Search results for: lipid lowering drug

Authors: Soyeon Kang, Youn-Jee Chung, Jung Namkung

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Objective: This retrospective study investigated the association between uric acid level and bone mineral density (BMD) in the postmenopausal period. Methods: The study included 328 menopausal women (mean age, 57.3 ± 6.5 years; mean serum uric acid level, 4.6 ± 1.0 mg/dL). Patients were divided into three groups by tertile of serum uric acid level. Patients who used hormone treatment (HT), bisphosphonates, or lipid-lowering agents were included. Results: Blood urea nitrogen, serum creatinine, and serum triglyceride levels were significantly higher in the upper uric acid tertiles. No significant difference was found in the mean uric acid levels between medication users and non-users. Distinct HT regimens showed different mean serum uric acid levels. In a cross-sectional analysis, higher serum uric acid levels showed a tendency toward increased BMD in the spine and femoral neck. Longitudinal analysis of 186 women who underwent follow-up examination at a mean interval of 14.6 months revealed a trend toward a smaller reduction in femoral neck BMD in women in the upper serum uric acid tertiles. Conclusion: A positive correlation exists between serum uric acid levels and BMD in menopausal women.

Keywords: menopause, antioxidant, uric acid, bone mineral density

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Authors: Naima Nur, Safa Islam, Saeema Islam, Faridul Alam

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Background: Drug-resistant pulmonary tuberculosis (DR-PTB), particularly multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant (pre-XDR), is a major challenge in effectively controlling TB, especially in developing. This study aimed to identify the strains of M. tuberculosis complex (MTC) and drug resistance patterns among the pulmonary tuberculosis patients. Methods: The study used a cross-sectional design, and 815 patients were recruited randomly in three study periods. In the first-period, 210 treated PTB patients, who were completed their treatment, received their diagnoses using light microscopy, fluorescence microscopy and cultured on Lowenstein-Jensen (L-J) slant, and then strains were identified as MTC by biochemical tests, and then sensitivity test in National Institute of Diseases of the Chest and Hospital. In the second-period, 220 re-treated PTB patients, who were completed their treatment, received their diagnoses using culture on L-J slant, line probe assay (LPA), and GeneXpert in the same hospital. In the last-period, during treatment, 385 MDR-PTB patients received their diagnoses using culture on L-J slant and LPA in the same hospital. Results: Among sixty-two (29.5%) PTB patients, 13% were sensitive to all first-line anti-TB drugs, 26% were MDR-TB patients, and 14.2% were pre-XDR-TB among 14 MDR-TB patients. After three years, 31% were MDR-TB among 220 re-treated PTB patients. After five years, 16.4% was pre-XDR-TB among 385 MDR-TB patients. Compared to females, male patients were significantly higher at all times. Conclusion: The current study demonstrated that in three study periods, the proportions of DR-TB, MDR-TB, and pre-XDR patients were an alarming issue and increasing daily.

Keywords: multi-drug resistant, drug-resistant, pre-extensive drug resistant, pulmonary tuberculosis

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Authors: Amin Adeli, Maryam Zarei

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Background and purpose: Royal jelly (RJ) is a natural product with anti-hyperlipidemic and antioxidant properties. In ovo administration of RJ may improve lipid profile and antioxidant properties. This study was conducted to evaluate, for first time, the effects of in ovo injection of the RJ on hatchability, one-day old chick quality, total antioxidant status and blood lipoproteins. Methods: 400 incubating eggs produced by Ross 308 strain (52 weeks of age in first stage of production) were prepared and assigned into 4 groups (n=100) and 4 replications per group (n=25). These 4 groups were injected by the following pattern: 1) 0.1 ml normal saline (control), 2) 0.1 mg RJ+0.1 ml normal saline, 3) 0.2 mg RJ+0.1 ml normal saline, and 4) 0.3 mg RJ+0.1 ml normal saline. Injections were performed using a laminar flow system Lipid profile, antioxidant properties, hatchability, and one-day old chicken quality were assessed. Results: The administration of RJ at concentration of 0.1increased the percentage of hatchability compared to concentration of 0.2 and control, significant differences have not been observed among groups for quality scores (P>0.05). The results showed that in ovo injection of the RJ did not have any significant effects on lipid profile; but administration of the RJ only decreased High-density lipoprotein (HDL cholesterol, HDL-C) (P<0.05). The results showed that injection of the RJ at concentration of 0.3 increased total antioxidant capacity (TAC) compared to control group (p<0.05). Injection of the RJ progressively increased gluthation peroxidase (GPx) activity (p<0.05). The results showed that injection of the RJ decreased superoxide dismutase (SOD) compared to control group (p<0.05). Conclusion: In ovo injection of the RJ at the highest concentration increased TAC and GPx, but it did not have significant effects on lipid profile. Future studies are needed to investigate the effects of the RJ on the above-mentioned mechanisms.

Keywords: antioxidant enzymes, chicken quality, hatchability, royal jelly

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Authors: Hsiang-Ru Lin

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Cholesterol plays an essential role in the regulation of the progression of numerous important diseases including atherosclerosis and Alzheimer disease so the generation of suitable cholesterol-lowering reagents is urgent to develop. Liver X receptor (LXR) is a ligand-activated transcription factor whose natural ligands are cholesterols, oxysterols and glucose. Once being activated, LXR can transactivate the transcription action of various genes including CYP7A1, ABCA1, and SREBP1c, involved in the lipid metabolism, glucose metabolism and inflammatory pathway. Essentially, the upregulation of ABCA1 facilitates cholesterol efflux from the cells and attenuates the production of beta-amyloid (ABeta) 42 in brain so LXR is a promising target to develop the cholesterol-lowering reagents and preventative treatment of Alzheimer disease. Engelhardia roxburghiana is a deciduous tree growing in India, China, and Taiwan. However, its chemical composition is only reported to exhibit antitubercular and anti-inflammatory effects. In this study, four compounds, engelheptanoxides A, C, engelhardiol A, and B isolated from the root of Engelhardia roxburghiana were evaluated for their agonistic activity against LXR by the transient transfection reporter assays in the HepG2 cells. Furthermore, their interactive modes with LXR ligand binding pocket were generated by molecular modeling programs. By using the cell-based biological assays, engelheptanoxides A, C, engelhardiol A, and B showing no cytotoxic effect against the proliferation of HepG2 cells, exerted obvious LXR agonistic effects with similar activity as T0901317, a novel synthetic LXR agonist. Further modeling studies including docking and SAR (structure-activity relationship) showed that these compounds can locate in LXR ligand binding pocket in the similar manner as T0901317. Thus, LXR is one of nuclear receptors targeted by pharmaceutical industry for developing treatments of Alzheimer and atherosclerosis diseases. Importantly, the cell-based assays, together with molecular modeling studies suggesting a plausible binding mode, demonstrate that engelheptanoxides A, C, engelhardiol A, and B function as LXR agonists. This is the first report to demonstrate that the extract of Engelhardia roxburghiana contains LXR agonists. As such, these active components of Engelhardia roxburghiana or subsequent analogs may show important therapeutic effects through selective modulation of the LXR pathway.

