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Purpose The purpose of this double-blind, randomized, controlled trial was to evaluate the use of intravenous (IV) tranexamic acid (TXA) in patients undergoing primary bone–patellar tendon–bone (BPTB) anterior cruciate ligament reconstruction (ACLR) regarding postoperative hemarthrosis, pain, opioid consumption, and quadriceps atrophy and activation. Methods A controlled, randomized, double-blind trial was conducted in 110 patients who underwent ACLR with BPTB autograft. Patients were equally randomized to the control and experimental groups. The experimental group received two 1-g boluses of IV TXA, one prior to tourniquet inflation and one prior to wound closure; the control group did not receive TXA. If a clinically significant hemarthrosis was evident, the knee was aspirated and the volume of blood (in milliliters) was recorded. Additionally, we recorded perioperative blood loss (in milliliters); visual analog scale scores on postoperative days 1, 4, and 7 and at postoperative weeks 1, 6, and 12; postoperative opioid consumption on postoperative days 1, 4, and 7; range of motion (ROM) and ability to perform a straight leg raise at postoperative weeks 1, 6, and 12; and preoperative and postoperative thigh circumference ratio. Results There was no significant difference in perioperative blood loss between the TXA and control groups (32.5 mL vs 35.6 mL, P = .47). In the TXA group, 23 knees were aspirated; in the control group, 26 knees were aspirated (P = .56). No significant difference in postoperative hemarthrosis volume was seen in patients who received IV TXA versus those who did not (26.7 mL vs 37.3 mL, P = .12). There was no significant difference in visual analog scale scores between the 2 groups (P = .15); in addition, there was no difference in postoperative opioid consumption (P = .33). No significant difference in ROM, ability to perform a straight leg raise, or postoperative thigh circumference ratio was observed (P > .05 for all). Conclusions IV TXA in patients who undergo ACLR with BPTB autograft does not significantly impact perioperative blood loss, postoperative hemarthrosis, or postoperative pain levels. Additionally, no significant differences were seen in early postoperative recovery regarding ROM or quadriceps reactivation. Level of Evidence Level I, randomized controlled trial.

The anticancer effects of metformin (an antihyperglycaemic agent) and itraconazole (an antifungal agent), which are established non-oncologic drugs, were investigated in the present study. The weight, diameter, volume, density, surface, surface to volume ratio and immunohistochemistry of experimental fibrosarcoma tumors were investigated in hamsters treated with metformin and itraconazole. Briefly, the hamsters were injected with BHK-21/C13 cells in order to induce fibrosarcoma, and the animals were treated daily with metformin, itraconazole or a combination of the two drugs. Subsequently, blood samples were obtained for biochemical analyses and the tumors were excised, weighed and measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, hematopoietic progenitor cell antigen CD34, cytochrome c oxidase subunit 4 (COX4), glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and vital organs were toxicologically tested. Ki-67-positivity and cytoplasmic marker (CD34, COX4, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The results revealed that the combination of metformin and itraconazole significantly altered the physicochemical and pathohistological characteristics of the hamster fibrosarcoma tumors, including absolute and relative weight, volume, density, length, surface area, surface to volume ratio, Ki-67-positivity and the immunoexpression of cytoplasmic markers, without indications of toxicity. Furthermore, metformin with itraconazole demonstrated antiproliferative functions in cervical carcinoma HeLa, colon carcinoma HT-29, lung carcinoma A549 and fibrosarcoma BHK-21/C13 cells, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, the administration of metformin in combination with itraconazole may inhibit the growth of fibrosarcoma tumors in vivo and the proliferation of various malignant cell lines in vitro, suggesting that this may be an effective and safe approach as a nontoxic anticancer adjuvant and relapse prevention therapy.

Introduction/Objective. Thrombosis of hemodialysis catheters is one of the major complications, which leads to catheter dysfunction. Although tissue plasminogen activator has been proven to be effective in reestablishing blood flow rate through dysfunctional catheters, clinical data in Serbia are missing. The objective of the study was to analyze tissue plasminogen activator efficacy in reestablishing blood flow rate and the influence on catheter survival. Methods. The study included 53 tunneled catheters from 32 patients on hemodialysis. After catheter dysfunction was established, 580,000 units of tissue plasminogen activator was applied into each catheter lumen for about two hours before hemodialysis. The criteria for success was blood flow rate on the next hemodialysis ? over 200 mL/minute was considered to be complete success, 180?200 mL/minute partial success, and under 180 mL/minute was considered a failure. Results. Out of 53, 25 catheters (47%) had dysfunction with an incidence of 3.8/1,000 catheter days. Catheters placed in femoral veins, ?after-first? catheters, catheters with infection, and catheters in older patients had higher risk for dysfunction. Multivariate logistic regression analysis confirmed that only older age was significantly related to catheter dysfunction. Of the total of 50 applications of tissue plasminogen activator, 35 (70%) were successful, seven procedures (14%) were partially successful and eight (16%) dysfunctional catheters failed to respond to therapy. Six-, 12- and 24-month survival was 87%, 81%, and 20%, respectively, for catheters without dysfunction, and 71%, 47.5%, and 12%, respectively, for catheters with dysfunction. Conclusion. Tissue plasminogen activator dosing is noninvasive, efficient, and safe in reestablishing blood flow rate through dysfunctional catheters, thus prolonging catheters life and sparing patients from additional vascular procedures.

