David R. Foster

Endothelial colony forming cells and mesenchymal stem cells are enriched at different gestational ages in human umbilical cord blood.

: Endothelial progenitor cells (EPCs) are used for angiogenic therapies and as biomarkers of cardiovascular disease. Human umbilical cord blood (UCB) is a rich source of endothelial colony forming cells (ECFCs), which are EPCs with robust proliferative potential that may be useful for clinical vascular regeneration. Previous studies show that hematopoietic progenitor cells are increased in premature UCB compared with term controls. Based on this paradigm, we hypothesized that premature UCB would be an enriched source of ECFCs. Thirty-nine UCB samples were obtained from premature infants (24–37 wk gestational age (GA)) and term controls. ECFC colonies were enumerated, clonally isolated, and identified by expression of endothelial cell surface antigens and functional analysis. GA of 33–36 wk UCB yielded predominantly ECFC colonies at equivalent numbers to term infants. UCB from 24 to 28 wk GA infants had significantly fewer ECFCs. Surprisingly, 24–28 wk GA UCB yielded predominantly mesenchymal stem cell (MSC) colonies, capable of differentiating into adipocytes, chondrocytes, and osteocytes. MSCs were rarely identified in 37–40 wk GA UCB. These studies demonstrate that circulating MSCs and ECFCs appear at different GA in the human UCB, and that 24–28 wk GA UCB may be a novel source of MSCs for therapeutic use in human diseases.

Drug-induced acute liver failure and gastrointestinal complications.

The objective of this article is to describe adverse drug events related to the liver and gastrointestinal tract in critically ill patients. PubMed and other resources were used to identify information related to drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis in critically ill patients. This information was reviewed, and data regarding pathophysiology, common drug causes, and guidelines for prevention and management were collected and summarized. In cases in which data in critically ill patients were unavailable, data were extrapolated from other patient populations. Drug-induced acute liver failure can be caused by many drugs routinely used in the intensive care unit and may be associated with significant morbidity and mortality. Drug-related hypomotility and constipation and drug-related diarrhea are reported with many drugs, and these are common adverse drug events in critically ill patients that can substantially complicate the care of these patients. Drug-induced gastrointestinal bleeding and drug-induced pancreatitis occur less frequently, can range in disease severity, and can be associated with morbidity and mortality. Many drugs used in critically ill patients are associated with adverse drug events related to the liver and gastrointestinal tract. Critical care clinicians should be aware of common drug causes of drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis, and should be familiar with the prevention and management of these diverse conditions.

Suitability of digoxin as a P‐glycoprotein probe: Implications of other transporters on sensitivity and specificity

The study of transporter‐mediated drug–drug interactions (DDI) requires use of appropriate probes to reflect transporter function. Digoxin is often used as a probe in DDI studies involving P‐glycoprotein (P‐gp) and is recommended by FDA for this purpose, despite several lingering questions regarding suitability of digoxin as P‐gp probe. This review aims to critically evaluate use of digoxin as a probe for P‐gp‐mediated clinical DDI studies, with focus on sensitivity and specificity of digoxin for P‐gp. Although previous reviews have evaluated digoxin transport by P‐gp, the purpose of the current review is to critically evaluate such literature in light of newly evolving literature suggesting digoxin transport by non‐P‐gp transporters.

Interferon-γ increases expression of the di/tri-peptide transporter, h-PEPT1, and dipeptide transport in cultured human intestinal monolayers

