Kim G. Adcock

Tumor necrosis factor alpha -- 308 polymorphism associated with increased sepsis mortality in ventilated very low birth weight infants.

Background: Sepsis commonly complicates the clinical course of critically ill very low birth weight infants, with as many as 30% developing hospital-acquired bacteremia. The tumor necrosis factor &agr; (TNF-&agr;) −308 G/A single nucleotide polymorphism (SNP) is associated with adverse outcome in septic adult patients. Methods: One hundred seventy-three mechanically ventilated very low birth weight infants were genotyped for the TNF-&agr; −308 G/A SNP. Results: One hundred twenty (69%) infants were homozygous GG, 45 (26%) were heterozygous AG and 8 (5%) were homozygous AA; 2 of 120 (2%) infants developed early bacteremia in the GG group, and 1 of 53 (2%) developed early bacteremia in the AA/AG group (P = 0.919). One or more episodes of late bacteremia/fungemia developed in 59 of 120 (49%) infants with the GG genotype and 23 of 53 (43%) infants with the AG/AA genotype (P = 0.484). Endotracheal tube colonization rates were 65 of 120 (54%) for infants with the GG genotypes and 28 of 53 (53%) for infants with the AG/AA genotypes (P = 0.871). Nosocomial pneumonia developed in a similar number of infants in both genotype groups (9 of 120 infants vs. 3 of 53 infants; P = 0.461). Mortality from sepsis was 3 times greater in infants with the AA/AG genotypes than in those with the GG genotype (10%vs. 3%; P = 0.038). This difference in sepsis mortality was even greater when only bacteremic/fungemic infants are considered (4 of 59 infants vs. 6 of 23 infants; P = 0.026). Conclusions: These data suggest that the TNF-&agr; −308 A allele does not affect the development of sepsis in ventilated premature infants but may increase mortality once sepsis develops.

Single-Dose Pharmacokinetics of Oral and Intravenous Pantoprazole in Children and Adolescents

The primary objective was to determine the pharmacokinetics of single oral and intravenous doses of pantoprazole in children 2 to 16 years of age. The secondary objective was to assess the safety and tolerability of these doses. Male and female hospitalized and nonhospitalized patients from ages 5 to 16 years received single oral doses (20 mg or 40 mg), and those from ages 2 to 16 years received single intravenous doses (0.8 mg/kg or 1.6 mg/kg) of pantoprazole. The plasma concentration‐time data for each patient were analyzed using noncompartmental methods. Routine safety and tolerability assessments were also obtained. The mean values for peak plasma concentration and total area under the plasma concentration‐time curve increased with increasing dose. Pharmacokinetic values were similar in patients from ages 2 to 16 years and to those previously obtained in adults. Statistically significant differences were observed for dose‐normalized pantoprazole area under the plasma concentration‐time curve when compared between CYP2C19 extensive metabolizers with 1 versus 2 functional alleles. All adverse events were mild in severity and considered to be unrelated to study drug. The pharmacokinetic profile of oral and intravenous pantoprazole was similar in children ages 2 to 16 years. The doses used here were safe and well tolerated in this population.

Randomized, open-label, multicentre pharmacokinetic studies of two dose levels of pantoprazole granules in infants and children aged 1 month through <6 years with gastro-oesophageal reflux disease.

AbstractBackground and Objective: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA. Methods: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6mg/kg equivalent) or the high-dose pantoprazole group (1.2mg/kg equivalent) in a 1:1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout. Results: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2,17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ngh/mL and 3602 (3269) ng • h/mL, respectively, in study 1, and 293 (146) ng • h/mL and 2448 (2170) ng • h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rota virus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study. Conclusions: Exposure increased with increasing doses of pantoprazole granules, even though wide inter-individual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD.

