Eczacılık Fakültesi / Faculty of Pharmacy

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Analysis of 3-hydroxyisovaleric acid and 3-hydroxybutyric acid in plasma samples by LC-MS/MS
(2022) Recber, Tuba; Ozkan, Ece; Nemutlu, Emirhan; Beksac, Mehmet Sinan; Kir, Sedef
Down syndrome is a common genetic disorder that results from the presence of an extra chromosome in the 21st chromosome pair of humans. Metabolomics is an alternative method in discovery of new biomarkers for the screening and diagnosis of Down syndrome. In this study, quantitative analyzes of 3-hydroxybutyric acid and 3hydroxyisovaleric acid, selected as possible markers for prenatal diagnosis of Down syndrome were performed. LCMS/MS analyzes were performed on a Phenomenex Luna NH2(100 x 4.6 mm, 3 mu m) column using a mobile phase mixture of 0.1% formic acid and acetonitrile containing 0.1% formic acid at a flow rate of 0.35 mL/minute. The MRM transitions were 103.0 -> 59.0 for 3-hydroxybutyric acid and 117.1 -> 59.0 for 3-hydroxyisovaleric acid. Under these conditions, the retention times of 3-hydroxyisovaleric acid 3-hydroxybutyric acid were 2.7 and 3.1 minute, respectively. The method was found linear from 0.1 to 10.0 mu g/mL for both metabolites. The limit of detection (LOD) was 0.017 mu g/mL for 3-hydroxybutyric acid and 0.003 mu g/mL for 3-hydroxyisovaleric acid. The lower limit quantification (LLOQ) was 0.045 mu g/mL for 3-hydroxybutyric acid and 0.008 mu g/mL for 3-hydroxyisovaleric acid. The method has been proven to be selective, precise, accurate, sensitive, and robust based on the validation studies results. Finally, the method was applied to plasma samples of the pregnant women with healthy fetus (n = 30) and with Down syndrome fetus (n = 17). As a result of the analysis, a statistically significant increase (p <0.01) was observed in the 3-hydroxybutyric acid level of the group with Down syndrome compared to the healthy group. This result strengthens the use of 3-hydroxybutyric acid as an important biomarker in the prenatal screening/diagnosis of Down syndrome.
Anti-Tyrosinase and Antimelanogenic Effect of Cinnamic Acid Derivatives from Prunus Mahaleb L.: Phenolic Composition, Isolation, Identification And Inhibitory Activity
(2023) Guven, Zuhal Bayrakceken; Saracoglu, Iclal; Nagatsu, Akito; Yilmaz, Mustafa Abdullah; Basaran, A. Ahmet; 36924865; AAI-6606-2021
Ethnopharmacological relevance: The traditional use of Prunus species against skin diseases and especially for skin lightning cosmeceutical purposes is widespread in many cultures. Prunus mahaleb L. is a well known food plant and used in the baking industry for flavoring. The fruit kernels (endocarp) are used in India for hyperpigmentation. Aim of the study: To investigate the chemical composition with the antimelanogenesis effect of P. mahaleb seed and kernel extracts and isolated compounds. Materials and methods: Isolation studies performed from the methanol extracts obtained from kernels and structures were determined using NMR and MS analysis. Antimelanogenesis effect was determined by mushroom tyrosinase assay, cellular tyrosinase assay and melanin content assay using B16F10 murine melanoma cells. Results: Five cinnamic acid derivatives were isolated and their structures (2-O-& beta;-glucopyranosyloxy-4-methoxyhydrocinnamic acid (1), cis-melilotoside (2), dihydromelilotoside (3), trans-melilotoside (4), 2-O-& beta;-glucosyloxy4-methoxy trans-cinnamic acid (5)) were elucidated using advanced spectroscopic methods. Mushroom tyrosinase enzyme inhibition of extracts, fractions and pure compounds obtained from P. mahaleb kernels were investigated and structure-activity relationship revealed. According to a detailed, comprehensive and validated LC-MS/MS technique analysis, vanilic acid (41.407 mg/g), protocatechuic acid (8.992 mg/g) and ferulic acid (4.962 mg/g) in the kernel ethylacetate fraction; quinic acid (14.183 mg/g), fumaric acid (8.349 mg/g) and aconitic acid (5.574 mg/g) were found as major phenolic compounds in the water fraction. The correlation of trace element copper content in extracts and fractions with mushroom enzyme activity was determined. By examining the enzyme kinetics of the compounds with effective cinnamic acid derivatives, inhibition types and enzyme binding constants Ki were calculated. Compounds 1,3 and 5 exhibited high noncompetitive tyrosinase inhibitory activity against L-tyrosine substrates, with IC50 values of 0.22, 0.31 and 0.37 mM respectively. In addition compounds 1, 3 and 5 showed dose-dependent inhibitory effects on intracellular tyrosinase and melanin levels in & alpha;-melanocyte-stimulating hormone (& alpha;-MSH)-induced B16F10 melanoma cells. Conclusions: Potent tyrosinase inhibitory compounds and extracts of P. mahaleb kernels suggest that it could be a new, non-toxic and inexpensive resource for the cosmeceutical industry and in skin diseases associated with hyperpigmentation.