The di/tri-peptide transporter h-PEPT1 plays an important role in the oral absorption of di/tri-peptides and numerous drugs. Inflammatory conditions may influence intestinal xenobiotic transporter function; however, the effects of inflammation on h-PEPT1 have not been well described. This study was conducted to determine the effects of the inflammatory cytokine interferon-gamma (IFN-gamma) on h-PEPT1 mediated dipeptide absorption. Caco-2 monolayers were grown on permeable supports. The effective apical-to-basolateral permeability (P(eff)) of glycylsarcosine (Gly-Sar) was measured following incubation with IFN-gamma or control media. Additional experiments were conducted at 4 degrees C, and with escalating concentrations of Gly-Sar. h-PEPT1 expression was determined using semiquantitative RT-PCR. IFN-gamma 50 ng/ml increased Gly-Sar P(eff) 28.6% compared to controls (p=0.03). In experiments conducted at 4 degrees C, Gly-Sar P(eff) decreased 39.6% in IFN-gamma treated cells (p=0.003) and 28.4% in controls (p=0.006). In controls and IFN-gamma treated cells, concentration dependent transport was seen with escalating concentrations of Gly-Sar. Compared to controls, IFN-gamma 50 and 100 ng/ml increased h-PEPT1 mRNA expression by 14.2% and 11.5%, respectively (p=0.019). In summary, IFN-gamma increases h-PEPT1 expression and permeation of the dipeptide Gly-Sar in Caco-2 monolayers. These findings imply that intestinal absorption of peptides and peptidomimetic drugs may be increased in certain inflammatory conditions.

A systematic review of vancomycin dosing and monitoring in burn patients

Vancomycin pharmacokinetics are significantly altered following burn injury, requiring a higher total daily dose to achieve adequate serum concentrations. Wide interpatient variability necessitates close, frequent monitoring of serum concentrations for efficacy and safety. The aim of this study is to systematically evaluate published data regarding vancomycin pharmacokinetic alterations in burn patients, to determine whether evidence-based recommendations for dosing and monitoring can be formulated, and to identify future research opportunities. The systematic review included studies published in English, involved human subjects with at least a 10% TBSA burn who received vancomycin intravenously, and obtained serum concentration(s). Database searches returned 130 titles for review. Twelve studies met a priori inclusion criteria. The most common dosing regimens in adult and pediatric patients were 5 to 20 mg/kg/dose every 6 to 8 hours. Mean trough concentrations were 7.24 ± 1.5 mg/L. Only 12.5% of reported trough concentrations were within the currently recommended range of 10 to 20 mg/L. Although no consistent dosing recommendations were provided, all studies recommended close monitoring of trough concentrations. Based on limited clinical outcomes data, standardized recommendations for vancomycin dosing and monitoring in burn patients cannot be made. Higher total daily doses (40–70 mg/kg/day) and increased dosing frequency (every 6–12 hr in adults) may be necessary to achieve current target trough concentrations. Future research goals include prospective investigation of clinical outcomes related to initial doses, loading doses, monitoring peak and trough concentrations, and adverse effects. Further data on the effects of burn size, concomitant diseases, inhalation injury, and time since injury may improve the accuracy of vancomycin dosing in burn patients.

Outcomes Following the Use of Nebulized Heparin for Inhalation Injury (HIHI Study).

Inhalation injury (IHI) causes significant morbidity and mortality in burn victims due to both local and systemic effects. Nebulized heparin promotes improvement in lung function and decreased mortality in IHI by reducing the inflammatory response and fibrin cast formation. The study objective was to determine if nebulized heparin 10,000 units improves lung function and decreases mechanical ventilation duration, mortality, and hospitalization length in IHI with minimal systemic adverse events. This retrospective, case–control study evaluated efficacy and safety of nebulized heparin administered to mechanically ventilated adults admitted within 48 hr of confirmed IHI. Nebulized heparin 10,000 units was administered Q4H for 7 days, or until extubation if sooner, alternating with albuterol and a mucolytic. Patients were matched on a case-by-case basis based on percent TBSA burn and age to patients from a historical group with IHI before heparin protocol implementation. The primary outcome was duration of mechanical ventilation. Secondary outcomes included lung injury score, ventilator-free days during the first 28 days, 28-day mortality, hospitalization length, ventilator-associated pneumonia incidence, bronchoscopy incidence, and bleeding events. Data were collected in 72 patients, 36 of which received nebulized heparin and 36 historical controls. Two patients from the heparin group and three patients from the control group died/were discharged while on the ventilator. Data were analyzed separately with 1) all subjects included and 2) with subjects who died/were discharged on the ventilator excluded. In the latter comparison, patients receiving nebulized heparin demonstrated a statistically significant decrease in median (interquartile range) duration of initial mechanical ventilation compared with controls [7.0 (4.0, 13.5) vs. 14.5 (5.3, 22.3) days; P = .044]. Patients in the heparin group had a significantly increased number of median (interquartile range) ventilator-free days in the first 28 days [21.0 (14.5–24.0) vs 13.5 (4.3–22.8) days; P = .031]. There were no differences in hospitalization length, lung injury score during the first 7 days post injury, 28-day mortality, ventilator-associated pneumonia rate, or bleeding events. Nebulized heparin 10,000 units in conjunction with a beta-agonist and mucolytic produced a significant decrease in duration of mechanical ventilation and increase in ventilator-free days in adult patients with IHI. Nebulized heparin was safe and did not result in an increase in bleeding events. To our knowledge, this is the first case–control study with matched cohorts based on age and %TBSA which are significant factors contributing to morbidity and mortality in IHI.

