Factors associated with potentially inappropriate prescribing in elderly patients with various degrees of chronic kidney disease.

INTRODUCTION: This study aimed to compare the prevalence of potentially inappropriately prescribed drugs in hemodialysis patients and patients with chronic kidney disease who did not require renal replacement therapy, as well as to identify risk factors associated with potentially inappropriate prescribing. METHODS: The study was designed as a cross-sectional study conducted at the Department of Nephrology, Clinical Center in Nis, Serbia. The patients were divided into two groups: (1) patients on hemodialysis treatment and (2) patients with various degrees of chronic kidney disease without renal replacement therapy. The presence or absence of potentially inappropriate prescribing was determined using the 2015 AGS Beers criteria. FINDINGS: The study included a total of 218 patients aged 65 years and over. The number of patients with potentially inappropriate prescribed drugs did not differ significantly (chi-square = 0.000, p = 1.000) between patients on hemodialysis (27 of 83, i.e., 32.5%) and patients with various degrees of chronic kidney disease without renal replacement therapy (44 of 135, i.e., 32.6%). Factors associated with potentially inappropriate prescribing in hemodialysis patients were the number of drugs (hazard ratio [HR] = 1.919, 95% confidence interval [CI]: 1.325-2.780) and number of comorbidities (HR = 1.743, 95% CI: 1.109-2.740). The number of drugs (HR = 1.438, 95% CI: 1.191-1.736) was the only independent factor associated with increased risk of potentially inappropriate prescribing in patients without renal replacement therapy. DISCUSSION: Our study showed that potentially inappropriate prescribing is a relatively frequent phenomenon present in about a third of patients in both study groups. The number of prescribed drugs was the main factor associated with the increased risk of potentially inappropriate prescribing in both groups.

Chloroquine and cinchonine affect rat vascular smooth muscle tonus through calcium channels - in silico and in vitro approaches.

BACKGROUND: In the present study, two structurally similar alkaloids from trees of Cinchona genus, chloroquine and cinchonine, were examined for their vasorelaxant effects in a model of phenylephrine-induced smooth muscle contractions. METHODS: Potential mechanisms of action associated with endothelial vasorelaxant compounds, voltage-gated Ca2+ channels (LTCCs), and inositol triphosphate receptors were examined in isolated rat aortic rings. Also, an in silico approach was used to predict the activity of the two test compounds. RESULTS: Experimental results revealed that both chloroquine and cinchonine significantly decrease phenylephrine-induced smooth muscle contractions, although to a different extent. Evaluated mechanisms of action indicate that endothelium is not involved in the vasorelaxant action of the two tested alkaloids. On the other hand, voltage-gated Ca2+ channels were found to be the dominant way of action associated with the vasorelaxant action of chloroquine and cinchonine. Finally, IP3R is found to have only a small impact on the observed activity of the tested compounds. CONCLUSION: Molecular docking studies predicted that chloroquine possesses a significant activity toward a suitable model of LTCCs, while cinchonine does not. The results of the present study point to the fact that great caution should be paid while administering chloroquine to vulnerable patients, especially those with cardiovascular disorders (Tab. 3, Fig. 3, Ref. 28).

Decreased Activity of Erythrocyte Catalase and Glutathione Peroxidase in Patients with Schizophrenia.