A Bayesian Estimation Framework for Pharmacogenomics Driven Warfarin Dosing: A Comparative Study
(2015) Oztaner, Serdar Murat; Temizel, Tugba Taskaya; Erdem, S. Remzi; Ozer, Mahmut; 0000-0002-7537-2170; 25020183; AAJ-2370-2021
The incorporation of pharmacogenomics information into the drug dosing estimation formulations has been shown to increase the accuracy in drug dosing and decrease the frequency of adverse drug effects in many studies in the literature. In this paper, an estimation framework based on the Bayesian structural equation modeling, which is driven by pharmacogenomics, is proposed. The results show that the model compares favorably with the linear models in terms of prediction and explaining the variations in warfarin dosing.
Clinical pharmacist assessment of drug-related problems among intensive care unit patients in a Turkish university hospital
(2022) Albayrak, Aslinur; Basgut, Bilgen; Bikmaz, Gulbin Aygencel; Karahalil, Bensu; 35033079
Background Critically ill patients treated in the intensive care units (ICUs) often suffer from side effects and drug-related problems (DRPs) that can be life-threatening. A way to prevent DRPs and improve drug safety and efficacy is to include clinical pharmacists in the clinical team. This study aims to evaluate the classification of drug-related problems and the implementation of clinical pharmacy services by a clinical pharmacist in the ICU of a university hospital in Turkey. Methods This study was carried out prospectively between December 2020 and July 2021 in Gazi University Medical Faculty Hospital Internal Diseases ICU. All patients hospitalized in the intensive care unit for more than 24 h were included in the study. During the study, the clinical pharmacist's interventions and other clinical services for patients were recorded. DRPs were classed according to the Pharmaceutical Care Network Europe V.8.02. Results A total of 151 patients were included during the study period corresponding to 2264 patient-days. Patients with DRPs had a longer hospital stay and a higher mortality rate (p < 0.05). 108 patients had at least one DRP and the total number of DRPs was 206. There was an average of 1.36 DRPs per patient, 71.5% of patients experienced DRP and 89.22 DRPs per 1000 patient-days. A total of 35 ADEs were observed in 32 patients. ADE incidence was per 1000 patient-days 15.45. ADEs were caused by nephrotoxicity (48.57%), electrolyte disorders (17.14%), drug-induced thrombocytopenia (17.14%), liver enzyme increase (8.57%) and other causes (8.57%). Drug selection (40.29%) and dose selection (54.36%) constituted most of the causes of DRPs. Dose change was the highest percentage of planned interventions with a rate of 56.79%. Intervention was accepted at a rate of 90.8% and it was fully implemented. Conclusion In this study, the importance of the clinical pharmacist in the determination and analysis of DRPs was emphasized. Clinical pharmacy services like the one described should be implemented widely to increase patient safety.
Community Pharmacists Preparedness and Barriers for Cancer Health Promotion in North Cyprus
(2023) Bosah, Dubem Henry; Birand, Nevzat; Basgut, Bilgen; https://orcid.org/0000-0002-5883-5583; 35234102; JKS-4834-2023
Introduction The role of a community pharmacist is well recognized in the literature as the most accessible health care provider that promotes health wellness and disease prevention. Evidence supports their role in cancer health promotion though this is not seen yet in practice. The aim of the study was to assess community pharmacists' preparedness in terms of knowledge, role perception and barriers for providing cancer health promotion in North Cyprus. Methods A cross-sectional face-to-face questionnaire-based study was carried among a randomly selected representative sample of community pharmacists in North Cyprus between June 2020 and August 2020. A pre-validated 31-item questionnaire tool was revised by an expert panel and adopted for purpose of this study. Results 200 (64.5%) out of 310 approached community pharmacists' have accepted and responded to the questionnaire of which 183 were fully answered. The community pharmacists' awareness of cancer was moderate, as 70% answered correctly. Most respondents (93.4%) agree that pharmacists should be involved in cancer health promotion. Most respondents (> 90%) agree that pharmacist's lack of interest in oncology, lack of educational material and pharmacist's hesitancy about their knowledge of cancer are respectively the most important barriers for cancer health promotion. Conclusion The study shows that community pharmacist well perceives their role in cancer health promotion despite moderate awareness of cancer related facts and hesitancy of their knowledge necessary for assuming their role. Lack of interest, motivation and cancer educational materials availability are also major barrier to address.