Keywords: Liver X receptor (LXR), Engelhardia roxburghiana, CYP7A1, ABCA1, SREBP1c, HepG2 cells

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Authors: Courtney Evans, Yuto Morimitsu, Tsubasa Hisadome, Futo Inomoto, Masahiro Yoshida, Takayuki Takei

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Hydrogels are useful biomaterials due to their highly biocompatible nature and their ability to absorb large quantities of liquid and mimic soft tissue. They are often used as therapeutic drug delivery systems. However, it is sometimes difficult to sustain controlled release when using hydrophobic medicines, as hydrogels are frequently hydrophilic. As such, this research shows the success of chitosan hydrogels modified through hydrophobic interaction. This was done through the imide bonding of the alkyl groups in fatty aldehydes and the amino groups in chitosan, followed by reductive animation. The resulting cryogels could be optimized for strength as well as sorption and desorption (of a hydrophobic dye used to mimic hydrophobic medicine) by varying the alkyl chain length and the substitution degree of the fatty aldehyde. Optimized cryogels showed potential as biomedical materials, particularly as drug delivery systems.

Keywords: biomedical materials, chitosan, drug carriers, hydrophobic modification

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Authors: Sengly Sroy, Elodie Arnaud, Adrien Servent, Sokneang In, Sylvie Avallone

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In Cambodia, fish plays an important role for local community in term of food habits, preference and contribution to several nutritional intakes. Consumed on a daily basis, fishes and their derivatives products are good sources of proteins, essential fatty acids and fat-soluble vitamins. They mainly obtain from the Tonle Sap Lake but, during the last decade, the fish population decreased drastically due to climate change and human activities as well. Contamination by agricultural residues and heavy metals were identified. However, fishes are currently used in several nutrition programs for children and pregnant women to improve their nutritional status. The aim of our work was to characterize the nutritional profile and contamination of 10 fish species consumed near the Tonle Sap Lake with a special attention to fatty acid and fat-soluble vitamin profiles. Fish samples were analyzed for their nutritional profiles (AOAC methods for macronutrients and micronutrients), their lipid content (Folch modified method), their Fatty acid (FAME method), their vitamin A (HPLC) and their heavy metals (ICP-MS). The total lipid contents ranged from 1.43 to 10.00% according to fish species. Lipid profile was mainly dominated by saturated fat (from 47.95 to 57.32%) but some fish species were particularly rich in ω-3 and ω-6 especially eicosapentaenoic acid EPA (3.05%) and docosahexaenoic acid DHA (2.82%). The more the fishes were fats, the more they contained vitamin A, DHA and EPA. Vitamin A is particularly abundant in small fishes (250.10 μg RE/100 g) compare to big ones (13.77 μg RE/100 g) because they are consumed as a whole with their organs (liver) and head. However, the contents of heavy metal in some species are higher than the maximum permitted level (MPL) from codex alimentarius, especially Mn. The results obtained provided important information on the most interesting fish in term of human nutrition and the potential risk of contaminants. The fatty acids are important for child development and pregnant women. These data are useful for supply chain stakeholders and the people in charge of nutrition program.

Keywords: fat-soluble vitamin, fatty acid, freshwater fish, lipid content, Tonle Sap Lake

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Authors: Osama M. Ahmed, Walaa G. Hozayen, Haidy Tamer Abo Sree

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The effect of doxorubicin (4 mg/kg b.w.week) without or with oral administration of ethanolic purslane (Portulaca oleracea) shoot (leaves and stems) extract (50 mg/kg b.w.day) or ethanolic purslane seeds extract (50 mg/kg b.w.day) co-treatments for 6 weeks was evaluated in adult male rats. There was an increase in serum levels of ALT, AST, ALP, GGT and total bilirubin. In addition, hepatic glutathine, glutathione transferase, peroxidase, SOD, CAT activities were decreased while lipid peroxidation in the liver was increased. Co-administration of ethanolic purslane and seed extracts successfully improved the adverse changes in the liver functions with an increase in antioxidants activities and reduction of lipid peroxidation.

Keywords: antioxidants, doxorubicin, hepatotoxicity, purslane

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Authors: Kheireddine El-Boubbou

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Drug delivery to target human acute myeloid leukemia (AML) using a nanoparticulate chemotherapeutic formulation that can deliver drugs selectively to AML cancer is hugely needed. In this work, we report the development of a nanoformulation made of polymeric-stabilized multifunctional magnetic iron oxide nanoparticles (PMNP) loaded with the anticancer drug Doxorubicin (Dox) as a promising drug carrier to treat AML. Dox@PMNP conjugates simultaneously exhibited high drug content, maximized fluorescence, and excellent release properties. Nanoparticulate uptake and cell death following addition of Dox@PMNPs were then evaluated in different types of human AML target cells, as well as on normal human cells. While the unloaded MNPs were not toxic to any of the cells, Dox@PMNPs were found to be highly toxic to the different AML cell lines, albeit at different inhibitory concentrations (IC₅₀ values), but showed very little toxicity towards the normal cells. In comparison, free Dox showed significant potency concurrently to all the cell lines, suggesting huge potentials for the use of Dox@PMNPs as selective AML anticancer cargos. Live confocal imaging, fluorescence and electron microscopy confirmed that Dox is indeed delivered to the nucleus in relatively short periods of time, causing apoptotic cell death. Importantly, this targeted payload may potentially enhance the effectiveness of the drug in AML patients and may further allow physicians to image leukemic cells exposed to Dox@PMNPs using MRI.

