Search

Lejla Burnazovic-Ristic,1 Andrea Todic,2 Sanita Maleskic Kapo,1 Jasna Kusturica,1 Aida Kulo Cesic,1 Svjetlana Loga-Zec,1 Izeta Aganovic-Musinovic,3 Maida Rakanovic-Todic1 1Department of Pharmacology and Toxicology, Medical Faculty University of Sarajevo, Sarajevo, Bosnia and Herzegovina; 2Sendcloud B.V., Eindhoven, the Netherlands; 3Immunology Department, Medical Faculty University of Sarajevo, Sarajevo, Bosnia and HerzegovinaCorrespondence: Sanita Maleskic Kapo, Department of Pharmacology and Toxicology, Medical Faculty University of Sarajevo, Sarajevo, Bosnia and Herzegovina, Tel +387 61 394 144, Email sanita.maleskic@mf.unsa.baPurpose: Educational interventions have already been shown to positively affect awareness of clinical trials (CTs) among medical students. We aimed to explore basic knowledge and attitudes about CTs among medical students in terms of educational interventions that should be reflected in their further involvement in performing CTs and their role in raising awareness about CTs.Methods: This cross-sectional, self-report anonymous online survey involved undergraduate medical students of the Medical Faculty University of Sarajevo enrolled in classes held within the Department of Pharmacology and Toxicology in the academic year 2015– 2016. To include all accessible subjects for better representation of the whole population, consecutive sampling was applied.Results: Among 142 students who completed questionnaire, 50% of them expressed partial or full agreement with the questionnaire statement that they were satisfied with the available information on CTs. Only 38% said they would participate in a CT, 21% would not, while 41% were not sure. Positive correlations were detected for composite subscale scores of agreement with questionnaire statements conveying the student’s knowledge about ethical and legal aspects of CTs and their perception about reliability/integrity and impact of CTs on medical practice.Conclusion: Students have knowledge of the basic design and ethical aspects of CTs. Positive attitudes toward the impact of CTs on medical practice were shown in students of higher years of study, where educational intervention of additional knowledge of CTs was inserted and those students expressed better knowledge of CTs. However, no significant impact was detected between knowledge and willingness to participate in CTs, irrespective of years of study, reflecting the third of students that would participate in CTs. Changes in medical curricula led to the change in students’ knowledge and attitudes regarding CTs as well as their involvement in CTs.Keywords: students, knowledge, education, questionnaire, intervention

Background Vaccination coverage in Bosnia and Herzegovina has been declining over recent years. A World Health Organization Tailoring Immunization Programmes (TIP) project is underway to gain insights into the underlying reasons for this, to develop tailored interventions. As part of TIP, this study aimed to investigate the views of health workers on their barriers and drivers to positive childhood vaccination practices. Methods Face-to-face qualitative interviews explored 38 health workers’ views on vaccination coverage, their vaccination attitudes, and system, programme and institutional influences on their vaccination practices. The data were analysed using content analysis and organised by the COM (Capability, Opportunity and Motivation) factors. Findings Very few differences in barriers and drivers were evident between high and low coverage primary care centres or across different professional roles. Capability: Drivers included awareness of the risks of low vaccination coverage, regular use of the Rulebook and Order, knowledge of how to advise parents on mild side effects and recognition of the importance of good communication with parents. Key barriers were the use of false contraindications to postpone vacination and poor skills in tailoring communication with parents. Opportunity: Drivers were sufficient time for adminstering vaccination and good availability of vaccines. Several barriers were evident: lack of implementation of mandatory vaccination, no uniform recall and reminder system or system for detecting under-vaccinated children, staff shortages and lack of time to discuss vaccination with parents. Motivation: Drivers were a belief in the value, safety and effectiveness of vaccination and seeing that they have an important role to play. Barriers were a tendency to blame external factors e.g. anti-vax movement and a fear of being blamed for adverse events. Conclusions The study identified complex and inter-related barriers and drivers to health worker positive vaccination practices. These insights will now inform a process to identify and prioritize interventions.