Comparison of in vitro activities of plazomicin and other aminoglycosides against clinical isolates of Klebsiella pneumoniae and Escherichia coli
(2021) Ince, Gizem; Mirza, Hasan Cenk; Guclu, Aylin Uskudar; Gumus, Hale; Erol, Cigdem; Basustaoglu, Ahmet; 0000-0001-9071-9606; 0000-0002-1872-028X; 0000-0002-2535-2534; 0000-0002-8853-3893; 34499728; AAJ-2108-2021; AAU-6196-2020; AAJ-1219-2021; F-1232-2015
Objectives: To compare the in vitro activity of plazomicin and two older aminoglycosides (gentamicin and amikacin) against 180 isolates of Escherichia coli and Klebsiella pneumoniae, including subsets of 60 non-ESBL-producing, 60 ESBL-producing and 60 carbapenem-resistant (46 carrying bla(OXA-48), 11 carrying bla(NDM) and 3 carrying bla(OXA-48) and bla(NDM)) strains. Methods: MICs of plazomicin, gentamicin and amikacin were determined by a gradient diffusion method. Gentamicin and amikacin MICs were interpreted according to CLSI criteria and EUCAST breakpoint tables. Plazomicin MICs were interpreted using FDA-defined breakpoints. Results: All non-ESBL-producing and ESBL-producing isolates were susceptible to plazomicin. The plazomicin susceptibility rate (71.7%) in carbapenem-resistant isolates was significantly higher than those observed for gentamicin (45%) and amikacin (56.7% and 51.7% according to CLSI and EUCAST breakpoints, respectively). Gentamicin, amikacin and plazomicin susceptibility rates (35.6% for gentamicin; 44.4% and 37.8% for amikacin according to CLSI and EUCAST breakpoints, respectively; 64.4% for plazomicin) in carbapenem-resistant K. pneumoniae were significantly lower than those observed for carbapenem-resistant E. coli isolates (73.3% for gentamicin; 93.3% for amikacin and plazomicin). Gentamicin, amikacin and plazomicin susceptibility rates for bla(NDM)-positive isolates were lower than those observed for bla(OXA-48)-positive isolates, but differences were not statistically significant. Among the isolates that were non-susceptible to both gentamicin and amikacin, the plazomicin susceptibility rate was less than 30%. Conclusions: Although plazomicin showed excellent in vitro activity against carbapenem-susceptible isolates, the plazomicin resistance rate increased to 35.6% among carbapenem-resistant K. pneumoniae and further increased to 45.5% among bla(NDM)-positive isolates.
Cyclodextrin-Based Nanogel Of Flurbiprofen For Dermal Application: In Vitro Studies And In Vivo Skin Irritation Evaluation
(2022) Oktay, Ayse Nur; Celebi, Nevin; Ilbasmis-Tamer, Sibel; Kaplanog, Guelnur Take
The aim of this study was to develop and characterize flurbiprofen (FB)-loaded cyclodextrin (CD) based nanogel formulations for dermal application. Nanogels were produced via emulsification solvent evaporation and then incorporated into a hydroxypropyl methyl cellulose (HPMC) gel. The visual examination, pH, viscosity, dynamic rheological measurements and drug content analysis of nanogels were assessed. In vitro and ex vivo permeation, stability, and skin irritation were performed. pH of the FB-loaded nanogel and the nanogels in HPMC were 10.6 +/- 0.1 and 7.5 +/- 0.1 (neutral) respectively. The highest and lowest viscosities were observed in FB-loaded nanogels and in FB-free nanogels in HPMC, respectively. The tangent delta and storage modulus values of FB-loaded nanogel in HPMC were higher than those of FB-loaded nanogel. FB from nanogels in HPMC was 100% by 48 h. The final nanogel formulation was physically and chemically stable over 12 months. Skin irritation test showed no skin irritation or cellular infiltration on the histological level. In vitro and ex vivo permeation showed that the nanogels could be effective and stable formulations, especially in the dermal application of a hydro-phobic molecule.
