Essential medicines containing ethanol elevate blood acetaldehyde concentrations in neonates.

UNLABELLED: Neonates administered ethanol-containing medicines are potentially at risk of dose-dependent injury through exposure to ethanol and its metabolite, acetaldehyde. Here, we determine blood ethanol and acetaldehyde concentrations in 49 preterm infants (median birth weight = 1190 g) dosed with iron or furosemide, medicines that contain different amounts of ethanol, and in 11 control group infants (median birth weight = 1920 g) who were not on any medications. Median ethanol concentrations in neonates administered iron or furosemide were 0.33 (range = 0-4.92) mg/L, 0.39 (range = 0-72.77) mg/L and in control group infants were 0.15 (range = 0.03-5.4) mg/L. Median acetaldehyde concentrations in neonates administered iron or furosemide were 0.16 (range = 0-8.89) mg/L, 0.21 (range = 0-2.43) mg/L and in control group infants were 0.01 (range = 0-0.14) mg/L. There was no discernible relationship between blood ethanol or acetaldehyde concentrations and time after medication dose. CONCLUSION: Although infants dosed with iron or furosemide had low blood ethanol concentrations, blood acetaldehyde concentrations were consistent with moderate alcohol exposure. The data suggest the need to account for the effects of acetaldehyde in the benefit-risk analysis of administering ethanol-containing medicines to neonates. WHAT IS KNOWN: • Neonates are commonly treated with ethanol-containing medicines, such as iron and furosemide. • However, there is no data on whether this leads to appreciable increases in blood concentrations of ethanol or its metabolite, acetaldehyde. What is New: • In this study, we find low blood ethanol concentrations in neonates administered iron and/or furosemide but markedly elevated blood acetaldehyde concentrations in some infants receiving these medicines. • Our data suggest that ethanol in drugs may cause elevation of blood acetaldehyde, a potentially toxic metabolite.

An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Enteral absorption and haemodynamic response of clonidine in infants post-cardiac surgery.

BACKGROUND: Clonidine is a useful analgesic-sedative agent; however, few data exist regarding its use in infants after congenital heart disease surgery. We thus aimed to assess the absorption and safety of enterally administered clonidine in this setting. METHODS: Sixteen infants (median age 6.7 months) received a single nasogastric dose of 3 µg kg(-1) clonidine 2-6 h after surgery. Blood samples were obtained at seven time intervals (up to 480 min). Plasma concentration profiles were obtained, and then pooled with a previous study (137 samples, 30 infants) for estimation of population pharmacokinetic parameters (NONMEM version 7.2). RESULTS: Enteral absorption showed considerable inter-individual variability, with clonidine Cmax ranging from 0.15 to 1.55 ng ml(-1) (median 0.73), and Tmax from 12 to 478 min (median 190). Although therapeutic sedative plasma concentrations were achieved in 94% of patients, only half had attained this by 70 min post-dose. Patients who did not receive inotropes exhibited a positive association between cumulative morphine dose and Tmax (interaction effect P=0.03); this was not seen among those receiving inotropes. The haemodynamic profile was favourable; few patients required fluid boluses, and this bore no relationship to plasma clonidine concentration. Population pharmacokinetic parameter estimation yielded results similar to previous paediatric studies: clearance 13.7 litre h(-1) 70 kg(-1) and Vd 181 litre 70 kg(-1). CONCLUSIONS: Early postoperative enteral clonidine produces favourable haemodynamic profiles and therapeutic plasma concentrations in the majority of cardiac surgical infants; however, the time to achieve this can be erratic. Thus, parenteral administration may be preferable if rapid analgo-sedative effects are needed.

Ceftriaxone pharmacokinetic properties during continuous veno-veno haemofiltration using an in vitro adult, paediatric and neonatal model.

