Blood myo-inositol concentrations in preterm and term infants.

OBJECTIVE: To describe relationship between cord blood (representing fetal) myo-inositol concentrations and gestational age (GA) and to determine trends of blood concentrations in enterally and parenterally fed infants from birth to 70 days of age. DESIGN/METHODS: Samples were collected in 281 fed or unfed infants born in 2005 and 2006. Myo-inositol concentrations were displayed in scatter plots and analyzed with linear regression models of natural log-transformed values. RESULTS: In 441 samples obtained from 281 infants, myo-inositol concentrations varied from nondetectable to 1494 µmol/L. Cord myo-inositol concentrations decreased an estimated 11.9% per week increase in GA. Postnatal myo-inositol concentrations decreased an estimated 14.3% per week increase in postmenstrual age (PMA) and were higher for enterally fed infants compared to unfed infants (51% increase for fed vs. unfed infants). CONCLUSIONS: Fetal myo-inositol concentrations decreased with increasing GA. Postnatal concentrations decreased with increasing PMA and were higher among enterally fed than unfed infants.

First evidence for a pharmacist-led anticoagulant clinic in a medicare part A long term care environment.

Anticoagulation risks in older adult, long-term care patients are known to be high, especially in those with frequent transitions between care environments. Introduction of collaborative practice agreements (CPA) in specific settings is encouraged in the United States and has provided an additional option for the care of medically challenging patients. The aim of this study was to investigate the time in therapeutic range (TTR) in a Medicare Part A sponsored long-term care environment managed by pharmacists through a collaborative practice agreement in South-Central Appalachia. A retrospective review of all warfarin patient admissions from a large long-term care pharmacy's anticoagulant clinic was conducted for residents over an 18-month period. For all patients (n = 104), the overall TTR was 46.7% (INR 43% in range). Average management duration was 19.5 days per patient. Further studies are required to optimize CPA and transition strategies for complex, advanced age warfarin patients.

Inositol Analysis by HPLC and Its Stability in Scavenged Sample Conditions.

Inositol is a 6-carbon sugar alcohol that has been shown in limited studies to reduce retinopathy of prematurity and chronic lung disease in premature newborns. Developmentally it has a high concentration in the fetus that decreases with gestational age. It is transported from the fetus to the mother across the placenta. Although studies are underway to determine inositol kinetics in premature newborns treated therapeutically, the effects of gestational age, age after birth, and feeding on inositol concentrations after birth have not been studied adequately in premature newborns. Such studies would minimize blood removal and trauma in preterm newborns by using plasma samples scavenged from the clinical laboratory to measure inositol after birth, if they remain stable. This report describes a new high pressure liquid chromatographic assay for inositol and its use to study the stability of inositol in conditions of storage that might be encountered within the clinical laboratory. The assay is linear from 0 to 1000 Mm with a lower limit of quantitation of 50 µM. Inositol in human plasma remains stable in refrigeration and at room temperature for up to 14 days and is not affected by storage in red blood cells that are intact or lysed. Anticoagulants encountered in clinical blood samples do not interfere with the chromatograms. Thus, it is feasible to measure the changes in inositol concentrations in plasma from preterm newborns that is scavenged from the clinical laboratory after storage for as long as 14 days.

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children.

BACKGROUND: The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l(-1) , while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l(-1) . The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). METHODS: Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. RESULTS: A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l.70 kg(-1) , peripheral volumes of distribution V2 75.1 (23%) l.70 kg(-1) and V3 484 (8%) l.70 kg(-1) , clearance (CL) 9.45 (11%) l·h(-1) .70 kg(-1) , and intercompartment clearances Q2 325 (21%) l·h(-1) .70 kg(-1) and Q3 136 (14%) l·h(-1) .70 kg(-1) . EDDP formation clearance was 9.1 (11%) l·h(-1) .70 kg(-1) , formation clearance of EMDP from EDDP 7.4 (63%) l·h(-1) .70 kg(-1) , elimination clearance of EDDP was 40.9 (26%) l·h(-1) .70 kg(-1) and the rate constant for intermediate compartments 2.17 (43%) h(-1) . CONCLUSIONS: Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg(-1) per 8 h in neonates achieves a target concentration of 0.06 mg·l(-1) within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Stability of extemporaneously prepared lansoprazole suspension at two temperatures.