Development of on-site treatment strategies for PFAS-containing investigation derived waste (IDW) will decrease the potential for secondary release following off-site disposal, lower disposal costs, and promote more effective long-term management of PFAS-laden waste. Herein, we report the application of a simple, drop-in treatment that utilizes one of two PFAS sorbents: bituminous granular activated carbon (GAC) or strong base anion exchange resin (IX) and a small circulation pump to adsorb and concentrate PFAS impacted mass from liquid IDW collected from two sites with disparate water chemistries and synthetic IDW amended with PFAS-containing aqueous film forming foam (AFFF). Bench scale intermittent circulation experiments revealed that bituminous granular activated carbon (GAC, 0.5 mg/mL) removed up to 97.0 ± 1.4% and 96.4 ± 0.5% of PFOS and PFOA, respectively, in both site-derived IDW sources. Improved performance was observed in experimental treatments containing a strong base anion exchange resin (IX, 0.5 mg/mL), where up to 99.4 ± 0.1% and 96.7 ± 0.2% of PFOS and PFOA were removed, respectively. High chloride concentrations (20 g/L) reduced removal of short chain perfluorocarboxylates (PFBA and PFHxA) using GAC or IX, but high salt concentrations had negligible effects on the removal of PFOA, PFBS, PFHxS, or PFOS. Excellent scalability was observed in mesoscale experiments, where the majority of amended PFAS mass was removed from synthetic IDW within five days of vessel circulation using two different PFAS-capture configurations. Combined PFOS and PFOA concentrations were reduced to levels below 0.07 μg/L using either GAC or IX for both configurations. Results generated in this study support the application of this approach as an economical strategy for potential waste volume reduction in IDW destined for off-site disposal.

Background and Aims Home hemodialysis (HOHD) has been available as a modality of renal replacement therapy since the 1960s, in our center since 1972. Despite better patients’ outcome provided by HOHD comparing to hospital hemodialysis (HHD), its adoption has been limited worldwide. The aim of this study was to compare anemia, nutrition, mineral metabolism and morbidity in patients on HOHD and HHD. Method we analyzed dialysis and uremia related complications and morbidity in 19 HOHD patients in comparison with patients on HHD (N= 57). Each HOHD patient was previously matched with three patients on HHD by sex, age and reason for end stage renal disease (ESRD). Patients on HHD were on dialysis 3x4 h per week while patients on HOHD had dialysis on consecutive days in duration of 5-6 hours. Also, patients on HOHD were more frequent on hemodiafiltration (HDF), 89.5% of them, as compared to HHD patients (only 21.4%). Results All patients on HOHD were using AVF as vascular access for HD, and most of the analyzed HHD patients (only 5.3% used AVG). As revealed by hemoglobin level (Hgb) patients on HOHD had significantly better anemia control than HHD patients (12±2.3 vs. 10.2±1g/dl, p=0.004), despite the lower ferritin level (94±117 vs. 256±175ng/ml, p=0,001) and less frequent use of erythropoietin-stimulating agents (ESA), (and only 31% on HOHD vs 80% patients on HHD, p=0,001). By analyzing patients that used ESA therapy, we revealed that HOHD patients had lower weekly dose of ESA (5333±3265 IU vs. 6068±4145 IU). The values of intact parathyroid hormone (iPTH), did not differ significantly between HOHD (311±419pg/ml ; min 5,25, max 1529) and HHD (233±212pg/ml; min 19,25, max 926), but higher percentage of patients in HOHD group underwent parathyroidectomy (63% vs. 3.5%). The average values of calcium, and phosphorus did not significantly differ between HOHD and HHD patients (2.4±0.3 vs. 2.3±0.2mmol/l; 1.5±0.5 vs. 1.6±0.5mmol/l, respectively). HOHD patients had significantly higher albumin level (43±4.5 vs. 40.6±4g/l, p=0,035). There was no difference in annual hospital admission rate (0.4±0.5 vs. 0.6±0.7, p=0.35) between groups, but HHD patients had longer in-hospital stay. (4.8±5.3 days for HOHD vs. 7.3±9.3 days for HHD; p=0.16). Vascular access complications were most frequent reason for hospitalization in both groups (37%), followed by cardiovascular complications 13.6%, in HOHD group and infectious complications in HHD group 24%. Conclusion Our study has shown that HOHD provides some advantages over HHD including better quality of life and better anemia and nutrition control, better control of parathyroid function and shorter in-hospital stay. More frequent and longer dialysis sessions may be possible reason including HDF.

Background and Aims Serum levels of parathyreoid hormone is the main cause of mineral disorders in patients on chronic hemodialysis, and it well known that this hormone acts as an uremic toxine and contributes to oxidative stress and overall mortality rate. However, there are many observations which imply that the protean manifestations of renal bone disease cannot be explained simply by abnormalities of PTH or vitamin D metabolites. For example, levels of PTH correlate relatively poorly with various parameters of bone histology. It has been shown that uremia leads to cytokijne imbalance with overbalance of proinflammatory citokines such as TNF. Also, studies showed that calcimimetic therapy decreases not only PTH levels, but also levels of TNF. The aim was to analyse tumor necrosis factor (TNF) gene polymorphisms in group of hemodialysis patients and to correlate the findings with presence of secondary hyperparathyroidism. Method This cross sectional study included 202 patients on regular hemodialysis for more than six months in University Medical Centar Zvezdara. Venous blood for genotyping and for PTH analysis was collected on midweek dialysis session from each patient. Genetic analysis was performed by using polymerase chain reaction. Patients are diveded in two groups regarding the level of PTH, so that first group had normal PTH levels or mild SHPT, while patients in second group had sever SHPT. We analysed influence of genetic polymorphism for TNF on apperance of SHPT. Results The results have shown 3 fold lower risk for developing SHPT in GG homozygots for TNF gene with statistical significance (p=0,01)- Table 1. Conclusion Parathyreoid gland hyperfunction is multifactorial disorder and there are emerging evidence that cytokines as endogenous modulators have an important impact on its pathogenesis.