Introduction: Although many predictive tools have already been developed, efforts are still proceeding to identify a reliable biomarker to predict the prognosis of the patients with acute heart disorders. Objectives: The aim was to evaluate the role of renal injury biomarkers (serum cystatin C, serum and urine interleukin-18, IL-18) and heart failure biomarkers (plasma B-type natriuretic peptide, BNP) in the prediction of the postdischarge requirement of renal replacement therapy (RRT) and/or 6-month mortality in patients with acute heart disorders. Patients and Methods: In patients diagnosed with acute heart disorders (acute heart failure [AHF] and/or acute coronary syndrome [ACS]) and admitted to the intensive care units, baseline clinical parameters, renal and cardiac biomarkers were determined. Patients were followed up for 6 months. The composite outcome was the postdischarge requirement of RRT and/or 6-month mortality. Results: Of 120 patients, 5.8% continued RRT after discharge. The 6-month mortality was 20%. Cox logistic regression analysis showed that urine IL-18 (P=0.021), plasma BNP (P=0.046), Acute Physiology and Chronic Health Evaluation (APACHE) II score (P=0.002), and left ventricular diastolic dysfunction (P=0.045) were independent predictors of the postdischarge requirement of RRT and/or 6-month mortality. For predicting RRT and/or 6-month mortality, using urine IL-18 cutoff value of 29.1 pg/mL showed 66.7% sensitivity and 67.7% specificity (area under the curve, AUC 0.70, P=0.003), while using plasma BNP cutoff value of 881.6 pg/mL showed 66.7% sensitivity and 70.8% specificity (AUC 0.76, PConclusion: Urine IL-18 and plasma BNP are independently predictive for the postdischarge requirement of RRT and/or 6-month mortality in patients with acute heart disorders.

Vaccination coverage in the Federation of Bosnia and Herzegovina, in Bosnia and Herzegovina, has been declining since 2014. This qualitative study aimed to identify barriers and drivers to childhood vaccination for parents. The COM-B (capability-opportunity-motivation-behavior) model was the underpinning theoretical framework. Face-to-face interviews with 22 parents of fully (n = 6), delayed/partially vaccinated (n = 9) and unvaccinated (n = 7) children were conducted. Interviews explored individual factors (capability-knowledge and skills; motivation-attitudes, confidence and trust) and context factors (physical opportunity-information, access, health systems; and social opportunity - social support, norms). Data were analyzed in NVivo using content analysis exploring differences in COM factors by vaccination status and location. Parents of fully vaccinated children typically reported individual and context drivers to vaccination. They accepted vaccination, trusted health workers, and were content with services. Parents of delayed/partially vaccinated children fell into two subgroups: (1) Those who accepted vaccination and attributed delays to their organizational skills or frustration with appointment times. (2) Those fitting the profile of "vaccine hesitant" - generally valuing vaccination and health worker advice, yet with concerns often triggered by media/social media. Parents of unvaccinated children mentioned individual and context barriers to vaccination, notably significant concerns about safety, some distrust of health workers and resentment of mandatory vaccination. Urban/rural differences included urban parents being more likely to report experiences with vaccine shortages and very few had received information leaflets. The study identified complex and inter-related barriers and drivers to parents' childhood vaccination behaviors. These insights have informed the development of tailored interventions to improve coverage.