During continuous venoveno haemofiltration (CVVH), extracorporeal drug clearance is dependant on blood flow, ultrafiltration rate, albumin binding, and the drug's molecular weight and volume of distribution. Drug doses are adjusted assuming reduced drug clearance by the renal system and CVVH. High volume haemofiltration, pre-dilution and different filter membranes can greatly alter drug clearance. Consequently, assessing the adequacy of cephalosporin dosing during CVVH is complex; under- or overdosing may occur. We studied the pharmacokinetic properties of ceftriaxone during CVVH in vitro. Renaflow filters were used to model 6, 20 and 50 kg patients. Each circuit and reservoir was prepared with a known volume of Hartmann's solution, human albumin solution 4.5% or blood. Pump speed and exchange rate were standardised for weight. Haemosol BO was used as the replacement fluid with 70% pre-dilution. Following paired sampling from the circuit and ultrafiltrate fluid, ceftriaxone was injected into the circuit. Paired samples were taken up to 720 minutes. Ceftraxione concentrations were determined using high performance liquid chromatography (HPLC). Maximum circuit concentrations (Cmax) at 2 minutes for albumin were 3.5, 2.65 and 4.85 mg/l, for blood were 4.5, 6.5 and 5.55 mg/l and for Hartmann's were 1.65, 2.95 and 3.65 mg/l for 6 kg, 20 kg and 50 kg models. The sieving coefficients (Sc) from blood (ratio of mean concentrations in the ultrafiltrate/circuits samples) were 0.31 and 0.51 with T1/2 (the half life) 62 and 20 minutes in the 6 kg and the 20 kg circuits, respectively. The data suggest in an in vitro model of ceftriaxone is rapidly cleared during CVVH. Albumin circuits had the lowest Sc and longest terminal T1/2, reflecting protein binding of the drug and suggest ceftriaxone clearance may be more rapid in hypoalbuminaemic patients. The Cmax was lower in the Hartmann circuits, possibly reflecting precipitation of the drug with calcium in this solution.

Dosing dilemmas in obese children.

With the epidemic of childhood obesity, it is not uncommon for prescribers to puzzle over an appropriate drug dose for an obese child. Defining the optimum therapeutic dose of a drug relies on an understanding of pharmacokinetics and pharmacodynamics. Both these processes can be affected by body composition and the physiological changes that occur in obese children. As a rule of thumb, 75% of excess weight in obese subjects is fat mass, and the remainder lean mass. Although it is reasonable to assume that increases in fat mass alter the distribution of lipophilic drugs and increases in lean mass alter drug clearance, good quality and consistent clinical data supporting these assumptions are lacking for the majority of drugs. The relatively few clinical studies that have evaluated the impact of obesity have often been limited by poor design and insufficient sample size. Moreover, clinical studies conducted during drug development rarely include (or are required to include) obese subjects. Guidance on dosing obese children ought to be provided by drug manufacturers. This could be achieved by including obese patients in studies where possible, enabling the effect of body size on pharmacotherapy to be evaluated. This approach could be further augmented by the use of physiologically based-pharmacokinetic models during early (preclinical) development to predict the impact of obesity on drug disposition, and subsequent clinical studies later in development to provide confirmatory proof. In the meantime, for the majority of drugs already prescribed in children, particularly those where the therapeutic range is narrow or there is significant toxicity, the lack of a validated body size descriptor to use at the bedside means the choice of dose will rely on empirical experience and application of the precautionary principle.

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature.

BACKGROUND: Sepsis is common in neonates and a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic during the first week of life, with penicillins being the most frequently administered antibiotics. The clearance (Cl), serum half-life (t((1/2))) and volume of distribution (Vd) of penicillins are different in the neonate than in the adult. As such, the pharmacokinetics of penicillins need be studied in neonates in order to optimise therapy in this age class with these drugs. OBJECTIVES: The aim of this study was to review the published data on the pharmacokinetics of penicillins in the neonate in order to provide a critical analysis of the literature and, consequently, a useful tool in the hands of the physician. METHODS: The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines. An initial search was performed with the keywords "pharmacokinetics", "penicillins" and "neonates". Secondly, other searches were performed using the keywords "pharmacokinetics" and "neonates", followed by the name of a single antibiotic. The search included articles up to 2007. RESULTS: There have been few pharmacokinetic studies on the use of penicillins in neonates. The results from those few studies that have been carried out suggest that the Cl is reduced and t((1/2)) prolonged in the neonate as compared with the more mature infant. There is little variation in Vd during the first week of life. In the premature neonate, Cl is reduced compared to the full-term infant. As postnatal age proceeds, the Cl of penicillins increases. CONCLUSIONS: More pharmacokinetic studies are required to provide a sound scientific basis for planning a dosage regimen with penicillins in the neonate.

Association of acanthosis nigricans with risk of diabetes mellitus, and hormonal disturbances in arabian females: case-control study.