Background/Aim. Drug-drug interactions involving antimicrobials present important and often unrecognized complications of pharmacotherapy which can be prevented. The aim of the present study was to identify the frequency and type of potential drug-antimicrobial agent interactions among outpatients and to define recommendations for their management. Methods. Crosssectional prescription database study was conducted. The analysis randomly included 823 patients who visited Health Center Novi Sad over 1-month period (November 1?30, 2011) and had prescribed ? 2 drugs where at least one drug was antimicrobial agent for systemic use. All interacting drug combinations involving antimicrobials were identified according to Drug Interaction Facts. Additionally, based on the compendium, potential interactions were classified into categories: pharmacological mechanisms, potential clinical outcomes and management advice. Results. Overall, 88 potential clinically significant drug-antimicrobial agent interactions were identified among 69 (8.4%) exposed outpatients [the mean age 61.7 years (SD ? 15.4); the mean number of prescribed drugs 7.5 (SD ? 2.9); 56.5% females]. The most common identified potential interacting pairs were benzodiazepines undergoing oxidative metabolism and clarithromycin or erythromycin, and aminophylline and ciprofloxacin. In 83.0% of all cases underlying mechanism was pharmacokinetic involving primary inhibition of metabolic pathways mediated by CYP3A4 and CYP1A2 isoenzymes. Excessive sedation (22.7%), cardiotoxicity (20.5%), miscellaneous aminophylline adverse effects (13.6%), and bleeding (10.2%) were the most frequently implicated potential clinical outcomes. Risk for adverse interactions could be managed by close monitoring of simultaneous administration of drugs (37.5%), different risk-modifyng strategies (31.8%), and avoiding combinations (30.7%). Conclusion. Among outpatients, there was common potential for clinically significant interactions involving antimicrobials. Information based on the results of the present study could be integrated in existing computerized physician order entry system in the Health Center as a form of clinical support.

We investigated the anticancer effect of disulfiram and metformin combination on fibrosarcoma in hamsters. Hamsters of both sexes (~ 70 g) were randomly allocated to control and experimental groups (8 animals per group). In all 10 groups, 2 × 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals’ backs. Peroral treatments were carried out with disulfiram 50 mg/kg daily, or with metformin 500 mg/kg daily, or with their combination. Validation and rescue grups were treated by double doses of the single therapy and by the combination with addition of rescue daily doses of ROS inhibitor nitroglycerin 25 mg/kg or NF-κB stimulator mebendazole 460 mg/kg, via a gastric probe after tumor inoculation. After 19 days all animals were sacrificed. Blood samples were collected for hematological and biochemical analyses, the tumors were excised and weighed, and their diameters and volumes were measured. The tumor samples were pathohistologically and immunohistochemically assessed (Ki-67, PCNA, CD34, CD31, COX4, Cytochrome C, GLUT1, iNOS), and the main organs were toxicologically tested. The combination of disulfiram and metformin significantly inhibited fibrosarcoma growth in hamsters without toxicity, compared to monotherapy or control. The single treatments did not show significant antisarcoma effect. Co-treatment with nitroglycerin partly rescued tumor progression, probably by ROS inhibition, while mebendazole completely blocked anticancer activity of the disulfiram and metformin combination, most likely by NF-κB stimulation. Combination of disulfiram with metformin may be used as an effective and safe candidate for novel nontoxic adjuvant and relapse prevention anticancer therapy.

Objectives: Tranexamic acid (TXA) is a commonly used medication in orthopaedic procedures, reducing perioperative bleeding and need for transfusion. The purpose of this double-blind randomized controlled study was to evaluate if IV TXA for primary anterior cruciate ligament (ACL) reconstruction with bone-patella tendon-bone (BTB) could reduce perioperative blood loss or postoperative intra-articular hemarthrosis without postoperative drains. Methods: A controlled, randomized, double-blinded trial was conducted in 110 patients who underwent ACLR with BTB autograft. Patients were equally randomized to the control and experimental groups. The experimental group received two 1-gram boluses of IV TXA, one prior to tourniquet inflation and one prior to wound closure; the control group did not receive TXA. If a clinically significant hemarthrosis was evident, the knee was aspirated, and the volume of blood (ml) was recorded. Additionally, perioperative blood loss (ml); Visual Analog Scale (VAS) on postoperative days (POD) 1-7 and post-operative weeks (POW) 1, 6 and 12; postoperative opioid consumption POD 1-7; range of motion (ROM) and ability to straight leg raise (SLR) at POW 1, 6, 12; and pre and postoperative thigh circumference ratio (TCR). Results: There was no significant difference in perioperative blood loss between the experimental and control groups (32.5ml v. 35.6ml, p=0.47). The experimental group had 23 knees aspirated; control group had 26 knees aspirated (p=0.56). No significant difference seen in postoperative hemarthrosis volume with IV TXA (26.7ml v. 37.3ml, p=0.12). There was no significant difference in VAS score between the two groups (p=0.15), additionally, there was no difference in postoperative opioid consumption (p=0.33). There was no significant difference in ROM or ability to SLR, or pre- nor post-operative TCR (p > 0.05 for all). Conclusions: IV TXA in patients who undergo ACLR with BTB autograft does not significantly impact perioperative blood loss, postoperative hemarthrosis, or postoperative pain levels. Additionally, no significant differences were seen in early post-operative recovery regarding ROM or quadriceps reactivation.

