Cary E. Johnson

Gentamicin Pharmacokinetics in Term Neonates Receiving Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) may affect the pharmacokinetics of certain drugs. The objectives of this study were to determine (1) the pharmacokinetics of gentamicin in neonates on ECMO and compare them to reported values for a similar patient population not on ECMO, (2) if the pharmacokinetics of gentamicin differ between venous‐venous and venous‐arterial bypass, and (3) if the pharmacokinetics of gentamicin are affected by oxygenator surface area (0.6 m2 vs 0.8 m2 oxygenators). The medical records of 29 term neonates who received gentamicin while on ECMO were reviewed. Data collected included gentamicin dosage, peak and trough serum concentrations determined at steady state, duration of treatment, time on ECMO, daily weights, and pertinent laboratory values. An initial dosage of gentamicin 2.5 mg/kg every 18 hours is suggested for term neonates on ECMO. Dosage adjustments should be based on gentamicin serum concentrations, and modifications may also be required after ECMO.

Antiinflammatory therapies for cystic fibrosis: past, present, and future.

Inflammation is a major component of the vicious cycle characterizing cystic fibrosis pulmonary disease. If untreated, this inflammatory process irreversibly damages the airways, leading to bronchiectasis and ultimately respiratory failure. Antiinflammatory drugs for cystic fibrosis lung disease appear to have beneficial effects on disease parameters. These agents include oral corticosteroids and ibuprofen, as well as azithromycin, which, in addition to its antimicrobial effects, also possesses antiinflammatory properties. Inhaled corticosteroids, colchicine, methotrexate, montelukast, pentoxifylline, nutritional supplements, and protease replacement have not had a significant impact on the disease. Therapy with oral corticosteroids, ibuprofen, and fish oil is limited by adverse effects. Azithromycin appears to be safe and effective, and is thus the most promising antiinflammatory therapy available for patients with cystic fibrosis. Pharmacologic therapy with antiinflammatory agents should be started early in the disease course, before extensive irreversible lung damage has occurred.

Pharmacokinetics and Pharmacodynamics of Nifedipine in Children with Bronchopulmonary Dysplasia and Pulmonary Hypertension

ABSTRACT: The pharmacokinetics and associated pharmacodynamics of nifedipine were studied in nine children aged 5 to 68 mo with bronchopulmonary dysplasia and pulmonary artery hypertension after a single oral dose of 1.44 μmol/kg (0.5 mg/kg). In the cardiac catheterization laboratory, hemodynamic measurements were made in duplicate just before the nifedipine dose and at 5 min and 0.5 and 1.0 h after the dose. The plasma nifedipine concentration was measured by HPLC at each of the above times and at 2.5, 4.0, 6.0, and 8.0 h after the dose. The mean (± SD) maximum plasma concentration and the time to maximum plasma concentration were 243.4 ± 194.5 nmol/L and 1.0 ± 0.8 h, respectively. The mean area under the plasma concentration-time curve was 761 ± 509 nmol·h/L. The mean elimination rate constant and t½ were 0.456 ± 0.194 h-1 and 1.8 ± 0.8 h, respectively. Nifedipine caused a significant (p ≤ 0.05) reduction in the mean pulmonary artery pressure by 5 min and in the mean pulmonary vascular resistance index and mean aortic pressure by 30 min, and these reductions remained significant through the 1-h measurement interval. The magnitude of acute hemodynamic response correlated closely with the plasma nifedipine concentrations. No significant change occurred in the mean arterial oxygen saturation or cardiac index during the study period. The percentage changes from baseline in the mean pulmonary artery pressure and mean pulmonary vascular resistance index were approximately double the percentage change in the mean aortic pressure, suggesting that nifedipine had some degree of selective impact on the pulmonary vascular bed. Based on these results, an initial oral maintenance regimen of 1.44 μmol/kg (0.5 mg/kg) every 6 h would be needed for this patient population. If the safety‘ and efficacy after chronic therapy can also be shown, nifedipine may prove to be an important therapeutic addition to the management of children with bronchopulmonary dysplasia and pulmonary hypertension.

