August 2001
TRENDS
In Pediatric Pharmacology
and Toxicology
Volume 3, Number 7, August, 2001
Abstracts
Otitis media with effusion (OME) is a common disorder seen in many pediatric
offices. It is characterized by an accumulation of fluid in the middle ear in the
absence of acute inflammation and is the most common cause of acquired hearing
loss in children. It is often the result of recurrent otitis media. Currently, the only
treatment option available is the placement of ventilation tubes. However, steroids
have been considered but their efficacy is controversial. An extensive literature
search of randomized-controlled trials of oral and topical nasal steroid treatment in
OME was conducted. Ten of the best studies were evaluated. Enrollments ranged
from 15 to 274 children. Overall, steroids alone or combined with an antibiotic
lead to shortened time for OME resolution. In 4 of the 10 studies, long-term
benefit was evaluated, and there was no benefit for the prevention of hearing loss.
The authors concluded that "these treatments are, therefore, not recommended".
Butler CC et al. Steroids for Otitis Media with Effusion. A Systemic Review. Arch Pediar
Adolesc Med. 2001; 155: 641- 7
It is believed that the judicious use of antibiotics will prevent (or slow down) the
incidence of bacterial resistance. Thus, educating the prescribers and the parents
who ask for the medications may decrease inappropriate antibiotic use. Twelve
practices were randomized to intervention or control groups. The intervention
included meetings with the physician practice using CDC prescribing
recommendations, mailers to the parents on antibiotic use, and supporting
materials in the waiting rooms. The most common diagnoses accounting for
antibiotic courses included otitis media, sinusitis, pharyngitis, and colds/coughs. In
children 3 to 36 months of age, antibiotic prescriptions decreased significantly in
the intervention group compared to the control. Similar reductions were seen in
the older age group.
Finkelstein JA et al. Reducing Antibiotic Use in Children: A Randomized Trial in 12
Practices. Pediatrics. 2001; 108: 1- 7
Editor's Note: This study not only documented a decrease in antibiotic prescribing in the
intervention group, but also in the control group. This would lead to the conclusion that a little
education may go a long way. Bringing the issue to the attention of physicians and other prescribers
(e.g., nurse practitioners) and increasing parental education can only help in the fight against
bacterial resistance from inappropriate prescribing.
In the recent past, the medical literature and lay press have documented a drastic
increase in the use of psychotropic drugs in children and adolescents. This largely
has been associated with methylphenidate and other stimulants for the treatment of
ADHD. Researchers sought to describe the prescribing trends for stimulants,
serotonin - reuptake inhibitors (SSRI) and combination prescriptions in the
Medicaid population in North Carolina. A retrospective population-based analysis
of prescription claims files was performed. Annual number of prescriptions,
patients filling a presciption claim, and the prevalence for stimulants and SSRIs
were reviewed. The number of children who received stimulant prescriptions
increased from 6407 in 1992 to 27,951 in 1998. The number of children who
received prescriptions for SSRIs increased from 510 children in 1992 to 25,392
SSRI claims in 1998. Age, sex, and racial differences were apparent. The increase in
the prevalence of combination therapy was also noted. The authors state that the
"increase use does not necessarily equal inappropriate use". However, more
information is needed on the long-term safety and efficacy of these drugs in young
children.
Rushton JL, et al. Pediatric Stimulant and Selective Serotonin Reuptake Inhibitor Prescription
Trends. Arch Pediatr Adolesc Med. 2001; 155: 560-5
Editor’s Note: It must be recognized that the use of these drugs should only be contemplated
when the proper diagnosis of ADHD is made by properly trained medical professionals using
proper (i.e., standardized) methods.
Athletes, including adolescents, try to gain an advantage over their competitors.
Unfortunately, one way is to take performance enhancing drugs, such as creatine,
a naturally occurring nitrogen compound found in skeletal muscle. It is thought
that increasing creatine levels may prolong skeletal muscle activity, thus enhancing
work output. Taking exogenous creatine may propose problems, especially for the
adolescent. A survey of adolescent athletes was performed to assess the use of oral
creatine in southeast Tennessee and northwest Georgia. Of the 674 athletes
surveyed, all complied. Five hundred four of the athletes (75%) were aware of
creatine supplements, and 110 (16%) used them. Awareness and use was
significantly higher in males and use increased with age. They were most likely to
learn of the drug through a friend (43%), media (22%), or an athletic coach (19%).
The majority took a "loading dose" followed by a maintenance dose. Twelve of the
110 (11%) reported using other performance enhancers including androstenedione.
Ray TR, et al. Use of Oral Creatine as an Ergogenic Aid for Increased Sports Performance:
Perceptions of Adolescent Athletes. S Med J 2001; 94: 608-12
Editor's Note: Although the author's state that these athletes should be "provided with
accurate information about the true benefits…as well as proper instructions on how to take the
supplements and the associated risks", there are no controlled trials of this "dietary supplement"
that support existing claims of effect.