Although clinical trials have not been completed, it has already been confirmed that mebendazole, a well-known anti-parasitic drug widely used in the tropical areas, inhibits cancer cell growth. Preclinical studies show that mebendazole notably impedes the growth of malignant and metastatic tumors such as osteosarcoma and soft tissue sarcoma, melanoma, carcinoma (lung, colorectal, breast, ovarian, hepatocellular and adrenocortical), acute myeloid leukaemia, glioblastoma multiforme and meduloblastoma. Mebendazole can induce the depolymerization of microtubules in neoplasms and newly formed vasculature, stopping tumor growth and neoangiogenesis, along with other proposed mechanisms of action.Keywords: Anthelmintic, Mebendazole, Cancer treatment, Antimicrotubullar effect, Antineoangiogenesis

Purpose: To investigate the effect of mebendazole on an in vivo solid tumor model of fibrosarcoma in hamsters.Methods: 24 Syrian golden hamsters of both sexes with the approximate body weight of 100g were randomly distributed in 2 experimental and 2 control groups, with 6 animals in each group. BHK-21/C13 cells (2 x 106) in 1 mL Glasgow Minimum Essential Medium (GMEM) were injected subcutaneously into the back of each animal in 3 groups. The experimental groups were treated with mebendazole (460 mg/kg) via a gastric tube on a daily basis, immediately after tumor inoculation. In addition, one experimental group received deoxycholic acid 20 mg/kg once a day. After 2 weeks, when the tumors were approximately 1 - 2 cm in the control group, all the animals were sacrificed, and their blood collected for laboratory analysis. The tumors were excised, their weight and diameters measured, and the volumes calculated. The tumor samples were histopathologically assessed and the main organs toxicologically analyzed. Images were taken and processed by an imaging software, and Ki-67-positive cells in the tumor samples were quantified.Results: Mebendazole diminished tumor mitosis from 18.5 ± 3.02 to 13.5 ± 3.45 (p < 0.05), vasculature and tissue penetration, and increased necroses in tumor slices. Tumor volume and weight were insignificantly attenuated. Toxicity was not observed.Conclusion: Mebendazole might be an effective non-toxic agent in sarcoma therapy.Keywords: Mebendazole, Hamsters, BHK-21/C13 cells, Fibrosarcoma therapy, Tumor mitosis

The roles of the pharmacist were transformed throughout the history and modern pharmacist as we know now beside providing products and playing in optimization of medicines has a crucial role in ensuring the efficacy and safety of applied drugs. A better life quality, global health and safety is the major goal of the 21st century and to achieve that great span of roles pharmacy profession involves now. The paper highlighted new roles of the pharmacist today in order to better understand the transition of the pharmacy profession.

For adequate hemodialysis, functional vascular access is obligatory. Neointimal hyperplasia (NIH) has a central role in stenosis and thrombosis development, which represent the most frequent causes of vascular access failure. Polymorphism of different genes that have a significant role in endothelial function may have an impact on NIH development. Therefore, the aim of our study is to determine the effect of angiotensin-converting enzyme (ACE) I/D and matrix metalloproteinase-3 (MMP3) 5A/6A polymorphism on risk for developing vascular access failure in hemodialysis patients. The study included 200 patients on regular hemodialysis at Nephrology Department, University Medical Center Zvezdara. Retrospective analysis included a collection of general and vascular access data from medical records. Genetic analysis was performed by using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Patients were divided into two groups: Group 1-patients who have never experienced vascular access failure and Group 2-patients who have at least one spontaneous vascular access failure. There was no difference in age, gender, hemodialysis vintage, main diagnosis, presence of hypertension, and diabetes mellitus between the two groups. There were no statistically significant differences in the frequencies of ACE and MMP3 genotypes between the two groups. Without statistical significance, it was found that homozygotes for I allele had two times higher risk for developing vascular access failure than homozygotes for D allele (OR 2.00; 95%CI: 0.727-5.503; P = 0.180). In addition, patients with 5A allele have 1.7 times higher risk for developing vascular access failure compared with patients without this allele (OR 1.745; 95% CI: 0.868-3.507; P = 0.118). Patients with vascular access failure do not have different genotype distribution regarding ACE gene and MMP3 gene polymorphism as compared with patients without vascular access failure. Still, homozygotes for I allele and homozygotes for 5A allele have higher risk for developing vascular access failure compared with other patients.

ObjectiveIgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.MethodsWe used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.ResultsIn the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, pConclusionWe identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

We investigated the effect of nitroglycerin with metformin on fibrosarcoma in hamsters. Syrian golden hamsters of both sexes, weighing approximately 60 g, were randomly allocated to control and experimental groups, with 8 animals per group. In all groups, 2 × 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals’ backs. Peroral treatment carried out with nitroglycerin 25 mg/kg daily, or with metformin 500 mg/kg daily, or with a combination of nitroglycerin 25 mg/kg and metformin 500 mg/kg daily. Later validation experiments were conducted with double doses of the single therapy and additional rescue doses of mebendazole 460 mg/kg daily, via a gastric probe after tumor inoculation. After 2 weeks, when the tumors were approximately 2−3 cm in the control group, all animals were sacrificed. Blood samples were collected for hematological and biochemical analyses, the tumors were excised and weighed, and their diameters and volumes were measured. The tumor samples were pathohistologically and immunohistochemically assessed for proliferation marker protein Ki-67, proliferating cell nuclear antigen PCNA, hematopoietic progenitor cell antigen CD34, cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX4), mitochondria marker Cytochrome C, glucose transporter 1 (GLUT1) and inducible nitric oxide synthase (iNOS), and the main organs were toxicologically tested. The Ki-67 and PCNA positivity and the cytoplasmic marker (CD34, CD31, COX4, Cytochrome C, GLUT1, iNOS) immunoexpression in the tumor samples were quantified. The combination of nitroglycerin and metformin significantly inhibited fibrosarcoma growth in hamsters without toxicity, compared to monotherapy or control. The results were validated and confirmed in the subsequently accomplished experiment with doubled doses of the single drug therapy and in the rescue experiment with addition of mebendazole. The single treatments did not show significant antisarcoma effect, regardless of the dose. Co-treatment with mebendazole inhibited anticancer activity of the nitroglycerin and metformin combination. Mebendazole rescued tumor progression suppressed by the combination of nitroglycerin and metformin. Administration of nitroglycerin with metformin might be an effective and safe approach in novel nontoxic adjuvant and relapse prevention anticancer treatment.

