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Introduction: Our study aimed to investigate the effect of zonisamide (ZNS) on bone metabolism in the rat model. Methods: Eight-week-old rats were divided into four groups. The sham-operated control group (SHAM) and the control group after orchidectomy (ORX) received the standard laboratory diet (SLD). The experimental group after orchidectomy (ORX+ZNS) and the sham-operated control group (SHAM+ZNS) received SLD enriched with ZNS for 12 weeks. Bone marker concentrations in serum of receptor activator of nuclear factor kappa B ligand, PINP, and osteoprotegerin, and the levels of sclerostin and bone alkaline phosphatase in bone homogenate, were measured using an enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The femurs were used for biomechanical testing. Results: We found a statistically significant reduction in BMD and biomechanical strength 12 weeks after orchidectomy of the rats (ORX). After ZNS administration to orchidectomized rats (ORX+ZNS) and the sham-operated control rats (SHAM+ZNS), there were no statistically significant changes in BMD, bone turnover markers, or biomechanical properties as compared with the ORX group and SHAM group. Conclusions: The results suggest that administration of ZNS to rats exerts no negative effect on BMD, bone metabolism markers, or biomechanical properties. [ABSTRACT FROM AUTHOR]

The primary objective was to determine levels of C3-epi-25(OH)D in very low birth weight infants. The secondary objective was to evaluate the possible influence of preterm birth, intrauterine growth restriction (IUGR), and season of birth on the production of C3-epimers. A total of 127 infants with birth weight less than 1,500 g met the inclusion criteria of the study. We examined 25-hydroxyvitamin-D [25(OH)D] levels and C3-epi-25(OH)D in maternal serum before labor, and in cord blood and infants' serum on days 14 and 28, and at discharge. The mean levels (±SD) of C3-epi-25(OH)D of the cord, on day 14, on day 28, and at discharge were 2.2 (2.9), 7.7 (5.5), 11.7 (7.6) and 14.9 (11.7) nmol/L respectively. The proportion of total 25(OH)D as the C3-epimer was 6.9% (cord), 16.3% (day 14), 22.4% (day 28) and 23.3% (discharge). A statistically significant correlation between 25(OH)D and C3-epi-25(OH)D can be demonstrated from birth. The severity of immaturity and IUGR did not affect the production of C3-epimers. In summer/autumn vs. winter/spring, the mean (SD) percentage of total 25(OH)D as the C3-epimer significantly differs only in maternal serum samples and umbilical cord samples (p value <0.001). The production of C3-epi-25(OH)D is functional even in the most immature newborns, has fetal origins, and is largely dependent on circulating 25(OH)D. At the end of the first month of life, C3-epimers make up more than 20% of 25(OH)D. [ABSTRACT FROM AUTHOR]

Aim: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. Methods: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC–MS/ MS. A pharmacokinetic population model was developed using a nonlinear mixedeffects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. Results: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m² of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. Conclusion: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections. [ABSTRACT FROM AUTHOR]