Background and Objectives: Catalase and glutathione peroxidase (GPx) are important antioxidant enzymes that break down hydrogen peroxide (H2O2) in order to control its intracellular concentration, thus enabling its physiological role and preventing toxic effects. A lack or disruption of their function leads to the accumulation of hydrogen peroxide and the occurrence of oxidative stress. Accumulating studies have shown that the activities of key antioxidant enzymes are impaired in patients with schizophrenia. Since the published results are contradictory, and our previous studies found significantly higher erythrocyte superoxide dismutase (SOD) activity in patients with schizophrenia, the aim of this study was to determine the activity of enzymes that degrade hydrogen peroxide in the same group of patients, as well as to examine their dependence on clinical symptoms, therapy, and parameters associated with this disease. Materials and Methods: Catalase and GPx activities were determined in the erythrocytes of 68 inpatients with schizophrenia and 59 age- and gender-matched healthy controls. The clinical assessment of patients was performed by using the Positive and Negative Syndrome Scale (PANSS). The catalase activity was measured by the kinetic spectrophotometric method, while the GPx activity was determined by the commercially available Ransel test. Results: Erythrocyte catalase and GPx activities were significantly lower (p < 0.001 and p < 0.01, respectively) in subjects with schizophrenia than they were in healthy individuals. Lower catalase activity does not depend on heredity, disease onset, the number of episodes, or disease duration, while GPx activity showed significant changes in patients who had more than one episode and in those who had been suffering from the disease for over a year. Significantly lower catalase activity was noted in the PANSS(+/−) group in comparison with the PANSS(+) and PANSS(−) groups. The lowest catalase activity was found in subjects who were simultaneously treated with first- and second-generation antipsychotics; this was significantly lower than it was in those who received only one class of antipsychotics. Conclusion: These results indicate the presence of oxidative stress in the first years of clinically manifested schizophrenia and its dependence on the number of psychotic episodes, illness duration, predominant symptomatology, and antipsychotic medication.

Risk Factors and Predictive Value of Depression and Anxiety in Cervical Cancer Patients.

Background and Objectives: Women with cervical cancer may experience depression or anxiety, influencing their quality of life and even their adherence to cancer treatments. This study aimed to explore and measure the levels of anxiety and depression in patients suffering from cervical cancer and to identify the possible predictors among known risk factors such as age, cancer stage, smoking status, number of partners, use of contraceptives, and annual gynecological visits. Materials and Methods: In total, 59 patients with cervical cancer were included. A consecutive sampling method was used to select participants in this research. Depression and anxiety were assessed using the Zung Anxiety Scale (SAS) and Zung Depression Scale (SDS). The subjects were divided into three groups, according to the stage of cancer. Results: Scores of depression and anxiety were increased in all recruited cervical cancer patients. A significant correlation was found between disease stage and the scores of depression (p = 0.002) and anxiety (p = 0.016). More severe depressive symptoms correlated to a more advanced stage of the disease. A multiple linear regression showed that disease stage and annual visits to the gynecologist are the risk factors associated with higher depression scores. Conclusions: Patients diagnosed with cervical cancer are a vulnerable group for the development of the psychiatric disorders and they require screening programs, which could potentially detect candidates for co-psychiatric and/or psychotherapeutic treatment. They demand particular attention because anxiety and depression are associated with the significant burden of the underlying disease and unfavorable survival rates.

Lycopene and Caffeic Acid Phenethyl Ester Affect Caspase-3 Activity, but Do Not Alter the NO Pathway in Lung Tissue Damage Induced by Cisplatin.

INTRODUCTION: Antioxidants such as lycopene (LCP) and caffeic acid phenethyl ester (CAPE) represent ideal molecules for the treatment of different reactive oxygen species (ROS) associated disorders. Cisplatin is a chemotherapeutic agent, causing an increase in ROS and DNA damage, with numerous side effects, which include lung toxicity. In the presents study, we evaluated and mutually compared the potential of LCP and CAPE in preventing cisplatin-induced rat lung damage. METHODS: The study was done using pathohistological analysis and a panel of biochemical parameters that reflect lung oxidative tissue damage, inflammation, and apoptosis. RESULTS: The obtained results suggest that cisplatin (10 mg/kg) causes significant disturbances in the lung tissue morphology, followed by an increase in lipid peroxidization and protein modification. Also, a pronounced inflammatory response and cell apoptosis cascade activation was noted. Both LCP and CAPE were able to mitigate the changes, to a different extent, in oxidative damage and apoptosis progression induced by cisplatin. However, they both had limited effect on inflammation since they only prevented an increase in myeloperoxidase activity but had not been able to prevent the NO generation. CONCLUSION: It is hard to be exact in saying whether LCP or CAPE is better in preventing cis-platin-induced lung damage since they obviously possess different mechanisms of action.