The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4–19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2–5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post’s and Newton’s method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

Introduction. Retrospective studies showed that hemodiafiltration was associated with a reduced risk of mortality compared with standard hemodialysis in the patients with end-stage renal disease. Recently, a few prospective randomized clinical trials found no advantage in survival with hemodiafiltration as compared with high-flux hemodialysis and low-flux hemodialysis. The aim of this study was to compare the parameters of hemodialysis adequacy and two-year survival of patients depending on the modality of hemodialysis. Material and Methods. A total of 159 hemodialysis patients were divided into 3 groups according to the type of hemodialysis treatment: group A - lowflux hemodialysis, group B - high-flux hemodialysis, and group C - hemodiafiltration. All patients had the same duration of hemodialysis sessions. The analysis included average one-year biochemical parameters, and two-year survival of patients. Results. The patients on hemodiafiltration were significantly younger, they had longer dialysis vintage and higher index of dialysis adequancy as compared with the patients on low-flux hemodialysis and high-flux hemodialysis, but without a difference between the two latter groups. Compared to the patients on low-flux hemodialysis, the patients on hemodiafiltration and high-flux hemodialysis had significantly higher hemoglobin value with less frequent erythropoietin stimulating agent use. According to Kaplan-Meier survival analysis, the patients on hemodiafiltration and high-flux hemodialysis had significantly better two-year survival than the patients on low-flux hemodialysis. Cox proportional hazards model confirmed that high-flux hemodialysis caused a significantly lower relative risk of mortality (56% reduction) compared to low-flux hemodialysis (hazard ratio 0.44; P=0.026), and hemodiafiltration caused a 58% reduction in the relative risk of mortality compared to low-flux dialysis (hazard ratio 0.42; P=0.105), but without a statistical significance. Conclusion. This study has demonstrated two-year survival benefit with high-flux hemodialysis and hemodiafiltration compared with low-flux hemodialysis. There was no difference in survival between high-flux hemodialysis and hemodiafiltration groups.

Background/Aims: Vascular calcifications are frequently found among dialysis patients, and the calcification process may influence the patient's outcome. The aim of the present study was to determine the role that vascular calcifications may have on autologous arteriovenous fistula (AVF) survival. Methods: This study included 90 patients (49 males, mean age 62 ± 11) with a native AVF treated by chronic hemodialysis (HD) for more than one year. The overall vascular calcification scores ranged from 0-11 (Adragao score + vascular access calcification score); patients were categorized into mild (score 0-3; n = 36), moderate (score 4-7; n = 24) and severe (score 8-11; n = 30) calcification groups. AVF survival was then followed for 5 years after calcification measurement or until the patient's death/transplantation. Results: Patients with more pronounced vascular calcifications were more frequently diabetic and male. Multiple linear regression analysis showed a significant relationship between calcification score and male gender, diabetes mellitus, previous duration of AVF, low dialysis flow rate and intact parathormone (iPTH) values. After multivariate adjustment for basal differences, Cox proportional analysis revealed a graded impact of calcification scores on AVF failure: moderate scores (were associated with a hazard rate (HR) of 3.82 (95% confidence interval (CI) 1.10-13.23) and severe scores with an HR of 4.65 (CI 0.97-22.38). Conclusion: Vascular calcifications are associated with worse survival of native arteriovenous hemodialysis fistulas.

Cardiovascular morbidity is the leading cause of death in dialysis patients and many risk factors have been involved in its pathogenesis. Genetic susceptibility may be of importance including polymorphism for matrix metalloproteinase 3 (MMP3), which is an enzyme that catalyzes the degradation of collagen, proteoglycans, fibronectin, laminine and elastin. The MMP3 gene promoter contains an insertion/deletion polymorphism characterised by an array of 5 or 6 adenosine residues (5A/6A) at -1612 position. Literature data show that the 5A or 6A allele of the MMP3 gene shows different risk for cardiovascular and overall outcome in general population. The aim was to analyze the -1612 5A/6A promoter polymorphism in a group of hemodialysis patients and to correlate the findings with cardiovascular morbidity and 7-year all-cause and cardiovascular mortality. This study included 196 patients on hemodialysis for longer than six months at University Medical Center Zvezdara. The leading causes of end stage renal disease were hypertension and diabetes mellitus. Venous blood was collected on midweek dialysis session and genotype analysis was performed by using polymerase chain reaction-restriction fragment length polymorphism method. Among the 198 hemodialysis patients, there were 142 (72%) 5A/6A heterozygotes, 12 (6%) 5A/5A homozygotes, and 44 (22%) 6A/6A homozygotes. These data are consistent with Hardy-Weinberg equilibrium. After 7-year follow-up, the 5A homozygotes showed the lowest all-cause and cardiovascular survival, while the 6A homozygotes showed the highest cardiovascular survival. The 5A allele of the MMP3-gene promoter polymorphism is a potential risk factor in the poor outcome of hemodialysis patients.