OBJECTIVE: To aim of the present study is to determine the association of acanthosis nigricans(AN) with risk of diabetes mellitus, and hormonal levels in female subjects from the United Arab Emirates (UAE). DESIGN: Matched case-control study. SETTING: Tawam Teaching Hospital of Faculty of Medicine and Health Sciences. SUBJECTS: 184 female subjects (92 females with AN and 92 females without AN); (age range 16-65 years) were recruited. METHODS: Height, weight, and sitting blood pressure were recorded on 184 female subjects with AN and without AN. Fasting blood samples were obtained for measurement of uric acid, glucose, cholesterol, HDL-cholesterol, and triglyceride levels. MAIN OUTCOME MEASURE: Risk factors were investigated. Analysis was based on univariate and multivariate analysis. RESULTS: The present study showed that BMI, family history of DM, fasting glucose, HDL-cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significantly higher in obese women in acanthosis and non acanthosis groups. The results revealed that BMI, family history of DM, total cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significant higher in diabetic women in non-acanthosis. Furthermore, systolic blood pressure, total cholesterol (mmol/l), triglycerides (mmol/l) and uric acid (mmol/l) levels were statistically significantly higher in diabetic women in acanthosis groups. Overall, DM subjects had significantly higher values for hormone levels of TSH, FSH, LH, progesterone, testosterone, cortisol, prolactin, GH, and ferritin. CONCLUSION: The conclusion has been stated as follows: patients in the UAE who have AN have a high prevalence of DM and insulin resistance. Since AN is rather prevalent in the UAE, identifying this skin lesion can help detect those subjects with a higher risk of DM and hormonal disturbances.

Intravenous salbutamol for childhood asthma: evidence-based medicine?

Intravenous salbutamol is commonly used to treat children with severe asthma unresponsive to inhaled ß2-agonist therapy. However, in this setting, there is little clinical trial data demonstrating its effectiveness. Additionally, there are significant concerns that intravenous salbutamol-dosing recommendations for children with acute asthma are excessive, and unnecessarily raise the potential for adverse reactions, such as lactic acidosis and tachycardia which, by increasing respiratory workload, exacerbate respiratory failure. Here, we review salbutamol clinical pharmacology and toxicology, evidence relating to its use in acute asthma and highlight gaps in the evidence base.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support.

Extracorporeal membrane oxygenation (ECMO) is known to affect pharmacokinetics and hence optimum dosing. The aim of this open label, prospective study was to investigate the pharmacokinetics of oseltamivir (prodrug) and oseltamivir carboxylate (active metabolite) during ECMO. Fourteen adult patients with suspected or confirmed H1N1 influenza were enrolled in the study. Oseltamivir 75 mg was enterally administered twice daily and blood samples for pharmacokinetic assessment were taken on day 1 and 5. A multi-compartmental model to describe the pharmacokinetics of oseltamivir and oseltamivir carboxylate was developed using a non-linear mixed effects modelling approach. The median (range) clearance of oseltamivir carboxylate was 15.8 (4.8-36.6) l/hour, lower than the reported mean value of 21.5 l/hour in healthy adults. The median (range) steady state volume of distribution of oseltamivir carboxylate was 179 (61-436) litres, much greater than healthy adults but similar to previous reports in critically ill patients. Substantial 'between subject' variability in systemic exposure to oseltamivir carboxylate was revealed; median (range) area under the curve and Cmax were 4346 (644-13660) ng/hour/ml and 509 (54-1277) ng/ml, respectively. Both area under the curve and Cmax were significantly correlated with serum creatinine (r2=0.37, P=0.02 and r2=0.29, P=0.02, respectively). Systemic exposure to oseltamivir carboxylate following the administration of enteral oseltamivir 75 mg twice daily in adult ECMO patients is comparable to those in ambulatory patients and far in excess of concentrations required to maximally inhibit neuraminidase activity of the H1N1 virus. Dosage adjustment for ECMO, per se, appears not to be necessary; however, doses should be reduced in patients with renal dysfunction.

Assessment of liquid captopril formulations used in children.

OBJECTIVE: Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form. DESIGN: An open label, single dose, three-treatment, three-period, crossover trial. SETTING: Outpatient. PATIENTS: Healthy adult volunteers (n=18). INTERVENTIONS: Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose. MAIN OUTCOME MEASURES: Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of C(max) (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25 RESULTS: Both liquid formulations failed the bioequivalence assessment with respect to C(max) and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both C(max) and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in C(max) (97.5%) and AUC (78.5%). CONCLUSIONS: Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.

Toxic additives in medication for preterm infants.

