A. baumannii and A. lwoffii respectively and overall MDR of 42.11% in all isolates. The occurrence of multidrug-resistance pathogen in carrot is a serious challenge to public health care, especially in a rapidly growing urban population where subsistence agriculture contributes greatly to urban livelihood and source of vegetables.

Keywords: urban agriculture, public health, fluoroquinolone, sulfonamide, multidrug-resistance

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Authors: Amy Halseth, Kevin Shan, Kye Gilder, John Buse

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The study assessed the effect of prolonged-release naltrexone 32 mg/bupropion 360 mg (NB) on cardiovascular (CV) events in overweight/obese participants at elevated CV risk. Participants must lose ≥ 2% body weight at 16 wks, without a sustained increase in blood pressure, to continue drug. The study was terminated early after second interim analysis with 50% of all CV events. Data on CV endpoints has been published. Current analyses focus on weight change. Intent-to-treat (ITT) population (placebo [PBO] N=4450, NB N=4455) was 54.5% female, 83.5% white, mean age 61 yrs, mean BMI 37.3 kg/m2; 85.2% had type 2 diabetes, 32.1% had CV disease, 17.4% had both. At 52 wks, ITT-LOCF analysis showed greater least squares mean percent change in weight (LSM%ΔBW) with NB (-3.1%; 95% CI -4.8, -1.4) vs PBO (-0.3%; 95% CI -1.9, 1.4). Both groups demonstrated greater weight loss while on-treatment (NB [-7.3%], PBO [-3.9%]). Odds ratios of 5% and 10% weight loss were 3.3 and 4.1 (ITT-LOCF), respectively, in NB over PBO. At 104 wks, on-treatment LSM%ΔBW was -6.3% with NB (n=1137) vs -3.5% with PBO (n=741). Major reasons for NB withdrawal were adverse events (AE, 29%) and patient decision (21%), with GI disorders being the most common. Weight loss with NB in this study, in an older population predominantly with diabetes and elevated CV risk, was somewhat lower than that observed in overweight/obese participants without diabetes and similar to participants with diabetes in Phase 3 studies.

Keywords: contrave, mysimba, obesity, pharmacotherapy, weight loss

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Authors: Zsolt Szucs, Viktor Kelemen, Son Le Thai, Magdolna Csavas, Erzsebet Roth, Gyula Batta, Annelies Stevaert, Evelien Vanderlinden, Aniko Borbas, Lieve Naesens, Pal Herczegh

Abstract:

The approval of modern glycopeptide antibiotics such as dalbavancin and oritavancin which have excellent activity against Gram-positive bacteria, encouraged our research group to prepare semisynthetic compounds from several members of glycopeptides by various chemical methods. Derivatives from the aglycone of ristocetin, eremomycin, vancomycin and a pseudoaglycon of teicoplanin have been synthesized in a systematic manner. Interestingly, some of the aglycoristocetin derivatives displayed noteworthy anti-influenza activity. More recently our group has been focusing on the modifications of one of the pseudoaglycons of teicoplanin. The reaction of N-ethoxycarbonyl maleimide derivatives with the primary amino function, the copper-catalysed azide-alkyne click reaction and the sulfonylation of the N-terminus were utilized to obtain systematic series of compounds. All substituents provide a more lipophilic character to the new molecules compared to the parent antibiotics, which is known to be favourable for activity against resistant bacteria. Lipoglycopeptides are also known to have antiviral properties, which has been predominantly studied on HIV by others. The structure-activity relationship study of our compounds revealed the influence of a few structural elements on biological activity. In many cases, minimal changes in lipophilicity and structure produced great differences in efficacy and cytotoxicity. In vitro experiments showed that these compounds are not only active against glycopeptide resistant Gram-positive bacteria but in several cases they prevent the infection of cell cultures by different strains of influenza viruses. This is probably related to the inhibition of the viral entry into the host cell nucleus, of which the exact mechanism is unknown. In some instances, reasonably low concentrations were sufficient to observe this effect. Several derivatives were highly cytotoxic at the same time, but some of them displayed a good selectivity index. The antiviral properties of the compounds are not restricted to influenza viruses e.g., some of them showed good activity against Human Coronavirus 229E. This work could potentially lead to the development of antiviral drugs which possess the crucial structural motifs that are needed for antiviral activity, while missing those which contribute to the antibacterial effect.

Keywords: antiviral, glycopeptide, semisynthetic, teicoplanin

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Authors: Latifeh Navidpour, Shabnam Shabani, Alireza Heidari, Manouchehr Bashiri, Azadeh Ebrahim-Habibi, Soraya Shahhosseini, Hamed Shafaroodi, Sayyed Abbas Tabatabai, Mahsa Toolabi

Abstract:

A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABAA/ benzodiazepine receptor complex (IC50 values of 0.04–4.1 nM), relative to diazepam as the reference drug (IC50 value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r2 = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025–0.1 mg/kg, relative to diazepam (0.025 mg/kg).

