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Öğe Deneysel diyabetin neden olduğu depresyon tedavisinde minosiklin ve minosiklin+metformin kullanımı(Ankara Üniversitesi Eczacılık Fakültesi, 2022) Çamçi, Merve İnci; Erdinç, Meral; Uyar, Emre; Kelle, İlkerAmaç: Minosiklin, santral sinir sistemine geçebilen, ikinci kuşak tetrasiklin grubu bir antibiyotiktir. Minosiklinin anti-inflamatuar, mikroglial aktivasyonu azaltma, anti-apoptotik, antioksidan özellikleri olduğu bilinmektedir. Son yıllarda diyabet ve depresyon arasında çift yönlü bir ilişki olduğunun ve fizyopatolojilerinde ortak yolaklardan birinin inflamasyon olduğunun ileri sürülmesi ile minosiklinin depresyon üzerine etkileri çalışılmaya başlanmıştır. Bu çalışmada minosiklinin tek başına ve diyabet tedavisinde kullanılan metformin ile kombinasyonu şeklinde kullanımının, diyabet ile ilişkili depresyon üzerine etkilerinin ortaya konması amaçlandı. Gereç ve Yöntem: Farelerde insandakine benzer tip 2 diyabet modeli oluşturmak için 4 haftalık yüksek kalorili diyetin ardından ardışık beş gün, günde 1 defa streptozotosin (50mg/kg) uygulandı, uygulamadan 1 hafta sonra açlık kan glukoz düzeyi 200 mg/dl’nin üzerinde olan deneklerde diyabetin oluştuğu kabul edilip deneye dahil edildi. Streptozotosin (STZ) enjeksiyonundan iki hafta sonra minosiklin (40mg/kg), fluoksetin (20mg/kg) ve metformin (200mg/kg) 7 gün süre ile günde bir defa uyguladı. İlaç uygulamaları tamamlandıktan sonra; lokomotor aktivitenin belirlenmesi için açık alan testi, depresyon düzeyinin belirlenmesi için zorunlu yüzme testi yapıldı. Sonuç ve Tartışma: Diyabetin ve uygulanan ilaçların lokomotor aktivitede anlamlı bir değişiklik oluşturmadığı, minosiklin ve minosiklin-metformin kombinasyonunun ise depresyon tedavisinde en az fluoksetin kadar etkili olduğu sonucuna varıldı. Antidepresan etkinin kısa sürede başlamasının hastanın tedaviye uyuncu ve diyabetin prognozu açısından oldukça önemli olduğu bilinmektedir. Bu nedenle de minosiklin uygulamasının gösterdiği antidepresan etki üzerine yapılan çalışmalar derinleştirilmeli, etkinin mekanizması araştırılmalıdır.Öğe The effects of melatonin, fluoxetine and their combinations on stress induced behavioral and cognitive impairments in mice(Ankara Üniversitesi Eczacılık Fakültesi, 2023) Çamçi, Merve İnci; Erdinç, Meral; Kelle, İlker; Uyar, Emre; Erdinç, LeventObjective: Melatonin (Mel) is a hormone with anti-depressant and anti-oxidant features. It is well known that melatonin protects brain cells from reactive oxygen species and that the brain's high oxygen consumption and lipid content make it particularly vulnerable to oxidative stress caused by prolonged stress. This study aims to investigate the effects of melatonin, fluoxetine and their combinations on emotional memory, depression, and anxiety-like behavioral changes induced by immobilization (Imb) stress. Material and Method: 48 male Balb/c mice were divided into eight groups: Cnt (control), Imb, Imb+Mlt, Imb+Flx (fluoxetine), Imb+Mlt+Flx, Mlt, Flx and Mlt+Flx. For seven days in a row, the mice underwent daily immobilization stress for 6 hours. Mice were treated with Mlt (10 mg/kg) and Flx (20 mg/kg). All animals were subjected to the behavioral tests; forced swimming test (FST), open field test (OFT), elevated plus maze (EPM), passive avoidance test (PAT) and hot plate (HP) test. After all behavioral tests, brain tissues were obtained for malondialdehyde level analysis. Result and Discussion: OFT test data showed the time spent in the central zone and the number of entrances to the central area were significantly lower in the Imb group compared to the Cnt group, these were higher in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Also, according to the data obtained from FST, immobile time was significantly higher in the Imb group compared to the Cnt group, it was lower in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Besides, it was demonstrated that the emotional memory index was statistically higher in the Imb group compared to the Cnt group, and the increasing of memory index returned to normal in the Imb+Mlt and Imb+Mlt+Flx groups with PAT. And also, lipid peroxidation level, which increased in the Imb group, decreased significantly in the Imb+Flx, Imb+Mlt, and Imb+Mlt+Flx groups. As a result, it was observed that melatonin has anti-depressant, anxiolytic, antioxidant effects and normalized emotional memory. Also, melatonin, fluoxetine and their combinations exert similar effects in the present study.