Keywords: magnetic nanoparticles, drug delivery, acute myeloid leukemia, iron oxide, cancer nanotherapy

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Authors: Mohammad Najmuddin Khan, Mohamad Khaleel Albalwi

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The prevalence of obesity has risen dramatically in past several decades. Hormonal and genetic factors are rarely the cause of childhood obesity. Because obese adult may suffer life-long physical and emotional consequences, it is imperative to discuss prevention with parents during well-child examinations. Purpose of the study was to compare the serum lipid profile of obese and non-obese males. Twenty two male students were selected from Al-Jouf University. Their age ranged from 19 to 29. They were divided into groups. One group (N=15) having more than 20% fat was considered as obese group, another group (N=7) was considered as non-obese group. Fasting blood samples were analysed for blood cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Independent test was applied to compare mean difference. In obese group, significantly higher cholesterol and triglycerides were observed. On the contrary, obese group had significantly lower HDL-C concentration than the non-obese group. The adult obese has relatively larger changes in serum lipids at any given level of obesity. On the average, higher amount of fat makes it more likely for an individual to be dyslipidemic and to express elements of the metabolic syndrome. Increased triglycerides level in obese impaired lipolysis which reduced the HDL-C concentrations.

Keywords: obesity, serum lipid profile, Al-Jouf, HDL, LDL

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Authors: Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H. Pigney, Taishi Hashiguchi

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Non-alcoholic steatohepatitis (NASH) is a chronic liver disease, often associated with type II diabetes, which sometimes progresses to more serious conditions such as liver fibrosis and hepatocellular carcinoma (HCC). NASH has become an important health problem worldwide, buttherapeutic agents for NASH have not yet been approved, and animal models with high clinical correlation are required. TheSTAM™ mouse shows the same pathological progression as human NASH patients and has been widely used for both drug efficacy and basic research, such as lipid profiling and gut microbiota research. In this study, we analyzed the RNA-seq data of STAM™mice at each pathological stage (steatosis, steatohepatitis, liver fibrosis, and HCC) and examined the clinical correlation at the genetic level. NASH was induced in male mice by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feeding with high fat dietafter 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16, and 20 weeks of age. For liver samples, the left lateral lobe was snap frozen in liquid nitrogen and stored at -80˚C for RNA-seq analysis. Total RNA of the cells was isolated using RNeasy mini kit. The gene expression of the canonical pathways in NASH progression from steatosis to hepatocellular carcinoma were analyzed, such as immune system process, oxidation-reduction process, lipid metabolic process. Moreover, since it has been reported that genetic traits are involved in the development of NASH-HCC, we next analyzed the genetic mutations in the STAM™mice. The number of individuals showing mutations in Mtorinvolved in Insulin signaling increases as the disease progresses, especially in the liver cancer phase. These results indicated a clinical correlation of gene profiles in the STAM™mouse.

Keywords: steatosis, non-alcoholic steatohepatitis, fibrosis, hepatocellular carcinoma, RNA-seq

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Authors: Maryam Shayani Rad, Seyed Ahmad Mohajeri, Mohsen Mouhebati, Seyed Danial Mousavi

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High blood pressure is one of the most important and serious health-threatening because of no symptoms in most people, which can lead to sudden heart attack, heart failure, and stroke. Nowadays, herbal medicine is one of the best and safest strategies for treatment that have no adverse effects. Apium graveolens (celery) can be used as an alternative treatment for many health conditions such as hypertension. Natural compounds reduce blood pressure via different mechanisms in which Apium graveolens extract provides potent calcium channel blocking properties. A randomized, double-blind, placebo-controlled, cross-over clinical trial was done to evaluate the efficacy of formulated Apium graveolens extract with a maximum yield of 3-n-butylphthalide to reduce systolic and diastolic blood pressure in patients with hypertension. 54 hypertensive patients in the range of 20-68 years old were randomly assigned to the treatment group (26 cases) and the placebo control group (26 cases) and were crossed over after washout duration. The treatment group received at least 2 grams of formulated powder in hard capsules orally, before each meal, 2 times daily. The control group received 2 grams of placebo in hard capsules orally, exactly as the same as shape, time, and doses of treatment group. Treatment was administrated in 12 weeks with 4 weeks washout period at the middle of the study, meaning 4 weeks drug consumption for the treatment group, 4 weeks washout and 4 weeks placebo consumption, and vice versa for the placebo control group. The clinical assessment was done 4 times, including at the beginning and ending of the drug and placebo consumption period by 24-hour ambulatory blood pressure monitoring (ABPM) holter, which measured blood pressure every 15 minutes continuously. There was a statistically significant decrease in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the end of drug duration compared to baseline. The changes after 4 weeks on average was about 12.34 mm Hg for the SBP (P < 0.005) and 7.83 mm Hg for the DBP (P < 0.005). The results from this clinical trial study showed this Apium graveolens extract formulation in the mentioned dosage had a significant effect on blood pressure-lowering for hypertensive patients.

Keywords: Apium graveolens extract, clinical trial, cross-over, hypertension

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Authors: Abbas Jafarizad, Duygu Ekinci

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In this work targeted drug delivery is proposed to decrease adverse effect of drugs with concomitant reduces in consumption and treatment outgoings. Nanoparticles (NPs) can be prepared from a variety of materials such as lipid, biodegradable polymer that prevent the drugs cytotoxicity in healthy cells, etc. One of the most important drugs used in chemotherapy is mitoxantrone (MTX) which prevents cell proliferation by inhibition of topoisomerase II and DNA repair; however, it is not selective and has some serious side effects. In this study, mentioned aim is achieved by using several nanocarriers like magnetite (Fe3O4) and their composites with magnetic graphene oxide (Fe3O4@GO). Also, cytotoxic potential of Fe3O4, Fe3O4-MTX, and Fe3O4@GO-MTX nanocomposite were evaluated on mesenchymal stem cells (MSCs). In this study, we reported the synthesis of monodisperse Fe3O4 NPs and Fe3O4@GO nanocomposite and their structures were investigated by using field emission scanning electron microscope (FESEM), Fourier transform infrared (FTIR) spectra, atomic force microscopy (AFM), Brauneur Emmet Teller (BET) isotherm and contact angle studies. Moreover, we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cytotoxic effects of MTX, Fe3O4 NPs, Fe3O4-MTX and Fe3O4@GO-MTX nanocomposite on MSCs. The in-vitro MTT results indicated that all concentrations of MTX and Fe3O4@GO-MTX nanocomposites showed cytotoxic effects while all concentrations of Fe3O4 NPs and Fe3O4-MTX NPs did not show any cytotoxic effect on stem cells. The results from this study indicated that using Fe3O4 NPs as anticancer drug delivery systems could be a trustworthy method for cancer treatment. But for reaching excellent and accurate results, further investigation is necessary.