Do we really know how to overcome trastuzumab resistance in hormone sensitive metastatic breast cancer?

PURPOSE: This article focuses on how the status of hormone receptors (HR) influences the efficacy of trastuzumab in patients with metastatic HER2-positive breast cancer treated with first-line trastuzumab in combination with taxane-based chemotherapy. METHODS: A prospective study was carried out at the Clinic for Oncology, Clinical Centre in Nis, from January 2015 to until June 2018. A total of 121 patients were treated with first-line trastuzumab in combination with taxane-based chemotherapy. None of the patients from the HR-positive group received hormonotherapy after completion of chemotherapy with trastuzumab. RESULTS: Clinical benefit rate was present in 76% of the patients, including partial response (PR) in 37%, stable disease (SD) in 38%, and complete response (CR) in almost 8% of the patients. Progressive disease (PD) occurred in almost a quarter of the patients, i.e. 24%. Progression-free survival (PFS) in the entire group of patients amounted to 9 months, whereas overall survival (OS) was 30 months. PFS in the HR-negative tumor group was significantly longer (13 months) compared to 8 months in the HR-positive tumor group (p<0.0001; HR 0.49;95% CI 0.31-0.69). Furthermore, OS was significantly longer in the HR-negative tumor group (34 months), compared to 26 months in the HR-positive tumor group (p=0.0073, HR 0.57; 95% CI 0.36-0.90). CONCLUSIONS: These data indicate a different response to anti-HER2 therapy in patients with HER2+ metastatic breast cancer (MBC) according to HR status, thus emphasizing that ER most likely represents an escape pathway for the response to anti-HER2 target therapy and vice versa. Combining hormonotherapy with anti-HER2 therapy surely represents a promising strategy which could help overcome resistance to trastuzumab and other anti-HER2 agents.

In silico studies and the design of novel agents for the treatment of systemic tuberculosis.

Tuberculosis (TB) is an ancient infectious disease, which re-emerged with the appearance of multidrug-resistant strains and acquired immune deficiency syndrome. Enoyl-acyl-carrier protein reductase (InhA) has emerged as a promising target for the development of anti-tuberculosis therapeutics. This study aims to develop quantitative structure-activity relationship (QSAR) models for a series of arylcarboxamides as InhA inhibitors. The QSAR models were calculated on the basis of optimal molecular descriptors based on the simplified molecular-input line-entry system (SMILES) notation with the Monte Carlo method as a model developer. The molecular docking study was used for the final assessment of the developed QSAR model and designed novel inhibitors. Methods used for the validation indicated that the predictability of the developed model was good. Structural indicators defined as molecular fragments responsible for increases and decreases of the studied activity were defined. The computer-aided design of new compounds as potential InhA inhibitors was presented. The Monte Carlo optimization was capable of being an efficient in silico tool for developing a model of good statistical quality. The predictive potential of the applied approach was tested and the robustness of the model was proven using different methods. The results obtained from molecular docking studies were in excellent correlation with the results from QSAR studies. This study can be useful in the search for novel anti-tuberculosis therapeutics based on InhA inhibition. Communicated by Ramaswamy H. Sarma.

Ten years of using adjuvant trastuzumab in breast cancer in Serbia - Single institution experience.