Management of Acute, Severe Asthma in Children:

OBJECTIVE: To briefly present the current options available for the treatment of acute, severe asthma in children, with a special focus on emergency department and inpatient treatment, and to describe newer therapies that may aid treatment in the future. DATA SOURCES AND STUDY SELECTION: A MEDLINE search (1966–May 2001) of the English-language literature pertaining to drug therapy of acute asthma was performed. Key word searches included acute asthma, albuterol, ipratropium, corticosteroids, magnesium, and theophylline. Additional articles from these sources and published national guidelines were identified. Relevant studies pertaining to current therapy of acute asthma in pediatric patients were selected; if there were minimal pediatric data, adult data were included. DATA SYNTHESIS: Asthma is a chronic, inflammatory disorder of the airways. Acute exacerbations can occur and are challenging to manage. Albuterol, ipratropium, and systemic corticosteroids have been shown to be effective in acute asthma exacerbations. Because some patients do not respond to maximal therapy, older therapies such as magnesium and theophylline are being reevaluated. Theophylline may have some therapeutic effect, but given its toxicity profile, it is unclear whether it offers any advantage over maximal β2-agonist therapy. There are only minimal published data evaluating the use of magnesium in pediatrics, and most are small trials or case reports. Newer therapies such as ventilation strategies with heliox and intravenous leukotriene modifiers currently being evaluated may or may not prove to be beneficial in the future. CONCLUSIONS: β2-agonists, ipratropium, and corticosteroids remain the most useful therapeutic agents for acute asthma exacerbations in pediatric patients. However, these agents are not ideal in all patients and, given the existing questions regarding safety and/or efficacy of available alternatives, more effective options are needed.

Isradipine Therapy in Hypertensive Pediatric Patients

OBJECTIVE: To evaluate the dosage and effectiveness of isradipine to control acute or chronic hypertension in pediatric patients. DESIGN: Retrospective medical record review. SETTING: University teaching hospital. PARTICIPANTS: Hospitalized pediatric patients aged 1 day to 16 years with hypertension treated with isradipine between January 1994 and March 1996. MEASURES: Patient age, gender, weight, disease states, current medications, isradipine dosage and formulation, pre- and postsystolic, and pre- and postdiastolic blood pressure measurements with each dose of isradipine. RESULTS: Fifty-three patients with a mean age of 5.8 ± 4.0 years were evaluated. A mean change in the blood pressure measurements taken before the first dose of isradipine compared with the values recorded after the last dose or at discharge for all patients was −11.8% ± 12.5% and −17.4% ± 19.6%, respectively, for systolic and diastolic pressure. The mean dosage of isradipine in 46 patients who received regularly scheduled doses was 0.38 ± 0.22 mg/kg/d. Patients who demonstrated a response received a mean dosage of 0.40 ± 0.20 mg/kg/d. The total daily dosage was administered in one dose for 1 patient, two doses for 15 patients, three doses for 27 patients, and four doses for 3 patients. CONCLUSIONS: Isradipine was an effective antihypertensive agent to reduce the systolic and/or diastolic blood pressure 10% or more compared with pretreatment measurements in 43 (81 %) of 53 pediatric patients. The mean dosage was 0.38 ± 0.22 mg/kg/d, most frequently administered in two or three equally divided doses, which is higher than the normal recommended dosage for adults.