Detection of COVID-19 by Machine Learning Using Routine Laboratory Tests
(2021) Cubukcu, Hikmet Can; Topcu, Deniz Ilhan; Bayraktar, Nilufer; Gulsen, Murat; Sari, Nuran; Arslan, Ayse Hande; 0000-0002-1219-6368; 0000-0002-7886-3688; 34791032; E-3717-2019; Y-8758-2018
Objectives The present study aimed to develop a clinical decision support tool to assist coronavirus disease 2019 (COVID-19) diagnoses with machine learning (ML) models using routine laboratory test results. Methods We developed ML models using laboratory data (n = 1,391) composed of six clinical chemistry (CC) results, 14 CBC parameter results, and results of a severe acute respiratory syndrome coronavirus 2 real-time reverse transcription-polymerase chain reaction as a gold standard method. Four ML algorithms, including random forest (RF), gradient boosting (XGBoost), support vector machine (SVM), and logistic regression, were used to build eight ML models using CBC and a combination of CC and CBC parameters. Performance evaluation was conducted on the test data set and external validation data set from Brazil. Results The accuracy values of all models ranged from 74% to 91%. The RF model trained from CC and CBC analytes showed the best performance on the present study's data set (accuracy, 85.3%; sensitivity, 79.6%; specificity, 91.2%). The RF model trained from only CBC parameters detected COVID-19 cases with 82.8% accuracy. The best performance on the external validation data set belonged to the SVM model trained from CC and CBC parameters (accuracy, 91.18%; sensitivity, 100%; specificity, 84.21%). Conclusions ML models presented in this study can be used as clinical decision support tools to contribute to physicians' clinical judgment for COVID-19 diagnoses.
Development of Cyclosporine A Nanosuspension: Cytotoxicity and Permeability on Caco-2 Cell Lines
(2021) Celebi, Nevin; 34931593
Cyclosporine A is a calcineurin inhibitor and is usually used as an immunosuppressant medication. The main purpose of this study is to develop nanosuspension of polypeptide cyclosporine A by using the wet milling method for oral administration. Cell culture studies were also performed with human intestinal Caco-2 cell lines. Hydroxypropyl methylcellulose and sodium dodecyl sulfate were used as stabilizers in nanosuspension. In vitro characterization studies such as Fourier-transform infrared analysis and morphological imaging with scanning electron microscopy have been carried out with obtained cyclosporine A nanosuspension. The particle size, particle size distribution, and zeta potential values of the nanosuspension were measured approximately 400 nm, 0.4, and -25 mV, respectively. The solubility of cyclosporine A was increased 4.5 times in nanosuspension compared to the coarse cyclosporine A powder. As a result of cytotoxicity studies conducted with different concentrations, it was decided to conduct permeability studies at a dose equivalent to 150 mu g/mL cyclosporine A. Permeation studies have shown that the nanosuspension increases cyclosporine A transport by 5 and 1.5 times, respectively, compared to coarse powder and commercial product.
Drug-related problems and health-related quality of life among chronic disease patients in a rural region of North Cyprus
(2022) Goksin, Servet; Abdi, Abdikarim; Alsaloumi, Louai; Basgut, Bilgen
Purpose: To evaluate the various types of drug-related problems (DRPs) and health-related quality of life (HRQoL) among chronic disease patients in a rural region of North Cyprus.Methods: A cross-sectional study of patients visiting a rural community pharmacy in North Cyprus was conducted. Patient demographic information, quality of life (QoL), laboratory data, adherence, and beliefs about medicine were assessed using standardized tools. Drug-related problems were evaluated using PCNE V.9.1.Results: Among the 200 screened participants, 97 fulfilled the enrollment criteria and were interviewed. The median age of the participants was 62 years (interquartile range = 15), with 58.8 % women. Only 54 % of hypertensive (HTN) patients reached their target blood pressure level. Over 40 % of type 2 diabetes mellitus (T2DM) patients failed to achieve their target HbA1c level. The majority (71 %) of patients with HTN, T2DM or coronary artery disease were not compliant with lifestyle recommendations and 86.6 % had >= 1 DRP. Insufficient dosing and inappropriate indication for a drug were the DRPs associated with failure to achieve target and inappropriate drugs was the DRP type mostly associated with lower quality of life scores. Other factors associated with lower QoL levels included female gender, unemployment status, and high agreement with the statement "medications do more harm than good". Conclusion: Drug related problems and non-adherence are prevalent, while therapy targets are rarely met in rural Cyprus. Community pharmacists have the potential to improve outcomes in the management of non-communicable diseases (NCDs).