Öğe The Effects of nifedipine on renal perfusion pressure and kidney during cisplatin-induced nephrotoxicity in rats(Dicle Üniversitesi Tıp Fakültesi, 2007) Erdinç, Meral; Erdinç, Levent; Nergiz, Yusuf; Kelle, İlkerCisplatin is one of the most effective cancer chemotherapeutic agent used against various solid tumors. Nephrotoxicity is one of the major dose-limiting side effects of cisplatin. It has been known that different mechanisms as oxidative stress may play an important role in cisplatin induced nephrotoxicity resulted with changes in renal haemodynamics. This study was performed to investigate the effect of nifedipine –one of the dihydropyridine calcium antagonist on changes in renal perfusion pressures and kidneys of rats with cisplatin nephrotoxicity. Male wistar albino rats were divided into 3 groups (n=8):1-Control group(1 ml saline. i.p) 2-Cisplatin group (a single dose of cisplatin (5 mg/kg, i.p) 3- A single dose of cisplatin (5 mg/kg, i.p) + Nifedipine (2 mg/kg/day, i.p) for five days. When those pre-treated groups compared with control group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels were found significantly higher in cisplatin group (p<0.001). Histopathological examination showed widespread tubular necrosis and dilatation in cisplatin-treated group versus other groups. In cisplatin + nifedipine pretreated group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels found significantly lower than cisplatin group (p<0. 001) and less tubular dilatation and necrosis was observed. As a result it was demonstrated that Nifedipine has protective effects against cisplatin nephrotoxicity. We suggest that this is partly provided by the beneficial effects of nifedipine on altered renal haemodynamics during cisplatin nephrotoxicity.Öğe The involvement of the serotonergic system in ketamine and fluoxetine combination-induced cognitive impairments in mice(Ataturk Univ, 2024) Uyar, Emre; Erdinç, Meral; Kelle, İlker; Erdinç, Levent; Şeker, Uğur; Nergiz, YusufBackground: Gluta mater gic N-methyl-D-aspartate (NMDA) receptors play vital roles in memory formation. Changes in the activity of these receptors influence memory processes. Ketamine is a noncompetitive NMDA receptor antagonist drug with promising mood-altering and pain-reducing effects ff ects in low doses. These effects ff ects are believed to be related to altered serotonergic transmission. Methods: The present study investigated the involvement of the serotonergic system in low-dose ketamine administrations' effects ff ects on memory acquisition, consolidation, and retrieval processes. Sixty-four male BALB/c mice were used in this experiment and separated into 8t groups. Mice were treated subchronically with a selective serotonin reuptake inhibitor, fluoxetine, and a serotonin depletion agent, p-chlorophenylalanine (pCPA). A serotonin antagonist, methiothepin, and ketamine were acutely administered 60 minutes before or after the behavioral tests. A passive avoidance (PA) test measured emotional memory acquisition, consolidation, and retrieval processes. Hippocampi malondialdehyde (MDA) levels were analyzed, and histopathological examinations were performed. Results: Ketamine alone did not significantly affect ff ect memory encoding processes in the PA test, while the ketamine-fluoxetine combination disrupted memory consolidation. Fluoxetine negatively affected ff ected the memory acquisition process, which was normalized during the consolidation and retrieval trials. Drug applications did not significantly alter hippocampal MDA levels. In all ketamine-applied groups, histopathologic alterations were evident. Conclusion: Low-dose ketamine administration induces neurodegeneration, and it also impairs memory functions when combined with fluoxetine, indicating increased serotonergic transmission may be involved in the memory-impairing and neurotoxic effects ff ects of ketamine.