Keywords: mitoxantrone, magnetite, magnetic graphene oxide, MTT assay, mesenchymal stem cells

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Authors: Bollu Mounica

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Background: Nowadays drug related problems were seen very commonly within the health care practice. These could result in the medication errors, adverse events, drug interactions and harm to patients. Pharmacist has an identified role in minimizing and preventing such type of problems. Objectives: To detect the incidence of drug related problems for the hospitalized patient, and to analyze the clinical pharmacist interventions performed during the review of prescription orders of the general medicine, psychiatry, surgery, pediatrics, gynaecology units of a large tertiary care teaching hospital. Methods: It was a retrospective, observational and interventional study. The analysis took place daily with the following parameters: dose, rate of administration, presentation and/or dosage form, presence of inappropriate/unnecessary drugs, necessity of additional medication, more proper alternative therapies, presence of relevant drug interactions, inconsistencies in prescription orders, physical-chemical incompatibilities/solution stability. From this evaluation, the drug therapy problems were classified, as well as the resulting clinical interventions. For a period starting November 2012 until December 2014, the inpatient medication charts and orders were identified and rectified by ward and practicing clinical pharmacists within the inpatient pharmacy services in a tertiary care teaching hospital on routine daily activities. Data was collected and evaluated. The causes of this problem were identified. Results: A total of 360 patients were followed. Male (71.66%) predominance was noted over females (28.33%). Drug related problems were more commonly seen in patients aged in between 31-60. Most of the DRP observed in the study resulted from the dispensing errors (26.11%), improper drug selection (17.22%), followed by untreated indications (14.4%) Majority of the clinical pharmacist recommendations were on need for proper dispensing (26.11%), and drug change (18.05%). Minor significance of DRPs were noted high (41.11 %), whereas (35.27 %) were moderate and (23.61 %) were major. The acceptance rate of intervening clinical pharmacist recommendation and change in drug therapy was found to be high (86.66%). Conclusion: Our study showed that the prescriptions reviewed had some drug therapy problem and the pharmacist interventions have promoted positive changes needed in the prescriptions. In this context, routine participation of clinical pharmacists in clinical medical rounds facilitates the identification of DRPs and may prevent their occurrence.

Keywords: drug related problems, clinical pharmacist, drug prescriptions, drug related problems, intervention

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Authors: Agung A. Ginanjar, Lilitasari, Indra Prasetya, Rizal R. Hanif, Yusrina Rismandini, Atina Hussaana, Nurita P. Sari

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Hyperlipidemia is an increase of lipids and cholesterol in the blood that causes the formation of atherosklerosis. The recent pharmacological therapy nowadays is statin. Many Indonesian people use of medicinal plants. There are several medical plants that people always use to cure hyperlipidemia such as bulbs onion sabrang, areca nuts, and seed of fenugreek. Most people often use a combination therapy of conventional medicine and herbs to achieve the desired therapeutic effect of combination therapy. The use of combination therapy might cause the interaction of pharmacodynamic from those medicines so that it influences the pharmacological effect of one of medicine. The aim of this study is to know the interaction of simvastatin and a cholesterol-lowering herb seen in rats pharmacodynamic simvastatin phase. This research used post-test only controlled group design. Analysis of statistical data normality and homogenity were tested by Kolmogorov Smirnov. The ANOVA test is used when the data is obtained homogeneous but if it is found that the data are not homogeneous then kruskal-wallis test is used. Normal (63.196 mg/dl), negative (70.604 mg/dl), positive (62.512 mg/dl), areca nuts (56.564 mg/dl), fenugreek seed (47.538 ,g/dl), onion sabrang (62.312 mg/dl). The results prove that the combination of herbs and simvastatin did not have a significant difference (P>0,05). The conclusion of this study is that the combination of simvastatin and a cholesterol-lowering herb can cause some pharmacodynamic interactions such as a synergistic effect, antagonist, and a powerful additive, so that combination therapy is not more effective than single simvastatin therapy. The use of the combination therapy is not given in the same time. It would be better if there are some period of time when the combination therapy is applied.

Keywords: onion bulb sabrang, areca nuts, seed of fenugreek, interaction medicine, hyperlipidemia

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

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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

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Authors: Ashley R. Logsdon, Becky F. Antle, Cynthia M. Kamer

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This study examines the cost and benefits of a family treatment drug court in an urban county in a southeastern state. Additionally, this cost analysis will provide a detailed description of the type and cost of activities to produce the services provided to child welfare families. This study utilized return-on-investment analysis, which uses child welfare practices, disaggregates them into separate activities and estimates costs for these activities including child-level placement data for total cost of care for the child. Direct and indirect costs were considered as well as saving calculations what costs would be associated with child welfare outcomes both short and long term. The costs included were general program costs (salaries, drug screens, transportation, childcare, parent education, program evaluation, visitation, incentives) or personnel costs for other team members (judges, court administrators, child welfare workers, child welfare supervisors, and community mental health provider). The savings that were used in the study were length of time in out of home care, Medicaid costs, substance exposed births, emergency room utilization and jail/probation costs. This study documents an overall savings of between $168,993.30 and $837,993.30. The total savings per family divided by the 40 families who have participated in the program was between $4,224.83 to $20,949.83 per family. The results of this cost benefit analysis are consistent with prior research documenting savings associated with out of home care and jail/probation; however, there are also unique contributions of this study to the literature on cost effectiveness of family treatment drug courts. We will present recommendations for further utilization of family treatment drug courts and how to expand the current model.

