advances in pediatric pharmacology, therapeutics, and toxicology

CHAPTER 6

Advances in PediatricPharmacology,Therapeutics, andToxicology

Ian M. Paul, MD, MScAssistant Professor of Pediatrics, Department of Pediatrics, The MiltonS. Hershey Medical Center, The Pennsylvania State University College ofMedicine, Hershey

Cheston M. Berlin, Jr, MDUniversity Professor of Pediatrics, Department of Pediatrics, andProfessor of Pharmacology, The Milton S. Hershey Medical Center, ThePennsylvania State University College of Medicine, Hershey

This is an exciting time for pediatric therapeutics. The federalgovernment, Food and Drug Administration (FDA), and indus-

try have increasingly become aware of the need for clinical trialsthat demonstrate the safety, efficacy, and pharmacology of medica-tions used to treat children. This recognition combined with the re-cent advances made in areas such as immunomodulation, atopicdisease, growth hormone, diabetes mellitus, and probiotics hasmade recent years particularly remarkable. Corticosteroids and theiralternatives are a recurring theme in several therapeutic areas in pe-diatrics. This chapter highlights these and other developments inpediatric pharmacology, therapeutics, and toxicology, focusing onstudies published between July 2000 and July 2002.

THE BEST PHARMACEUTICALS FOR CHILDREN ACT, THE PEDIATRICRULE, AND OFF-LABEL USES OF DRUGS

A majority of medications continue to lack pediatric labeling, butprogress is being made. The FDA Modernization Act (FDAMA)1

Advances in Pediatrics®, vol 50 147Copyright 2003, Mosby, Inc. All rights reserved.

gave an incentive to pharmaceutical companies to develop pediatriclabeling of marketed drugs by extending the patent by 6 months (ex-clusivity provision). Just as FDAMA expired, Congress enacted TheBest Pharmaceuticals for Children Act in January 2002.2 This legis-lation provides similar incentive for industry to conduct trials inchildren with drugs already approved for adults. As of April 30,2003, the FDA has issued written requests to industry to conductstudies on 276 different drugs.3 In addition, by June 10, 2003, 74active moieties such as enalapril, famotidine, loratadine, and omep-razole had been granted exclusivity under Section 505A of the Fed-eral Food, Drug, and Cosmetic Act.4

In addition to the congressional legislation, the FDA and the De-partment of Health and Human Services were enforcing the 1998Final Rule,5 which required that new drugs be studied in children ifthey provide a significant therapeutic benefit over existing pediatrictherapies, if the absence of labeling could pose a risk to patients, or ifthe medication fills a void in the treatment of a childhood illness. Arecent review provides significant detail regarding FDAMA and theFinal Rule.6 Unfortunately, a court ruling in late 2002 has, for now,led to the suspension of the Final Rule pending further judiciary orlegislative action.

Although these developments have addressed patented drugsand those medications under development, a large group of off-patent and over-the-counter (OTC) medications have never been ad-equately studied. Many are routinely used in children without ad-equate safety, efficacy, and pharmacologic data. Because these drugsare off patent, there has been little incentive for the pharmaceuticalindustry to fund investigations to study these medications. A primeexample of this dilemma is nifedipine, a drug that has been used fornearly 2 decades in hypertensive childrenwithout pharmacokineticdata or a pediatric formulation.7 Funding for such studies may soonbecome available through the National Institute of Child Health andHuman Development.

Drugs that do not have pediatric labeling are often used “off la-bel.” The American Academy of Pediatrics published a policy state-ment that provides guidelines for the use of these medications.8 Therecommendation was that the use of such drugs be evidence based,rely on expert opinion, or both. A discussion with the patients orfamily regarding the off-label use may be part of the informationgiven to the family about the drug.

148 I. M. Paul and C. M. Berlin

ATOPIC DISEASESASTHMAAsthma continues to be the most prevalent chronic disease of child-hood. The growing body of literature describing the positive effectsof inhaled corticosteroids without long-term side effects will hope-fully begin to chip away at the significant morbidity caused by thedisease. Inhaled corticosteroids have replaced inhaledmast cell sta-bilizers such as cromolyn and nedocromil as the preferred mainte-nancemedication for thosewith persistent asthma.When comparedwith each other in 2- to 6-year-old children with persistent asthma,once-daily budesonide was superior to cromolyn administered 4times per day in preventing asthma exacerbations (1.23 vs 2.41 peryear).9 Budesonide also improved the time to first exacerbation, re-sulted in fewer additions of a second long-term medication, and re-duced the use of rescue medications, oral corticosteroids, and ur-gent care visits. Similar resultswere found in the ChildhoodAsthmaManagement Program (CAMP) study.10 During a treatment period of4 to 6 years, budesonide and nedocromil were compared with pla-cebo for the treatment of 5- to 12-year-old childrenwithmild tomod-erate asthma. Although no improvement in lung function was seenin the treatment groups, budesonide was superior to placebo in pre-venting hospitalizations, urgent care visits, albuterol use, and pred-nisone courses. Nedocromil was also superior to placebo for severalof the health-related outcomes, but budesonide was better for pre-venting hospitalizations and prednisone courses than nedocromiland placebo.

Inhaled corticosteroids are extremely effective as controllermedications, but their widespread acceptance has been tempered bythe concern over side effects such as growth suppression. TheCAMPstudy put many of those fears to rest. During the 4 to 6 years of thestudy, the mean increase in height for the patients treated withbudesonide was 1.1 cm less than the placebo group, with the major-ity of that difference occurring in the first year of treatment. Simi-larly, a European study found children treated with budesonide foran average of 9.2 years achieved normal adult height without evi-dence of a cumulative dose effect.11 The subject of inhaled cortico-steroids and their effect on growth has recently been reviewed.12

The other class of anti-inflammatory controllermedications thathas been warmly welcomed by clinicians is the leukotriene modifi-ers. The ease of oral administration and once-daily dosing has mademontelukast an extremely attractive medication for patients, fami-

Pediatric Pharmacology, Therapeutics, and Toxicology 149

lies, and their health care providers. A recent review, however, cau-tioned that currently there are few data on the efficacy of leukotrienemodifiers as monotherapy for moderate to severe asthma, and thatefficacy in mild asthma in unknown.13 These medications can cer-tainly be used as adjunctive therapy for school-aged children al-ready receiving inhaled corticosteroids. Also, because they are safeand well tolerated, leukotriene modifiers can be used as first-linetherapy in childrenwithmild intermittent symptoms of reactive air-ways disease. Exercise-induced asthma has also been cited as an in-dication.