Background The frequency of total joint arthroplasties (TJAs) performed in ambulatory surgery centers (ASCs) is increasing. However, not all TJA patients are healthy enough to safely undergo these procedures in an ambulatory setting. We examined the percentage of arthroplasty patients who would be eligible to have the procedure performed in a free-standing ASC and the distribution of comorbidities making patients ASC-ineligible. Methods We reviewed the charts of 3444 patients undergoing TJA and assigned ASC eligibility based on American Society of Anesthesiologists (ASA) status, a set of exclusion criteria, and any existing comorbidities. Results Overall, 70.03% of all patients undergoing TJA were eligible for ASC. Of the ASA class 3 patients who did not meet any exclusion criteria but had systemic disease (51.11% of all ASA class 3 patients), 53.69% were deemed ASC-eligible because of sufficiently low severity of comorbidities. The most frequent reasons for ineligibility were body mass index >40 kg/m 2 (32.66% of ineligible patients), severity of comorbidities (28.00%), and untreated obstructive sleep apnea (25.19%). Conclusion A large proportion of TJA patients were found to be eligible for surgery in an ASC, including over one-third of ASA class 3 patients. ASC performed TJA provides an opportunity for increased patient satisfaction and decreased costs, selecting the right candidates for the ambulatory setting is critical to maintain patient safety and avoid postoperative complications.

The objective of this study was to estimate the prevalence of potential drug-drug interactions (DDIs) among outpatients of city region Novi Sad, Serbia, and to investigate predictors of potential DDIs. Cross-sectional prescription database study was conducted. In the analysis were randomly included 10% outpatients with polypharmacy (n=4467), who visited Health Center over 1-month period (November 1–30, 2011). All drug combinations with potential for clinical significant DDIs were identified, according to Drug Interaction Facts by David S Tatro. A logistic regression analysis was conducted to examine patient and drug therapy characteristics as predictors of potential DDIs. The prevalence of clinical significant potential DDIs was 33.31%. Odds of exposure were the highest among those aged 65 years or older (odds ratio (OR)=5.204; 95% confidence interval (CI) 2.694–10.052, p

Introduction. Cardiovascular morbidity and mortality are the major concern in dialysis patients and many risk factors are thought to be involved in its pathogenesis. Apart from traditional and non-traditional risk factors, the genetic susceptibility may be of importance, including renin-angiotensin system gene polymorphism. The aim of this study was to analyse renin-angiotensin system polymorphism in our group of hemodialysis patients and to correlate the findings with cardiovascular morbidity. Material and Methods. The study included 196 patients on regular hemodialysis on polysulphone membrane three times per week for more than six months. Genetic analysis was performed by using polymerase chain reaction - restriction fragment length polymorphism method. Results. Out of 196 patients, 55% had I/D genotype, 35% had D/D and 10% had I/I, including angiotensin-converting enzyme polymorphism. It was shown that the patients with D allele genotype developed a significantly higher incidence of left ventricular hypertrophy and peripheral vascular disease. The angiotensin-converting enzyme polymorphism showed a significant association with the incidence of cerebrovascular accident and hyperlipoproteinemia in our group of hemodialysis patients. Conclusion. The angiotensin-converting enzyme gene polymorphism is associated with the development of cerebrovascular accidents and hyperlipoproteinemia. Allele D of this gene increases the risk for the development of left ventricular hypertrophy and peripheral vascular disease significantly in hemodialysis patients. A longer follow-up is needed to make the definitive conclusion about the influence of angiotensin-converting enzyme polymorphism on cardiovascular morbidity and its importance in everyday clinical practice.

Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. The impact of vascular calcification process on AVF survival remains unclear and results of several studies about this issue are controversial. In the light of the new knowledge about the different susceptibility for calcification process in different blood vessels, the aim of our study was to analyze whether the calcification of AVF-blood vessels may have an impact on AVF longevity. The study included 90 patients, 49 males and 41 females, all of them Caucasians, with a mean age 62 ± 11 years, on regular hemodialysis for more than 1 year with patent primary AVFs. Vascular calcification in AVF-blood vessels or in the anastomotic region was detected using X-ray examination. Calcification in AVF-blood vessels was found in 62% of patients. Binary logistic regression analysis demonstrated that male gender, presence of diabetes mellitus and longer duration of AVF before calcification determination were associated with calcification of AVF-blood vessels. Using a Cox proportional hazard model adjusted for these standardized predicted values revealed that patients with present AVF-blood vessels calcification had increased risk to develop AVF failure with a hazard rate of 3.42 (95% confidence interval 1.00–11.67; P = 0.049). Calcifications of AVF-blood vessels are found frequently among dialysis patients and may jeopardize the survival of native AVF. We suggested the local X-ray as simple and valid method for detection of patients that are at risk for AVFs failure which should be monitored more closely.