OBJECTIVE: The purpose of this study was to examine the stability of a generic lansoprazole product in a 3 mg/mL sodium bicarbonate suspension under room temperature and refrigerated conditions. METHODS: Lansoprazole suspensions (3 mg/mL) were prepared in triplicate using an 8.4% sodium bicarbonate vehicle for each storage condition (room temperature and refrigerated). During 1 month, samples from each replicate were periodically removed and analyzed for lansoprazole concentration by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Each sample was spiked with 10 mg/L omeprazole to serve as the internal standard. A positive electrospray LC-MS/MS method was validated over the calibration range of 5 to 25 mg/L using Food and Drug Administration Guidance. The identities of the analyte and internal standard in the samples were verified by monitoring the MS/MS transitions of m/z 370 to m/z 252 and m/z 346 to m/z 198 for lansoprazole and omeprazole, respectively. Additionally, the pH of the suspensions was monitored throughout the study. RESULTS: The stability of lansoprazole in the oral sodium bicarbonate suspension under refrigeration is compromised prior to what has been previously reported in the literature. Samples kept at room temperature lost >10% of the lansoprazole after 48 hours compared with the refrigerated samples, which maintained integrity up to 7 days. No statistically significant difference was found between the pH of the room temperature and refrigerated suspension samples, indicating that this factor is not the cause for the differences in stability at these two conditions. CONCLUSIONS: This study suggests that the extemporaneously compounded lansoprazole oral suspension prepared in 8.4% sodium bicarbonate should not be stored in plastic oral syringes longer than 48 hours at room temperature and no longer than 7 days when refrigerated. These data indicate an expiration time earlier than that previously reported for the refrigerated product (14 days).

Quantification of Lansoprazole in Oral Suspension by Ultra-High-Performance Liquid Chromatography Hybrid Ion-Trap Time-of-Flight Mass Spectrometry.

An LC-MS/MS method was developed and validated to be used as a stability indicating assay for the study of a 3 mg/mL lansoprazole oral suspension. The method utilizes a UPLC (ultra-performance liquid chromatography) column and unique mass spectrometric detection (ion-trap time-of-flight (IT-TOF)) to achieve a sensitive (LOD 2 ng/mL), accurate, and reproducible quantification of lansoprazole. This method reports an intraday and interday coefficient of variation of 2.98 ± 2.17% (n = 5 for each concentration for each day) and 3.07 ± 0.89% (n = 20 for each concentration), respectively. Calibration curves (5-25 µg/mL) were found to be linear with an R(2) value ranging from 0.9972 to 0.9991 on 4 different days. Accuracy of the assay, expressed as % error, ranged from 0.30 to 5.22%. This method is useful for monitoring the stability of lansoprazole in oral suspension.

Cardiovascular drugs for the newborn.

This article reviews the various cardiovascular drugs for newborns, including antiarrhythmics, antihypertensives, inotropes, and pulmonary vasodilators. Antiarrhythmic drugs are classified according to their mechanisms of action, such as effects on ion channels, duration of repolarization, and receptor interaction, which help with understanding the effects of individual antiarrhythmic drugs and selection of drugs for specific arrhythmias. Drug treatment for hypertension should start with a single drug from one of the following classes: ACE inhibitors, angiotensin-receptor antagonists, beta-receptor antagonists, calcium channel blockers, or diuretics. The inotropic drug should be selected according to its specific pharmacologic properties and the specific cardiovascular abnormality to be corrected. An effective pulmonary vasodilator must dilate the pulmonary vasculature more than the systemic vasculature.