Keywords: 1, 2, 4-triazole, flexible benzodiazepines, GABAA/bezodiazepine receptor complex, onset of action, PTZ induced seizure threshold

Procedia PDF Downloads 90

Authors: K. Veluraja

Abstract:

Glycan of glycolipids and glycoproteins is playing a significant role in living systems particularly in molecular recognition processes. Molecular recognition processes are attributed to their occurrence on the surface of the cell, sequential arrangement and type of sugar molecules present in the oligosaccharide structure and glyosidic linkage diversity (glycoinformatics) and conformational diversity (glycoconformatics). Molecular Dynamics Simulation study is a theoretical-cum-computational tool successfully utilized to establish glycoconformatics of glycan. The study on various oligosaccharides of glycan clearly indicates that oligosaccharides do exist in multiple conformational states and these conformational states arise due to the flexibility associated with a glycosidic torsional angle (φ,ψ) . As an example: a single disaccharide structure NeuNacα(2-3) Gal exists in three different conformational states due to the differences in the preferential value of glycosidic torsional angles (φ,ψ). Hence establishing three dimensional structural and conformational models for glycan (cartesian coordinates of every individual atoms of an oligosaccharide structure in a preferred conformation) is quite crucial to understand various molecular recognition processes such as glycan-toxin interaction and glycan-virus interaction. The gycoconformatics models obtained for various glycan through Molecular Dynamics Simulation stored in our 3DSDSCAR (3DSDSCAR.ORG) a public domain database and its utility value in understanding the molecular recognition processes and in drug design venture will be discussed.

Keywords: glycan, glycoconformatics, molecular dynamics simulation, oligosaccharide

Procedia PDF Downloads 122

Authors: Ikram Mohamed Eltayeb Elsiddig, Abdel Khalig Muddather, Hiba Abdel Rahman Ali, Saad Mohamed Hussein Ayoub

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Anogeissusleiocarpus (Combretaceae) is well known for its medicinal uses in African traditional medicine, for treating many human diseases mainly skin diseases and infections.Mycetoma disease is a fungal and/ or bacterial skin infection, mainly cause by Madurella mycetomatis fungus.This study was carried out in vitro to investigate the antifungal activity of Anogeissusleiocarpus leaf extracts against the isolated pathogenicMadurellamycetomatis, by using the NCCLS modified method compared to Ketoconazole standard drug and MTT assay. The bioactive fraction was subjected to chemical analysis implementing different chromatographic analytical methods (TLC, HPLC, and LC-MS/MS). The results showed significance antifungal activity of A. leiocarpus leaf extractsagainst the isolated pathogenicM. mycetomatis, compared to negative and positive controls. The chloroform fraction showed the highest antifungal activity.The chromatographic analysis of the chloroform fraction with the highest activity showed the presence of important bioactive compounds such as ellagic and flavellagic acids derivatives, flavonoids and stilbenoid, which are well known for their antifungal activity.

Keywords: Anogeissus leiocarpus, crude extracts and fractions of Anogeissus leiocarpus, in vitrosusceptibility of Madurella mycetomatis, Madurella mycetomatis

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Authors: Salma Ainine, Colin Ritchie, Tracey McFee

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Background: The societal impact of antibiotic resistance is a major public health concern. The increase in the incidence of resistant bacteria can ultimately be fatal. Objective: To analyse the appropriateness of antibiotic prescribing in Dundee Dental Hospital, ultimately improving the safety and quality of patient care. Methods: Two examiners independently cross-checked approximately fifty consecutive prescriptions, and corresponding patient case notes, for three data collection cycles between August 2014–September 2015. The Scottish Dental Clinical Effectiveness Program (SDCEP) Drug Prescribing for Dentistry guidelines was the standard utilised. The criteria: clinical justification, regime justification, and review arrangements was measured, and compared to the standard. Results: Cycle one revealed 42% of antibiotic prescriptions were appropriate. Interventions included: multiple staff meetings, an introduction of a checklist attached to the prescription pack, and production of patient leaflets explaining indications for antibiotics. Cycle two and three revealed 44%, and 30% compliance, respectively. Conclusion: The results of the audit have yet to meet target standards set out in prescribing guidelines. However, steps are being taken and change has occurred on a cultural level.

Keywords: antibiotic resistance, antibiotic stewardship, dental infection, hygiene standards

Procedia PDF Downloads 212