Electrochemical Detection of Antioxidant Activities of 4-Indolyl-5-Oxo-6,6 (Or 7,7)-Dimethyl-1,4,5,6,7,8-Hexahydroquinoline Derivatives
(2021) Suslu, Incilay; Kablan, Sevilay Erdogan; Safak, Cihat; Simsek, Rahime
Antioxidants used in different medical and industrial fields in order to prevent and delay oxidative stress. They play a crucial role in the protecting biological systems against many diseases. 1,4-dihydropyridines are known as calcium channel modulators. Electrochemical techniques are simple, cheap and fast detection techniques and require small amounts of sample, so they offer advantages over commonly used analytical methods. Voltammetric methods have been applied to investigated the antioxidant activity of compounds in different fields. The proposed work is aimed at examining the electrochemical behavior of the 1,4-dihydropyridines by differential pulse voltammetry and hence the assessment of its antioxidant activity from the cathodic reduction peak of oxygen values. The peak current due to oxygen reduction was found to be proportional to the 1,4-dihydropyridines concentration of 0.1 - 0.5 mg/mL. The coefficient of antioxidant activity of 1,4-dihydropyridine derivatives were calculated and compared each other. Nifedipine used as a reference drug that is known as the calcium channel modulator and it is used to compare the antioxidant activities of 1,4-dihydropyridine-derived compounds.
Enhanced Dermal Delivery of Flurbiprofen Nanosuspension Based Gel: Development and Ex Vivo Permeation, Pharmacokinetic Evaluations
(2021) Oktay, Ayse Nur; Ilbasmis Tamer, Sibel; Uludag, Orhan; Celebi, Nevin; 34086139
Purpose The objective of this study was to optimize the Flurbiprofen (FB) nanosuspension (NS) based gel and to investigate the in vitro release, ex vivo permeation, the plasma concentration-time profile and pharmacokinetic parameters. Methods FB-NSs were developed using the wet milling process with the Design of Experiment (DoE) approach. The optimum FB-NS was characterized on the basis of SEM, DSC, XRPD, solubility and permeation studies. The dermal gel was prepared by incorporating FB-NS into HPMC gel. Then the in-vitro release, ex vivo permeation studies were performed, and pharmacokinetic studies were evaluated on rats. Results The particle size, polydispersity index and zeta potential values of optimum NS were determined as 237.7 +/- 6.8 nm, 0.133 +/- 0.030 and - 30.4 +/- 0.7 mV, respectively. By means of the surfactant content and nanosized particles of the nanosuspension, the solubility of FB was increased about 7-fold. The percentage permeated amount of FB from FB-NS gel (8.40%) was also found to be higher than the physical mixture (5.25%) and coarse suspension (reference) (2.08%) gels. The pharmacokinetic studies showed that the C-max of FB-NS gel was 2.5 times higher than the reference gel, while AUC(0-24) was 2.96 times higher. Conclusion FB-NSs were successfully prepared with a wet milling method and optimized with the DoE approach. The optimized FB nanosuspension gel provided better permeation and pharmacokinetic performance compared to FB coarse suspension gel.
Estimation of Low-Density Lipoprotein Cholesterol Concentration Using Machine Learning
(2021) Cubukcu, Hikmet Can; Topcu, Deniz İlhan; 0000-0002-1219-6368; 34635916; E-3717-2019
Objective Low-density lipoprotein cholesterol (LDL-C) can be estimated using the Friedewald and Martin-Hopkins formulas. We developed LDL-C prediction models using multiple machine learning methods and investigated the validity of the new models along with the former formulas. Methods Laboratory data (n = 59,415) on measured LDL-C, high-density lipoprotein cholesterol, triglycerides (TG), and total cholesterol were partitioned into training and test data sets. Linear regression, gradient-boosted trees, and artificial neural network (ANN) models were formed based on the training data. Paired-group comparisons were performed using a t-test and the Wilcoxon signed-rank test. We considered P values .2 to be statistically significant. Results For TG >= 177 mg/dL, the Friedewald formula underestimated and the Martin-Hopkins formula overestimated the LDL-C (P <.001), which was more significant for LDL-C <70 mg/dL. The linear regression, gradient-boosted trees, and ANN models outperformed the aforementioned formulas for TG >= 177 mg/dL and LDL-C <70 mg/dL based on a comparison with a homogeneous assay (P >.001 vs. P <.001) and classification accuracy. Conclusion Linear regression, gradient-boosted trees, and ANN models offer more accurate alternatives to the aforementioned formulas, especially for TG 177 to 399 mg/dL and LDL-C <70 mg/dL.