Keywords: child welfare, cost analysis, family drug court, family treatment drug court

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Authors: Hend Ben Tkhayat , Khaled Al Zahabi, Husam Younes

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Introduction: Vildagliptin (VG), a dipeptidyl peptidase-4 inhibitor (DPP-4), was proven to be an active agent for the treatment of type 2 diabetes. VG works by enhancing and prolonging the activity of incretins which improves insulin secretion and decreases glucagon release, therefore lowering blood glucose level. It is usually used with various classes, such as insulin sensitizers or metformin. VG is currently only marketed as an immediate-release tablet that is administered twice daily. In this project, we aim to formulate an extended-release with a zero-order profile tableted lipid microparticles of VG that could be administered once daily ensuring the patient’s convenience. Method: The spray-congealing technique was used to prepare VG microparticles. Compritol® was heated at 10 oC above its melting point and VG was dispersed in the molten carrier using a homogenizer (IKA T25- USA) set at 13000 rpm. VG dispersed in the molten Compritol® was added dropwise to the molten Gelucire® 50/13 and PEG® (400, 6000, and 35000) in different ratios under manual stirring. The molten mixture was homogenized and Carbomer® amount was added. The melt was pumped through the two-fluid nozzle of the Buchi® Spray-Congealer (Buchi B-290, Switzerland) using a Pump drive (Master flex, USA) connected to a silicone tubing wrapped with silicone heating tape heated at the same temperature of the pumped mix. The physicochemical properties of the produced VG-loaded microparticles were characterized using Mastersizer, Scanning Electron Microscope (SEM), Differential Scanning Calorimeter (DSC) and X‐Ray Diffractometer (XRD). VG microparticles were then pressed into tablets using a single punch tablet machine (YDP-12, Minhua pharmaceutical Co. China) and in vitro dissolution study was investigated using Agilent Dissolution Tester (Agilent, USA). The dissolution test was carried out at 37±0.5 °C for 24 hours in three different dissolution media and time phases. The quantitative analysis of VG in samples was realized using a validated High-Pressure Liquid Chromatography (HPLC-UV) method. Results: The microparticles were spherical in shape with narrow distribution and smooth surface. DSC and XRD analyses confirmed the crystallinity of VG that was lost after being incorporated into the amorphous polymers. The total yields of the different formulas were between 70% and 80%. The VG content in the microparticles was found to be between 99% and 106%. The in vitro dissolution study showed that VG was released from the tableted particles in a controlled fashion. The adjustment of the hydrophilic/hydrophobic ratio of excipients, their concentration and the molecular weight of the used carriers resulted in tablets with zero-order kinetics. The Gelucire 50/13®, a hydrophilic polymer was characterized by a time-dependent profile with an important burst effect that was decreased by adding Compritol® as a lipophilic carrier to retard the release of VG which is highly soluble in water. PEG® (400,6000 and 35 000) were used for their gelling effect that led to a constant rate delivery and achieving a zero-order profile. Conclusion: Tableted spray-congealed lipid microparticles for extended-release of VG were successfully prepared and a zero-order profile was achieved.

Keywords: vildagliptin, spray congealing, microparticles, controlled release

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Authors: Thippharat Wongsilarat, Parichat tuntilanon, Chonlakan Prataksitorn

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Recurrent adverse drug reactions are harmful to patients with mild to fatal illnesses, and affect not only patients but also their relatives, and organizations. To compare safe use of medicine among patients before and after using the recurrent adverse drug reaction prevention program . Quasi-experimental research with the target population of 598 patients with drug allergy history. Data were collected through an observation form tested for its validity by three experts (IOC = 0.87), and analyzed with a descriptive statistic (percentage). The research was conducted jointly with a multidisciplinary team to analyze and determine the weak points and strong points in the recurrent adverse drug reaction prevention system during the past three years, and 546, 329, and 498 incidences, respectively, were found. Of these, 379, 279, and 302 incidences, or 69.4; 84.80; and 60.64 percent of the patients with drug allergy history, respectively, were found to have caused by incomplete warning system. In addition, differences in practice in caring for patients with drug allergy history were found that did not cover all the steps of the patient care process, especially a lack of repeated checking, and a lack of communication between the multidisciplinary team members. Therefore, the recurrent adverse drug reaction prevention program was developed with complete warning points in the information technology system, the repeated checking step, and communication among related multidisciplinary team members starting from the hospital identity card room, patient history recording officers, nurses, physicians who prescribe the drugs, and pharmacists. Including in the system were surveillance, nursing, recording, and linking the data to referring units. There were also training concerning adverse drug reactions by pharmacists, monthly meetings to explain the process to practice personnel, creating safety culture, random checking of practice, motivational encouragement, supervising, controlling, following up, and evaluating the practice. The rate of prescribing drugs to which patients were allergic per 1,000 prescriptions was 0.08, and the incidence rate of recurrent drug reaction per 1,000 prescriptions was 0. Surveillance of recurrent adverse drug reactions covering all service providing points can ensure safe use of medicine for patients.

Keywords: recurrent drug, adverse reaction, safety, use of medicine

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Authors: M. S. Deshpande, Snehal D. Bomble

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Tuberculosis (TB) is a deadly contagious disease that is caused by a bacterium called Mycobacterium tuberculosis. More than sixty years ago, the introduction of the first anti-TB drugs for the treatment of TB (streptomycin (STR), p-aminosalcylic acid (PAS), isoniazid (INH), and then later ethambutol (EMB) and rifampicin (RIF)) gave optimism to the medical community, and it was believed that the disease would be completely eradicated soon. Worldwide, the number of TB cases has continued to increase, but the incidence rate has decreased since 2003. Recently, highly drug-resistant forms of TB have emerged worldwide. The prolonged use of classical drugs developed a growing resistance and these drugs have gradually become less effective and incapable to meet the challenges, especially those of multi drug resistant (MDR)-TB, extensively drug resistant (XDR)-TB, and HIV-TB co-infections. There is an unmet medical need to discover newer synthetic molecules and new generation of potent drugs for the treatment of tuberculosis which will shorten the time of treatment, be potent and safe while effective facing resistant strains and non-replicative, latent forms, reduce adverse side effect and not interfere in the antiretroviral therapy. This paper attempts to bring out the review of anti-TB drugs, and presents a novel method of synthesizing new anti-tuberculosis drugs and potential compounds to overcome the bacterial resistance and combat the re-emergence of tuberculosis.

Keywords: tuberculosis, mycobacterium, multi-drug resistant (MDR)-TB, extensively drug resistant (XDR)-TB

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Authors: Anita, Sari Septiani Tangke, Rusdina Bte Ladju, Nasrum Massi

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New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. The microscopic-observation drug-susceptibility (MODS) assay is a rapid, accurate and simple liquid culture method to detect multidrug-resistant tuberculosis (MDR-TB). MODS were evaluated to determine a lower and same concentration of isoniazid and rifampin for detection of MDR-TB. Direct drug-susceptibility testing was performed with the use of the MODS assay. Drug-sensitive control strains were tested daily. The drug concentrations that used for both isoniazid and rifampin were at the same concentration: 0.16, 0.08 and 0.04μg per milliliter. We tested 56 M. tuberculosis clinical isolates and the control strains M. tuberculosis H37RV. All concentration showed same result. Of 53 M. tuberculosis clinical isolates, 14 were MDR-TB, 38 were susceptible with isoniazid and rifampin, 1 was resistant with isoniazid only. Drug-susceptibility testing was performed with the use of the proportion method using Mycobacteria Growth Indicator Tube (MGIT) system as reference. The result of MODS assay using lower concentration was significance (P<0.001) compare with the reference methods. A lower and same concentration of isoniazid and rifampin can be used to detect MDR-TB. Operational cost and application can be more efficient and easier in resource-limited environments. However, additional studies evaluating the MODS using lower and same concentration of isoniazid and rifampin must be conducted with a larger number of clinical isolates.