Failure of nasogastric omeprazole suspension in pediatric intensive care patients.

OBJECTIVES: To determine the efficacy of nasogastric administration of omeprazole suspension in raising the gastric pH >4 in critically ill pediatric patients and to determine the most appropriate dosing regimen for this indication. DESIGN: Open-label pharmacodynamic study. SETTING: Twenty-six bed tertiary-care pediatric intensive care unit. PATIENTS: Mechanically ventilated children aged 1-18 yrs with an additional risk factor for stress ulcer formation. INTERVENTIONS: Continuous gastric pH monitoring was performed during administration and dose titration of omeprazole suspension to achieve the goal of gastric pH >4 for greater than 75% of the dosing interval. MEASUREMENTS AND MAIN RESULTS: Data were collected from 18 patients. Subjects were categorized based on the pharmacologic response to nasogastric administration of 1 mg/kg omeprazole suspension (maximum 20 mg) as rapid (n = 9), late (n = 5), and nonresponders (n = 4). Rapid responders required 0.72 mg/kg per day omeprazole suspension to achieve adequate gastric pH elevation for stress ulcer prophylaxis. Late responders required 1.58 mg/kg per day. Nonresponders did not achieve adequate elevation of gastric pH for stress ulcer prophylaxis. CONCLUSIONS: Nasogastric administration of omeprazole suspension has variable efficacy in critically ill pediatric patients. Half of the studied subjects either required significant dose titrations to achieve gastric acid suppression or did not respond to nasogastric administration of omeprazole suspension.

The accuracy and precision of measuring Lorazepam from three liquid preparations.

OBJECTIVES: Commercially available lorazepam solution contains both polyethylene glycol (PEG) and propylene glycol. When large doses are administered for deep sedation in the pediatric intensive care unit (PICU), PEG may cause diarrhea, and the accumulation of propylene glycol may result in toxicity. These adverse effects may be avoided by preparing a slurry from crushed lorazepam tablets suspended in water immediately prior to administration. This slurry, which is extemporaneously prepared at bedside by nurses, lacks a suspending agent, and, therefore, the rapid settling of drug particles may produce suspensions that are not homogeneous. Thus, there may be significant inaccuracy and imprecision in dosage measurement. The objective of this study was to compare the accuracy and precision of lorazepam dosage measurement from three liquid preparations: 1) tablet slurry prepared at bedside by a nurse; 2) lorazepam suspension extemporaneously prepared by a pharmacist; and 3) the commercially available lorazepam solution. METHODS: Sixteen PICU nurses measured three doses of lorazepam (0.5 mg, 1.5 mg, 3.5 mg) in triplicate from each of the three liquid preparations using oral syringes. PICU nurses prepared the slurry by mixing crushed lorazepam tablet(s) with water and drawing up the appropriate dose in an oral syringe. Additionally, nurses drew up the appropriate dose from a pharmacist-prepared lorazepam suspension (1 mg/mL) and the commercially available lorazepam solution (2 mg/mL). All samples were analyzed by HPLC and the groups were compared using two-way ANOVA. RESULTS: Dosage accuracy for the slurry (91.2 ± 7.8%) and suspension (109.2 ± 4.9%) were significantly different from the commercially available solution (101.5 ± 3.1%) (P < .05). Imprecision in dosage measurement, as determined by the relative standard deviation, was greatest for the slurry (8.6%) as compared to the suspension (4.5%) and commercially available solution (3.0%). CONCLUSIONS: Dosage measurement from lorazepam slurry and suspension led to significant deviation from the intended dose. Dosage measurement using the slurry was the least precise among the three preparations.

Pharmacokinetics of methadone.

