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    In silico molecular docking and in vitro analysis of atomoxetine
    (Taylor & Francis Ltd, 2025) Bolat, Nurullah; Hiz-celikliyurt, Merve Meliha; Akinci, Erhan; Akkus, Gulsum; Gunay, Melih; Korkmaz, Sukru Alperen
    Although atomoxetine, a selective norepinephrine reuptake inhibitor, is widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD), there is limited data on its cytogenetic effects. This study aimed to investigate the cytotoxicity and genotoxicity of atomoxetine in vivo and silico. Chromosome aberration and micronucleus assays were used to analyze the genotoxic effect of atomoxetine in human peripheral blood lymphocytes under culture conditions. The mitotic index was assessed for cytotoxic potential. For the docking analysis, DNA receptor (1BNA) was prepared with ChimeraX, and the Atomoxetine molecule was optimized by Avogadro2.0 software. In silico molecular docking analysis was carried out utilizing SwissDock online platform. The results obtained were visualized using ChimeraX and Pymol software. Atomoxetine doses of 9.6 mu g/mL (equal to about 1.2 mg/kg as a maintenance dose), 14.4 mu g/mL (equal about to 1.8 mg/kg as the highest dose systematically tested), 48.0 mu g/mL (equal about to 6 mg/kg as five times the maintenance dose) and 96.0 mu g/mL (equal about to 12 mg/kg as ten times the maintenance dose) were analyzed. The findings clearly indicate that atomoxetine has no genotoxic effect at the therapeutic dose. However, we observed genotoxic effects at 48.0 and 96.0 mu g/mL doses. No strong binding affinity occurs in silico analyses. As one of the initial inquiries into the in silico and in vivo appraisal of atomoxetine's genotoxic impacts, the research has established that atomoxetine does not significantly affect the frequency of chromosomal damage or micronucleus formation. Genotoxic effects should be kept in mind at doses above clinical practice.
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    Neutrophil/high-density lipoprotein cholesterol (HDL), monocyte/HDL and platelet/HDL ratios are increased in acute mania as markers of inflammation, even after controlling for confounding factors
    (Taylor & Francis Ltd, 2023) Korkmaz, Sukru Alperen; Kizgin, Sadice
    ObjectiveRecent studies show that inflammation is related to the pathogenesis of acute mania of bipolar disorder. Neutrophil/high-density lipoprotein (HDL) ratio (NHR), lymphocyte/HDL ratio (LHR), monocyte/HDL ratio (MHR) and platelet/HDL ratio (PHR) have recently been investigated as novel markers of inflammation. In addition, the atherogenic index of plasma (AIP) and atherogenic coefficient (AC) are the leading atherogenic indices. The study aimed to investigate these inflammation and atherogenic index markers in acute mania of bipolar disorder. Another aim was to determine whether there is a relationship between these markers and disease severity and psychotic symptoms.MethodsA total of 109 BD-M and 101 (HC) were enrolled in the study. The differences in NHR, LHR, MHR, PHR, AIP and AC and their association with illness severity and psychotic symptoms were analyzed after adjusting for age, sex, total cholesterol level, body-mass index and smoking status. Then, a receiver operating characteristic (ROC) curve and linear discriminant analysis (LDA) were used to analyze these parameters' diagnostic potential. Moreover, the Young Mania Rating Scale (YMRS) and Clinical Global Impression Scale for use in bipolar illness-Severity subscale (CGI-BP-S) were used to assess the severity of clinical symptoms.ResultsWe found higher levels of NHR, MHR, PHR and AIP, but not LHR and AC, after adjusting confounding factors in patients with BD-M compared to HCs. In logistic regression analysis, higher levels of MHR and NHR were associated with BD-M. MHR, NHR and PHR were predictors for differentiating the BD-M group from the HC group. However, the severity of the illness or the psychotic feature of the manic episode did not significantly affect the parameters. In the ROC curve analysis of BD-M, the indicators with an area under the curve (AUC) higher than 0.6 were the MHR, NHR, PHR and LHR.ConclusionsThese results provide information about the role of inflammation in the pathophysiology of BD-M. Even after controlling for confounding factors, MHR, NHR, PHR and AIP are potential biomarkers for BD-M. Moreover, the increase in AIP may explain the co-morbidity between BD and cardiovascular diseases. However, the severity of the illness or the psychotic feature of the manic episode did not significantly affect the levels of inflammation ratios used in our study. Due to the low cost and widespread use of lipid metabolism and related inflammation rates, it may be beneficial to know the MHR, NHR, PHR and AIP levels in BD-M patients.