Several important articles have also been published concerningthe treatment of acute asthma exacerbations. First, ipratropriumbro-mide was previously shown to decrease hospitalization rates whengiven in the emergency department,14 but 2 studies found no advan-tage with the routine use of ipratroprium once a child was admittedto the hospital, except for a possible reduction in length of stay forchildren older than 6 years.15,16 The use of inhaled corticosteroidsfor acute exacerbations has been evaluated. One study found thatparents could control 94% of acute asthma exacerbations at homeby increasing their child’s dose of inhaled budesonide.17 The medi-cation was increased at the first sign of a flair and resulted in signif-icantly fewer courses of oral corticosteroids. This clinical result wassupported by the laboratory observation that levels of exhaled nitricoxide, a marker of airway inflammation, are markedly reduced by asingle dose of nebulized budesonide and correlate with an increasein peak expiratory flow rate in children.18 Alternatively, when com-pared with oral corticosteroids given in standard doses to childrenwith severe asthma exacerbations, inhaled fluticasone was signifi-cantly worse in preventing hospitalizations and improving forcedexpiratory volume in 1 second.19 Thus, childrenwith severe asthmaattacks should still be given a course of systemic steroids. Finally, asa reminder that an old treatment can be a helpful one, intravenoustheophylline, when added to otherwise maximal medical manage-ment for children with severe status asthmaticus, improved asthmascores and recovery times for patients in a pediatric intensive careunit.20

ALLERGIC RHINITISBecause second-generation antihistamineswere shown to be less se-dating compared with their predecessors in adults, their use for thetreatment of allergic rhinitis in children is very common. However,no difference in school performance or symptoms of somnolence


was found when loratadine was compared with diphenhydramineand placebo.21

A new approach to treating allergic rhinitis was also developed.Omalizumab, a recombinant humanized monoclonal anti-IgE anti-body given subcutaneously every 3 to 4weeks, decreased serum freeIgE levels and resulted in a significantly decreased amount of nasaland ocular symptoms in patients at least 12 years of age.22 In addi-tion, quality-of-life scores improved in areas such as activity limita-tions, sleep impairment, and emotional function. The authors indi-cated that this therapy, if proven cost-effective,might be particularlyuseful in patients with moderate to severe seasonal allergic rhinitiswith evidence of specific IgE antibodies to clinically relevant aller-gens.

ATOPIC DERMATITISTraditionally, topical corticosteroids have been the mainstay oftreatment for moderate to severe atopic dermatitis, largely becausethere were no other options. Their use was complicated by local andsystemic side effects. Fortunately, a new class of topical medica-tions, the calcineurin inhibitors, has been developed that appears tohave the same therapeutic effect as topical corticosteroids withoutthe adverse effects. These agents, tacrolimis and pimecrolimus, aretopical immune suppressants that work by inhibiting T-cell cyto-kine production and appear to be very well tolerated. The details oftheir mechanism of action, pharmacokinetics, side-effect profile,and potential uses have been the subject of 2 recent reviews.23,24

This development is an important breakthrough, but it does nothingto slow the rising number of childrenwith eczema. To prevent atopicdermatitis, one group of investigators gave the probiotic Lactobacil-lus rhamnosus prenatally by mouth to mothers with a first-degreerelative with atopic dermatitis and postnatally for 6 months to theirinfants.25 In this double-blind, placebo-controlled trial, the treat-ment group had half as many children as the control group who de-veloped eczema, leading the investigators to conclude that probiot-ics may be useful in the primary prevention of atopic diseasethrough an immunomodulatory mechanism.

NONATOPIC SINOPULMONARY DISEASESINUSITISThe debate over the clinical criteria for, diagnosis of, and treatmentof acute bacterial sinusitis continues. Because of concerns about an-timicrobial resistance, a study comparing amoxicillin, amoxicillin-


clavulanate, and placebo is particularly noteworthy.26 Neither anti-biotic improved sinus symptoms more than placebo during the first14 days of treatment, nor did they result in a decrease in relapse orrecurrence rates. Several months later, the American Academy ofPediatrics published a practice guideline on the management of si-nusitis that reviewed the existing literature and did recommend pre-scribing antibiotics under certain circumstances.27 Antibioticsshould be considered for those children with persistent respiratorysymptoms without signs of improvement in the second week of anillness, or with particularly severe symptoms in the first week of theailment. Amoxicillin continues to be the preferred first-line agent,whereas cephalosporins or macrolides should be reserved for thosechildrenwith significant hypersensitivity reactions. Antibiotic ther-apy should continue for 7 days after the patient becomes symptomfree according to the recommendations.

From the adult literature, one consideration for the treatment ofacute sinusitis may be the addition of intranasal corticosteroids.When added to cefuroxime axetil, intranasal fluticasone improvedclinical cure rates and accelerated recovery compared with placeboin patients with a history of chronic rhinitis or recurrent sinusitispresenting with acute sinusitis.28

OBSTRUCTIVE SLEEP APNEAFluticasone nasal spray was also recently shown to be helpful in thetreatment of pediatric obstructive sleep apnea.29 A blinded, placebo-controlled study in 25 children aged 1 to 10 years showed signifi-cant improvements in the mixed/obstructive apnea/hypopnea in-dex for those given fluticasone. These patients had less oxygendesaturation and respiratory movements/arousals than controls.

CROUPDexamethasone has become standard therapy for patientswithmod-erate to severe acute laryngotracheobronchitis. Two recent studiesexamined different routes of administration for thismedication. Thefirst found no difference in the need for subsequent intervention be-tween oral and intramuscular dexamethasone given in the samedose to children with moderate croup.30 The second trial examinedchildren with mild croup and found that oral dexamethasone re-sulted in fewer treatment failures and need for subsequent medicalcare with a more rapid improvement in symptoms than childrentreated with nebulized dexamethasone or placebo.31


BRONCHIOLITISPediatricians continue to be frustrated by the lack of proven thera-peutic options available for the treatment of acute bronchiolitis, themost common lower respiratory tract infection in the first year oflife. One therapeutic option recently developed and used for asthmaand upper airway obstruction is the use of helium-oxygen mixtures(heliox). Heliox contains 70%helium and 30%oxygen. Supplemen-tal oxygen can be added to the combination. Because this mixturehas a lower density compared with air-oxygen mixtures, it deliversoxygen to the lower airways more easily under pathologic condi-tions, thereby reducing the work of breathing. Heliox plus standardtherapywas comparedwith standard therapy alone in children aged1month to 2 years admitted to a pediatric intensive care unit (PICU)for treatment of moderate to severe acute bronchiolitis.32 Althoughthe study was nonblinded, the patients treated with heliox demon-strated a rapid reduction in both heart and respiratory rates. In ad-dition, the treatment armhad a significantly shortermean PICU stay.

Another investigation opened an old controversy regarding therole of corticosteroids in the treatment of bronchiolitis. A double-blind, randomized, placebo-controlled trial of 70 children youngerthan 2 years seen in an emergency department with clinical diseasewas conducted, in which the patients were given either a relativelylarge dose of oral dexamethasone, 1 mg/kg, or placebo.33 The pa-tients in the treatment arm had a significant reduction in a clinicalrespiratory score that evaluated retractions and wheezing over 4hours. Of importance was the outcome of a significant 50% reduc-tion in hospitalizations for those receiving the steroid.

VIRAL UPPER RESPIRATORY TRACT INFECTIONYet another common condition with limited therapeutic options isviral upper respiratory tract infection (URI). Two articles describethe continued futility. Evidence has existed that inhaled mast cellstabilizers could shorten the course of viral illnesses in childrenwith asthma and that intranasal administration could be used toshorten symptoms associated with URI in adults. Therefore, chil-dren with diagnosed viral URI were given either intranasal sodiumcromoglycate or intranasal saline spray for 5 days. A symptom diarythen was kept for 2 weeks.34 The active drug though was not supe-rior to placebo in relieving the symptoms of URI.