Elevated platelet-derived growth factor-BB concentrations in premature neonates who develop chronic lung disease

BackgroundChronic lung disease (CLD) in the preterm newborn is associated with inflammation and fibrosis. Platelet-derived growth factor-BB (PDGF-BB), a potent chemotactic growth factor, may mediate the fibrotic component of CLD. The objectives of this study were to determine if tracheal aspirate (TA) concentrations of PDGF-BB increase the first 2 weeks of life in premature neonates undergoing mechanical ventilation for respiratory distress syndrome (RDS), its relationship to the development of CLD, pulmonary hemorrhage (PH) and its relationship to airway colonization with Ureaplasma urealyticum (Uu).MethodsInfants with a birth weight less than 1500 grams who required mechanical ventilation for RDS were enrolled into this study with parental consent. Tracheal aspirates were collected daily during clinically indicated suctioning. Uu cultures were performed on TA collected in the first week of life. TA supernatants were assayed for PDGF-BB and secretory component of IgA concentrations using ELISA techniques.ResultsFifty premature neonates were enrolled into the study. Twenty-eight infants were oxygen dependent at 28 days of life and 16 infants were oxygen dependent at 36 weeks postconceptual age. PDGF-BB concentrations peaked between 4 and 6 days of life. Maximum PDGF-BB concentrations were significantly higher in infants who developed CLD or died from respiratory failure. PH was associated with increased risk of CLD and was associated with higher PDGF-BB concentrations. There was no correlation between maximum PDGF-BB concentrations and Uu isolation from the airway.ConclusionsPDGF-BB concentrations increase in TAs of infants who undergo mechanical ventilation for RDS during the first 2 weeks of life and maximal concentrations are greater in those infants who subsequently develop CLD. Elevation in lung PDGF-BB may play a role in the development of CLD.

Do Illustrations Improve Children's Comprehension of Assent Documents?

OBJECTIVE The purpose of this study was to assess childrens comprehension of a new assent booklet, (K(id)S(ent)), which uses pictures and written information. STUDY DESIGN A randomized, crossover study evaluated the comprehension of assent documents by children, 7 to 11 years of age at a local elementary school. The two types of documents tested were the standard assent form and the K(id)S(ent) Assent Booklet. Participants were randomized as to which test document they received first by using a cluster randomization design. Participants read the document and then took a short quiz. The process was repeated for the other document on a separate day. Study participants were assigned a percentage score and a binary perfect score for each quiz. Mixed effects logistic and linear regression models with random intercepts were applied to the continuous percent quiz scores and binary perfect quiz scores, respectively. RESULTS A total of 190 participants completed the standard quiz, and 195 students completed the booklet quiz. A statistically significant difference in perfect quiz scores (p=0.004) and percent quiz scores (p≤0.001) between booklet and standard form was noted. CONCLUSIONS The quiz scores may indicate that the style of document is not the only factor influencing participant understanding.

Pathways to Improve Student Pharmacists' Experience in Research.

Objective. To describe the implementation of a student research program and to provide outcomes from the initial 4 years’ experience. Design. Students conducted individual research projects in a 4-year longitudinal program (known as Pathway), with faculty member advising and peer mentoring. A prospective assessment compared perceptions of those who completed the Pathway program with those of students who did not. Descriptive statistics, t tests, and analysis of variance (ANOVA) were used. Assessment. The class of 2013 was the first to complete the Pathway program. In the Pathway assessment project, 59% (n=47) of students who responded reached self-set goals. Pathway students agreed that this research experience improved their ability to work/think independently, evaluate literature, and distinguish themselves from other students. Conclusion. The Pathway program helped students understand the research process and reach other self-set goals.

Pharmacokinetics of intranasal and intratracheal pentoxifylline in rabbits.

Study Objective. To evaluate the disposition of pentoxifylline and its metabolite, lisofylline, in New Zealand rabbits after two alternative routes of administration, intranasal and intratracheal.

Managing acute bacterial skin and skin structure infections: Focus on new lipoglycopeptides

Acute bacterial skin and skin structure infections (ABSSSI) are some of the most commonly encountered infections worldwide. Hospitalizations as a result of ABSSSI are associated with high mortality. This article discusses the role of oritavancin and dalbavancin, two new lipoglycopeptides, in the context of the other I.V. available standard therapy options.