PURPOSE: The purpose of this study was to determinate disease-free interval (DFI) and overall survival (OS) in HER2-positive breast cancer patients who received adjuvant trastuzumab at the University Clinic of Nis, Serbia, and to investigate the influence of clinicopathological and biological characteristics of the tumor on prognosis. The second aim was to determinate the most frequent cause for the treatment discontinuation, recurrence rate, as well as the site of most common localization of the first recurrence of disease. METHODS: This research was conducted as a retrospective study at the University Oncology Clinic, Clinical Centre in Nis. The study included 238 patients who were operated and treated for HER2-positive breast cancer between January 1st, 2007 to September 30th, 2012 and followed up until December 31st, 2016. Trastuzumab was administered concurrently with taxanes, if administered, or after the completed anthracycline-based chemotherapy. RESULTS: After a median follow up of 69 months the 5-year DFI was 65.9% and 5-year OS was 81.8% and, as expected, significantly longer in the group of patients with smaller tumors, a smaller number of positive axillary lymph nodes, as well as a lower stage of disease (p<0.0001). Patients older than 65 years had a longer DFI compared to the 45-65 and under 45 age groups of patients (p=0.01). No statistical significance was found in the length of DFI in relation to the histological tumor subtype, tumor grade, or the status of hormone receptors. Unlike DFI, a longer OS was recorded in the group of patients with lower tumor grade (p=0.03) and there was no statistically significant difference in survival regarding the age of patients (p=0.07). Recurrence occurred in approximately one third of the patients (38.23%), mostly in the form of local recurrence. Adjuvant therapy with trastuzumab was not completely carried out in 18.49% of the patients, the most common reason being the progression of disease. CONCLUSIONS: A long median follow up period of 69 months indicated that anti-HER2 monoclonal antibody trastuzumab, after anthracycline-based chemotherapy or concurrently with taxanes, is efficient and safe in treating early breast cancer.

The anesthetic action of some polyhalogenated ethers-Monte Carlo method based QSAR study.

Up to this date, there has been an ongoing debate about the mode of action of general anesthetics, which have postulated many biological sites as targets for their action. However, postoperative nausea and vomiting are common problems in which inhalational agents may have a role in their development. When a mode of action is unknown, QSAR modelling is essential in drug development. To investigate the aspects of their anesthetic, QSAR models based on the Monte Carlo method were developed for a set of polyhalogenated ethers. Until now, their anesthetic action has not been completely defined, although some hypotheses have been suggested. Therefore, a QSAR model should be developed on molecular fragments that contribute to anesthetic action. QSAR models were built on the basis of optimal molecular descriptors based on the SMILES notation and local graph invariants, whereas the Monte Carlo optimization method with three random splits into the training and test set was applied for model development. Different methods, including novel Index of ideality correlation, were applied for the determination of the robustness of the model and its predictive potential. The Monte Carlo optimization process was capable of being an efficient in silico tool for building up a robust model of good statistical quality. Molecular fragments which have both positive and negative influence on anesthetic action were determined. The presented study can be useful in the search for novel anesthetics.

Modulatory effect of curcumin on ketamine-induced toxicity in rat thymocytes: Involvement of reactive oxygen species (ROS) and the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway.

Ketamine is a widely used anesthetic in pediatric clinical practice. Previous studies have demonstrated that ketamine induces neurotoxicity and has a modulatory effect on the cells of the immune system. Here, we evaluated the potential protective effect and underlying mechanisms of natural phenolic compound curcumin against ketamine-induced toxicity in rat thymocytes. Rat thymocytes were exposed to 100 µM ketamine alone or combined with increasing concentrations of curcumin (0.3, 1, and 3 µM) for 24 hours. Cell viability was analyzed with CCK-8 assay kit. Apoptosis was analyzed using flow cytometry and propidium iodide as well as Z-VAD-FMK and Z-LEHD-FMK inhibitors. Reactive oxygen species (ROS) production and mitochondrial membrane potential [MMP] were measured by flow cytometry. Colorimetric assay with DEVD-pNA substrate was used for assessing caspase-3 activity. Involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was tested with Wortmannin inhibitor. Ketamine induced toxicity in cells, increased the number of hypodiploid cells, caspase-3 activity and ROS production, and inhibited the MMP. Co-incubation of higher concentrations of curcumin (1 and 3 µM) with ketamine markedly decreased cytotoxicity, apoptosis rate, caspase-3 activity, and ROS production in rat thymocytes, and increased the MMP. Application of Z-VAD-FMK (a pan caspase inhibitor) or Z-LEHD-FMK (caspase-9 inhibitor) with ketamine effectively attenuated the ketamine-induced apoptosis in rat thymocytes. Administration of Wortmannin (a PI3K inhibitor) with curcumin and ketamine significantly decreased the protective effect of curcumin on rat thymocytes. Our results indicate that ketamine-induced toxicity in rat thymocytes mainly occurs through the mitochondria-mediated apoptotic pathway and that the PI3K/Akt signaling pathway is involved in the anti-apoptotic effect of curcumin.