Öğe Oksitosin ile uyarılan sıçan uterus şeritlerinde L-arjinin gevşeme yanıtlarının gebelik dönemleri süresince değişimi.(2000) Erdinç, Meral; Yıldızhan, Pekin Begüm; Çiçek, Ramazan; Erdinç, Levent; Güneli, EnsariAMAÇ: L-arjinin - nitrik oksit sisteminin siklik guanozin monofosfat aracılığı ile ,uterus düz kası dahil olmak üzere birçok düz kasta gevşemeye yolaçtığı bilinmektedir. Uterusda L-arjinin-nitrik oksit sisteminin gebelik süresince Jzole sıçan ve insan uterus şeritlerinin spontan kontraksiyonları üzerine değişen şekilde inhibe edici etkisi olduğu bildirilmiştir. Bu çalışmada gebeliğin farklı dönemlerinde oksitosin ile uyarılan sıçan uterus şeritlerindeki kontraksiyonlara L-arjinin 'in etkisi araştırıldı. GEREÇ VE YÖNTEM: Gebe olmayan ve gebeliğin orta ve geç dönemlerinde izole edilen sıçan uterus şeritlerinde organ banyosunda 0,5 mU/mi konsantrasyonunda oksitosin ile uyarılan kontraksiyonlar ve buna L-arjinin'in 1.5, 3 mM konsantrasyonlarındaki etkisi izotonik kasılma olarak kimografa kaydedilerek değerlendirildi.İstatistiksel hesaplamalarda p<0,05 olarak kabul edilerek, Kruskall Wallis ve Mann Whitney U -testleri ile analiz edildi. BULGULAR: Gebe olmayan sıçanlardan izole edilen uterus şeritlerinde 0.5 mU/ml oksitosin ile uyarılan kasılmalar 1.5-3 mM L-arjinin ile anlamlı olarak azaldı (p< 0,05). Gebeliğin orta döneminde gerek oksitosin gerekse L-arjinin yanıtları gebe olmayan gruba göre anlamlı olarak değişmezken, gebeliğin son döneminde oksitosin yanıtları, gebeliğin orta dönemi ile karşılaştırıldığında anlamlı olarak arttığı görüldü (p< 0,05). Buna karşılık yine gebeliğin son döneminde L-arjinin gevşeme yanıtlarının gebeliğin orta dönemi ve gebeliğin olmadığı grupla karşılaştırıldığında anlamlı olarak azaldığı görüldü (p< 0,05). SONUÇ: L-arjininin-nitrik oksit sisteminin uterus düz kasında gevşetici etkisinin gebelik dönemlerinde değişiklik gösterdiği .gebeliğin son döneminde azaldığı tesbit edilerek, bu değişim sürecinin uterusun gebelik süresince sessiz kalmasında ve doğumun başlamasında kontraktil aktivitenin baskın hale geçmesinde rolü olduğu kanısına varıldı.Öğe Protective effects of melatonin on doxorubicin induced cardiotoxicity in isolated rat heart(2016) Erdinç, Meral; Akkoç, Hasan; Kelle, İlker; Erdoğmuş, Zeynep OzgenDoxorubicin is a highly effective cancer chemotherapeutic agent and its clinical use is limited by its serious cardiotoxicity. Oxidative damage is suggested to play a major role in its cardiotoxicity. In this study we aimed to research the protective effects of melatonin-which is a free radical scavenger and antioxidant -on Doxorubicin-induced cardiotoxicity in isolated perfused rat heart. Male wistar albino rats were divided into four groups: 1.group: control (1ml (i.p) sterile saline), 2.group: Doxorubicin (Dox) (one dose, 10 mg/kg (i.p)), 3.group: Dox (one dose, 10 mg/kg (i.p)) + Melatonin (Mel) for 7 days once a day 10 mg/kg (i.p)), 4.group: Melatonin (for 7 days once a day 10 mg/kg (i.p)). After 7 days, the hearts were isolated and perfused by Langendorff system. Heart rate, coronary perfusion pressure, Left ventricular developed pressure (LVDP), LV (dP/dt)max and LV(dP/dt)min which shows max and min pressures during systole and diastole per time were recorded. As a result; a significant increase in coronary perfusion pressure and LV(dP/dt)min and also a significant decrease in LVDP, LV(dP/dt)max and heart rates in the Dox group according to control group showed altered cardiac functions induced by Dox. versus the Dox group, in the Dox+Mel group the coronary perfusion pressure and LV(dP/dt)min significantly decreased and LVDP and LV(dP/dt)max significantly increased. So it is concluded that melatonin has protective effects on doxorubicin induced cardiotoxicity characterized with altered heart contractility and hemodynamics.