Because cough is perhaps the most bothersome part of a URI,numerous OTC medicines have been used to treat this symptom. Arecent topic review concluded, however, that based on the existing


literature, OTC coughmedicines are notmore effective than placeboin relieving symptoms of acute cough and should not be recom-mended as a first-line treatment.35

GASTROENTEROLOGYDIARRHEADiarrhea continues to be a major public health problem worldwideand a significant nuisance in developed countries. The lack of ac-cepted treatments and current hold on rotavirus vaccination haveleft pediatricians with little in their therapeutic armamentarium. Arecent review summarized the available literature relating to use ofagents such as loperamide, bismuth subsalicylate, lactobacillus, opi-ates, and anticholinergics.36 The authors concluded that none of themedications were currently indicated for routine use in acute wa-tery diarrhea during childhood because of the cost of therapy andthe potential for serious adverse effects.

Alternatively, numerous publications have emerged discussingold and new therapeutic options. Racecadotril, an enkephalinase in-hibitor with antisecretory and antidiarrheal actions, prevents thebreakdown of enkephalins in the gastrointestinal tract. This medi-cation, when combinedwith oral rehydration solution, significantlyreduced stool output and duration of diarrhea in children youngerthan 3 years with and without rotavirus as the cause of their diar-rhea.37 Similarly, 3 times the recommended daily allowance of zincwhen given to Nepalese children decreased stool frequency and du-ration, and was not enhanced by coadministration of vitamin A.38

Bismuth subsalicylate was evaluated in Bangladeshi children withacute diarrhea (56% caused by rotavirus).39 This study also reporteddecreased diarrhea intensity and duration.

Finally, there has been increasing interest in the use of probioticLactobacillus strains in the treatment and prevention of acute diar-rhea. It is thought that this organism alters the microbial milieu in-side the gastrointestinal tract, making it less favorable for patho-genic organisms. Several recent studies and review articles haveaddressed this issue. First, otherwise healthy children with acutediarrhea attending day-care centers were given either Lactobacillusrhamnosus and Lactobacillus reuteri or placebo twice daily for 5days.40 The treatment arm had a significantly reduced duration ofdiarrhea. Second, for hospitalized patients, the same combinationshortened the duration of diarrhea and hospitalization for thosetreated during the first 5 days of their illness.41 In addition, the du-ration of rotavirus shedding was reduced. Lactobacillus has also


shown to be very effective in preventing the development of noso-comial diarrhea including that caused by rotavirus.42 Two reviewarticles summarized the current research related to this probioticand found it to be safe and effective for the treatment of acute infec-tious diarrhea, both bacterial and viral, while cautioning that addi-tional research is still needed.43,44

VOMITINGBecause the side effect profile of most antiemetic agents such asprochlorperazine, promethazine, and metoclopromide include se-dation and extrapyramidal reactions, their routine use in acute gas-troenteritis is not recommended. An antiemetic with a better sideeffect profile, ondansetron, is commonly used to treat nausea andvomiting in oncology and postoperative patients. To evaluate its ef-fect on vomiting caused by gastroenteritis, 107 patients aged 1month to 22 years seen in an emergency department were given ei-ther ondansetron, a selective 5-HT3 (serotonin receptor) antagonist,or placebo.45 The treatment arm had a significantly greater percent-age of patients with resolution of vomiting than did placebo.

CONSTIPATIONLike diarrhea, constipation can be a frustrating condition for pa-tients, parents, and physicians. A difference between the two is thatthere are numerous accepted therapeutic options for constipation.Recently, a new osmotic agent, polyethylene glycol 3350 (Miralax;Braintree Laboratories, Braintree, Mass) has been added to the list ofdrugs used to treat constipation and encopresis. Because it is virtu-ally tasteless, it has a substantial advantage over some of the oldermedications. Two recent studies showed it to be safe and effective.The first found that when given to children with chronic constipa-tion, there was a large increase in stool frequency with a large de-crease in soiling.46 The mean effective dose was 0.84 g/kg/d. Thesecond compared polyethylene glycol 3350 with milk of magne-sia.47Milk ofmagnesiawas superior in reducing soiling and improv-ing symptoms at 1 month, but the treatment arms were comparableat 3- and 6-month follow-ups. In addition, 33% of children refusedto take the milk of magnesia, but none refused polyethylene glycol3350.

ESOPHAGITIS AND GASTRITISProton pump inhibitors have been used successfully for esophagitisand gastritis in adults for many years, yet there has been a paucity ofdata in the pediatric population. The International Pediatric Ome-


prazole Study Group examined the effect of omeprazole on childrenaged 1 to 16 years with erosive esophagitis, 50% of whom had neu-rologic impairment.48 The proton pump inhibitor proved to be ex-tremely effective in healing the esophagitis and relieving symptoms.The starting dosewas 0.7mg/kg/d, but some patients required dosesup to 2.8 mg/kg/d. Omeprazole at all doses was well tolerated. Anadditional study examined a 1-week course of omeprazole in com-bination with amoxicillin and clarithromycin for the treatment ofHelicobacter pylori gastritis in children ranging from 3 to 15 years ofage.49 This combination eradicatedHpylori in 75%of the patients, aresult similar to that in adult trials.

INFLAMMATORY BOWEL DISEASECorticosteroids have been the preferred treatment for control ofmoderate to severe exacerbations of Crohn’s disease. However, theiruse has been complicated in pediatrics by the plethora of side effectsassociated with long-term use. Therefore, as immunomodulatingdrugs have emerged, their application to Crohn’s disease therapy hasbeen an area of active investigation. One of these medications, in-fliximab, was recently tested in children.50 Infliximab is a monoclo-nal antibody that appears to block the cytokine tumor necrosis fac-tor-� by binding to its transmembrane form, thereby exerting its anti-inflammatory effect. The medication was shown to quickly reducedisease activity and the need for corticosteroids, but was associatedwith some cases of relapse after the drugwas discontinued. The sideeffects of continued corticosteroids and use of several immuno-modulating drugs in children with steroid-dependent and steroid-refractory Crohn’s disease have recently been reviewed.51

PAIN AND SEDATIONA joint policy statement from the American Academy of Pediatricsand the American Pain Society addressed numerous issues relatingto the assessment andmanagement of pain in the pediatric patient.52

The groups acknowledged that pain resulting from acute illness,procedures, trauma, and operations has been commonly misman-aged. In addition, they wrote that the dearth of potent analgesics ap-proved by the FDA for children was unacceptable. Among the rec-ommendations set forth was the call for a multimodal approach topain management including pharmacologic, cognitive behavioral,and physicalmeasures. The International Evidence-BasedGroup forNeonatal Pain composed a similar statement for the newborn popu-lation.53 Since newborns may experience a greater sensitivity topain and are more susceptible to the long-term effects of painful


stimulation, they suggested the appropriate use of environmental,behavioral, and pharmacologic interventions. Examples were givenfor many procedures from heel lance to circumcision to chest tubeinsertion.