Airway-Rehydrating Agents for the Treatment of Cystic Fibrosis: Past, Present, and Future

Objective To review and evaluate airway-rehydrating agents used for the treatment of cystic fibrosis (CF). Data Sources: Literature was retrieved through MEDLINE (1977-August 2010), Cochrane Library, and International Pharmaceutical Abstracts (1977-August 2010). Search terms used included hypertonic saline, inhaled mannitol, denufosol, Moli 1901, lancovutide, and cystic fibrosis. Reference citations from selected articles were reviewed. Study Selection And Data Extraction: All articles published in English identified from the data sources were evaluated for inclusion. Clinical trials in humans and relevant review articles were evaluated for each airway-rehydrating agent, Data Synthesis: Use of airway-rehydrating agents for the treatment of CF is an expanding area. Hypertonic saline (7% NaCl) is currently the only commercially available airway-rehydrating agent recommended for chronic therapy in patients with CF and is being evaluated in younger patients. Inhaled mannitol is an investigational dry-powder inhalation agent that improves mucus clearance in a similar manner to hypertonic saline and produced a statistically significant increase in forced expiratory volume in 1 second in a Phase 3 trial. Denufosol, a P2Y2 agonist, rehydrates the airway surface liquid bypassing the basic CF transmembrane conductance regulator (CFTR) protein defect. It produces improvement in pulmonary function and is being further evaluated in a Phase 3 trial. Lancovutide (Moli 1901) is an investigation at agent in early-phase trials that activates a calcium-dependent chloride channel, allowing chloride to enter the airway. Conclusions: Hypertonic saline is the primary airway-rehydrating agent used in the treatment of CF. Inhaled mannitol may become an alternative to hypertonic saline since it is faster and easier to administer. It remains unclear whether Denufosol and lancovutide will be synergistic or antagonistic with hypertonic saline. Both agents have a unique mechanism of action that bypasses the basic CFTR defect.

Hemodynamic and Clinical Effects of Oral Levodopa in Children With Congestive Heart Failure

OBJECTIVES This study was undertaken to evaluate the safety, efficacy and pharmacodynamic variables of oral levodopa in pediatric patients with congestive heart failure refractory to standard therapy. BACKGROUND Therapeutic options for children with congestive cardiomyopathies are limited to digoxin, diuretic agents and angiotensin-converting enzyme inhibitors. Previous work in adults with congestive heart failure has shown a short-term effectiveness of levodopa and improvement of cardiac function. METHODS Baseline two-dimensional and M-mode echocardiography, surface electrocardiography, Holter monitoring and exercise testing, when applicable, were performed. Levodopa was administered in a dose escalation scale from 8 mg/kg body weight per dose to 20 mg/kg per dose over 3 days with concomitant metoclopramide and pyridoxine. Catecholamine levels at initiation of the trial and throughout dose escalation were measured, with echocardiographic and electrocardiographic correlation. After 24-h drug washout, cardiac catheterization was performed both before and after administration of levodopa. RESULTS Between February 1992 and December 1995, nine children (age 10 +/- 1.7 years, weight 27.8 +/- 4.3 kg) were enrolled in this study. At cardiac catheterization, serum dopamine levels rose from 108.5 +/- 59.2 pg/ml to 1,375.8 +/- 567.9 pg/ml (p = 0.03) at 100 +/- 14.8 min after levodopa administration without a significant change in serum norepinephrine or epinephrine levels. Paralleling these increases, there were significant changes in the cardiac index (1.7 +/- 0.3 to 3.2 +/- 0.7 liters/min per m2), stroke volume index (16.1 +/- 3.2 to 31.2 +/- 7.0 ml/m2 per min), oxygen consumption (138.6 +/- 24.4 to 188.3 +/- 30.8 ml/min per m2) and systemic vascular resistance (36.8 +/- 8 to 21.9 +/- 5.5 indexed Woods units; all p < 0.01). There was a significant reversal of the daily fluid volume output/input ratio from 0.8 +/- 0.1 to 1.2 +/- 0.1 (p < 0.01). Levodopa administration was complicated by hypertension or tachycardia, or both, requiring a dose reduction in three patients, and by significant gastrointestinal distress in one. There was sustained symptomatic improvement a median of 19.5 months after drug initiation in seven of the patients. CONCLUSIONS These preliminary data support the hemodynamic value of oral levodopa in the treatment of severe congestive heart failure in children.