Etodolac nanosuspension based gel for enhanced dermal delivery: in vitro and in vivo evaluation
(2021) Celebi, Nevin; 0000-0002-6402-5042; 33752553
Aim The objective of this study was to develop dermal nanosuspension (NS) based gel formulation of etodolac (ETD). Methods Etodolac nanosuspension (ETD-NS) was prepared by wet milling method and dispersed in hydroxypropyl methylcellulose (NS-HPMC) or hydroxyethyl cellulose (NS-HEC) gels. Rheologic and mechanical properties were investigated. In vitro and ex vivo permeability studies were performed. Topical anti-inflammatory and analgesic activity were evaluated in regard to carrageenan-induced inflammatory paw oedema and radiant heat tail-flick method, respectively. Results The ETD-NS with approximately 190 nm particle size (PS), 0.16 polydispersity index (PDI), and -15 mV zeta potential (ZP) values were obtained. The work of bioadhesion values of NS-HEC and NS-HPMC gels were 0.229 mJ/cm(2) for both gels. Dermal permeation of ETD from NS-HEC gel (7.18%) was found significantly higher than the NS-HPMC gel (4.56%). Enhanced anti-inflammatory and analgesic activity of NS-HEC gels were observed in comparison with micronised ETD. Conclusions ETD-NS based gel formulation is promising for topical delivery of ETD.
Evaluation of the hypoglycemic effect of exendin-4's new oral self-nanoemulsifying system in rats
(2021) Celik Tekeli, Merve; Celebi, Nevin; Tekeli, M. Yasin; Aktas, Yesim; 33197556
The objective of this study is to develop a new self-nanoemulsifying system containing exendin-4 with or without enzyme inhibitor chymostatin and to evaluate the effects of oral administration of exendin-4 and exendin-4/chymostatin loaded self nanoemulsifying system on plasma exendin-4, plasma insulin, blood glucose levels and to compare with the oral and subcutaneous administration of exendin-4 in non-diabetic and streptozotocin-induced type 2 diabetic rats. Exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying system containing ethyl oleate as the oil phase, Cremophor EL (R)/Labrasol (R) as the surfactants and propylene glycol as the co-solvent were prepared. The mean droplet size, polydispersity index, zeta potential and viscosity of exendin-4 loaded self-nanoemulsifying system were found as 24.28 +/- 0.43 nm, 0.17 +/- 0.01, -1.28 +/- 3.61 mV, 79.60 +/- 3.30 m.Pas, respectively. The mean droplet size, polydispersity index, zeta potential and viscosity of exendin-4/chymostatin loaded self-nanoemulsifying system were found as 20.25 +/- 0.35 nm, 0.11 +/- 0.02, -1.85 +/- 2.49 mV, 100.02 +/- 7.65 m.Pas, respectively according to our previous study. In the present study, we focused on long-term physical stability studies, pharmacokinetic studies and pharmacodynamic studies of prepared self-nanoemulsifying systems. According to the long-term physical stability data, exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying systems were found stable both at 5 degrees C +/- 3 degrees C and at 25 degrees C +/- 60% RH for 12 months. Exendin-4 and exendin-4/chymostatin loaded self-nanoemulsifying systems increased AUC and C-max values in non-diabetic rats compared to the oral exendin-4 solution. In diabetic rats, exendin-4/chymostatin loaded self nanoemulsifying systems increased C-max values compared to the exendin-4 solution. Exendin-4/chymostatin loaded self-nanoemulsifying system decreased inter-subject variability compared to commercial Byetta (R). At 30th minute after administration of exendin-4 loaded self-nanoemulsifying system, exendin-4/chymostatin loaded self nanoemulsifying system and Byetta (R), blood glucose levels decreased to 23%, 25%, 29%, respectively. It has been shown that pharmacodynamic response is close to Byetta (R) with exendin-4/chymostatin self-nanoemulsifying system oral administration. In conclusion, a self nanoemulsifying system was found to be a suitable carrier system, and the combination with enzyme inhibitor chymostatin is thought to be promising for oral delivery of exendin-4.