Potentially inappropriate prescribing of drugs in elderly patients on chronic hemodialysis treatment
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PURPOSE: The aim of this study was to determine the prevalence of potentially inappropriate drug prescription (PIP) in older patients who were on chronic hemodialysis treatment and to explore the factors that lead to PIP. MATERIALS AND METHODS: The study was performed at the Department of Nephrology, Clinical Center Nis, Serbia. It included patients who were 65 years old and older who suffered from the end-stage of kidney failure and were treated by hemodialysis. Univariate and subsequent multivariate logistic regression was used to analyze risk factors for PIP or omission (PPO) according to the STOPP and START criteria. RESULTS: The study included 83 patients. According to the START criteria, PPO was found in 18 (22%) patients, and 32 (39%) patients experienced PIPs according to the STOPP criteria. The following factors were associated with PIP according to the START criteria: a number of comorbidities, reading the patient leaflet, and having the habit of drinking coffee. According to the STOPP criteria, polypharmacy was associated with PIP (OR = 1.287, p = 0.021): each additional drug increased the risk of potentially inadequate medications (PIM) by 28.7%. CONCLUSION: Adequate consideration of potential risk factors, as well as the implementation of valid criteria for assessment of PIP, are just some of the measures that would contribute to solving complex therapeutic problems and designing strategies for rational prescribing according to the individual characteristics of patients.
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Curcumin attenuates Mancozeb-induced toxicity in rat thymocytes through mitochondrial survival pathway.

The widely used fungicide Mancozeb (Man) has been shown to cause genotoxic effects in rodents and toxicological manifestations in different cells, mainly by altering the antioxidant defense in cells. On the other hand, curcumin (Cur), a natural phenolic compound, is thought to possess anti-inflammatory and antioxidant properties. Here, we investigated the possible protective role of Cur on Man-induced toxicity in rat thymocytes and potential mechanism involved. Rat thymocytes were treated with Man(0.01 µg/ml) and/or increasing Cur(0.3, 1, 3 µM) concentrations and levels of cell viability, apoptosis, mitochondrial membrane potential (MMP),Bcl-2, Bax protein expression, caspase-3 and -9 activity and p38 MAPK signaling involvement were examined. Cells treated with Man displayed increased cell toxicity, hypodiploid cells, caspase-3 and -9 activity, Bax protein expression, followed with decreased MMP and Bcl-2 protein expression. Inhibition of p38 MAPK signaling pathway markedly reduced apoptosis rate and caspase-3 activity in thymocytes exposed to Man. Application of increasing Cur (1, 3 µM) concentrations resulted with significantly reduced cytotoxicity, apoptosis, caspase-3, -9 activity, Bax protein expression, together with increased MMP and Bcl-2 protein expression in rat thymocytes. These result suggest that certain Cur concentrations may mediate Man-induced rat thymocytes toxicity through mitochondrial survival pathway, which may be useful in preventing possible secondary immunological consequences induced by Man.

Metastatic malignant melanoma of the uterus diagnosed by colposcopy.