Although progress is evident in the effective treatment of joint replacement-related infections, it still remains a serious issue in orthopedics. As an example, the local application of antibiotics-impregnated bone grafts supplies the high drug levels without systemic side effects. However, antibiotics in the powder or solution form could be a risk for local toxicity and do not allow sustained drug release. The present study evaluated the use of an antibiotic gel, a water-in-oil emulsion, and a PLGA microparticulate solid dispersion as depot delivery systems impregnating bone grafts for the treatment of joint replacement-related infections. The results of rheological and bioadhesive tests revealed the suitability of these formulations for the impregnation of bone grafts. Moreover, no negative effect on proliferation and viability of bone marrow mesenchymal stem cells was detected. An ex vivo dissolution test of vancomycin hydrochloride and gentamicin sulphate from the impregnated bone grafts showed a reduced burst and prolonged drug release. The PLGA-based formulation proved to be particularly promising, as one-day burst release drugs was only 15% followed with sustained antibiotics release with zero-order kinetics. The results of this study will be the basis for the development of a new product in the Tissue Section of the University Hospital for the treatment of bone defects and infections of joint replacements. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to compare clinical outcomes of very low birth weight (VLBW) infants with 25-hydroxy vitamin D [25(OH)D] levels <25 nmol/l in umbilical cord blood versus VLBW infants with 25(OH)D levels in cord blood >25 nmol/l. The secondary objective was to evaluate umbilical cord vitamin D as a risk factor for respiratory distress syndrome (RDS) in preterm infants. We examined 25(OH)D levels in umbilical cord blood and in infants' serum at discharge from the neonatal intensive care unit. We evaluated the associations between severe vitamin D deficiency and various laboratory findings and clinical outcomes. Eighty one infants with birth weight less than 1500 g met the entry criteria for this study and were divided to groups according to umbilical cord blood vitamin D [Group A: 25(OH)D < 25 nmol/l; 10 ng/ml and Group B: 25(OH)D > 25 nmol/l; 10 ng/ml]. Overall, 81.5% of the infants had a 25(OH)D level <50 nmol/L and 44.4% had a level <25 nmol/L. The laboratory findings and the subsequent clinical outcomes were comparable in infants in both groups (non-significant difference). Only the infants in the 25(OH)D 25 nmol/L group had a lower calcium in urine at age 28 d (p=.0272). In addition, we found in this study that umbilical cord vitamin D level does not lead to a higher or lower risk of RDS (odds ratio 1.044; 95% confidence interval 0.349–0.88; p=.0771). In our prospective cohort study, we found no significant association between vitamin D status and selected clinical outcomes when using a cut-off of 25 nmol/l (severe vitamin D deficiency) in preterm infants. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate vitamin D status in mothers and their very low birth weight infants (VLBW) at birth (umbilical cord blood) and at discharge with currently recommended supplementation of vitamin D.Methods: Ninety-four infants with birth weight less than 1500 g completed the study. The total daily vitamin D intake was 800-1000 IU. We examined 25-hydroxyvitamin-D [25(OH)D] levels in maternal serum before labor, in cord blood, and in infants' serum at discharge.Results: Median (IQR) serum 25(OH)D was 21 (14-36) nmol/l [8 (6-15) ng/ml] in cord blood, and 46 (37-60) nmol/l [18 (15-24) ng/ml] at discharge. Serum 25(OH)D was <50 nmol/L in 71.3% of mothers, in 91.5% of cord blood samples, and in almost 60% of preterm newborns at discharge (after 8 weeks of supplementation). Serum 25(OH)D was <75 nmol/L in 88.3% of mothers, in 97.9% of cord blood samples, and in 91.4% of preterm newborns at discharge.Conclusions: In our cohort, we found that due to the very high prevalence of 25(OH)D deficiency among mothers, the current generally recommended dose of vitamin D (800-1000 IU per day) for VLBW infants was unable to improve vitamin D levels above the desired 50 or even 75 nmol/L before discharge. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this study was to compare clinical outcomes of very low birth weight (VLBW) infants with 25-hydroxy vitamin D [25(OH)D] levels <25 nmol/l in umbilical cord blood versus VLBW infants with 25(OH)D levels in cord blood >25 nmol/l. The secondary objective was to evaluate umbilical cord vitamin D as a risk factor for respiratory distress syndrome (RDS) in preterm infants.Methods: We examined 25(OH)D levels in umbilical cord blood and in infants' serum at discharge from the neonatal intensive care unit. We evaluated the associations between severe vitamin D deficiency and various laboratory findings and clinical outcomes.Results: Eighty one infants with birth weight less than 1500 g met the entry criteria for this study and were divided to groups according to umbilical cord blood vitamin D [Group A: 25(OH)D < 25 nmol/l; 10 ng/ml and Group B: 25(OH)D > 25 nmol/l; 10 ng/ml]. Overall, 81.5% of the infants had a 25(OH)D level <50 nmol/L and 44.4% had a level <25 nmol/L. The laboratory findings and the subsequent clinical outcomes were comparable in infants in both groups (non-significant difference). Only the infants in the 25(OH)D 25 nmol/L group had a lower calcium in urine at age 28 d (p=.0272). In addition, we found in this study that umbilical cord vitamin D level does not lead to a higher or lower risk of RDS (odds ratio 1.044; 95% confidence interval 0.349-0.88; p=.0771).Conclusions: In our prospective cohort study, we found no significant association between vitamin D status and selected clinical outcomes when using a cut-off of 25 nmol/l (severe vitamin D deficiency) in preterm infants. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this pilot study was to estimate physiological parathyroid hormone (PTH) levels and their relationship with bone metabolism parameters in otherwise healthy preterm newborns with birth weight 1000-1500 g. Methods: PTH, 25(OH)D, S-Ca, S-P, and ALP were analysed from blood samples obtained from 20 preterm infants once a week up to the 36th gestational week. Results: Of the total 134 examined serum samples for PTH levels, the estimated range was 1.6-9.3 pmol/l (15.1-87.7 pg/ml). No statistically significant correlation of PTH level with that of S-Ca, S-P, or ALP was observed, except for the 56th day of life (p = .03; Rho = 0.76; n = 8). From the second month of life, there was a statistically significant relationship only between PTH and 25(OH)D (Rho = -0.71, p ≤ .0001). In our cohort, vitamin D deficiency (20 ng/ml) occurred in 75% at birth and at 30% in the 36th gestational week. Conclusions: The physiological range indicated by the measurements was close to the reference limits for adults (1-7 pmol/l; 9.4-66 pg/ml). PTH level above this range can be considered as hyperparathyroidism in preterm neonates. [ABSTRACT FROM AUTHOR]