Keywords: isoniazid, MODS assay, MDR-TB, rifampin

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Authors: Nurlaili E. P., Astuti M., Marsono Y., Naruki S.

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Iron is an essential nutrient with limited bioavailability. Nutritional anemia caused mainly by iron deficiency is the most recognized nutritional problem in both countries as well as affluent societies. Rice (Oryza sativa L.) has become the most important cereal crop for the improvement of human health due to the starch, protein, oil, and the majority of micronutrients, particularly in Asian countries. In this study, the iron availability and profile lipid were evaluated for the extracts from Cibeusi varieties (black rices) of ancient rice brans. Results: The quality of K, B, R, E diets groups shows the same effect on the growth of rats. This indicate that groups is as efficiently utilized by the body as E diets. Hematocrit and MCHC levels of rats fed K, B, R and E diets were not significantly (P< 0.05). MCV and MCH levels of rats K, B, R were significantly (P< 0.05) with E groups but rats K, B, R were not significantly (P< 0.05). The iron content in the serum of rats fed with K, B, R and E diets were not significantly (P< 0.05). The highest level of iron in the serum was founded in the B group. The iron content in the liver of rats fed with K, B, R and E diets were not significantly (P< 0.05). The highest level of iron in the liver was founded in the R group. HDL cholesterol levels were significantly (P< 0.05) between rats of fed B, E with K, R, but K and R were not significantly (P< 0.05). LDL cholesterol levels of rats fed K and E significantly (P< 0.05) with B and R. Conclusions: the bran of pigmented rice varieties has, with some exceptions, greater antioxidant and free-radical scavenging activities. The results also show that pigmented rice extracts acted as pro-oxidants in the lipid peroxidation assay, possibly by mechanisms described for the pro-oxidant activities of tocopherol and ascorbic. Pigmented rice bran extracts more effectively increases iron stores and reduces the prevalence of iron deficiency. And reduces cholesterol, TG and LDL cholesterol and increses HDL cholesterol.

Keywords: anemia, black rice bran extract, iron, profile lipid

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Authors: Muhammad Ajmal

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- Thermal processing and subsequent storage of ultra-heat treated (UHT) milk leads to alteration in protein profile, Maillard reaction and lipid oxidation. Concentration of carbohydrates in normal and flavored version of UHT milk is considerably different. Transition in protein profile, Maillard reaction and lipid oxidation in UHT flavored milk was determined for 90 days at ambient conditions and analyzed at 0, 45 and 90 days of storage. Protein profile, hydroxymethyl furfural, furosine, Nε-carboxymethyl-l-lysine, fatty acid profile, free fatty acids, peroxide value and sensory characteristics were determined. After 90 days of storage, fat, protein, total solids contents and pH were significantly less than the initial values determined at 0 day. As compared to protein profile normal UHT milk, more pronounced changes were recorded in different fractions of protein in UHT milk at 45 and 90 days of storage. Tyrosine content of flavored UHT milk at 0, 45 and 90 days of storage were 3.5, 6.9 and 15.2 µg tyrosine/ml. After 45 days of storage, the decline in αs1-casein, αs2-casein, β-casein, κ-casein, β-lactoglobulin, α-lactalbumin, immunoglobulin and bovine serum albumin were 3.35%, 10.5%, 7.89%, 18.8%, 53.6%, 20.1%, 26.9 and 37.5%. After 90 days of storage, the decline in αs1-casein, αs2-casein, β-casein, κ-casein, β-lactoglobulin, α-lactalbumin, immunoglobulin and bovine serum albumin were 11.2%, 34.8%, 14.3%, 33.9%, 56.9%, 24.8%, 36.5% and 43.1%. Hydroxy methyl furfural content of UHT milk at 0, 45 and 90 days of storage were 1.56, 4.18 and 7.61 (µmol/L). Furosine content of flavored UHT milk at 0, 45 and 90 days of storage intervals were 278, 392 and 561 mg/100g protein. Nε-carboxymethyl-l-lysine content of UHT flavored milk at 0, 45 and 90 days of storage were 67, 135 and 343mg/kg protein. After 90 days of storage of flavored UHT milk, the loss of unsaturated fatty acids 45.7% from the initial values. At 0, 45 and 90 days of storage, free fatty acids of flavored UHT milk were 0.08%, 0.11% and 0.16% (p<0.05). Peroxide value of flavored UHT milk at 0, 45 and 90 days of storage was 0.22, 0.65 and 2.88 (MeqO²/kg). Sensory analysis of flavored UHT milk after 90 days indicated that appearance, flavor and mouth feel score significantly decreased from the initial values recorded at 0 day. Findings of this investigation evidenced that in flavored UHT milk more pronounced changes take place in protein profile, Maillard reaction products and lipid oxidation as compared to normal UHT milk.

Keywords: UHT flavored milk , hydroxymethyl furfural, lipid oxidation, sensory properties

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Authors: Prakash Singh

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Schools throughout the world are facing increasing challenges in dealing with school violence and drug abuse by pupils. Therefore, the question of the fear of failure to meet the aims and objectives of education inevitably surfaces as it places increasing and challenging demands on educators and all other stakeholders to address this malaise. Multiple studies on the construct tobephobia (TBP) simply define TBP as the fear of failure in education. This study is a continuation of the exploratory studies on the manifestation of fear in education. The primary purpose of this study was to establish how TBP, caused by school violence and drug abuse affects teaching and learning in our schools. The qualitative research method was used for this study. Teachers admitted that they fear for their safety at school. Working in a fearful situation places a high rate of stress and anxiety on them. Tobephobic educators spend most of their time worrying about their fear of violence and drug abuse by pupils and are too frightened to carry out their normal duties. They prefer to stay in familiar surroundings for fear of being attacked by inebriated learners. This study, therefore, contributes to our understanding of the effects of TBP in our schools caused by school violence and drug abuse. Also, this study supplements the evidence accumulated over the past fifteen years that TBP is not a figment of someone’s imagination; it is a gruesome reality affecting the very foundation of our educational system globally to provide quality and equal education to all our learners in a harmonious, collegial school environment.