Introduction: Primary and metastatic malignant melanomas represent a rare diagnosis with a small number of described cases. The aggressive nature of the tumor, non-specific symptoms, difficult diagnosis, and no official protocol about the treatment result in poor disease prognosis. Case Outline: The authors presented a 41-year-old multigravida patient. She had an operation of malignant melanoma in the occipital area of the head. She went to her gynecologist because of increased pale pink vaginal secretion. Gynecological examination didn't show any significant abnormalities apart from a slightly enlarged uterus. Papanicolaou test and vaginal secretion examination were normal. Colposcopically, a significant dark brown hyperpigmented area around 1 cm in size was observed on the posterior lip of the cervix, near the orifice and cervical canal, suspicious of melanoma, which was proven on targeted biopsy of the hyperpigmented change on the cervix, and by magnetic resonance imaging of the lesser pelvis. Classic hysterectomy with adnexectomy and regional pelvic lymphadenectomy were performed. Conclusion: This case report pointed out the significance of applying colposcopy in diagnosing suspected metastatic melanoma of the uterine cervix, along with other diagnostic methods and anamnestic data.

Relation between bone mineral density and IL-17 serum levels in Serbian patients with early Rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and destruction of joint cartilage and bone. Different cytokines play important role in the processes that cause articular destruction and extra-articular manifestations in RA. The contribution of cytokines representing the Th1 (INF-γ), Th2 (IL-4) and IL-17A to the pathogenesis of early RA and bone mineral density (BMD) loss in still poorly understood. Serum samples of 38 early RA patients were evaluated for erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibodies (anti-CCP) and for the tested cytokines (IL-17A, IL-4 and INF-γ). BMD was evaluated by dualenergy X-ray absorptiometry (DXA). Disease activity score (DAS28) calculation was assessed for all patients. Control serum samples were obtained from 34 healthy volunteers. The levels of tested cytokines were significantly higher (IL-17A, p<0.001; INF-γ, P<0.001; IL-4, P<0.01) in patients with early RA, compared to the healthy controls. In early RA patients, strong correlation of serum IL-17A was found with DAS28, ESR and CRP. Also, a significant negative correlation was found between serum INF-γ levels and the DAS28 score. Significantly positive correlation of BMD values and CRP, DAS28 IL-17A were also demonstrated. DXA analysis revealed that the most common site for osteoporosis was the lumbar spine followed by the femoral neck. BMD values significantly correlated with CRP, DAS28 score and IL-17A serum levels. The mean serum IL-17A levels, in patients with early RA, corresponded with disease activity, severity and BMD loss, indicating the potential usefulness of serum IL-17A in defining the disease activity and bone remodeling.

Serum levels of IL-17, IL-4, and INFγ in Serbian patients with early rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease with autoimmune etiology, characterized by synovial inflammation and destruction of joint cartilage and bone. There are controversial data about the profile of interleukin-17 (IL-17A), interleukin-4 (IL-4), and interferon-gamma (INFγ), indicating in some studies the key role of IL-17, while in others the Th1 cytokines. MATERIALS AND METHODS: Serum samples of 31 early RA patients were evaluated for erythrocytes sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibodies (anti-CCP), and for the tested cytokines (IL-17A, IL-4, and INFγ). Disease activity score (DAS28) calculation was done for all patients. Control serum samples were obtained from 29 healthy volunteers. RESULTS: The levels of tested cytokines were significantly higher (IL-17A, p < 0.001; INFγ, p < 0.001; IL-4, p < 0.01) in patients with early RA, compared to the healthy controls. In early RA patients, a strong correlation of serum IL-17A was found with DAS28, ESR, and CRP. Also, significant negative correlation was found between serum INFγ levels and the DAS28 score, indicating that INFγ may play a key role in maintaining immune homeostasis in patients with RA. CONCLUSION: The mean serum IL-17A levels in patients with early RA, corresponded with the disease activity and severity. This might highlight the usefulness of the serum IL-17A level in defining the activity and predictive patterns, for aggressive disease therapy, and it might express specific therapeutically targets.