Öğe Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart(Sage Publications INC., 2022) Özgen, Zeynep Erdoğmuş; Erdinç, Meral; Kelle, İlker; Erdinç, Levent; Nergiz, YusufBackground: Doxorubicin (Dox) is one of the most effective antineoplastic drugs which has severe cardiotoxic effects, limiting its clinical usage. Though the exact mechanism of doxorubicin-induced cardiotoxicity is yet to be elucidated, it is shown that production of reactive oxygen species (ROS) increases oxidative stress and leads to cardiomyocyte apoptosis and necroptosis which is also defined as a programmed cell death. Purpose: In the present study, we investigate the effects of necrostatin-1 (Nec-1)-an inhibitor of receptor interaction proteins 1 (RIP1) and necroptosis-on doxorubicin-induced cardiotoxicity in rats. Research Design: Hearts were isolated and perfused by the Langendorff system in all four groups. Perfusion pressure (PP), left ventricular developed pressure (LVDP) and heart rate per minute (HR), LV (dP/dt) max, and LV (dP/dt) min which shows cardiac contractility and relaxation were recorded. Results: Results showed that PP significantly increased with Dox treatment and significantly decreased with Nec-1 treatment, while HR, LVDP, LV (dP/dt) max, and LV (dP/dt) min values significantly decreased with the Dox-treated group and significantly increased with Nec-1 treatment. Also with Nec-1 treatment, gene expression levels of anti-apoptotic Bcl-2 significantly increased and pro-apoptotic protein Bax, apoptotic marker caspase-3, and Nox-2 significantly decreased compared to the Dox-treated group. In heart tissues, MDA levels were significantly increased with Dox and decreased with Nec-1 treatment. These results were supported by the histological analysis indicated that Nec-1 reduced doxorubicin-induced cellular injury. Conclusions: In conclusion, our data indicate that Nec-1 ameliorates doxorubicin-induced cardiotoxicity by reducing oxidative stress injury and attenuating apoptosis and necroptosis.Öğe QbD application for a fixed-dose combination with biowaiver potential: Evaluations of In vitro and In vivo applications(Springer, 2022) Yaşın, Diren Sarısaltık; Uslu, Abdullah; Uyar, Emre; Erdinç, Meral; Teksin, Zeynep ŞafakPurpose The purpose of this study was to use the quality by design (QbD) approach to design a directly compressed fixed-dose combination (FDC) tablet comprising amlodipine besylate and enalapril maleate with biowaiver potential in alignment with the Biopharmaceutical Classification System (BCS). Methods As a result of the risk assessment, the amounts of the formulation components such as disintegrant, binder, and lubricant were selected as critical material attributes, and the processes of blending and lubrication were accepted as critical process parameters in a screening design of Plackett-Burman. These factors were evaluated based on the statistical significance of their impact on the drug product's content uniformity, assay, friability, disintegration, and dissolution. The most significant factors determined with the use of Pareto charts and half-normal graphs were the amount of lubricant and disintegrant and blending time, all of which were subsequently optimized using Box-Behnken Design. The optimum formulation was evaluated with in vitro quality tests and in vivo blood pressure-lowering efficacy tests, the results of which were compared to the individual references in rats. Results As a result of the optimization process, a design space was established for the critical factors. FDC product showed quality and dissolution profiles similar to those of the references. Combination therapy was superior to individual drugs in rats (p < 0.05). Conclusion It was concluded that an FDC product eligible for BCS-based biowaiver can be developed systematically by using the QbD concept. It was demonstrated that using scanning designs prior to optimization can reduce the number of unnecessary experiments and yield more reliable results in less time.