Uremia-related inflammation is prone to be a key factor to explain high cardiovascular morbidity in hemodialysis patients. Genetic susceptibility may be of importance, including IL-10, IL-6, and TNF. The aim was to analyze IL-10, IL-6, and TNF gene polymorphisms in a group of hemodialysis patients and to correlate the findings with cardiovascular morbidity. This study included 169 patients on regular hemodialysis at Zvezdara University Medical Center. Gene polymorphisms for IL-10, IL-6 and TNF were determined using PCR. These findings were correlated with the cardiovascular morbidity data from patient histories. Heterozygots for IL-10 gene showed significantly lower incidence of cardiovascular events (p = 0.05) and twice lower risk for development of myocardial infarction, but experienced twice higher risk for left ventricular hypertrophy. Regarding TNF gene polymorphism, patients with A allele had 1.5-fold higher risk for cerebrovascular accident and cardiovascular events and 2-fold higher risk for hypertension and peripheral vascular disease. Patients with G allele of IL-6 gene experienced 1.5-fold higher risks for cerebrovascular accident. We need studies with larger number of patients for definitive conclusion about the influence of gene polymorphisms on cardiovascular morbidity in hemodialysis patients and its importance in everyday clinical practice.

The aim of this study is to investigate the protective effect of fullerenol C₆₀(OH)₂₄ in various doses, on lipid peroxidation of rat's kidneys, testes and lungs after application of doxorubicin. The experiment was performed on healthy male Wistar rats. The animals were randomly divided into five experimental groups and treated with saline (0.9 % NaCl i.v.), doxorubicin alone (10 mg/kg i.v.), combination of doxorubicin/fullerenol (50 and 100 mg/kg fullerenol, respectively, 30 min before the introduction of doxorubicin) and fullerenol alone (100 mg/kg), respectively. Animals were killed on the 2nd and 14th day after treatment. Products of lipid peroxidation and thiobarbituric acid are determined spectrophotometrically from the crude homogenate fraction of the kidney, testis and lung tissues of the rats. Fullerenol, applied as a pre-treatment of doxorubicin, significantly reduced or completely prevented the appearance of doxorubicin toxicity in kidneys and testes, in both tested doses. A dose of 100 mg/kg i.p. exhibited a better protective effect. When fullerenol was applied alone, at a dose of 100 mg/kg i.p, it did not significantly affect the intensity of lipid peroxidation in all tested organs.

Blood loss during cesarean section was calculated based on post-operative decrement of hemoglobin (Hb) and hematocrit (Hct) level. The model used for pregnant women was previously validated for non-pregnant women who underwent gynecological surgery. 1,068 pregnant women who underwent cesarean section and 517 women who underwent gynecological surgery were included in the study. Regression lines between collected (x) and calculated (y) blood loss in pregnant women (y = 0.164 + 0.602x) and non-pregnant (y = 0.255 + 0.750x) women were statistically parallel. This study confirmed the applicability of one-compartmental model based on the drop in Hb levels for blood loss calculations for both gynecological surgery and cesarean section. Improved methods for calculating blood loss, V after cesarean section as V = [0.0115 × body weight (kg) × ln (preoperative Hb/postoperative Hb)] + [0.1905 × height³ (m) × ln (preoperative Hb/postoperative Hb)] + 0.3158 and after gynecological surgery V = [0.004 × body weight (kg) × ln (preoperative Hb/postoperative Hb)] + [0.4624 × height ³(m) × ln (preoperative Hb/postoperative Hb)] + 0.0472 were suggested.

Purpose Intra-dialytic morbid events (IME; e.g. hypotension, cramps, headaches) are frequent complications during hemodialysis (HD), known to be associated with ultrafiltration-induced hypovolemia and body temperature changes. Feedback control of blood volume adjusts the ultrafiltration rate in order to keep the blood volume above the patient's individual limit; feedback control of blood temperature maintains the mean arterial blood temperature at the individual pre-dialytic level. Each of these methods reduces the frequency of IME. Methods In a randomized clinical trial the simultaneous application of both feedback controls was investigated for the first time. In 15 weeks, each patient went through 3 study phases: an observational screening phase, a standard phase (STD), and a blood temperature- and blood volume-control phase (CTL). Patients with at least 5 sessions with IME out of 15 sessions in the screening phase were eligible for the study and randomized either into sequence STD-CTL or CTL-STD. Results 26 patients completed the study according to protocol, and 778 HD treatments were analyzed. The general treatment parameters were similar in both study phases: treatment duration (STD: 244 min, CTL: 243 min, NS), pre-dialytic weight (STD: 72.3 kg, CTL: 72.2 kg, NS), and weight loss due to ultrafiltration (STD: 3.26 kg, CTL: 3.15 kg, NS). The proportion of HD treatments with IME was 32.8% during STD and 18.0% during CTL (p=0.024). Conclusions The frequency of HD sessions with IME was significantly reduced by 45% compared to standard HD in this randomized clinical trial by use of individualized HD treatments with simultaneous feedback control of blood volume and blood temperature.

Blood loss can be measured directly and indirectly. The latter reflects blood loss through the assessment of hemoglobin level. Thus aim of this study was to determine the applicability of the drop in hemoglobin levels blood loss calculation when transfused blood volume is taken into account on the patients who underwent aneurysmectomy and to estimate whether this model is applicable on geriatric population. In this study, 14 patients were included and their blood loss was calculated based on hemoglobin concentration. Linear correlation (y = 0.18467 + 1.19315·x) with high correlation coefficient (r = 0.90809) was found between calculated and collected blood loss only if transfused blood volume was taken into account. The coefficient of the regression slope for the blood volume measured during surgery and the calculated blood loss in eight patients ≤65 years (y = 0.90866 + 0.86296·x) and six patients >65 years (y = 0.0299 + 1.32707·x) did not show any significant difference. The applicability of the indirect measurement of surgical blood loss, when transfused blood volume was taken into account, was demonstrated in both populations, in the age of 65 and less and in the age over 65 years after aneurysmectomy.

