Propylene glycol (PG) is an unintentional frequently co-administered solvent together with a therapeutic compound, despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. By their nature, newborns are expected to have ‘physiological’ impaired hepatic and renal elimination capacity. Focused studies in neonates should enable us to unveil data on PG clearance and tolerance in this population. In consecutive steps, we documented PG disposition following iv administration of PG and renal PG elimination in neonates, and compared these findings with observations in adults. Finally, we documented aspects of tolerance of PG in neonates. The data on PG disposition and tolerance suggest that there is a lower limit of safe short term exposure to PG in neonates. Such a safer level of exposure should finally be based on clearance estimates and level of tolerated exposure. Besides the compound specific observations, we illustrated that it is feasible and possible to prospectively assess aspects of disposition and tolerance of solvents in neonates. Key-Words: formulation – propylene glycol – newborn – maturation – developmental toxicology

AIM To compare two schedules (continuous infusion or bolus i.v. of PPI) in treatment after endoscopic homeostasis of bleeding ulcers. METHODS Patients with gastrointestinal bleeding caused by peptic ulcer, or a recent history (< 24 h before presentation) were included in the study. All cases with actively bleeding ulcers were treated with epinephrine injection and/or thermal coagulation, and randomized to receive intravenous PPIs according to the continuous regimen (in continuous infusion) or the standard regimen (40 mg bolus twice a day for 3 days). RESULTS 69 patients were treated. Bleeding recurred in 5 of 34 patients (14.7%) receiving the intensive regimen, and in 8 of 35 (22.8%) patients receiving the standard regimen. Hemoglobine rate in standard regimen group was 93,5 g/L (SD 23,8), and in intensive regimen group 106,6 g/L (SD 22,4) (p = 0.042). Total protein rate in the standard regimen group was 65,1 g/L (SD 7,3) and in the intensive regimen group 67,7 g/L (SD 8,15), (p = 0.525). Albumin rate in the standard regimen group was 31,0 g/L (SD 5,2), whereas in the intensive regimen group it was 34,8 g/L (SD 7,4), (p = 0.652). Globulin rate in the standard regimen group was 31,0 g/L (SD 5,2) and in the intensive regimen group 32,3 g/L (5,3), (p = 0.875). Fibrinogen rate in the standard regimen group was 11,1 (SD 2,6) and 10,8 g/L (SD 2,4 p = 0.622) in the intensive regimen group. A mean number of units of blood transfusion for patients in the intensive group was 2,18 (SD 0,8) and 1,34 (SD 1,02) in the standard group, with statistical level of difference p = 0.0004, using Student t-test. The duration of hospital stay was 6,4 days (SD 2,8) in the standard group and 5,8 days (SD 2,8) in the intensive group (p = 0.40). There were fewer surgical interventions in the intensive versus standard regimen. CONCLUSION In patients with bleeding peptic ulcers with successful endoscopic hemostasis the standard IPP regimen had advantage for transfusion requirements, but no advantage with respect to in-hospital rates of re-bleeding, need for surgery, length of hospital stay, or death.

AIM To evaluate differences in the treatment quality between often used oral anticoagulants, warfarin and acenocoumarol in patients with nonvalvular atrial fibrillation (NVAF). METHODS This was an observational, comparative, one-year clinical study, conducted in the Blood Transfusion Institute of Sarajevo, Bosnia & Herzegovina. All patients who were using warfarin/ acenocoumarol and monitored were eligible. Patients who met inclusion criteria (the age of 40-80, diagnosed NVAF, CHADS index score > or = 2, the planned long-term treatment) were includes in two parallel groups of 60 patients, composed according to the warfarin/acenocoumarol treatment as well as the gender and age. Routinely measured International normalised ratio (INR) values were the basic parameter for individual quality and stability assessment. RESULTS All average, monthly INR values were in therapeutic range (2.0-3.0) in both therapeutic groups. There were no significant differences either in the number of therapeutic INR values per patient (50.53 +/- 23.72% vs. 51.74 +/- 26.68%, P = 0.795) or in individual quality of treatment: > 50% therapeutic INR values (60.0% vs. 64.9%, P = 0.721) and > 75% therapeutic INR values (18.3% vs. 22.8%, P = 0.714) in the warfarin and acenocoumarol group, respectively. Significantly better stability was determined for acenocoumarol as compared with warfarin treatment in terms of a longer period of the total observed time during which therapeutic INR values were stable (37.6% vs. 35.7%, P = 0.0002). CONCLUSION Both drugs have shown similar quality of individual anticoagulation control, but acenocoumarol have shown significantly better anticoagulation stability with therapeutic INR values covering significantly longer time of treatment.