Background: Indoor air quality (IAQ) in classrooms affects children’s health and academic performance. The aim of this pilot study was to determine IAQ in elementary schools different in their internal and external characteristics, in settings of COVID-19 epidemics. Methods: IAQ parameters: fine particulate matter (PM2,5) mass concentration, CO2 concentration, temperature and relative humidity were measured in parallel in four elementary schools/classrooms during October (non-heating season) and four months (including holiday in January) of heating season. IAQ parameters were measured in settings of anti-epidemic restrictions (≤13 students in classroom, frequent ventilation). Results: During October, except in one school, PM2,5 concentrations were below the upper recommended value (25μg/m³), but started rising in all schools in the heating season. The highest concentrations of PM2,5 were registered in two schools with closed or shortly opened windows. CO2 concentrations were mostly in the recommended range (up to 1000ppm) except in the school with constantly closed windows and in three schools in February when concentrations were higher. Except in one, the same school, and in January, both temperature and relative humidity were out of the recommended range (24,0–27,0°C in non-heating; 20,0–24,0°C in heating season; and 45–55%), with temperature mainly above and relative humidity mainly below it in three schools. The largest deviation in temperature and relative humidity were registered in urban schools. Registered differences may be explained by different internal and external characteristics. Conclusion: Despite anti-epidemic restrictions, most of the measured IAQ parameters were out of the recommended values in heating season. In addition, further deterioration of IAQ could be expected if all students had been presented in the classroom. Finally, to assure a healthy school environment in heating season, further optimisation of both indoor and outdoor conditions is needed in both pandemic and non-pandemic settings.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

Aims Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4–5 months postpartum, and males and nonpregnant females. Methods Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4–5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. Results For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. Conclusions Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

Objective. The aim of this study was to assess the re­lationship between the use of neuroenhancing sub­stances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) uni­versity students. Methods. In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, con­sumption of neuroenchancing substances, the West­side Test Anxiety Scale (WTAS) and academic perfor­mance. Results . A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the pur­pose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P

Aim In order to increase the database related to the antineoplastic potential of metformin, association between the use of metformin and risk of cancer occurence in patients with diabetes mellitus type 2 (DM2) was investigated. Methods In this cross-sectional study, medical records of patients with DM2 were reviewed for cancer occurence. Data on age, body mass index (BMI), alcohol and nicotine consumption, glucose and HbA1c levels, duration of DM2, medication used in the treatment of DM2 and cancer occurence were collected and analyzed. Unpaired Student's t-test or Mann-Whitney U test were used for comparisons between treatment groups, and logistic regression to asses how well our set of predictor variables predicts occurence of carcinoma. P-value less than 0.05 was considered statistically significant. Results The mean age of 234 included patients was 66.8±11.5 years, and DM2 duration was 7± 6.49 years. Mean glucose value was 8.51±4.17mmol/L, and HbA1c 7.74±1.53. Metformin therapy was prescribed in 190 (81%) patients. Cancer was diagnosed in 16 (6.8%) patients: prostate cancer in eight (3.4%), breast cancer in four (1.7%), rectal cancer in two (0.9%) and cancer of the uterus and cervix in one patient. Age, duration of DM2 and BMI did not contribute significantly to the model, while metformin use was shown to be a significant independent predictor (OR=0.049; 95% CI=0.013-0.181; p=0.001). Conclusion Our findings support the hypothesis that the use of metformin compared to the use of other oral antidiabetic drugs is associated with a lower risk of cancer in patients with DM2.

Aim: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. Methods: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m2) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. Results: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m2, at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). Conclusion: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers. ispartof: Bosnian Journal of Basic Medical Sciences vol:17 issue:1 pages:54-60 ispartof: location:Bosnia and Herzegovina status: published

Aminoglycosides pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed to treat neonates with (suspected) septicemia, however, none provide adjustments in the case of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations.Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published dataset, we assessed the impact of PATH on amikacin PK using population modelling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines.Amikacin clearance was decreased by 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that, increasing the dosing interval with 12 hours results in a decrease in percentage of neonates reaching toxic trough levels (> 5 mg/L) from 40-76% to 14-25%, while still reaching efficacy targets, compared to current dosing regimens.Based on this study, a 12-hour increase in amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required as their clearance may also be impaired. ispartof: Antimicrobial Agents and Chemotherapy vol:61 issue:12 ispartof: location:United States status: published

Aim A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. Methods Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10–15 weeks post-partum. Results Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h−1) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h−1), to oxidative metabolites (4.95 vs. 2.77 l h−1) and of unchanged paracetamol (1.15 vs. 0.75 l h−1). In contrast, there was no difference in clearance to paracetamol sulphate. Conclusion The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.

Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females.Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h.For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers.Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Propylene glycol is commonly used as an excipient in dose forms and is ingested by neonates when administering different drugs. • While propylene glycol is generally considered to be safe, toxic effects like bradycardia, lactic acidosis and convulsions have been reported. • Information on the pharmacokinetics of propylene glycol in neonates is lacking to provide insight into the possible risk of toxicity. WHAT THIS STUDY ADDS • This study describes the pharmacokinetics of propylene glycol in preterm and term neonates co-administered with paracetamol and phenobarbital. • A pharmacokinetic model was developed which identified birth weight and postnatal age as important covariates for clearance. • The model was used to simulate exposure to propylene glycol co-administered with both drugs. AIM Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630–3980 g, postnatal age (PNA) 1–30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24–40 weeks). RESULTS In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CLi= 0.0849 × {(bBW/2720)1.69× (PNA/3)0.201}). Volume of distribution scaled allometrically with current bodyweight (Vi= 0.967 × {(BW/2720)1.45}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33–144 and 28–218 mg l−1 (peak) and 19–109 and 6–112 mg l−1 (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.

Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported.At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30 mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5 months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy non-pregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined.Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5 months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07 L/h·m(2) respectively, P0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17 L/kg respectively, P0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP.Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830–4,200) g and a postmenstrual age (PMA) of 39 (25–45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10–0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R 2 = 0.39) had a slope significantly different from zero (p

Background The postpartum period affects drug disposition, but data of intravenous paracetamol loading dose pharmacokinetics immediately following caesarean delivery have not yet been reported. Methods Immediately following caesarean delivery, women received a 2-g loading dose of intravenous paracetamol. Plasma samples were collected at 1, 2, 4 and 6h. Individual pharmacokinetics were calculated assuming a linear one-compartment model with instantaneous input and first-order output. Data were reported using median and range. Results Twenty-eight patients undergoing caesarean delivery were recruited (age 31.5 [20–42] years, weight 79 [57–110] kg, body surface area 1.9 [1.5–2.4]m 2 ). Median paracetamol plasma concentrations after 1, 2, 4 and 6h were 22.5, 15.25, 7.9, and 3.9mg/L respectively. Paracetamol clearance was 20.3 (11.8–62.8) L/h or 10.9 (7–23.8)L/hm 2 , distribution volume 58.3 (42.9–156) L or 0.72 (0.52–1.56) L/kg. Conclusion Pharmacokinetics of intravenous paracetamol have been estimated following caesarean delivery. Although limited to a loading dose shortly after surgery, the results are clinically relevant since this is the first description in this patient population. These data provide evidence on which to base further integrated pharmacokinetic/pharmacodynamic studies in peripartum analgesia.

Pharmacokinetics is a first, but essential step to improve population-tailored postoperative analgesia, also after Caesarean delivery. We therefore aimed to quantify the impact of caesarean delivery on the pharmacokinetics of intravenous (iv) paracetamol (2 g, single dose) and iv ketorolac tromethamine (30 mg, single dose) in 2 cohorts eachof 8 women at caesarean delivery and to compare these findings with postpartum to quantify intrapatient changes. We documented a higher median paracetamol clearance at delivery when compared to 10–15 weeks postpartum (11.7 to 6.4 L/h⋅m2,P<0.01), even after correction for weight-related changes. Similar conclusions were drawn for ketorolac: median clearance was higher at delivery with a subsequent decrease (2.03 to 1.43 L/h⋅m2,P<0.05) in postpartum (17–23 weeks). These differences likely reflect pregnancy- and caesarean-delivery-related changes in drug disposition. Moreover, postpartum paracetamol clearance was significantly lower when compared to estimates published in healthy young volunteers (6.4 versus 9.6 L/h⋅m2), while this was not the case for ketorolac (1.43 versus 1.48 L/h⋅m2). This suggests that postpartum is another specific status in young women that merits focused, compound-specific pharmacokinetic evaluation.