Twenty soybean cultivars, originating from the United States, Russia, Serbia, and China, were analyzed for their isoflavone composition, total polyphenolic content, and antioxidant activity. Isoflavones were extracted by aqueous methanol (80%) and analyzed by high-performance liquid chromatography/diode array detection. Precision and linearity of the applied method were within the standard limits of validation. The highest and the lowest total isoflavone contents were 4.59 and 1.45 mg/g of dried soybean weight, respectively. A significant difference (P.05) was found in isoflavone concentration among the different cultivars, but it was observed that origin is not a significant factor that could influence isoflavone content in soybeans. Total polyphenolic content varied between 2.13 and 3.45 mg of gallic acid equivalents/g of dried soybean weight. The free radical scavenging activity of soybean extracts assayed by 2,2-diphenyl-1-picrylhydrazyl in terms of 50% inhibitory concentration (IC(50)) ranged from 1.40 to 3.35 mg/mL. Negative correlation between total polyphenolic content and IC(50) was observed, but there was no correlation between total isoflavone content and IC(50). On the basis of this study, soybean cultivars with larger potency for biological activity could be recognized.

This study presents a new two compartmental model and its application to the evaluation of diclofenac pharmacokinetics in a small number of healthy adults, during a bioequivalence trial. In the model the integer order derivatives are replaced by derivatives of real order often called fractional order derivatives. Physically that means that a history (memory) of a biological process, realized as a transfer from one compartment to another one with the mass balance conservation, is taken into account. This kind of investigations in pharmacokinetics is founded by Dokoumetzidis and Macheras through the one compartmental models while our contribution is the analysis of multi-dimensional compartmental models with the applications of the two compartmental model in evaluation of diclofenac pharmacokinetics. Two experiments were preformed with 12 healthy volunteers with two slow release 100 mg diclofenac tablet formulations. The agreement of the values predicted by the proposed model with the values obtained through experiments is shown to be good. Thus, pharmacokinetics of slow release diclofenac can be described well by a specific two compartmental model with fractional derivatives of the same order. Parameters in the model are determined by the least-squares method and the Particle Swarm Optimization (PSO) numerical procedure is used. The results show that the fractional order two compartmental model for diclofenac is superior in comparison to the classical two compartmental model. Actually this is true in general case since the classical one is a special case of the fractional one.

The bioavailability of a new retard tablet formulation of verapamil was investigated in a randomized cross-over bioequivalence study on 12 healthy subjects. The drug was given in the form of a single 240-mg oral dose of a new retard tablet formulation, or as a standard retard tablet at the same dose to all subjects, followed by a single intravenous (i.v.) dose of 5 mg to 8 of the 12 subjects. Plasma verapamil concentrations were determined by a high performance liquid chromatography (HPLC) method. The bioavailability of the new peroral retard formulation was (20.00 +/- 4.30)% and was in reasonable agreement with that determined for the already registered verapamil retard formulation, i.e. (19.46 +/- 4.02)%, thereby indicating bioequivalence. For the prediction of systemic availability and estimation of the first-pass metabolism, only based on the data for peroral plasma levels, a hepatic blood flow rate limited model was used. In our experience, this model has been found to be extremely useful in providing reasonable estimates of verapamil first-pass effect.

The Department of Pharmacy. The first 50 pharmacy students were enrolled at the Faculty of Medicine in Novi Sad in the academic year 2000/2001. The Institute of Pharmacy was established on July 10, 2001. The Department of Pharmacy was established on December 18, 2001, with more than 150 faculty members. Since then, 82 students have graduated with honours. Visiting professors from Athens, Skopje, Reading (Great Britain) and Banja Luka, and professors of the Faculty of Science and Mathematics and the Faculty of Technical Sciences in Novi Sad, together with the professors and associates of the Faculty of Medicine, are members of the Faculty of the Department of Pharmacy. Activities of the Department of Pharmacy. The Department offers a 5-year undergraduate program in pharmacy, practical courses in pharmacy, takes part in higher education reform in accordance with the Bologna objectives, organizes visits to European centers of the pharmaceutical industry, and provides mentoring activities in relation to writing a graduation paper. The First Balkan Congress of Pharmacy Students was held March 7-12, 2006 in Novi Sad. The Department of Pharmacy of the Faculty of Medicine in Novi Sad has achieved the objectives set for it when it was Established.

Herbicides, which are ubiquitously present in soil and food, have been proven to cause human health hazard effects, hence development of new herbicide-active compounds is recommended. In this paper, nine 2,4-bis(cycloalkyl)-6-chloro-s-triazines were considered as herbicide candidates and their pharmacokinetics and toxicity were reviewed on the basis of in silico descriptors. Both, pharmacokinetic and toxicity predictors were presented as functions of their lipophilicity, quantified with retention constants that were obtained by liquid chromatography. None of the candidates investigated has functional groups for genotoxicity hazards and endocrine disruptions; they have acceptable toxicity and favorable pharmacokinetic properties based on computer-aided analyses. Two candidates have been selected as lead compounds for further research.

Purpose: Ultrasound technology has been applied to increase both efficacy and safety of certain peripheral nerve blocks. This case report describes the first successful ultrasound-guided lumber plexus block. Clinical Features: We describe a 91-year-old woman with aortic stenosis who successfully underwent open reduction and internal fixation of a fractured right hip with a lumbar plexus block. Ultrasound provided direct visualization to help identify the anatomical structures and guide the block needle during performance of the block. Complete block of the lumbar plexus was attained within 15 min, and the surgical procedure was performed uneventfully. Conclusion: The use of ultrasound has gained popularity to perform peripheral nerve blocks. In this case report, a successful lumbar plexus block was performed with ultrasound guidance. By direct visualization, using this technology may potentially reduce complications associated with lumbar plexus blocks.