Coinciding with the publication of these recommendations, nu-merous investigationswere contributing to the data on painmanage-ment and sedation. One emergency department investigation com-paredmidazolam, nitrous oxide, the combination of the 2 drugs, andneither drug for children undergoing facial laceration repair.54 Eachtreatment arm also received the standard care of comfort measuresand topical anesthesia. The investigators reported that the childrenreceiving continuous nitrous oxidewere significantly less distressedthan those given midazolam or standard care alone. The recoverytime of the nitrous oxide group was similar to that of the standardcare group andwas less than that of the midazolam group. The com-bination therapy offered no advantage. Another study comparedoral midazolam plus either oral transmucosal fentanyl or placebofor children undergoing laceration repair.55 The addition of the fen-tanyl did not improve pain or activity scores for the children andresulted in more side effects. A third emergency department–basedinvestigation found propofol, a potent short-acting sedative and am-nesic agent, to be extremely effective for sedation during painfulprocedures such as fracture reduction.56 A subsequent retrospectiveanalysis of propofol use in a PICU for extubation, however, was un-able to determine optimal loading and dosing strategies for propofoluse in children and underscored the need for controlled clinicalpharmacology trials in infants and children.57 The side effects ofpropofol including hypotension and hyperlipidemia were also re-ported. The risks and benefits of propofol and other methods of se-dation for procedures were also the subject of a recent editorial thatemphasized the need for an awareness of side effects and the abilityto manage potential complications associated with sedation fromthese agents.58

Two studies addressed the pain from needles. First, a lidocaine-prilocaine topical anesthetic cream was shown to reduce intramus-cular immunization pain from the diphtheria, pertussis, and poliocombination vaccine when given 60 to 120minutes before the injec-tion in 4- to 6-year old children.59 A further study showed that atopical 4% liposomal lidocaine preparation reduced venipuncturepain when applied 30 minutes before the needle stick.60 The lipo-some-encapsulated structure is purported to enhance the rate andextent of drug absorption while protecting it from being rapidly me-tabolized.


For postoperative pain after craniofacial surgery, investigatorscompared the oral and rectal routes of acetaminophen administra-tion.61 A loading dose of 40 mg/kg of rectal acetaminophen was notsuperior to an oral dose of 20mg/kg for analgesia when patients whovomited after oral administration were excluded. The authors didreport that the plasma concentrations of acetaminophen after rectaladministration were highly variable.

FEVERA loading dose of 30 mg/kg of acetaminophen was compared with astandard dose of 15 mg/kg for the treatment of febrile, but otherwisehealthy children.62 The 30 mg/kg arm achieved a quicker, longer,and greater reduction in temperature. No clinical side effects werereported, but no laboratory datawere obtained. There is concern thatlabeling an OTC drug with such a loading dose may cause an in-crease in incidence of acetaminophen poisoning because parentsmay give the larger dose on subsequent occasions.

Another drug that was used in the past as an antipyretic, dipy-rone, was comparedwith standard doses of acetaminophen and ibu-profen in another study.63 Dipyrone,whichwaswithdrawn fromusein the United States and United Kingdom because of a reported as-sociation with agranulocytosis decades ago, was found to be an ex-tremely effective antipyretic with longer temperature normalizationthan either of the other 2 medications. The authors also presenteddata that questioned the purported side effects and called for furtherevaluation of its restricted use. Dipyrone is still used in SouthAmerica and parts of Europe.

INFECTIOUS DISEASES AND ANTIBIOTICSBACTERIAL INFECTIONSThe treatment of pharyngitis caused by groupA streptococci has tra-ditionally been effective at eradicating the organism from the oro-pharynx and preventing complications. More recently, many pa-tients have persistently positive throat cultures and are classified aseither treatment failures or carriers. To evaluate current therapy, 284children from 23 states with throat cultures positive for group Astreptococcus and signs and symptoms consistent with acute dis-ease were given oral penicillin V or intramuscular benzathine peni-cillin G in standard doses to determine the rate of microbiologiceradication of the organism.64 Despite no evidence of in vitro resis-tance, the microbiologic, not clinical, treatment failure rates were35% and 37%, respectively, based on follow-up throat cultures. An


investigation in Pittsburgh, Pennsylvania found a high rate of resis-tance to erythromycin in patients with pharyngitis caused by groupA streptococcus.65 Although 48% of isolates were resistant to eryth-romycin, none were resistant to clindamycin, leading the authors torecommend that the former not be used for penicillin-allergic pa-tients with active infection. Both articles have resulted in significantdebate over the treatment and relevant outcome measures in strep-tococcal pharyngitis therapy.

One condition where the use of a newer macrolide may beemerging is in the treatment of pertussis, an infection that has re-emerged in children. Although pertussis has traditionally beentreated with a 14-day course of erythromycin, a 7-day course ofclarithromycin was compared with the standard therapy and re-sulted in a 100% microbiologic and clinical cure rate.66 Theclarithromycin arm also had significantly fewer side effects.

Another condition receiving increasing recognition is Lyme dis-ease. Although current management consists of antibiotic initiationafter signs and symptoms of the disease develop, investigatorsevaluated the efficacy of prophylactic doxycycline for patients 12years and older who were bitten by the Ixodes scapularis tick.67 Asingle 200-mg dose given within 3 days of the bite was superior toplacebo at preventing erythema migrans and serologic evidence ofLyme disease. This result gives practitioners a therapeutic option foran anxious family from an endemic area after a tick bite. Doxycy-cline is the treatment of choice for older children and adults withLymedisease, but its toxicity has limited its use in younger children,leaving amoxicillin as the recommended therapy for children 8years and younger. To provide an additional choice, a study compar-ing cefuroxime axetil with amoxicillin for early treatment of Lymedisease in children younger than 12 years was published.68 Clinicalefficacy and side effect profiles were comparable in those treatedwith amoxicillin or 20 to 30 mg/kg/d of cefuroxime axetil, leadingthe authors to conclude that both are safe and effective for treatmentof early childhood Lyme disease.

In addition to new uses for old antibiotics, new dosing schemeshave also been developed. Continued work on once-daily dosing ofaminoglycosides has led to growing data that this schedule is supe-rior in efficacy without additional toxicity in all populations of chil-dren studied.69 A recent example compared once-daily and 3-times-daily administration of gentamicin in children with severe urinarytract infections and reached a similar conclusion.70 The doses usedfor both groupswere 7.5mg/kg for children younger than 5 years, 6.0


mg/kg for children aged5 to 10, and4.5mg/kg for childrenolder than10 years.

One new antibiotic that has been developed is linezolid. Thisdrug is the first in a new class of antibiotics, the oxazolidinones, andhas excellent in vitro activity against antibiotic-resistantStreptococ-cus pneumoniae, methicillin-resistant Staphylococcus aureus, andvancomycin-resistant enterococci. In adults, it is currently indi-cated for these infections, nosocomial pneumonia, complicated anduncomplicated skin and skin structure infections, and community-acquired pneumonia. Its safety, tolerance, pharmacokinetics, and ef-ficacywere tested in 78 children aged 1 to 12 yearswith community-acquired pneumonia.71 Linezolid cured 92% of the patients, withside effects of eosinophilia (18%), diarrhea (10%), and neutropenia(6%). The one patient in whom treatment was unsuccessful hadpneumonia and a pleural effusion caused by methicillin-resistant Saureus.