Keywords: tobephobia, tobephobic educators, fear of failure in education, school violence, drug abuse

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Authors: Jyothi Nagraj, Sudeshna Mukherjee, Rajdeep Chowdhury

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Autophagy has recently been linked with cancer cell survival post drug insult contributing to acquisition of resistance. However, the molecular signaling governing autophagic survival response is poorly explored. In our study, in osteosarcoma (OS) cells cisplatin shock was found to activate both MAPK and autophagy signaling. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. An increased sensitivity of the cells to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Furthermore, we observed that the autophagic stimulation upon drug stress regulates other developmentally active signaling pathways like the Hippo pathway in OS cells. Cisplatin resistant cells were thereafter developed by repetitive drug exposure followed by clonal selection. Basal levels of autophagy were found to be high in resistant cells to. However, the signaling mechanism leading to autophagic up-regulation and its regulatory effect differed in OS cells upon attaining drug resistance. Our results provide valuable clues to regulatory dynamics of autophagy that can be considered for development of improved therapeutic strategy against resistant type cancers.

Keywords: JNK, autophagy, drug resistance, cancer

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Authors: Maryam Vaezjalali, Koroush Rahimian, Maryam Asli, Tahmineh Kandelouei, Foad Davoodbeglou, Amir H. Kashi

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Objectives: The present study was conducted to assess the HBV molecular profiles including genotypes, subgenotypes, subtypes & mutations in hepatitis B genes. Materials/Patients and Methods: This study was conducted on 229 intravenous drug users who referred to three Drop- in-Centers and a hospital in Tehran. HBV DNA was extracted from HBsAg positive serum samples and amplified by Nested PCR. HBV genotype, subgenotypes, subtype and genes mutation were determined by direct sequencing. Phylogenetic tree was constructed using neighbor- joining (NJ) method. Statistical analyses were carried out by SPSS 20. Results: HBV DNA was found in 3 HBsAg positive cases. Phylogenetic tree of derived HBV DNAs showed the existence of genotype D (subgenotype D1, subtype ayw2). Also immune escape mutations were determined in S gene. Conclusion: There were a few variations and genotypes and subtypes among infected intravenous drug users. This study showed the predominance of genotype D among intravenous drug users. Our study concurs with other reports from Iran, that all showing currently only genotype D is the only detectable genotype in Iran.

Keywords: drug users, genotype, HBV, phylogenetic tree

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Authors: Kien Xuan Ngo

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Cassiicolin (Cas), a toxin produced by Corynespora cassiicola, is responsible for corynespora leaf fall (CLF) disease in rubber trees. Currently, the molecular mechanism of the cytotoxicity of Cas isoforms (i.e., Cas1, Cas2) on rubber leaves and its host selectivity have not been fully elucidated. This study analyzed the binding of Cas1 and Cas2 to membranes consisting of different plant lipids and their membrane-disruption activities. Using high-speed atomic force microscopy and confocal microscopy, this study reveals that the binding and disruption activities of Cas1 and Cas2 on lipid membranes are strongly dependent on the specific plant lipids. The negative phospholipids, glycerolipids, and sterols are more susceptible to membrane damage caused by Cas1 and Cas2 than neutral phospholipids and betaine lipids. In summary, This study unveils that (i) Cas1 and Cas2 directly damage and cause necrosis in the leaves of specific rubber clones; (ii) Cas1 and Cas2 can form biofilm-like structures on specific lipid membranes (negative phospholipids, glycerolipids, and sterols). The biofilm-like formation of Cas toxin plays an important role in selective disruption on lipid membranes; (iii) Vulnerability of the specific cytoplasmic membranes to the selective Cas toxin is the most remarkable feature of cytotoxicity of Cas toxin on plant cells. Finally, researcher’s exploration is crucial to understand the basic molecular mechanism underlying the host-selective toxic interaction of Cas toxin with cytoplasmic membranes in plant cells.

Keywords: cassiicolin, corynespora leaf fall disease, high-speed AFM, giant liposome vesicles

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Authors: Ragaa T. Darwish, Maha A. Demellawy, Haidy M. Megahed, Doreen N. Younan, Wael S. Kholeif

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The testing of drug abuse is authentic in order to affirm the misuse of drugs. Several analytical approaches have been developed for the detection of drugs of abuse in pharmaceutical and common biological samples, but few methodologies have been created to identify them from fingerprints. Liquid Chromatography-Mass Spectrometry (LC-MS) plays a major role in this field. The current study aimed at assessing the possibility of detection of some drugs of abuse (tramadol, clonazepam, and phenobarbital) from fingerprints using LC-MS in drug abusers. The aim was extended in order to assess the possibility of detection of the above-mentioned drugs in fingerprints of drug handlers till three days of handling the drugs. The study was conducted on randomly selected adult individuals who were either drug abusers seeking treatment at centers of drug dependence in Alexandria, Egypt or normal volunteers who were asked to handle the different studied drugs (drug handlers). An informed consent was obtained from all individuals. Participants were classified into 3 groups; control group that consisted of 50 normal individuals (neither abusing nor handling drugs), drug abuser group that consisted of 30 individuals who abused tramadol, clonazepam or phenobarbital (10 individuals for each drug) and drug handler group that consisted of 50 individuals who were touching either the powder of drugs of abuse: tramadol, clonazepam or phenobarbital (10 individuals for each drug) or the powder of the control substances which were of similar appearance (white powder) and that might be used in the adulteration of drugs of abuse: acetyl salicylic acid and acetaminophen (10 individuals for each drug). Samples were taken from the handler individuals for three consecutive days for the same individual. The diagnosis of drug abusers was based on the current Diagnostic and Statistical Manual of Mental disorders (DSM-V) and urine screening tests using immunoassay technique. Preliminary drug screening tests of urine samples were also done for drug handlers and the control groups to indicate the presence or absence of the studied drugs of abuse. Fingerprints of all participants were then taken on a filter paper previously soaked with methanol to be analyzed by LC-MS using SCIEX Triple Quad or QTRAP 5500 System. The concentration of drugs in each sample was calculated using the regression equations between concentration in ng/ml and peak area of each reference standard. All fingerprint samples from drug abusers showed positive results with LC-MS for the tested drugs, while all samples from the control individuals showed negative results. A significant difference was noted between the concentration of the drugs and the duration of abuse. Tramadol, clonazepam, and phenobarbital were also successfully detected from fingerprints of drug handlers till 3 days of handling the drugs. The mean concentration of the chosen drugs of abuse among the handlers group decreased when the days of samples intake increased.