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    Real-world effectiveness of long-acting injectable vs. oral antipsychotics in patients with bipolar I disorder: a 1-year retrospective observational study
    (Taylor & Francis Ltd, 2024) Korkmaz, Sukru Alperen; Gurler, Sumeyye
    ObjectiveLong-acting injectable (LAI) antipsychotics are recommended in the treatment non-adherence. Despite the widespread use of LAI antipsychotics, there is limited data on clinical outcomes in bipolar I disorder (BD-I) patients with real-world data. We aimed to compare BD-I patients treated with LAI and oral antipsychotics (OAP) in terms of treatment effectiveness in a 1-year follow-up period.MethodsThe study was conducted retrospectively with electronic health records of 116 BDI patients. The primary outcomes were whether patients in the LAI group and the OAP group differed in relapse, rehospitalization, emergency room (ER) visits, and all-cause treatment discontinuation at 1-year follow-up after a mania episode. Cox regression modeling was used to predict the recurrence of any mood episode and all-cause treatment discontinuation during follow-up. The secondary outcomes evaluated were the effects of sociodemographic and clinical parameters and concomitant psychotropic medications on the course of the illness and treatment adherence.ResultsOf all 116 patients, 33 (28.4%) were under LAI, and 83 (71.6%) were under OAP treatment. LAI users had a history of more hospitalizations and total mood episodes. Patients in the LAI group had more treatment non-adherence before the index hospitalization. At 1-year follow-up, there was no difference between the groups in terms of any mood relapse, rehospitalization, ER visits, and all-cause treatment discontinuation. As a secondary outcome, lithium users were found to have fewer new episodes and discontinuations of treatments.ConclusionsIn real-world data, there is no evidence that LAI antipsychotics (compared to OAP) are superior in the maintenance treatment of BD. These results are important in terms of reflecting clinical practices for the treatment of BD-I. These results do not devalue the use of LAI therapy in BD; however, more studies are needed to identify positive predictors for LAI treatments in BD.
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    Real-World Evidence of Antipsychotic Monotherapy Versus Polypharmacy in the Treatment of Schizophrenia Spectrum Disorders
    (Lippincott Williams & Wilkins, 2024) Korkmaz, Sukru Alperen; Koca, Esra; Yilmaz, Ozge; Ozbek, Tayfun; Guclu, Muhammed Alperen; Kizgin, Sadice
    Purpose/BackgroundIt is still not well known whether antipsychotic monotherapy versus polypharmacy differs in terms of efficacy in the emergency department (ED) utilization, presentation with agitation/aggression, and rehospitalization in schizophrenia spectrum disorders (SSD) patients. This study aimed to determine the effectiveness of antipsychotic monotherapy and polypharmacy for these outcomes in the real world.Methods/ProceduresThe study was conducted with electronic health records of 669 SSD patients admitted to the ED. Patients were evaluated in 4 groups according to antipsychotic use at the first admission to ED: antipsychotic noncompliance for more than 90 days, antipsychotic noncompliance for 15 to 90 days, antipsychotic monotherapy, and polypharmacy. All patients followed up for at least 1 year after index admission. The primary outcomes determined an association between antipsychotic monotherapy versus polypharmacy and all-cause psychiatric hospitalization between the groups after index admission in the SSD.Findings/ResultsThe groups, including patients with antipsychotic noncompliance, had higher ED visits, more hospitalizations, and more admissions with agitation/aggression compared with antipsychotic monotherapy or polypharmacy. However, no differences were found between monotherapy and polypharmacy groups regarding these outcomes. In addition, there was no difference in the risk of hospitalization in monotherapy antipsychotic users compared with polypharmacy users. Patients discharged with monotherapy or polypharmacy also had similar rehospitalization rates at follow-up.Implications/ConclusionsThere is no positive evidence that recommending polypharmacy over antipsychotic monotherapy is superior with regard to the resulting frequency of ED visits, ED admissions with agitation/aggression, hospitalization, and rehospitalization. In this context, antipsychotic monotherapy may be preferred over polypharmacy in patients who are not resistant to treatment.
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    Thiol-disulphide homeostasis, ischemia-modified albumin, complete blood count-derived inflammatory markers and C-reactive protein from acute mania to early remission in bipolar disorder
    (Elsevier, 2023) Korkmaz, Sukru Alperen; Kizgin, Sadice; Oguz, Esra Firat; Neselioglu, Salim; Erel, Ozcan
    Objectives: There is much recent evidence that inflammation contributes to the pathophysiology of acute mania in bipolar disorder (BD). However, no study was evaluated in which the change in thiol-disulphide homeostasis, ischemia-modified albumin (IMA), complete blood count-derived inflammatory markers (CBC-IMs) and C-reactive protein (CRP) levels in bipolar patients was followed-up from acute mania to early remission. Methods: Seventy-seven bipolar patients in acute mania and ninety-one HC were enrolled. We measured levels of thiol-disulphide parameters, IMA, and CBC-IMs such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red-cell-distribution-width (RDW)-to-platelet ratio (RPR), systemic immune-inflammatory index (SII), and systemic inflammatory response index (SIRI), CRP and platelet-to-albumin ratio (PAR), after adjusting for age, gender, body-mass index (BMI) and smoking status, during acute mania to subsequent early remission. The results were compared with HC. Results: The levels or ratios of all thiol-disulphide parameters except for disulphide, IMA and CRP of bipolar patients in both acute mania and early remission were significantly different from HC, after adjusting for confounders. The NLR, SII, CRP and PAR values of bipolar patients were significantly higher in only acute mania compared to HC. Significant changes in thiol-disulphide parameters and IMA levels were not found in early remission after acute mania. Limitations: Short follow-up period and lack of drug-naive patients. Conclusions: Our results suggest that thiol-disulphide parameters, IMA level and SIRI value might be a trait biomarkers of inflammation in BD. In addition, NLR, SII and PAR values and CRP level might be a state biomarker of inflammation in bipolar patients in a manic phase.