Whereas the development of new antibiotics is certainly wel-come, clinicians are encouraged to use the most narrow-spectrummedication possible in treating infections to prevent the develop-ment of antibiotic resistance. One obstacle to this is a patient or par-ent-reported allergy to antibiotics such as penicillin. A recent articlerelated to this topic reports that 80% to 90%of patientswho claim tobe allergic to penicillin are not when allergy skin testing is per-formed.72 The authors argue that by taking a detailed history thatincludes the characteristics of the reaction and the underlying ill-ness being treated, many of these nonallergic patients can be identi-fied. Most of these patients will be able to tolerate penicillin. Theseconclusionswere supported by an investigation in childrenwho de-veloped a rash after antibiotic ingestion given to treat a URI (otitismedia, sinusitis, or pharyngitis).73 Each of the 86 patients was giventhe same antibiotic that caused the rash while they were well, withnone developing a rash, leading the authors to conclude that thepractice of complete avoidance of antibiotics associated with a rashmay be unwarranted.

VIRAL INFECTIONSAdvances in pediatricmanagement of human immunodeficiency vi-rus infection have not been as dramatic as in the past, but there hasbeen progress in the treatment of viral hepatitis in childhood. La-mivudine, a nucleoside analogue used in adults, was comparedwithplacebo for the treatment of chronic hepatitis B in children betweenthe ages of 2 and 17 years.74 At the end of 1 year of therapy, 23% ofpatients in the treatment arm had a virologic response, a significant-


ly greater proportion than in the placebo group. In addition, therewas greater normalization of liver function tests and markers of in-fection. For hepatitis C infection therapy, there still has not been alarge-scale, prospective clinical trial, but interferon-� is the treat-ment of choice. An analysis of the current data from numeroussmaller trials concluded that the drug is reasonably safe and effec-tive for the treatment of chronic hepatitis C virus in children, withapproximately 36% of children achieving a sustained response tothe medication.75

FUNGAL INFECTIONSThe number of therapeutic options for treating fungal infections hasbeen static formanyyears. Lately, several newantifungal agentshavebeen developed including newer azoles and caspofungin, the first inanewclassof antifungals, theechinocandins.76Caspofungin is a fun-gicidal agent that is currently indicated for the treatment ofAspergil-lus refractory to other therapies. The newazoles, voriconazole, posa-conazole, and ravuconazole, have a broader spectrumof activity andincreasedpotency than theirpredecessors.Theseagents act by inhib-iting cell division.Voriconazole appears tobeverywell toleratedandhas activity against Aspergillus, Crypotococcus, and Candida spe-cies. Its excellent efficacy in invasive fungal infections inmostly im-munocompromised childrenwith aspergillosis, scedosporiosis, andother invasive fungal infections has been reported.77

Amore common, yet also difficult-to-treat fungal problem in pri-mary care is tinea capitis. Griseofulvin continues to be the first-linetreatment for this problem, but the required 1 to 2months of therapyis sometimes difficult and does not always result in a cure. There-fore, different courses of terbinafine were evaluated to determinetheir efficacy against Trichophyton tinea capitis.78 The optimal du-ration for treatment was 2 weeks with 3 to 6 mg/kg/d of medication.This regimen resulted in negative cultures for the organism in 76%of cases and was well tolerated.

CARDIOVASCULAR DISEASE AND HYPERTENSIONHYPERTENSIONOne drug that has been used for some time in children without ad-equate pharmacologic data is nifedipine. One retrospective studydescribed short-acting nifedipine use in severe childhood hyperten-sion and evaluated the doses used, the reductions in blood pressurefrom, and side effects of the medication.79 The mean dose used was0.23 mg/kg, with generally larger doses prescribed for younger chil-dren and smaller doses given to adolescents. By and large, the high-


er doses were associated with a more precipitous (>25%) drop insystolic, diastolic, andmean blood pressure. This reduction in bloodpressure occurred in approximately one third of the patients, but noclinically apparent symptoms were observed. Another calciumchannel blocker used in the treatment of severe hypertension is in-travenous nicardipine. Nicardipine, when given by infusion, is at-tractive because of the ability to titrate the dose and its favorableside effect profile. A retrospective assessment of 29 severely hyper-tensive PICU patients found 1.8 µg/kg/min to be the mean effectivedose required to achieve adequate blood pressure control.80 Ameanof 2.7 hours was required to achieve this stability. Nicardipine wasan effective single agent in 84% of cases, with side effects of tachy-cardia, flushing, palpitations, and hypotension.

CONGESTIVE HEART FAILUREIn the past, �-blocker therapy was contraindicated in patients withcongestive heart failure. During the last several years, studies to thecontrary have surfaced in the adult literature showing that theseagents reduce morbidity and mortality for patients in heart failure.These data are summarized in a recent review.81 Now, a retrospec-tive, nonrandomized study describes an experiencewith carvedilol,a nonselective �-blocker with �-blocking and antioxidant effects.82

When added to standard therapy for pediatric heart failure,carvedilol at an average maintenance dose of 0.46 mg/kg was asso-ciated with symptomatic improvement and increased left ventricu-lar function in children with dilated cardiomyopathy or congenitalheart disease. Unfortunately, side effects were common, but mainlyconsisted of dizziness, hypotension, and headache.

NEUROLOGIC AND PSYCHIATRIC DISEASEATTENTION-DEFICIT/HYPERACTIVITY DISORDERStimulant medications are standard therapy for the treatment of at-tention-deficit/hyperactivity disorder (ADHD). One problem withprescribing several of the first-generation stimulantmedicationswasthe need for repeated daily dosing that required children to take themedication at school. Several extended-release preparations havebeen developed to overcome this obstacle. One of them, Concerta(methylphenidate HCl) extended-release tablet, was compared withimmediate-release methylphenidate given 3 times daily, and pla-cebo for control of symptoms of ADHD.83 Both medications weresuperior to placebo in controllingADHD symptoms in children aged6 to 12 years and were no different for this purpose as judged byparents and teachers on reassessment at 1 week and at 1 month.


A condition in which these medications may be useful isTourette syndrome, since these children often carry the comorbiddiagnosis of ADHD. However, many clinicians have used caution inprescribing stimulant medications that are known to independentlycause tics. To evaluate whether methylphenidate, clonidine, or bothare effective therapy in children with both ADHD and chronic ticdisorder without worsening of tics, the Tourette’s Syndrome StudyGroup randomly assigned 136 children to receive clonidine alone,methylphenidate alone, combined therapy, or placebo.84 All 3 treat-ments were superior to placebo for the treatment of ADHD symp-toms, with the combination therapy achieving the greatest success.Surprisingly, all 3 treatments lessened tic severity, again with com-bination therapy being themost superior to placebo. This study doesnot support avoiding methylphenidate in children with tics. Otherthan sedation from clonidine, the medications were well tolerated.