Methadone is a synthetic opioid that is effective for the relief of moderate-to-severe pain and for the treatment of opioid dependence. The pharmacokinetics of methadone differ from those of morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are variable and an understanding of the factors that impact the onset, magnitude, and duration of analgesia is required to optimize therapy. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure. Special populations in whom a change from the usual dosage regimen may be necessary include pediatric patients, patients with renal failure, the elderly, and pregnant women. To achieve an optimal dosage regimen, the clinician must have an understanding of the pharmacokinetics and pharmacodynamics of methadone in addition to the relationship between these variables and their patients' demographic and pathophysiologic characteristics. AMEDLINE search was performed to identify literature published between 1966 and May 2005 relevant to the pharmacokinetics of methadone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of methadone disposition including its absorption profile, distribution, and metabolism/excretion. General dosing guidelines, dosage conversions from other opioids and pharmacokinetic issues in special populations are discussed.

The pharmacokinetics of the intravenous formulation of fentanyl citrate administered orally in children undergoing general anesthesia.

The bioavailability of oral transmucosal fentanyl citrate (OTFC) in children is similar to that of fentanyl solution administered orally to adults. We hypothesized that administering an oral fentanyl solution to children would result in similar fentanyl plasma concentrations and pharmacokinetic variables as administering comparable doses of OTFC. In this pilot study, 10 healthy children requiring postoperative analgesia were enrolled. Each received the undiluted IV fentanyl formulation orally (approximately 10-15 microg/kg; maximum, 400 microg). Venous blood samples were collected from 15 to 600 min after administration. Pharmacokinetic variables were determined using noncompartmental analysis and were compared with a previously studied population of children who received a similar dose of OTFC. Pharmacokinetic variables for the orally administered IV fentanyl formulation were as follows: time to reach peak concentration = 1.7 +/- 1.6 h, peak concentration = 1.83 +/- 1.19 ng/mL, half-life = 4.7 +/- 2.8 h, area under the plasma concentration time curve = 6.46 +/- 3.96 h . ng(-1) . mL(-1), apparent oral volume of distribution (V/F) = 17.5 +/- 7.2 L/kg, apparent oral clearance (CL/F) = 3.33 +/- 2.25 L . kg(-1) . h(-1). Although both OTFC and orally administered IV fentanyl resulted in similar pharmacokinetic variables and plasma concentrations for a given dose, there was marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl. This suggests that this method of administration be used with caution until further data are available.

Albuterol delivery from a metered-dose inhaler with spacer is reduced following short-duration manual ventilation in a neonatal ventilator-lung model.

INTRODUCTION: Albuterol aerosol is commonly administered to mechanically ventilated neonates via metered-dose inhaler (MDI) with spacer. The spacer increases the dead space in the ventilation circuit, and some institutions limit the amount of time the spacer remains in line, to minimize carbon dioxide retention and the risk of hypercarbia. However, minimizing the amount of time the spacer remains in line might also limit albuterol delivery to the patient. OBJECTIVE: To determine whether limiting the amount of time the spacer is left in line after MDI actuation significantly reduces albuterol delivery. METHODS: We conducted a bench study with a neonatal ventilator-lung model that included a Bird VIP ventilator, in a time-cycled, pressure-limited, continuous-flow mode, with settings to simulate a 1-kg infant with moderate lung disease: peak inspiratory pressure 25 cm H2O, positive end-expiratory pressure 4 cm H2O, respiratory rate 30 breaths/min, inspiratory time 0.35 s, tidal volume approximately 7 mL. The circuit was attached to a 3.0-mm inner-diameter endotracheal tube and a neonatal test lung. We tested 5 methods of MDI albuterol administration. The first 3 methods used a spacer attached to the ETT and either 5, 15, or 30 manual breaths (flow 6 L/min, respiratory rate 30 breaths/min, peak inspiratory pressure 25 cm H2O) were delivered after each MDI actuation (2 actuations). The final 2 methods used an in-line spacer (placed between the circuit Y-piece and the endotracheal tube) with the spacer kept in line for 30 or 60 s after each actuation (2 actuations). A breathing filter was placed between the ETT and test lung to trap the aerosolized albuterol. RESULTS: Mean +/- SD albuterol delivery was 2.3 +/- 0.5%, 3.6 +/- 1.8%, and 5.1 +/- 1.3% after 5, 15, and 30 manual breaths, respectively (p < or = 0.05 for 30 breaths vs 5 and 15 breaths). Albuterol delivery was 3.7 +/- 1.3% when the spacer was left in line for 30 s, versus 3.7 +/- 0.6% when it was left in line for 60 s. CONCLUSIONS: Limiting the time that the spacer was left in line after each MDI actuation significantly reduced albuterol delivery in our neonatal ventilator-lung model.