Keywords: drugs of abuse, fingerprints, liquid chromatography–mass spectrometry, tramadol

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Authors: Delband Yekta Moazami

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Background: For proper care and treatment of HIV patients and drug users, the medical staff and physicians must have a correct and positive attitude and knowledge towards such patients. We aimed to assess the attitudes in a sample of health care workers (HCW) working in different hospitals and clinics and medical students in Georgia towards HIV infected people and drug users in Tbilisi. Method: We conducted a cross-sectional study to assess attitudes of health care workers towards people living with HIV and drug users in hospitals and clinics in Tbilisi. The study was carried out from 1st of May 2020 till 30th of September 2020. Data were collected using a self-administered structured online questionnaire. With this tool we evaluated four facets of attitudes: Discrimination, Acceptance of HIV/AIDS patients, Acceptance of drug users and Fear. All data were imported and analyzed with the software SPSS 22 for windows. Results: In total data was collected from168 respondents, that among them 107 (65%) were women and majority of the participants were medical doctors. Women had more acceptance attitudes rather than men towards drug abusers. We found significant differences regarding expressing negative attitudes among HCW who were more than 50 years old comparing with other age groups in all four aspects. Medical doctors expressed more acceptances towards people with HIV and drug users comparing two other groups. Also our study revealed that the group with working experience 21 years and more, showed more discriminatory attitudes comparing other groups. Conclusion: Based on our study findings, there are significant differences regarding respondent’s attitudes based on gender, medical specialty and working experience in health care system. People struggling with HIV and drug use need nonjudgmental and positive behaviors from health care workers and physicians in order to help them for harm reduction and receiving appropriate treatment.

Keywords: hiv, addiction, attitudes, healthcare workers

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Authors: J. Desbrieres, M. Popa, C. Peptu, S. Bacaita

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Because of their favorable properties (non-toxicity, biodegradability, mucoadhesivity etc.), polysaccharides were studied as biomaterials and as pharmaceutical excipients in drug formulations. These formulations may be produced in a wide variety of forms including hydrogels, hydrogel based particles (or capsules), films etc. In these formulations, the polysaccharide based materials are able to provide local delivery of loaded therapeutic agents but their delivery can be rapid and not easily time-controllable due to, particularly, the burst effect. This leads to a loss in drug efficiency and lifetime. To overcome the consequences of burst effect, systems involving liposomes incorporated into polysaccharide hydrogels may appear as a promising material in tissue engineering, regenerative medicine and drug loading systems. Liposomes are spherical self-closed structures, composed of curved lipid bilayers, which enclose part of the surrounding solvent into their structure. The simplicity of production, their biocompatibility, the size and similar composition of cells, the possibility of size adjustment for specific applications, the ability of hydrophilic or/and hydrophobic drug loading make them a revolutionary tool in nanomedicine and biomedical domain. Drug delivery systems were developed as hydrogels containing chitosan or carboxymethylcellulose (CMC) as polysaccharides and gelatin (GEL) as polypeptide, and phosphatidylcholine or phosphatidylcholine/cholesterol liposomes able to accurately control this delivery, without any burst effect. Hydrogels based on CMC were covalently crosslinked using glutaraldehyde, whereas chitosan based hydrogels were double crosslinked (ionically using sodium tripolyphosphate or sodium sulphate and covalently using glutaraldehyde). It has been proven that the liposome integrity is highly protected during the crosslinking procedure for the formation of the film network. Calcein was used as model active matter for delivery experiments. Multi-Lamellar vesicles (MLV) and Small Uni-Lamellar Vesicles (SUV) were prepared and compared. The liposomes are well distributed throughout the whole area of the film, and the vesicle distribution is equivalent (for both types of liposomes evaluated) on the film surface as well as deeper (100 microns) in the film matrix. An obvious decrease of the burst effect was observed in presence of liposomes as well as a uniform increase of calcein release that continues even at large time scales. Liposomes act as an extra barrier for calcein release. Systems containing MLVs release higher amounts of calcein compared to systems containing SUVs, although these liposomes are more stable in the matrix and diffuse with difficulty. This difference comes from the higher quantity of calcein present within the MLV in relation with their size. Modeling of release kinetics curves was performed and the release of hydrophilic drugs may be described by a multi-scale mechanism characterized by four distinct phases, each of them being characterized by a different kinetics model (Higuchi equation, Korsmeyer-Peppas model etc.). Knowledge of such models will be a very interesting tool for designing new formulations for tissue engineering, regenerative medicine and drug delivery systems.

Keywords: controlled and delayed release, hydrogels, liposomes, polysaccharides

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Authors: Vadim Makarov, Stewart T.Cole

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PBTZ169 is novel drug candidate with high efficacy in animals models, and its combination treatment of PBTZ169 with BDQ and pyrazinamide was shown to be more efficacious than the standard treatment for tuberculosis in a mouse model. The target of PBTZ169 is famous DprE1, an essential enzyme in cell wall biosynthesis. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Furthermore, this drug candidate demonstrated during preclinical research ‘drug like’ properties what made it an attractive drug candidate to treat tuberculosis in humans. During first clinical trials several cohorts of the healthy volunteers were treated by the single doses of PBTZ169 as well as two weeks repeated treatment was chosen for two maximal doses. As expected PBTZ169 was well tolerated, and no significant toxicity effects were observed during the trials. The study of the metabolism shown that human metabolism of PBTZ169 is very different from microbial or animals compound transformation. So main pathway of microbial, mice and less rats metabolism connected with reduction processes, but human metabolism mainly connected with oxidation processes. Due to this difference we observed several metabolites of PBTZ169 in humans with antitubercular activity, and now we can conclude that animal antituberculosis activity of PBTZ169 is a result not only activity of the drug itself, but it is a result of the sum activity of the drug and its metabolites. Direct antimicrobial plasma activity was studied, and such activity was observed for 24 hours after human treatment for some doses. This data gets high chance for good efficacy of PBTZ169 in human for treatment TB infection. Second phase of clinical trials was started summer of 2017 and continues to the present day. Available data will be presented.

Keywords: clinical trials, DprE1, PBTZ169, metabolism

Procedia PDF Downloads 135