Exometabolomic analysis of susceptible and multi-drug resistant Pseudomonas aeruginosa
(2022) Kocak, E.; Nigiz, S.; Ozkan, E.; Kablan, S. Erdogan; Hazirolan, G.; Nemutlu, E.; Kir, S.; Sagiroglu, M.; Ozkul, C.; 35419823
Multidrug resistant (MDR) Pseudomonas aeruginosa strains have recently become one of the major public health concerns worldwide leading to difficulties in selecting appropriate antibiotic treatment. Thus, it is important to elucidate the characteristics of MDR isolates. Herein, we aimed to determine the unique exometabolome profile of P. aeruginosa clinical isolates in monocultures that comprise high resistance to multiple antibiotics, and compare the differential metabolite profiles obtained from susceptible isolates by using GC/MS. Our results showed that partial least square-discriminant analysis (PLS-DA) score plot clearly discriminated the MDR and susceptible isolates indicating the altered exometabolite profiles, and highlighted the significantly enriched levels of trehalose and glutamic acid in MDR isolates. Expression of trehalose synthase (treS) was also 1 center dot 5-fold higher in MDR isolates, relatively to susceptible isolates. Overall, our study provides insights into the distinct footprints of MDR P. aeruginosa isolates in mono-culture.
Food plant with antioxidant, tyrosinase inhibitory and antimelanoma activity: Prunus mahaleb L
(2022) Guven, Zuhal Bayrakceken; Dogan, Zeynep; Saracoglu, Iclal; Picot, Laurent; Nagatsu, Akito; Basaran, A. Ahmet
Prunus mahaleb L. seeds are used as spice and folk remedies in many countries. The aim of this study was bioactivity guided isolation and characterization phytoconstituents of P. mahaleb which have been studied very limited so far. The antioxidant capacities of seed and kernel (endocarp) extracts were studied by DPPH, nitric oxide (NO), superoxide (SO), TEAC, CUPRAC methods. The antiproliferative activity were investigated for the first time against B16F10, A2058, HeLa and L929 cell lines using MTT assay. Gallic acid and ursolic acid which have strong antioxidant and cell growth inhibitory effect, were isolated from the most active fractions. From the inactive fractions, quercetin-3-O(2-O,6-O-alpha-dirhamnopyranosyl beta-glucopyranoside), kaempferol-3-O(2-O,6-O alpha-dirhamnopyranosyl beta-glucopyranoside) and beta-sitosterol-3-O-beta-glucopyranoside were isolated. Our study is the first record for the isolation of ursolic acid from all parts of P. mahaleb, gallic acid from P. mahaleb kernels, two flavonol triglycosides from the Prunus species and their analysis by advanced NMR spectroscopic methods. Ursolic acid (IC50 : 170.2 mu M) and gallic acid (IC50 : 10.5 mu M) showed strong tyrosinase inhibition, gallic acid being 5.4 times more effective than standard compound. Kernel extracts have strong antioxidant activity, showed high growth inhibitory activity with dose-dependent manner on melanoma cells but no growth inhibitory on healthy L929 and HeLa cancer cells. The high antioxidant capacity of kernel, its selective growth inhibition of B16F10 and A2058 melanoma cells and its strong tyrosinase inhibitory compounds suggest that it could be a new, non-toxic and inexpensive resource for melanoma treatment and cosmetic industry.
In Vitro Caco-2 Cell Permeability Studies of Ziprasidone Hydrochloride Monohydrate Nanocrystals
(2021) Karakucuk, Alptug; Tashan, Emine; Ozturk, Naile; Celebi, Nevin; 0000-0002-6402-5042; 33902264
Objectives: The current study focused on the evaluation of the cytotoxic effect and permeability of ziprasidone hydrochloride monohydrate (ZHM) nanocrystals on Caco-2 cells. Materials and Methods: ZHM nanocrystals were prepared by the microfluidization method in the presence of polyvinylpyrrolidone as a stabilizer. Particle size (PS), particle size distribution (PDI), and zeta potential (ZP) values were measured in characterization studies. In vitro cytotoxic effects of ZHM nanocrystals were investigated using the 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Caco-2 transport studies were conducted with formulations of ZHM coarse powder and nanocrystals. Results: Nanocrystals were obtained with 400-600 nm PS, 0.1-0.4 PDI, and >20 mV ZP values. The cell viability remained 100% for all sample groups. The permeability value of ZHM nanocrystals through Caco-2 cells increased 2.3-fold in comparison with ZHM coarse powder. Cumulative drug transport also increased at the end of the sampling period. Conclusion: Nanocrystal technology helps to increase the permeability of drug particles by increasing the saturation solubility.