Effect of perioperative administration of ropivacaine with epinephrine on postoperative pediatric adenotonsillectomy recovery.

OBJECTIVES: To determine whether perioperative administration of ropivacaine hydrochloride with epinephrine decreases postoperative pain following adenotonsillectomy and to determine the pharmacokinetics of ropivacaine following injection. DESIGN: Prospective, randomized, double-blind clinical trial. SETTING: University pediatric ambulatory center. PARTICIPANTS: A total of 130 children, aged 2 to 12 years, undergoing adenotonsillectomy. INTERVENTION: Patients received injections, in the tonsillar fossae, of isotonic sodium chloride solution or 0.5% ropivacaine hydrochloride with epinephrine immediately following tonsillectomy. MAIN OUTCOME MEASURES: Modified objective pain score, time to 100 mL of oral intake, serial plasma ropivacaine levels, use of analgesics, incidence of retching and emesis, and other symptoms. RESULTS: Fifty-three patients (80%) in the ropivacaine group had detectable plasma levels in at least 3 of the 4 measurement time periods. The mean +/- SD peak concentration (C(max)) was 0.71 +/- 0.33 micro g/mL and the half-life was 0.96 hours. The average modified objective pain scores over all time points favored the placebo group (P =.06 test of between-subjects effects). Similarly, the average behavior score over time favored the placebo group (P =.046 test of between-subjects effects). Neck pain was better in the placebo group when averaged over postoperative days 1, 3, 7, and 14 (P =.04). The percentage of patients who had retching in the recovery room was greater in the ropivacaine group (41% vs 19%, P =.006). CONCLUSIONS: The injection of 0.5% ropivacaine with epinephrine immediately following adenotonsillectomy results in a measurable plasma level. Ropivacaine with epinephrine injection does not reduce pain postoperatively and adversely affects behavior scores, neck pain scores, and retching frequency compared with placebo. Ropivacaine with epinephrine injection for postoperative analgesia is not recommended for this patient population.

Postoperative opiate analgesia requirements of smokers and nonsmokers.

BACKGROUND: Smoking cigarettes and other forms of nicotine administration appear to blunt the perception of pain. Abrupt discontinuation of nicotine in nicotine-dependent patients appears to increase the perception of pain. The clinical importance of nicotine's effect on pain perception is not fully understood. OBJECTIVE: To determine whether smokers who abruptly discontinue smoking as a result of being hospitalized for coronary artery bypass graft (CABG) require more postoperative opiate analgesics than nonsmokers. METHODS: A retrospective review of patients who underwent a CABG was performed. Smokers (n = 20) were compared with nonsmokers (n = 69) with regard to opiate analgesic use during the first 48 hours postoperatively. The use of nonopiate sedatives was also compared between the groups. RESULTS: When normalized for weight and body mass index, smokers required 23% and 33%, respectively, more opiate analgesics than did nonsmokers (p = 0.027 and 0.023, respectively). The percentage of patients who received benzodiazepines postoperatively was similar in the 2 groups. CONCLUSIONS: In this study, smokers deprived of nicotine required a greater amount of opiates in the first 48 hours after CABG than did nonsmokers. Healthcare providers need to be aware of the potential for increased narcotic requirements among nicotine-deprived smokers. Further study is needed to determine whether nicotine replacement lessens the requirement for postoperative analgesics in smokers.

Chemical stability of extemporaneously prepared Lorazepam suspension at two temperatures.