OBSESSIVE-COMPULSIVE AND ANXIETY DISORDERSIn adults, selective serotonin reuptake inhibitors have emerged aseffective therapy for obsessive-compulsive disorder and other anxi-ety disorders. To evaluate their effect on children, an open-labelstudy with paroxetine was conducted in children with obsessive-compulsive disorder between 9 and 15 years of age.85 At amean doseof 20.7 mg/d, paroxetine was found to be effective in treating symp-toms with minimal side effects.

For other anxiety disorders including social phobia, separationanxiety disorder, and generalized anxiety disorder, 128 childrenaged 6 to 17 years were randomly assigned to receive either fluvox-amine or placebo for 8 weeks.86 Fluvoxamine was found to be farsuperior to placebo for treating symptoms associated with each ofthe studied anxiety disorders, with 76% of the patients in the treat-ment arm showing a significant improvement.

THERAPEUTICS FOR AUSTISM AND DOWN SYNDROMESecretin is a normal gastrointestinal hormone secreted by the cellsof the upper intestinal tract. For the last several years, there has beensome controversy regarding its place in the treatment of autism be-cause of case reports describing its possible therapeutic effect. In arandomized, placebo-controlled trial involving 60 childrenwith au-tism, a single dose of intravenous secretin was no better than pla-cebo in improving language skills and behavioral traits judged byparents 6weeks after administration.87 The authors did report amar-ginally significant improvement in behaviors at 3 weeks after injec-tion that was not sustained.


Piracetam, a member of the class of drugs called nootropics, isused in conditions associated with brain dysfunction such as Alz-heimer disease, stroke, and dyslexia because of its reported positiveeffect on cognitive function. As such, patients with Down syndromewere given themedication for 4months in a placebo-controlled trialto assess its effect on cognitive function in this population.88 Thissmall trial of 18 patients was unable to detect improvements in cog-nition or behavior but was associated with the development of ag-gressive behaviors.

MIGRAINESumatriptan nasal spray has been shown to be an effective medica-tion for fast relief of acute migraine headaches in adults. To evaluateits effect on this condition in adolescents, 653 patients aged 12 to 17years were given either 20 mg of sumatriptan nasal spray or placeboas treatment for an acute migraine.89 Sumatriptan was superior toplacebo for headache relief at 1 and 2 hours postdose while also im-proving photophobia and phonophobia. A taste disturbance waspresent in approximately one quarter of patients and was the mostcommonly reported adverse effect.

MUSCULAR DYSTROPHYDuchenne muscular dystrophy is a progressive condition with fewtherapeutic options. In the past, prednisone has preserved somemuscle function, but with the usual adverse effects. A prednisolonederivative, deflazacort, has appeared to have some of the positiveeffects without as many negative ones.90 Therefore, a retrospectivereview analyzed boys aged 7 to 15 years with Duchenne musculardystrophy and compared those who did and did not receive deflaza-cort. The patients in the treatment arm maintained their ability towalk an average of 2.5 years longer, had improved gross motor abil-ity, and had superior pulmonary function. The patients in the treat-ment arm did have poorer growth velocity, but other side effects ofcorticosteroids were not found to be clinically significant.

ENDOCRINOLOGYDIABETES MELLITUSMuch progress has been made in the treatment and understandingof both types 1 and 2 diabetesmellitus. The insulin pumpprovides acontinuous infusion of short-acting insulin, allowing increased flex-ibility in meal times and portion sizes but with the drawback of al-most constant attachment to the pump. Insulin glargine, a new, long-acting human insulin analogue, has been developed to provide a


similar basilar rate of insulin through a single injection. Its currentuse in both types of diabetes was the subject of 2 reviews,91,92 and acomparison of its pharmacokinetics and pharmacodynamics withthose of NPH insulin, ultralente insulin, and continuous subcutane-ous infusion of insulin lispro was published.93 This investigationdemonstrated that after subcutaneous injection, NPH and ultralenteinsulin showed peaks in action at 4 and 10 hours, respectively, fol-lowed by a decrease in action, whereas glargine reached a plateau 3hours after injection and maintained a similar level for approxi-mately 24 hours without any peaks. The authors concluded thatglargine is a more optimal basal insulin replacement drug thatclosely resembles the effect given by the insulin pump.

Immunomodulation has also been attempted in the manage-ment of new-onset type 1 diabetes by using anti-CD3 monoclonalantibody therapy.94 The CD3 complex is a binding site on the T cellthat plays a role in antigenic activation of the cell. It was hypoth-esized that by interrupting this key component of the pathogenesisof type 1 diabetes, immune destruction of islet cells could be slowed.Therefore, within 6 weeks of diagnosis, 24 patients were given ei-ther a single 14-day course of antibody or no treatment. Nine of the12 patients treated with antibody either maintained or improved in-sulin production compared with only 2 patients who sustained in-sulin production in the nontreatment arm. The patients in the treat-ment arm also had superior glycosylated hemoglobin values and asmaller insulin requirement without severe adverse reactions. Themechanism of action of this therapy is still under investigation.

An article published simultaneously described an attempt toprevent type 1 diabetes in at-risk nondiabetic relatives of patientswith the disorder.95 These familymembers with islet cell antibodieswere randomly assigned to receive daily low-dose subcutaneous ul-tralente insulin plus annual 4-day continuous insulin infusions orclose observation for a median of 3.7 years. Unfortunately, duringthe course of the study, the treatment arm was not superior in pre-venting or delaying the onset of diabetes.

Type 1 diabetes may not yet be preventable, but type 2 diabetesin childhood often is because it almost universally has the comorbidcondition of obesity. A recent trial in adults showed that lifestylemodification including a 7% weight loss and 150 minutes of physi-cal activity per week was superior to either metformin or placebo inreducing the incidence of diabetes in an at-risk population.96 Met-formin was also better than placebo. This adult study is mentionedbecause few data are available on the treatment of type 2 diabetesand obesity in children. A recent review of drug therapy for obesity


discussed the limited options for treatment of children with theproblem.97

GROWTH HORMONEGrowth hormone has been hailed as a miracle drug for patients withnumerous medical conditions. However, the effect of growth hor-mone therapy in children with idiopathic short stature is controver-sial, prompting investigators to perform a meta-analysis to deter-mine the magnitude of effect on growth in children with thiscondition.98 Through their analysis of 28 trials, the authors con-cluded that 1-year growth velocitywas increased by 2.86 cmper yearin those treated, and that final adult height was increased by be-tween 4 and 6 cm. The cost per increased inch in heightwas approxi-mately $35,000. This controversy may be heightened by the reportthat the increase in height is not associated with improvements inquality of life or self-esteem in children with idiopathic short stat-ure.99

Two other studies examined the use of growth hormone in chil-dren with chronic renal failure and cystic fibrosis. The meta-analy-sis for growth hormone in renal failure found that growth increasedsignificantly in the first year by 4 cm, but the authors were unable tomake any conclusions about final adult height because of a lack ofdata.100 For cystic fibrosis, in a 1-year randomized trial, height wasincreased by 4.3 cm with coincident improvement in forced vitalcapacity.101

HEMATOLOGYSICKLE CELL ANEMIASickle cell anemia continues to be a condition associated with highmorbidity. One of themost common complications of the disorder isthe occurrence of painful vaso-occlusive crises. Standard therapyconsists of hydration, oxygen, and analgesics. A recent placebo-controlled, multicenter investigation determined that purifiedpoloxamer 188 was an effective adjunctive agent.102 The compoundis a nonionic block copolymer surfactant with antithrombotic prop-erties that also improves blood viscosity. Painful episodes were re-duced in duration, particularly among children younger than 15years and in those receiving concurrent hydroxyurea.