Introduction: Imatinib mesylate is the drug of choice for patients with chronic myeloid leukemia (CML). Imatinib pharmacokinetics is affected by a number of transport proteins and enzymes.Material and Methods: In the present study we evaluated the association of eight polymorphisms in the seven genes CYP3A5*3 (rs776746), CYP3A4*1 (rs2740574), CYP2C9*3 (rs1057910), SLC22A1 (rs683369), ABCB1 (rs1045642, rs1128503), ABCG2 (rs2231142) and ABCC2 (rs717620) with imatinib plasma level and achieving an optimal clinical response in 112 CML patients (53 men and 59 women).Results: No association was found between the examined polymorphisms in rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 and the achieved imatinib plasma level. The influence of rs776746 (CYP3A5*3) on the achievement of a complete cytogenetic response (CCyR) at 6 months was borderline non-significant (p = 0.06). Furthermore, no association was demonstrated between rs776746 polymorphisms and the achievement of a major molecular response (MMR) at 12 or 18 months. Polymorphisms rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 showed no impact on the optimal therapeutic response.Conclusions: Despite the results of some other studies, no other polymorphism we analyzed was associated with imatinib plasma level or clinical response. The treatment outcomes cannot be predicted using the candidate gene approach and treatment decisions cannot be made according to the polymorphisms investigated in this study. [ABSTRACT FROM AUTHOR]

Purpose: Behavioral side effects of antiepileptic drugs (AEDs) are common including both positive and negative effects on mood, anxiety, depression, and psychosis. We aimed to evaluate behavioral patterns in rats after administration of lamotrigine, levetiracetam, phenytoin, topiramate, carbamazepine, gabapentin, pregabalin, and zonisamide.Methods: The open-field test was performed and locomotion, rearing, grooming, central latency and defecation were recorded over a 5min interval for each rat (8 rats in each group receiving AED and 16 controls). Kruskal-Wallis nonparametric test or ANOVA were used to assess differences among the groups.Results: The experimental groups did not differ in latency to enter the center compartment, neither in the decline of locomotor activity in the 1st and the 5th minute of the observation, nor in number of rears. Significant differences among groups were observed in the total number of lines crossed, grooming, as well in the number of fecal pellets. Locomotor activity was significantly increased in lamotrigine, if compared with gabapentin and pregabalin (ANOVA; p <0.05). Rats exposed to topiramate displayed a significantly increased number of grooming (when compared to pregabalin: p<0.01). Defecation (the number of fecal pellets) significantly increased in the gabapentin and carbamazepine group.Conclusion: There are significant differences between AEDs in terms of their behavioral profile. It is of great importance to evaluate these effects in clinical practice to bring more clear insight into these positive or negative side effects of AEDs. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal infections remain a major complication in orthopedic surgery. The local delivery of antibiotics provides the high levels required to treat an infection without systemic toxicity. However, the local toxicity of antibiotic carriers to the mesenchymal stem cells, as a result of both the peak concentrations and the type of carrier, may be significant.Methods: To address this concern, the elution kinetics of vancomycin and gentamicin from several commercially available antibiotic carriers and several carriers impregnated by a surgeon (10 ml of each sterile carrier were manually mixed with a 500 mg vancomycin and an 80 mg gentamicin solution, and the duration of impregnation was 30 min) were assessed. Moreover, the effects of these antibiotic carriers on stem cell proliferation were investigated. The following two types of stem cells were used: bone marrow and dental pulp stem cells.Results: The high eluted initial concentrations from antibiotic impregnated cancellous allogeneic bone grafts (which may be increased with the addition of fibrin glue) did not adversely affect stem cell proliferation. Moreover, an increased dental pulp stem cell proliferation rate in the presence of antibiotics was identified. In contrast to allogeneic bone grafts, a significant amount of antibiotics remained in the cement. Despite the favorable elution kinetics, the calcium carriers, bovine collagen carrier and freeze-dried bone exhibited decreased stem cell proliferation activity even in lower antibiotic concentrations compared with an allogeneic graft.Conclusions: This study demonstrated the benefits of antibiotic impregnated cancellous allogeneic bone grafts versus other carriers. [ABSTRACT FROM AUTHOR]