In order to enhance the sensitivity and to develop a method suitable for quantification of propylene glycol (PG) in low volume neonate plasma and urine samples, several steps in earlier described high performance liquid chromatographic methods were optimised. Chromatographic separation on a reversed-phase column and ultraviolet detection resulted in cleaner chromatograms without interfering compounds. Linearity of the standard curves was validated in the concentration range 0.25–50 mg L−1. The lower limit of quantification was 20 times lower than in earlier described methods. Presented method was suitable for quantification of PG concentrations in low volume neonate plasma (15–46 mg L−1) and urine samples (20–175 mg L−1) enabling us to document very low renal versus non-renal contribution of PG clearance in neonates.

Intravenous paracetamol (acetaminophen) has recently been registered for treatment of pain in neonates but the pharmacodynamics, including effects on body temperature, have not been reported.A pooled analysis on body temperature recordings in neonates exposed to intravenous paracetamol was performed. Body temperature was recorded by skin probe and registered before and every 2 h following initiation of single or repeated intravenous paracetamol administration (up to 48 h). Repeated measures ANOVA and paired analysis were used to quantify differences following paracetamol exposure.The pooled analysis was based on 99 neonates (median weight 2.7 (range 0.5-5.4) kg, median postmenstrual age 37 (range 27-50) weeks). Based on observations in 93 normothermic (37.8°C) neonates and six neonates with fever, it was documented that paracetamol administration does not affect body temperature in normothermic patients. In neonates with fever, the median decrease (-0.8°C) is most prominent in the first 2 h (p0.01) following paracetamol administration with subsequent further normalisation.Administration of intravenous paracetamol does not result in hypothermia in normothermic neonates. In those with fever, maximal temperature reduction is achieved within 2 h following paracetamol administration.

Elevated plasma homocysteine (Hcy) levels have been associated with Alzheimer’s disease (AD) and cognitive impairment. Studies have shown that Hcy may have direct and indirect neurotoxicity effects. The aim of the study was to investigate serum Hcy concentration in patients with probable AD with age-matched controls and to determine whether there was an association between serum Hcy and C-reactive protein concentration in patients with probable AD. We also aimed to determine whether there was an association between serum tHcy concentration and cognitive impairment in patients with probable AD. Serum concentration of total Hcy was determined by the fluorescence polarization immunoassay on the AxSYM system, and serum C-reactive protein (CRP) concentration was determined by means of particle-enhanced immunonephelometry with the use of BN II analyzer. Cognitive impairment was tested by the MMSE score. Body mass index (BMI) was calculated for each subject included in the study. Age, systolic and diastolic blood pressure and BMI did not differ significantly between the two groups. Mean serum tHcy concentration in the control group of subjects was 12.60 μmol/L, while in patients with probable AD the mean serum tHcy concentration was significantly higher than 16.15 μmol/L (p < 0.01). A significant negative association between serum tHcy concentration and cognitive impairment tested by the MMSE score in patients with probable AD was determined (r = −0.61634; p < 0.001). Positive, although not significant correlation between CRP and serum tHcy concentrations in patients with AD, was observed. Increased tHcy concentration in patients with probable AD, and the established negative correlation between serum tHcy concentration and cognitive damage tested by MMSE score in the same group of patients, suggests the possible independent role of Hcy in the pathogenesis of AD and cognitive impairment associated with this disease.

Objective. The aim was to study the association of the use of an oral antihyperglycemic agent metformin with the presence of ocular complications in patients with type 2 diabetes (T2D). Methods. Medical records were reviewed for 234 patients with diagnosed T2D. 81.2% (n=190) patients were using metformin and 18.8% (n=44) using other oral antihyperglycemic agents. Plasma glucose concentration, glycated haemoglobin, and the presence of ocular complications in patients treated with metformin were compared to those in patients treated with other oral antihyperglycemic agents. Results. Ocular complications occurred in 65 patients (27.8%). Patients treated with metformin had fewer ocular complications compared to patients treated with other oral antihyperglycemic agents (χ2=19.985; pthe odds of both glaucoma (OR=0.14, 95% CI: 0.03-0.57, p=0.006) and diabetic retinopathy (OR=0.33, 95% CI: 0.14-0.82, p=0.017) compared with other oral antihyperglycemic agents. Conclusion. Our results suggest that metformin may have a protective effect on ocular complications, especially glaucoma, in patients with T2D. The effects of metformin either regarding prevention of ocular complications or ocular complications already developed in patients with T2D, should be further investigated.