Lack of Interaction Between the Peptidomimetic Substrates Captopril and Cephradine

Intestinal peptide transporters, including hPEPT1, facilitate the absorption of cephalosporins and angiotensin‐converting enzyme inhibitors, and have been investigated as a means to improve oral drug absorption. Renal peptide transporters including hPEPT2, may also facilitate renal reabsorption of such compounds. In vitro and animal studies suggest that co‐administration of peptidomimetic compounds may alter oral pharmacokinetics, although this has not been well studied in humans. The purpose of this study was to determine whether co‐administration of the hPEPT substrates captopril and cephradine alters the oral pharmacokinetics of either agent. Nine healthy male volunteers received a single oral 25‐mg dose of captopril, a single oral 500‐mg dose of cephradine, or concurrent ingestion of captopril and cephradine in a cross‐over manner. Venous blood samples were taken and captopril and cephradine pharmacokinetics were determined using noncompartmental analyses. No significant differences were observed in captopril or cephradine pharmacokinetics when administered together as compared to each agent alone (a marginal decrease in Cmax was observed for both captopril and cephradine during co‐administration [5–15%]; however, differences were not statistically significant). The results of our study suggest that hPEPT1 and hPEPT2 are unlikely to contribute to clinically important drug interactions in humans.

Intestinal Dipeptide Absorption Is Preserved During Thermal Injury and Cytokine Treatment

BACKGROUND Intestinal barrier function is impaired during thermal injury; however, the effects of thermal injury on the absorption of dietary peptides are not well characterized. The purpose of this study was to determine the impact of thermal injury on dipeptide absorption in rats and to describe the influence of inflammatory cytokines on the expression of the oligopeptide transporter PEPT1 and dipeptide permeability in cultured intestinal cells (Caco-2 cells). METHODS Sprague Dawley rats were assigned to 30% body surface area burn (n = 7) or sham (n = 8) groups. Twenty-four hours following burn/sham, the proximal jejunum was cannulated. The jejunal segment was perfused with buffer containing the dipeptide glycylsarcosine (Gly-Sar), and intestinal permeability (P(eff)) was calculated. For in vitro experiments, Caco-2 cells were grown on permeable supports and treated with tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 (10 ng/mL) alone and in combination for 48 hours. The effective apical-to-basolateral permeabilities (P(eff)) of Gly-Sar were measured, and PEPT1 expression was determined using reverse transcription-polymerase chain reaction. RESULTS Gly-Sar P(eff) was similar in burn and sham rats (6.67 +/- 2.27 x 10(-5) vs 7.58 +/- 2.20 x 10(-5) cm/s, respectively, P = .45). In Caco-2 cells, cytokine treatment did not alter PEPT1 expression (P = .954) or the P(eff) of Gly-Sar (P = .806). CONCLUSIONS Intestinal absorption of the dipeptide Gly-Sar is preserved 24 hours following thermal injury in rats. Likewise, PEPT1 expression and peptide absorption are preserved following treatment with TNF-alpha, IL-6, and IL-10 in Caco-2 monolayers. These findings imply that intestinal dipeptide absorption may be preserved during burn injury. This may lead to new strategies to optimize enteral protein delivery in burn patients.