miR-16 rescues F508del-CFTR function in native cystic fibrosis epithelial cells.

Cystic fibrosis (CF) is due to mutations in the CFTR gene, which prevents correct folding, trafficking and function of the mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. The dysfunctional effect of CFTR mutations, principally the F508del-CFTR mutant, is further manifested by hypersecretion of the pro-inflammatory chemokine interleukin-8 into the airway lumen, which further contributes to morbidity and mortality. We have hypothesized that microRNA (miR)-based therapeutics could rescue the dysfunctional consequences of mutant CFTR. Here we report that a miR-16 mimic can effectively rescue F508del-CFTR protein function in airway cell lines and primary cultures, of differentiated human bronchial epithelia from F508del homozygotes, which express mutant CFTR endogenously. We also identify two other miRs, miR-1 and miR-302a, which are also active. Although miR-16 is expressed at basal comparable levels in CF and control cells, miR-1 and miR-302a are undetectable. When miR mimics are expressed in CF lung or pancreatic cells, the expression of the F508del-CFTR protein is significantly increased. Importantly, miR-16 promotes functional rescue of the cyclic AMP-activated apical F508del-CFTR chloride channel in primary lung epithelial cells from CF patients. We interpret these findings to suggest that these miRs may constitute novel targets for CF therapy.

Propylene glycol: the safe diluent that continues to cause harm.

Propylene glycol (PG) is present in many pharmaceutical products, lotions, ointments, and cosmetics. Although considered to be a relatively safe substance, overdoses have been associated with serious adverse effects. Propylene glycol intoxication occurred in a child and caused central nervous system depression and a severe metabolic acidosis. Initial assessment revealed an elevated serum anion gap, a slight increase in measured serum osmolality, and a normal osmolal gap. The child's acidosis was due to increased concentrations of lactate and pyruvate. The possibility of serious PG intoxication should be considered in any patient with an unexplained serious metabolic acidosis.

A multicenter evaluation of gentamicin therapy in the neonatal intensive care unit.

STUDY OBJECTIVE: To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 microg/ml, trough < 2 microg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. DESIGN: Retrospective chart review. SETTING: Three neonatal intensive care units. PATIENTS: Three hundred nine infants prescribed gentamicin. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 microg/ml or greater compared with 7% of patients receiving TN dosing (p<0.001). Trough concentrations exceeding 2 microg/ml were reported in 23% of patients receiving TN dosing compared with 2% of pharmacokinetic-dosed patients (p<0.001). Forty-two percent and 6%, respectively, required dosage adjustments (p<0.01). The mean number of concentrations obtained per patient was 2.8 and 2.1, respectively (p<0.01). Neither group had evidence of gentamicin-related nephrotoxicity. CONCLUSION: Compared with TN dosing, administering gentamicin loading doses and performing initial pharmacokinetic analysis resulted in rapid attainment of desired concentrations and fewer dosage adjustments, and allowed for a decrease in the number of gentamicin concentrations.

Vancomycin dosage requirements among pediatric intensive care unit patients with normal renal function.

PURPOSE: The purpose of this study was to determine a vancomycin dosage regimen among pediatric intensive care unit (PICU) patients with normal renal function resulting in desired peak and trough serum concentration and to determine the predictability of vancomycin peak concentrations based on reported trough concentrations. MATERIALS AND METHODS: The medical records of all PICU patients who received vancomycin over a 12-month period were identified through a hospital computer search and were obtained from the hospital's Department of Medical Records. Demographic and laboratory data as well as the patient's vancomycin dosing history were recorded. Patients who lacked appropriately timed vancomycin peak and trough concentrations or who exhibited renal dysfunction were excluded from the study population. The optimal vancomycin dose and the predictability of peak concentrations based on trough concentrations were assessed. RESULTS: A total of 135 patients were identified as having received vancomycin therapy during their PICU hospitalization between June 1997 and June 1998. Fifty-nine patients were excluded due to renal dysfunction or inappropriate vancomycin concentrations resulting in 76 patients representing our study population. The initial mean dose of vancomycin was 47 mg/kg/day resulting in a mean peak and trough serum concentration of 19 and 6 microg/mL, respectively. A mean of 2.2 (range, 1 to 5) and 2.1 (range, 1 to 5) peak and trough serum concentrations were reported for each patient, respectively. A mean of 1.1 (range, 0 to 4) dosing changes per patient was noted resulting in a final mean dose of 60 mg/kg/day corresponding to a mean peak and trough serum concentration of 26 and 8 microg/mL, respectively. A vancomycin trough concentration >5 microg/mL was highly predictive for a corresponding peak concentration >20 microg/mL (P > .0001). Eighty percent of the trough concentrations <5 microg/mL were associated with peak concentrations <20 microg/mL, whereas 81% of trough concentrations >5 microg/mL were associated with corresponding peak concentrations >20 microg/mL. CONCLUSIONS: PICU patients required higher doses of vancomycin than are typically prescribed to achieve conventionally accepted peak and trough vancomycin serum concentrations. In the absence of renal impairment, we recommend an initial dosage regimen of 60 mg/kg/day divided every 8 hours. Vancomycin trough concentrations are highly predictive of corresponding peak concentrations and therefore may negate the need to obtain routine peak concentrations.