HEMOPHILIAAlthough intravenous and high-concentration intranasal desmo-spressin acetate have been used in patients with hemophilia A ormild type 1 von Willebrand disease to improve hemostasis, the in-


tranasal form has previously not been studied in young childrenwith these disorders. In an open-label trial, 25 children weighing 50kg or less with one of the disorders were given a single 150-µg intra-nasal dose of desmospressin acetate.103 Significant increases weredetected in factor VIII procoagulant activity, ristocetin cofactor, andvon Willebrand factor antigen. These levels were comparable tothose in patients given the intravenous formulation, suggesting thatthe intranasal route of administration is effective in these children.

NEONATOLOGY AND THE TRANSFER OF DRUGS FROMMOTHER TO INFANT

POSTNATAL CORTICOSTEROIDSIt has beenwell established that postnatal corticosteroid administra-tion improves and prevents neonatal chronic lung disease, alsoknown as bronchopulmonary dysplasia. This effect is attributed totheir anti-inflammatory properties. Controversy has arisen becausenumerous neonatologists have argued that the risks and side effectsof this therapy outweigh the potential benefits. Several of these con-cerns were realized in an investigation that compared a 10-daycourse of dexamethasonewith placebowhen given to 220 extremelylow birth weight infants (501-1000 g) within 24 hours of birth.104

Although the infants in the treatment arm had a reduced incidenceof oxygen dependence at 28 days of life, they were more likely tohave hypertension, an insulin requirement for hyperglycemia, andintestinal perforation. The infants also had more difficulty gainingweight and increasing their head circumferences. These data plusthe results of numerous other studies were considered in a joint po-sition statement from the American Academy of Pediatrics and theCanadian Paediatric Society that recommended against routine useof corticosteroids in very low birth weight infants.105 While ac-knowledging the improvement in short-term lung function, the com-mittees believed that the side effects and lack of long-term benefitsoutweighed any transient gains.

INDOMETHACIN AND IBUPROFENIndomethacin has long been the first-line treatment of choice for pre-mature newborns with a patent ductus arteriosus (PDA). Because ofthe toxicity of indomethacin, including impairments in renal, gas-trointestinal, and cerebral blood flow, efficacious alternatives havebeen desired. As such, investigators compared the safety and effi-cacy of intravenous ibuprofen with that of indomethacin in 148 pre-mature infants with a PDA.106 The 2 drugs given on the third, fourth,and fifth days of life had similar efficacy in closing the ductus, but


the ibuprofen arm was associated with significantly less oliguria.The same institution then reported significant intraindividual andinterindividual variation in the pharmacokinetics of ibuprofengiven to these infants, necessitating further investigation before itcan be considered a replacement for indomethacin.107

Another use for indomethacin has been the prevention of intra-ventricular hemorrhage in very low birth weight infants. To deter-mine the effects of prophylactic administration of indomethacin,574 infants were randomly assigned to receive either 3 days of treat-ment or placebo shortly after birth.108 Themedicationdid reduce theincidence of PDA, severe periventricular hemorrhage, and intraven-tricular hemorrhage, but there was no improvement in the mortalityrate or incidence of cerebral palsy, cognitive delay, hearing loss,blindness, seizures, hydrocephalus with shunt, or microcephaly.

FUNGAL INFECTIONInvasive fungal infections are becoming an increasingly significantcauseofmorbidity andmortality in lowbirthweight infants formanyreasons, including that younger and smaller infants often requiremore frequent, sometimes broader-spectrum antibiotic coverage. Todetermine the value of prophylactic use of the antifungalmedicationfluconazole, 100 extremely low birth weight infants were randomlyassigned to receive prophylacticmedication or placebo for the first 6weeks of life.109 The infants in the treatment arm were significantlyless likely tobecolonizedwith fungus, andnonehadan invasive fun-gal infection, comparedwith 20%of those in the placebo arm. Therewere no apparent adverse effects of the fluconazole.

APNEA OF PREMATURITYManyclinicianshaveattributedat least someof theepisodesof apneaofprematurity togastroesophageal refluxdisease (GERD). It isnotun-common, therefore, for medications used for the treatment of GERDtobe given topremature infants. Todetermine the effect of prokineticGERDmedications, investigators reviewed the charts of 132 patientsgiven either metoclopramide or cisapride to determine whether ap-nea episodes were reduced after initiation of treatment.110 Unfortu-nately, neithermedication reduced thenumber of apneic episodes inthe 5 days after initiation of treatment when compared with the pre-vious 5 days.

TRANSFER OF DRUGS FROM MOTHER TO INFANTDURING PREGNANCYAnticonvulsant drugs often cannot be discontinued when womenbecome pregnant. Previous reports have described an anticonvul-


sant embryopathy characterized by microcephaly, growth retarda-tion, andminor abnormalities of the face and fingers, but it has beenuncertain whether the medications or underlying disorder were re-sponsible for these features. To clarify this issue, infants born towomen with seizures both on and off anticonvulsants were com-pared with each other and also with those born to women withoutepilepsy.111 The infants born to women taking anticonvulsants hada higher incidence of abnormalities than controls, and this inci-dence increased when multiple anticonvulsants were used. Thoseinfants born towomenwith epilepsy not taking anticonvulsants hadno increase in the incidence of abnormalities.

Another group of medications often taken during pregnancy arenonsteroidal anti-inflammatory drugs (NSAIDs). Because thesedrugs have previously been associated with persistent pulmonaryhypertension of the newborn (PPHN), investigators sought to deter-mine the prevalence of NSAID use inmothers before newborn deliv-ery and its effect on the occurrence of PPHN.112 It is thought that thecyclooxygenase inhibition by NSAIDs leads to premature closure ofthe ductus arteriosus, with a subsequent increase in pulmonary ar-terial smooth muscle thickness and pulmonary arterial hyperten-sion. In this study, half of the infants born had detectable NSAIDs intheir meconium, with 87.5% of those infants with PPHN having de-tectable drug in their stool. Investigators concluded that these drugscould be potentially dangerous to the newborn infant. The authorsalso noted that a very small percentage of women recalled takingany NSAIDs when questioned.