Aims. While most antiepileptic drugs (AEDs) have been associated with various adverse effects on bone health, for the recently introduced lacosamide (LCM) no corresponding data have been published. The present study evaluates the effect of LCM on bone mineral density, bone turnover markers, and bone mechanical strength in a rat model. Methods. 16 orchidectomized Wistar rats were divided into control and experimental groups, 8 rats each. Dual energy X-ray absorptiometry was used to measure bone mineral density (BMD). As bone metabolism markers, the concentrations of bone markers were assayed in bone homogenate. In addition, both femurs were measured and used for biomechanical testing. Results. Compared to the control group, we found lower BMD in the experimental group in the area of the left (8%) as well as the right femur (12%), all differences being statistically significant. In both femur diaphyses, but not in lumbar vertebrae, BMD was lower in the LCM group, suggesting a preferential effect on cortical bone. However, neither the thickness of the diaphyseal cortical bone nor the fragility in biomechanical testing was different between the groups. Of the bone metabolism markers, the significant decline was in procollagen type I N-terminal peptide (PINP) levels (37.4%), suggesting a decrease in osteoid synthesis. Conclusion: We assume then that long-lasting exposure to LCM can represent a certain risk to the health of bone in the setting of gonadal insufficiency. Further studies will be needed to confirm these findings and to determine how high the risk will be in comparison to the other AEDs. [ABSTRACT FROM AUTHOR]

This multicentre study focused on monitoring imatinib mesylate (IMA) trough plasma (Ctrough) and intracellular (IMA Cintrac) concentrations in 228 chronic myelogenous leukaemia patients. The median of measured IMA Ctrough in our patient group was 905.8 ng ml (range: 27.7-4628.1 ng/ml). We found a correlation between IMA Ctrough and alpha 1-acid glycoprotein plasma concentrations ( rS = 0.42; p < 0.001). All other analysed parameters revealed only weak (gender, dose of IMA per kg) or not significant (age, albumin, creatinine plasma concentration or body mass index) impact on measured IMA Ctrough. The IMA Ctrough decreased during the first 6 months and significantly increased later during treatment. The IMA Ctrough at the first month of therapy did not differ between patients with and without an optimal response at the 12th ( p = 0.724) and 18th month ( p = 0.135) of therapy. There were no significant differences in medians of IMA Ctrough between both groups measured during the first year of treatment. The IMA Cintrac during the first month were not different between patients with and without an optimal response at the 6th ( p = 0.273) and the 12th month ( p = 0.193) of therapy. Our data obtained from real life clinical practice did not find a benefit of routine and regular IMA Ctrough nor IMA Cintrac therapeutic drug monitoring in chronic myelogenous leukaemia patients or for subsequent adjustments of the IMA dose based on these results. Moreover, actual alpha 1-acid glycoprotein plasma concentration should be used for proper interpretation of IMA Ctrough results. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Warfarin is a well-known anticoagulant agent that occurs in two enantiomers, (R)-(+)-warfarin and (S)-(−)-warfarin. A new liquid chromatography method for the determination of both enantiomers was developed, validated and applied in in vitro studies with the aim of evaluating the accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line. OptiMEM cell cultivation medium samples and cellular lysates were purified using Waters Oasis® MAX extraction cartridges. The chiral separation of warfarin and the internal standard p-chlorowarfarin enantiomers was performed on an Astec Chirobiotic™ V2 column at a flow rate of 1.2mL/min. The mobile phase was composed of 31% acetonitrile, 5% of methanol and 64% of ammonium acetate buffer (10mmol/L, pH 4.1). The enantiomers were quantified using a fluorescence detector (λ excit =320nm, λ emiss =415nm). The limit of detection was found to be 0.121μmol/L of (S)-warfarin and 0.109μmol/L of (R)-warfarin. The range of applicability and linearity was estimated from 0.25 to 100μmol/L. The precision ranged from 1.3% to 12.2% of the relative standard deviation, and the accuracy reached acceptable values from 95.5% to 108.4%. The new bioanalytical method confirmed the same accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line. [Copyright &y& Elsevier]