BACKGROUND: Little is known about exposure of preterm infants to excipients during routine clinical care. OBJECTIVE: To document excipient exposure in vulnerable preterm babies in a single centre, taking into account chronic lung disease (CLD) as a marker of illness severity. DESIGN: Excipient exposure after treatment with eight oral liquid medications was determined by retrospectively analysing the drug charts of infants admitted to a neonatal unit. SETTING: The Leicester Neonatal Service. PARTICIPANTS: 38 infants born between June 2005 and July 2006 who were less than 30 weeks' gestation and 1500 g in weight at birth and managed in Leicester to discharge. RESULTS: The 38 infants represented 53% of the eligible target group; 7/38 infants had CLD. During their in-patient stay, infants were exposed to over 20 excipients including ethanol and propylene glycol, chemicals associated with neurotoxicity. Infants with CLD were exposed to higher concentrations of these toxins. Infants were also exposed to high concentrations of sorbitol, with some infants being exposed to concentrations in excess of recommended guidelines for maximum exposure in adults. CONCLUSIONS: Preterm infants are commonly exposed to excipients, some of which are potentially toxic. Strategies aimed at reducing excipient load in preterm infants are urgently required.

Plasma aluminum levels during sucralfate prophylaxis for stress ulceration in critically ill patients on continuous venovenous hemofiltration: a randomized, controlled trial.

OBJECTIVE: To investigate plasma aluminum levels in critically ill patients requiring continuous venovenous hemofiltration (CVVH), while receiving sucralfate for stress ulcer prophylaxis. DESIGN: Randomized, controlled study. SETTING: Cardiothoracic intensive care unit. PATIENTS: Twenty postoperative cardiac surgical patients INTERVENTIONS: Twenty patients requiring CVVH support for acute renal failure were randomized into two groups for concurrent stress ulcer prophylaxis. Group 1 (n = 10) received nasogastric sucralfate, and group 2 patients received intravenous ranitidine. Plasma aluminum samples were analyzed at baseline and on days 1, 4, 8, and 14. MEASUREMENTS AND MAIN RESULTS: In both the sucralfate and ranitidine groups, clinical characteristics, number of days the patients were on CVVH support (median, 5.5 [range, 2-32] days, and median, 3 [range, 2-18] days, respectively) and duration of prophylaxis (median, 12 [range, 4-42] days, and median, 16 [range, 3-62] days, respectively) were similar. There were no significant differences in the baseline aluminum concentrations (median, 0.37 [range, 0.15-1.63] micromol/L, vs. median, 0.32 [range, 0.11-1.0] micromol/L; p =.79). On initiation of therapy, aluminum levels in the sucralfate group increased dramatically on day 1 (median, 0.87 [range, 0.26-4.4] micromol/L) and peaked on day 4 (median, 2.84 [range, 1.52-4.44] micromol/L) with seven of the ten patients exhibiting levels of >2 micromol/L. In the ranitidine group, there were no significant elevations in aluminum levels above baseline. Analysis of the two groups at the four time points revealed that aluminum levels in the sucralfate group were up to 14 times higher, with the confidence intervals suggesting that the true value may be 2-27 times higher (p <.0001). On cessation of CVVH, a rapid decline in aluminum levels was observed. No clinical manifestations of these potentially toxic levels were observed. CONCLUSIONS: The use of sucralfate for stress ulcer prophylaxis in patients requiring CVVH results in toxic elevations in plasma aluminum levels. Alternative agents should be considered for prophylaxis in these patients.

In vitro evaluation of sedative drug losses during extracorporeal membrane oxygenation.

Sedative agents are routinely administered to critically ill patients, both on and off extracorporeal membrane oxygenation (ECMO), to enable patients to be comfortable and facilitate patient management. It has been observed empirically in our paediatric intensive care unit that doses of sedative drugs required to achieve desired levels of sedation in ECMO patients are far greater than those used in non-ECMO patients. These differences could not simply be accounted for by differences in patient types, clinical status or sedation levels. We therefore undertook an in vitro evaluation of drug binding in ECMO circuits. This study investigated how the polyvinyl chloride (PVC) and silicone rubber components of neonatal ECMO circuits affect drug delivery in patients through drug sorption. Phase 1 investigated drug uptake by the two polymers in static solutions of known concentrations of four commonly used sedative drugs: lorazepam, midazolam, diazepam and propofol. Phase 2 involved the setting up of a complete neonatal ECMO circuit, injecting the drug solutions pre reservoir at a flow rate of 350 ml/min and collecting samples post-oxygenator for analysis. Phase 1 results revealed significant uptake of drugs with losses in the range 40-98% and in the order propofol > diazepam > midazolam > orazepam. Phase 2 results were similar and in the first 40 min of running an ECMO circuit only 10% of propofol passed through the circuit. These results may help to explain observed clinical phenomena and raise important issues regarding drug dosing in ECMO patients.