The objective of this study was to determine the chemical stability of extemporaneously prepared lorazepam suspension (1 mg/mL) stored at two temperatures (4°C and 22°C) for 3 months. Lorazepam tablets marketed by two manufacturers (Mylan Pharmaceuticals and Watson Laboratories) were used to extemporaneously formulate two independently prepared suspensions. Each suspension was prepared using sterile water, Ora-Plus(®) and Ora-Sweet(®) to achieve a final concentration of 1 mg/mL. The two brands of tablets required different volumes of vehicles to prepare a pharmaceutically optimal suspension. The suspensions were stored in amber glass bottles at 4°C and 22°C for 91 days. Samples were analyzed by high performance liquid chromatography at baseline and on days 2, 3, 7, 14, 21, 28, 42, 63, and 91. The suspensions were considered stable if the mean lorazepam concentration remained greater than 90% of the initial concentration.The chemical stabilities of these two extemporaneously prepared lorazepam suspensions were comparable throughout the study. Both lorazepam suspensions were stable for 63 days when stored at 4°C or 22°C, and both were stable for 91 days when refrigerated at 4°C. When stored at room temperature, the suspension prepared from the Watson tablet retained 88.9 ± 1.4% of the initial concentration on day 91 and was therefore considered unstable, while the suspension prepared from the Mylan tablet was stable for the entire 91-day study.

The pharmacokinetics of oxycodone.

Oxycodone is among the most commonly used opioid analgesics for the relief of moderate-to-severe pain and is pharmacodynamically comparable to morphine. Oxycodone is available in the United States in oral dosage forms and controlled-release tablets. Studies have demonstrated marked interindividual variation in the pharmacokinetics of oxycodone. The pharmacokinetics of oral oxycodone differs from oral morphine in that it has a higher bioavailability, a slightly longer half-life, and is hepatically metabolized by cytochrome P450 rather than undergoing glucuronidation. Understanding oxycodone pharmacokinetics favors safe and effective use of this analgesic in a wide variety of patients with different levels of organ function. A MEDLINE search was conducted to identify literature published between 1966 and May 2004 relevant to the pharmacokinetics of oxycodone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of oxycodone disposition including its absorption profile (immediate release, controlled release, rectal administration, and intranasal administration), distribution, and its metabolism/excretion. Special populations, including children and those with liver/renal failure, have a unique oxycodone pharmacokinetic profile that must be taken into account in order to maximize analgesic efficacy and reduce the risk of adverse events.

Chronically inhaled salmeterol improves pulmonary function in heart failure.

Inhaled beta-agonists are commonly prescribed for the symptoms of exercise intolerance in heart failure despite a paucity of data regarding their safety and efficacy. This was a prospective, randomized, double-blind, double-dummy, placebo-controlled 14-day cross-over study to determine if chronic inhaled salmeterol therapy 84 microg every 12 hours improved pulmonary function without augmentation of neurohormonal systems or ventricular ectopy in 8 symptomatic heart failure subjects with left ventricular ejection fraction (LVEF) <40% and FEV1

Clinical pharmacokinetics of morphine.

Morphine, the most widely used mu-opioid analgesic for acute and chronic pain, is the standard against which new analgesics are measured. A thorough understanding of the pharmacokinetics of morphine is required in order to safely and effectively use this analgesic in a wide variety of patients with different levels of organ function. A MEDLINE search was conducted to identify literature published between 1966 and January 2002 relevant to the pharmacokinetics of morphine. These publications were reviewed and the literature summarized regarding unique and clinically important elements of morphine disposition relative to its parenteral administration (including intravenous, intramuscular, subcutaneous, epidural and intrathecal administration), absorption profile (immediate release, controlled release, and sublingual/buccal, and rectal administration), distribution, and its metabolism/excretion. Special populations, including infants, elderly, and those with renal/liver failure, have a unique morphine pharmacokinetic profile that must be taken into account in order to maximize analgesic efficacy and reduce the risk of adverse events.