Oral self-nanoemulsifying formulation of GLP-1 agonist peptide exendin-4: development, characterization and permeability assesment on Caco-2 cell monolayer
(2021) Celebi, Nevin; Tekeli, Merve Celik; Aktas, Yesim; https://orcid.org/0000-0002-6402-5042; https://orcid.org/0000-0002-5234-8434; 33398527; AAL-6931-2021
The objective of this study was to prepare a stable self-nanoemulsifying formulation of exendin-4, which is an antidiabetic peptide. As exendin-4 is commercially available only in subcutaneous form, several attempts have been made to discover an effective oral formulation. Self-nanoemulsifying drug delivery systems are known to be suitable carriers for the oral administration of peptide drugs. Various ratios of oil, surfactant, and co-surfactant mixtures were used to determine the area in the pseudoternary phase diagram for clear nanoemulsion. The Design of Experiment approach was used for the optimization of the formulation. Blank self-nanoemulsifying formulations containing ethyl oleate as oil phase, Cremophor EL(R), and Labrasol(R) as surfactant, absolute ethanol, and propylene glycol as co-solvent in various proportions were approximately 18-50 nm, 0.08-0.204 and - 3 to - 23 mV in droplet size, polydispersity index, and zeta potential, respectively. When all formulations were compared by statistical analysis, five of them with smaller droplet sizes were selected for further studies. The physical stability test was performed for 1 month at 5 degrees C +/- 3 degrees C and 25 degrees C +/- 2 degrees C/60% RH +/- 5% RH storage conditions. As a result of the characterization and physical stability test results, ethyl oleate: Cremophor EL(R):absolute ethanol (30:52.5:17.5) formulation and four formulations containing ethyl oleate: Cremophor EL(R):Labrasol(R):propylene glycol:absolute ethanol at varying concentrations were considered for peptide encapsulation efficiency. Formulation having the highest encapsulation efficiency of exendin-4 containing ethyl oleate: Cremophor EL(R):Labrasol(R):propylene glycole:absolute ethanol (15:42.5:21.25:15.94:5.31) was selected for in vitro Caco-2 intestinal permeability study. The permeabiliy coefficient was increased by 1.5-folds by exendin-4-loaded self-nanoemulsifying formulation as compared to the exendin-4 solution. It can be concluded that intestinal permeability has been improved by self-nanoemulsifying formulation.
The Phytochemical Profile and Biological Activity of Malva neglecta Wallr. in Surgically Induced Endometriosis Model in Rats
(2022) Akkol, Esra Kupeli; Karpuz, Busra; Turkcanoglu, Gizem; Cosguncelebi, Fatma Gul; Tastan, Hakki; Aschner, Michael; Khatkar, Anurag; Sobarzo-Sanchez, Eduardo; 000887409800001
Leaves and aerial parts of Malva neglecta Wallr. have been traditionally used in Anatolia for the treatment of pain, inflammation, hemorrhoids, renal stones, constipation, and infertility. This study investigated the effects of M. neglecta leaves in a rat endometriosis model. The dried plant material was extracted with n-hexane, ethyl acetate, and methanol, successively. Experimental endometriosis was surgically induced in six-week-old female, non-pregnant, Wistar albino rats by autotransplant of endometrial tissue to the abdominal wall. After twenty-eight days, rats were evaluated for a second laparotomy. Endometrial foci areas were assessed, and intraabdominal adhesions were scored. Rats were divided into five groups as control, n-hexane, ethyl acetate, methanol, and aqueous extracts, as well as reference. At the end of the treatment, all rats were sacrificed and endometriotic foci areas and intraabdominal adhesions were re-evaluated and compared with the previous findings. Moreover, peritoneal fluid was collected to detect tumor necrosis factor- alpha (TNF-alpha), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels, and cDNA synthesis, and a quantitative real-time polymerase chain reaction (PCR) test was done. The phytochemical content of the most active extract was determined using High-Performance Liquid Chromatography (HPLC). Both endometrial volume and adhesion score decreased significantly in the group treated with methanol extract. In addition, significant decreases were observed in TNF-alpha, VEGF, and IL-6 levels in animals administered methanol extract. HPLC results showed that the activity caused by the methanol extract of M. neglecta was due to the polyphenols. Taken together, these novel findings indicate that M. neglecta may be a promising alternative for the treatment of endometriosis.