In order to enhance the sensitivity and to develop a faster direct method for plasma and urine quantification of racemic ketorolac, its metabolites (p-hydroxy-ketorolac and ketorolac glucuronides) and ketorolac enantiomers, we developed an extraction procedure based on solid-phase extraction combined with specific and fast chromatographic separation. Extraction and chromatography resulted in cleaner chromatograms without interfering compounds. In both plasma and urine, linearity of the standard curves for racemic ketorolac and p-hydroxy-ketorolac was validated in the concentration range 0.025-10 mg L -1, while for ketorolac enantiomers in the concentration range 0.025-5 mg L-1. The lower limit of quantification was two times lower than in earlier described methods. The developed method was suitable for direct quantification of racemic ketorolac, p-hydroxy-ketorolac and ketorolac enantiomers in plasma and urine samples in women at delivery and in postpartum, enabling us to document significant intra-individual differences in pharmacokinetics between these physiological states. © 2014 Springer-Verlag. ispartof: Chromatographia vol:77 issue:3 pages:803-812 status: published

ispartof: Journal of Anaesthesiology, Clinical Pharmacology vol:28 issue:3 pages:409-410 ispartof: location:India status: published

CONTEXT Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. OBJECTIVES To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. DESIGN Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. SETTING Single, tertiary perinatal care centre. PATIENTS Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one-compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). MAIN OUTCOME MEASURES Individual paracetamol pharmacokinetics. RESULTS Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12

To analyze the usefulness of specified immunological parameters, proinflammatory IL-1α and profibrogenic, antiinflammatory TGF-β1, along with routinely used laboratory tests, in the differential - diagnostic procedure of chronic hepatitis of infectious and noninfectious etiology.A total of 150 subjects were divided into two groups, depending on the infectious or noninfectious etiology of liver damage, and the control group. Apart from standard laboratory tests, the analysis included serum levels of cytokines: IL-1α and TGF-β1.A high degree of correlation of serum level of IL-1α with viral hepatitis has been found, especially with active replication of genetic material ( HBV-DNA or HCV-RNA-PCR positive), p less 0.01. The highest mean concentration of TGF-β1 was noted in the group of malignant and toxic hepatitis, p less 0.0001. A negative correlation between the concentration of IL-1α and TGF-β1 has been found (-0.18). For IL-1 α significant predictive parameters included a previous infection of hepatitis B, lower serum level of TGFβ, age, use of alcohol, lower MELD and Chilld-Pugh scores. For TGF-β1 significant predictive parameters were age, lower MELD and Child-Pugh scores, history of receiving transfusions, lower serum level of IL-1α, higher serum level of fibrinogen. A predictive model has been delivered MELD = (TGF-β1) x 0,001- (IL-1 α) x 0,085 + CTP x 1,771-2,052; ( ± 2.04, R2=0,61; p less 0,001).Inflammatory and immune parameters, analyzed together could significantly contribute to the understanding of chronic liver damage and thus differential diagnostic procedure. IL-1α and TGF-β1 are important parameters of inflammatory activity and fibrosis evaluation in chronic liver damage.

Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates.A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24-40 weeks).In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL(i) = 0.0849 × {(bBW/2720)(1.69) × (PNA/3)(0.201)}). Volume of distribution scaled allometrically with current bodyweight (V(i) = 0.967 × {(BW/2720)(1.45)}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33-144 and 28-218 mg l(-1) (peak) and 19-109 and 6-112 mg l(-1) (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates.A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA.

Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery (n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p-hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) (p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60–45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62–73 %, p = 0.015) while the portion retrieved as p-hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38–28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p-hydroxy-ketorolac, reflecting increased oxidation activity.