Similarly, reports are surfacing concerning the relationship be-tween maternal and infant macrolide antibiotic use because of anassociation with subsequent infantile hypertrophic pyloric steno-sis.113 To evaluate this risk, a retrospective analysis was performedexamining the timing and usage of the drugs. The authors found acertain relationship between infantile oral erythromycin use in thefirst 2 weeks of life and development of pyloric stenosis, with noincreased risk from ophthalmic application. It is hypothesized thatsince the drug is a motilin agonist, the increase in antral motilitycauses strong gastric contractions, leading to hypertrophy. The au-thors also reported a possible association between maternal mac-rolides use in the 10 weeks before delivery, but this relationship didnot achieve statistical significance.

TRANSFER OF DRUGS FROM MOTHER TO INFANTTHROUGH HUMAN MILKBecausemanymedications takenbymothersachievesignificantcon-centrations in theirbreastmilkandsince theyoung infantmaybepar-


ticularly sensitive to someof thesemedications, theAmericanAcad-emyof Pediatrics recently reviewed the available data on the transferof drugs and other chemicals into human milk.114 The review in-cludes a list of medications and their reported signs and symptomswhen passed to an infant, as well as their effect on lactation. Particu-lar areas of focus include breast-feeding and smoking, psychotropicdrug use, and nursing for women with silicone breast implants. Al-though the committee provided details of those drugs to be avoidedor usedwith caution in pregnancy, it reported thatmostmedicationsprescribed to the nursing mother have no untoward effects on lacta-tion or the nursing infant. In the discussion describing smoking, thecommittee encouraged practitioners to recommend breast-feedingregardless of maternal smoking. It was argued that breast milk is stillsuperior to formula, and breast-feedingmay encourage themother torefrain from or reduce the amount of her smoking. For psychotropicmedication, thecommitteeacknowledged that theeffectsof thedrugsthat appear in milk during breast-feeding are largely unknown. Thereview does report that a commonly used selective serotonin reup-take inhibitor in pregnancy, fluoxetine,may be associatedwith colic,irritability, feeding and sleep disorders, and slow weight gain. Thiscluster of symptoms was echoed in a recent case report describingfluoxetine toxicity inabreast-fed infantwhosemother took themedi-cationduringpregnancy.115Becauseof the longhalf-life of theparentcompound and its metabolite, norfluoxetine, it was hypothesizedthat an infant exposed in utero and subsequently while nursingmaybe at greater risk for toxicity because of drug accumulation. The re-port concluded that considering current data, the presence of sili-cone breast implants is not a contraindication to breast-feeding.

TOXICOLOGYACETAMINOPHENAcetaminophen is widely regarded as a safe and effective analgesicand antipyretic medication. Repeated therapeutic doses over 48hours of therapy have been shown to be safe without evidence ofacetaminophen-induced hepatotoxicity.116 Because it is widelyavailable alone and in combination with other agents in OTC prepa-rations, both intentional and accidental toxic ingestions are not un-common. Its metabolism, nomogram for toxicity, and treatment ofoverdose are the subject of an extensive review.117

The American Academy of Pediatrics described the scope of ac-cidental toxic acetaminophen ingestion and strategies for its preven-tion and management in a recent position statement.118 The Com-mittee on Drugs’ recommendations included (1) that practitioners


address pain and fever management including dose, frequency, andduration of therapy at well-child visits; (2) that parents be madeaware of the need to read labels of combinationmedications; and (3)that health care providers consider acetaminophen in the differen-tial diagnosis of children with unexplained hepatic dysfunction.The use of N-acetyl-L-Cysteine (NAC) was also discussed. While thetraditional course of NAC has been 72 hours of treatment, the use ofshorter courses has been an area of recent controversy. To determinewhether shorter courses are safe in some patients with initially toxicserum levels of acetaminophen, investigators reviewed the charts of41 such patients.119 The authors found that laboratory data were un-reliable in predicting hepatotoxicity before 48 hours postingestion,and that courses shorter than 48 hours were inadvisable.

LEAD AND HEAVY METAL POISONINGBecause of the reduction in lead-containing products and improvedscreening methods, the incidence of lead poisoning has been signif-icantly reduced in recent years. Those living in older, deterioratedhousing remain the population at greatest risk. In 1991, the FDA li-censed the first orally active lead chelator, dimercaptosuccinic acidor succimer. To evaluate its safety and efficacy in children withblood lead levels between 20 and 44 µg/dL, 780 children between 12and 33 months of age were randomly given either succimer or pla-cebo for 26 days.120 Succimer was well tolerated and resulted in amean reduction in lead level of 4.5 µg/dLmore than placebo. Unfor-tunately, this treatment did not improve scores on tests of cognition,behavior, and neuropsychologic function, leading to the conclusionthat chelation therapy is not indicated for children with initial leadlevels of less than 45 µg/dL.121

Another potential source of lead ingestion is through the use ofalternative, herbal, or traditional Chinese medicines. A review ofheavy metals in traditional Chinese medicines reported that theseelements are not uncommonly found on evaluation of the drugs.122

The reasons for their presence include (1) intentional addition be-cause of alleged medicinal properties; (2) accidental contaminationduring manufacture; and (3) growth of herbs in contaminated soil.This topic is reinforced by a case report from Los Angeles that de-scribed a blood lead level of 86 µg/dL in a 4-year old child afterchronic ingestion of a Tibetal herbal vitamin.123

MISCELLANEOUSAMBLYOPIAPatching of the unaffected eye has long been the preferred treatmentof amblyopia, a leading cause of monocular blindness in childhood.


This treatment forces the child to use theweaker eye and itsmusclesto see, resulting in correction of strabismus. This method may havepoor compliance and potentially causes embarrassment for affectedchildren, but has remained the standard of care because of a lack oftherapeutic alternatives. A different approach that has been devel-oped is the application of atropine to the unaffected eye.124 Thismethod blurs the vision of the normal eye, forcing the child to usethe weaker eye to see. The 2 methods were compared in 419 chil-dren younger than 7 years with amblyopia and visual acuity be-tween 20/40 and 20/100. The investigators found that at 6 months,both methods were equally successful in improving vision.

JUVENILE RHEUMATOID ARTHRITISAnother condition in which immunomodulating agents are poten-tially helpful is juvenile rheumatoid arthritis. A recent review out-lined the definition, subtypes, prognostic factors, and current ap-proach to treatment of this condition.125 Nonsteroidal agentscontinue to be the first-line therapy of choice, with methotrexate asthe most common second-line drug. The roles of cyclooxygenase(COX)-2 inhibitors and the disease-modifying antirheumatic drugsincluding sulfasalazine, penicillamine, hydroxychloroquine, aura-nofin, and cylcosporine A are discussed. Finally, the great promiseheld by the immunomodulating agents such as leflunomide, entera-cept, and infliximab are discussed, even though most of the currentdata are from adults. Aswith somany other topicsmentioned in thisreview, the author concludes the review bymentioning the PediatricRule of the FDA and its importance in improving the pediatric phar-macologic data through clinical trials.

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79. Blaszak RT, Savage JA, Ellis EN: The use of short-acting nifedipine inpediatric patients with hypertension. J Pediatr 139:34-37, 2001.

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86. The Research Unit On Pediatric Psychopharmacology Anxiety StudyGroup: Fluvoxamine for the treatment of anxiety disorders in childrenand adolescents. N Engl J Med 344:1279-1285, 2001.

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