Management of Allergic Rhinitis: Focus on Intranasal Agents

The clinical manifestations of allergic rhinitis are the result of an immune‐mediated process after exposure of a sensitized individual to airborne allergens. The primary symptomatology includes nasal congestion, rhinorrhea, nasal and conjunctival pruritus, and sneezing. Principles of management include allergen avoidance, palliative therapy, immunotherapy, and pharmacotherapy. Oral decongestants stimulate α‐adrenergic receptors in the nasal cavity, resulting in vasoconstriction and decreased edema. Oral antihistamines block histamine1 (H1) receptors, and may relieve rhinorrhea, sneezing, and nasal and conjunctival pruritus. Topical decongestants have a local effect on adrenergic receptors in the nasal mucosa, resulting in rapid, marked vasoconstriction. Intranasal corticosteroids inhibit mediator release from mast cells and basophils, and reduce edema of the nasal mucosa. Dexamethasone sodium phosphate, beclomethasone dipropionate, and flunisolide are currently available for intranasal administration. Cromolyn sodium inhibits allergen‐induced degranulation and mediator release from sensitized cells, and is useful primarily as a prophylactic agent. Several agents, including the corticosteroids budesonide and flucortin butylester, the mast cell‐stabilizing agent nedocromil sodium, the antichololinergic agent ipratropium bromide, and the H1 receptor antagonist levocabastine are being investigated for intranasal use in the management of allergic rhinitis.

Pharmacotherapy of Otitis Media

The clinical manifestations of acute otitis media and otitis media with effusion are the result of abnormal eustachian tube function most often caused by inflammation from infection or allergy. The majority of cases involve bacterial infection of the middle ear caused by Streptococcus pneumoniae, Haemophilus influenzae, or Branhamella catarrhalis. Nearly half of all children will have had at least one episode of acute otitis media by 1 year of age, and over 70% by 3 years of age. The signs and symptoms include pain with rubbing or tugging at the ear, fever, irritability, lethargy, and hearing loss. The primary therapy for acute otitis media and otitis media with effusion is antibiotics with the goal of preventing possible complications and providing symptomatic relief. Amoxicillin remains the initial drug of choice in communities where β‐lactamase‐producing strains of the common middle ear pathogens are infrequently isolated. If resistant organisms are prevalent, cefaclor, amoxicillin‐clavulanate, or cotrimoxazole should be selected. Adjuvant agents such as decongestants have not been shown to provide additional therapeutic benefit. Children who develop chronic otitis media may require prophylactic antibiotic therapy and insertion of typanostomy tubes.

Stability of an extemporaneously prepared clopidogrel oral suspension

PURPOSE The stability of an extemporaneously prepared clopidogrel oral suspension was studied. Methods Clopidogrel oral suspension (5 mg/mL) was prepared using clopidogrel bisulfate tablets, Ora-Plus, and Ora-Sweet. Six 2-oz samples were prepared; three were stored at room temperature and three under refrigeration. One milliliter was withdrawn from each sample, diluted to 10 mL with methanol, and exposed to high-frequency sound waves in a water bath to ensure complete dissolution of clopidogrel. A 300-microL sample was then withdrawn, diluted with mobile phase to an expected concentration of 15 microg/mL, and assayed in duplicate using high- performance liquid chromatography immediately after preparation and at 7, 14, 28, and 60 days. The stability of the clopidogrel suspension was determined by calculating the percentage of the initial concentration remaining on each test day. Stability was defined as retention of at least 90% of the initial concentration. RESULTS At least 97% of the initial clopidogrel concentration remained throughout the 60-day study period, regardless of storage conditions. There were no detectable changes in color, odor, taste, or pH and no visible microbial growth in any sample. The preparation was palatable, with a slightly gritty consistency and a slightly bitter aftertaste; the bitterness intensified slightly between 28 and 60 days but remained fairly mild. CONCLUSION Extemporaneously compounded suspensions of clopidogrel, 5 mg/mL, in a 1:1 mixture of Ora-Plus and Ora-Sweet were stable for at least 60 days when stored in amber plastic bottles at room temperature and under refrigeration.