Öğe Sıçan uterus şeritlerinde nitrik oksit sentaz inhibisyonunun oksitosin kontraksiyonlarına etkisi(2000) Erdinç, Levent; Erdinç, Meral; Çiçek, Ramazan; Yıldızhan, Pekin Begüm; Güneli, EnsariAMAÇ: L-arjinin aminoasidinden nitrik oksit sentaz enzimi ile sentezlenen nitrik oksitin siklik guanozin monofosfat aracılığı ile birçok düz kasta ve uterusta gevşeme yaptığı bilinmektedir. Bu çalışmada izole uterus şeritlerinde nitrik oksit sentaz inhibisyonunun oksitosin ile uyarılan kontraksiyonlar üzerine etkisi araştırıldı. GEREÇ VE YÖNTEM: Dişi Sprague-Dawley sıçanlardan izole edilen uterus şeritleri, organ banyosundaki ortamda 3 mM konsantrasyonda L-Name varlığında ve yokluğunda, 0.5 mU/ml oksitosin ile uyarılarak, kontraksiyon yanıtları izonik olarak kimografa kaydedildi. Gruplar arasındaki fark istatistiksel olarak Mann Whitney U testi ile değerlendirilerek, p< 0.05 anlamlı olarak kabul edildi. BULGULAR: Oksitosin ile oluşturulan kontraksiyonların hem frekansının hem de amplitüdünün L-Name varlığında anlamlı şekilde arttığı gözlendi (p< 0.05). SONUÇ: L-arjinin-Nitrik oksit sisteminin inhibisyonunun uterus kasılmalarında anlamlı artışa yolaçtığımn gözlenmesi, bu sistemin uterusun kontraktil fonksiyonları üzerinde önemli etkiye sahip olduğu sonucunu ortaya çıkarmaktadır.Öğe Tavşanlarda deneysel olarak geliştirilen akut renal yetmezlikte EDRF aktivitesindeki değişiklik ve Allopurinol`ün etkisi(2014) Erdinç, MeralÖZET 1-Tavşanlarda gliserol ile oluşturulan akut renal yetmezlikte EDRF aktivitesi ve allopurinol'ün etkisi araştırıldı. 2-Deneyler izole perfüze tavşan böbreğinde yürütüldü. 3-Hayvanlar üç gruba ayrıldı. Birinci grup kontrol grubu, ikinci grup gliserol (10 ml/kg i.p) injeksiyonu yapılan grup,üçüncü grup ise allopurinol (50 ml/kg s.c) + gliserol (10 ml/kg i.p) injeksiyonu yapılan grup olarak belirlendi. 4-Gliserol injeksiyonundan 3 saat sonra böbrekler izole edilerek krebs çözeltisi ile perfüze edildi. Ekilibrasyon periyodundan sonra perfüzyon ortamına fenilefrin (10~5 M) ilavesiyle submaksimal kasılma sağlandı. Daha sonra bolus injeksiyonla asetilkolin'in (10_8-10"5 M) gevşeme cevapları test edildi. Bu deneyler her üç grup için tekrarlandı. 5-Gliserol injeksiyonunun asetilkolin'in gevşeme cevaplarını anlamlı olarak azalttığı (PO.001) ancak azalan bu gevşeme cevaplarının allopurinol + gliserol injeksiyonu ile anlamlı olarak arttığı (PO.001) gözlendi. 6-Böbreklerin histopatolojik incelemesinde allopurinol'ün, gliserol'ün oluşturduğu böbrek harabiyetini önlediği gözlendi. SUMMARY 1-EDRF activity and the effects of allopurinol were investigated in rabbits, in which acute renal failure was elicited by injection of glycerol. 2-The experiments were performed on isolated perfused rabbit kidneys. 3-Animals were divided into three groups. The first group was control group.the second group received glycerol (10 ml/kg i.p),and the third group received allopurinol (50 ml/kg s.c) + glycerol (10 ml/kg i.p). 4- 3 h. after the injection of glycerol, kidneys were isolated and perfused with krebs solution. After equilibration period, submaximal vasoconstriction was elicited by adding phenylephrine (10-5 M) into the perfusion medium. Than the vasodilator responses of acetylcholine (10"8-10_5 M) were tested by bolus injections. The experiments were repeated for all three groups. 5-lnjection of glycerol significantly reduced the vasodilation induced by acetylcholine (PO.001) but allopurinol+glycerol injection significantly increased that reduced vasodilation (P<0.001). 6-ln histopathological examinations of the kidneys it was observed that allopurinol prevented the kidney damage induced by glycerol.