Background and Aims: Coffee irritates the gastric mucosa disrupting its barrier and increasing the risk of peptic ulcers. However, caffeine's contribution to these effects has not yet been elucidated. In this study we looked at the local effect of caffeine on the microcirculation and nitric oxide production in rats together with systemic marker of oxidative stress malondialdehyde as possible mechanisms whereby caffeine might participate in mucosal barrier impairment. Materials and Methods: Four groups of rats were anesthetized and administered as a bolus four diff erent intraperitoneal doses of caffeine (0, 1, 10 and 50 mg kg-1 b.wt.). The gastric submucosal microcirculation and nitric oxide production were then recorded for 2.5 hours by in situ microdialysis using the flow marker ethanol. At the completion of the experiments, plasma caffeine and malondialdehyde levels as well as morphological mucosal injury were determined. Results: There were no major differences in the macro- or microscopic pictures of the mucosa among the groups. Local microcirculatory (ethanol out/in ratio) and nitric oxide monitoring failed to demonstrate statistically significant changes as did measurement of plasma malondialdehyde in response to caffeine injections. Conclusions: Caffeine perse seems unlikely to contribute to the gastric mucosal barrier injury associated with coffee consumption by alterations in nutritive blood flow, nitric oxide production or aggravation of systemic oxidative stress. This information is relevant for better understanding of the mechanisms involved in caffeine-mediated influences on gastric physiology in relation to the irritant effects of coffee. [ABSTRACT FROM AUTHOR]

Aim: Surgical-site infections are very serious complications of cardiac operations. Use of cardiopulmonary bypass (CPB) is associated with profound physiological changes, which affects the pharmacokinetic behaviour of prophylactic antibiotics. The aim of this study was to monitor tissue concentrations of cefuroxime in peripheral tissue (skeletal muscle) during cardiac surgery using CPB by means of a microdialysis. Methods: Eleven adult patients operated on using CPB were included in the study. Cefuroxime was the prophylactic antibiotic and study drug given. Microdialysis was performed by probe CMA 60 inserted into the patient's left deltoid muscle. Samples of dialysates were collected at intervals: before CPB, each 30 minutes of CPB and at the end of CPB. Samples of blood were collected at intervals: incision, start of CPB, each 30 minutes of CPB, at the end of CPB and at the end of surgery. Results: The mean (± S.D.) concentrations of cefuroxime in peripheral tissue were 105.4±41.1, 81.7±32.8, 74.6±26.0, 70.4±34.7, 60.5±27.2, 138.0±42.6 (mg 1-1). Total plasma concentrations of cefuroxime were 154.4±41.6, 73.3±20.7, 67.1±20.4, 59.2±21.0, 49.0±16.4, 110.9±33.6 (mg 1-1) and concentrations of free plasma fraction were 110.7±37.1, 62.2±18.8, 58.9±18.6, 48.4±16.6, 41.7±15.6, 97.6±28.6 (mg 1-1). The plasma and tissue concentrations exceed throughout the operation time the minimum inhibitory concentration for most common suspected pathogens in cardiac surgery. Conclusions: Results show that CPB can modify the time course of cefuroxime tissue and plasma concentrations. Microdialysis is suitable for antibiotic tissue measurement in cardiac surgery. [ABSTRACT FROM AUTHOR]