Introduction Intravenous paracetamol (actaminophen) has recently been registered for treatment of pain in neonates but the pharmacodynamics, including effects on body temperature, have not been reported. Methods 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. Results 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 (p<0.01) following paracetamol administration with subsequent further normalisation. Conclusions 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.

Introduction Propylene glycol (PG) is an unintentional frequently administered solvent in neonates despite the fact that PG accumulation potentially results in hyperosmolarity, lactic acidosis and renal/hepatic toxicity. Methods Prospective evaluation of renal (diuresis, creatinaemia, sodium), metabolic (base excess, anion gap, lactate, bicarbonate) and hepatic (alanine transaminase, aspartate aminotransferase, direct bilirubinaemia) tolerance to PG in (pre)term neonates following intravenous administration of formulations (paracetamol, phenobarbital, digoxin) that contain PG. Observations from 48 h before up to 48 after the last PG administration were described and compared (paired analysis). Clinical characteristics and observations collected following intravenous PG-paracetamol administration were compared with a historical cohort of neonates in whom similar (renal, hepatic) observations during exposure to a mannitol-containing paracetamol formulation were collected. Results 5566 observations were collected in 69 neonates before, during and following median PG exposure of 34 mg/kg/24 h (range 14–252). Progressive postnatal adaptation in renal, metabolic and hepatic function was documented, unrelated to the PG exposure. In the subgroup of 40 cases treated with intravenous PG-paracetamol, observations on renal and hepatic function were similar to a historical cohort of published observations following exposure to intravenous mannitol-paracetamol. Conclusions Unintended PG administration (34 mg/kg/24 h) for a maximum of 48 h seems to be tolerated in (pre)term neonates and does not affect short-term postnatal adaptations. Further studies on PG disposition and the level of safe exposure to PG, including long-term safety data in neonates are needed.

Due to heightened risk for thromboembolic complications, nonvalvular atrial fibrillation (NVAF) presents an absolute indication for long-term oral anticoagulation therapy. This was an observational, analytical, randomised, one-year clinical study, conducted in the Blood Transfusion Institute Sarajevo, Bosnia & Herzegovina. The aim of this study was to present the oral anticoagulation treatment in terms of International normalised ratio (INR) monitoring and warfarin/acenocoumarol dose titration in 117 patients with NVAF. INR values, the doses of warfarin and acenocoumarol, as well as the tendency and adequacy of their changes were monitored. Percentages of the therapeutic INR values were 51,77% and 53,62%, subtherapeutic 42,84% and 35,86%, and supratherapeutic 5,39% and 10,53% for the warfarin and acenocoumarol treatment, respectively. The average total weekly doses (TWD) which most frequently achieved the therapeutic INR values were 27,89+/-12,34 mg and 20,44+/-9,94 mg, for warfarin and acenocoumarol, respectively. The dose changes with the INR values 1,7 or lower/3,3 or higher were omitted in 13,46% and 15,63%, and with the INR values 1,8-3,2 were noted in 8,62% and 13,48% of all the check-up visits in the warfarin and acenocoumarol group, respectively. The annual dose changes were noted in 24,65% and 31,41%, and the daily dose changes in 74,43% and 73,36% of all the check-up visits of warfarin and acenocoumarol group, respectively. We can conclude that the management of the oral anticoagulation treatment in our country is in accordance with the relevant recommendations, but with the present tendency toward underdosing and unnecessary frequent dose changing.