The use of alteplase for the resolution of an intravesical clot in a neonate receiving extracorporeal membrane oxygenation.

We present a case of the use of alteplase for the lysis of a large urinary bladder clot. A neonate presented with respiratory failure, secondary to a left diaphragmatic hernia necessitating the need for extracorporeal membrane oxygenation (ECMO) support. On day 3 of ECMO support, hematuria was noted, and a subsequent urinary bladder ultrasound revealed a significant urinary bladder clot. Alteplase (0.5-1 mg) was instilled into the urinary bladder via a 10 French Foley catheter (Sherwood Medical, St. Louis, MO). The catheter was clamped for 1 hour, followed by irrigation with normal saline. Multiple doses of alteplase were administered, resulting in complete resolution of the bladder clot. No adverse effects were attributed to the use of the intravesical alteplase. Alteplase seems to be safe and effective for the resolution of bladder clots, thereby potentially avoiding more invasive surgical procedures.

Continuous propofol infusion for the relief of treatment-resistant discomfort in a terminally ill pediatric patient with cancer.

PURPOSE: To determine the effectiveness of propofol as adjunctive therapy in the treatment of drug-resistant discomfort in a terminally ill pediatric patient. PATIENT AND METHODS: A 3-year-old child with advanced rhabdomyosarcoma and severe drug-resistant discomfort was studied. Propofol was administered as adjunctive therapy to provide relief from severe discomfort. RESULTS: Propofol was initiated with a loading dose of 1.2 mg/kg followed by a continuous intravenous infusion of 1.2 mg/kg/h. Over the next 10 days, additional loading doses were administered and the infusion rate was increased to a maximum of 32 mg/kg/h. After the addition of propofol, our patient's discomfort improved greatly without the occurrence of propofol-associated adverse events. CONCLUSIONS: Propofol appears to be an effective adjunct to opioids and a promising alternative to barbiturate therapy in the treatment of drug-resistant discomfort in terminally ill pediatric patients.

The use of alteplase in a newborn receiving extracorporeal membrane oxygenation.

OBJECTIVE: To present a case of the use of alteplase for the successful resolution of an upper extremity occlusion in a newborn receiving extracorporeal membrane oxygenation (ECMO). CASE SUMMARY: A two-day-old full-term Hispanic girl receiving ECMO support developed a left upper extremity occlusion distal to the brachial artery. Alteplase therapy was initiated with a bolus dose of 0.48 mg/kg followed by a continuous infusion of 0.27 mg/kg/h for three hours. A repeat Doppler ultrasound revealed little improvement, resulting in continuation of alteplase therapy at an infusion rate of 0.27 mg/kg/h for an additional three hours. At the completion of the infusion, perfusion was greatly improved with palpable radial pulse present. While remaining on ECMO support, a brain ultrasound approximately 13 hours after alteplase therapy revealed a grade I right caudate head hemorrhage with normal ventricles. ECMO support was discontinued during the next 24 hours, with a repeat brain ultrasound three days later indicating no acute hemorrhage, normal ventricles, and almost complete resolution of the intraventricular hemorrhage. The neonate was discharged 19 days after discontinuing ECMO support. DISCUSSION: Patients receiving ECMO support are at risk of hematologic complications, including thrombi formation. Moreover, limited information is available regarding the most appropriate thrombolytic therapy for patients receiving ECMO support. Alteplase is an attractive thrombolytic agent given its antigenicity, clot specificity, and pharmacokinetic profile. However, both ECMO support and thrombolytic therapy are risk factors for the development of intraventricular hemorrhage, which our patient developed. Therefore, close monitoring of patients receiving ECMO support and alteplase therapy is essential given the potential for hematologic adverse effects. CONCLUSIONS: Alteplase is an effective thrombolytic agent in neonates receiving ECMO support. Additional experience with alteplase is necessary to determine the optimal dose and duration of therapy in this patient population.