Another important part of the adolescent history includes occupation and
exposures to potentially harmful risks, including exposure to toxins. Few
incidents regarding exposure to harmful toxins will be reported; however, poison
centers may be called about the adverse effects. Occupational toxic exposures
occurring in the US were analyzed using the Toxic Exposure Surveillance System
database compiled by the American Association of Poison Control Centers. The
authors found that among over 300,000 workplace toxic exposures reported over 5
years, 3% (8779) involved adolescents younger than 18. The most common agents
involved were alkaline corrosives, gases and fumes, cleaning agents, bleaches,
drugs, acids, and hydrocarbons. One-third of the exposures required medical
attention. Injuries were severe in 14% of cases with 2 deaths occurring. Adolescent
occupational toxic exposures are under- recognized in the US and should be
addressed when seen by their primary care provider.
Woolf, A, et al. Adolescent Occupational Toxic Exposures. A National Study. Arch Pediatr
Adoleesc Med. 2001; 155; 704- 10
Recent & Relevant Review
Cystic fibrosis (CF), the most common, lethal, genetic disorder in Caucasians, is a
multisystem disease affecting approximately 30,000 people in the US. Chronic
obstructive pulmonary disease, the primary complication of CF, is responsible for
more than 90% of disease-related morbidity and mortality in these patients. The
pulmonary disease is largely related to a continuous cycle of airway obstruction,
chronic infection, and excessive local inflammation that leads to development of
end-stage bronchiectasis. The recurrent acute bacterial exacerbations stimulate an
excessive inflammatory response. This local inflammation alters lung integrity
and worsens airway obstruction.
The inflammation is characterized by persistent and excessive neutrophil
infiltration. The degradation of neutrophils leads to release of DNA and
destructive oxidases and proteases, including neutrophil elastase. Neutrophil
elastase damages the airway wall ultimately leading to bronchiectasis. Neutrophils
and macrophages stimulate the production of pro-inflammatory cytokines and
chemokines. Usually, pulmonary epithelia are protected by the adverse effects of
neutrophil elastase. However, the excessive amounts of inflammatory mediators
overwhelm the normal pulmonary protective mechanisms leading to structural
damage.
The inflammation begins early in patients with CF and is present even in the
absence of symptomatic pulmonary disease. However, the etiology of chronic
inflammation remains unclear. It is largely accepted that chronic bacterial infection
and colonization result in pulmonary inflammation. However, evaluation of
bronchoalveolar fluid from young children with no infection revealed substantial
inflammation. Comparing the amount of inflammation in children with CF to
children with other chronic respiratory conditions reveals a greater inflammatory
response in patients with CF. Investigators believe that the CF airway epithelial
cells actively produce IL-8 and express large amounts of intercellular adhesion
molecule 1 (ICAM-1), a pro-inflammatory adhesion molecule. Resultant chronic
inflammation damages the airway wall, ultimately leading to bronchiectasis and
progressive decline in pulmonary function.
Antiinflammatory therapy is a new strategy for treating CF pulmonary disease as it
is directed at one of the primary pathophysiologic mechanisms causing progressive
pulmonary disease. The primary goal is to reduce the rate of decline in pulmonary
function, thereby slowing the disease progression. Efforts are largely focused on
reducing local neutrophil infiltration using corticosteriods (oral and inhaled) and
ibuprofen.
Oral corticosteroids are commonly used for refractory airflow obstruction and
steroid-responsive wheezing. They have been considered to have a role in reducing
local inflammation and rate of decline in pulmonary function. However, their
mechanism in reducing CF- related inflammation is largely unknown. It has been
proposed that they may inhibit neutrophil synthesis and neutrophil priming in the
active state. They may also inhibit neutrophil migration by blocking chemotaxins,
such as IL-8. The safety and efficacy of long-term corticosteriod therapy has been
evaluated. One study documented a significant improvement in FEV1 in
prednisone treated subjects; however, important adverse events occurred including
growth impairment, glucose intolerance, cataract formation and multiple bone
fractures. The authors noted that these same adverse events may be seen in CF
patients as part of their disease progression. Low dose corticosteroids may be as
beneficial as high dose therapy with fewer associated adverse events. Therapy
should be discontinued if no benefit is observed after 6 months and should be
limited to 24 months to minimize the risk of adverse events. The lowest dosage
that sustains the desirable antiinflammatory effects should be given, with periodic
functional assessment of the hypothalamic-pituitary-adrenal axis. Few CF centers
use this therapy most likely secondary to the questionable long-term safety
associated with it.
Inhaled corticosteroids have been considered for treatment of pulmonary
inflammation in patients with CF. Initial studies focused on short-term effects of
high dose inhaled steroids on pulmonary function and bronchial hyperresponsiveness. While symptoms improved, there was not a significant difference
in FEV1 between inhaled steroids and placebo. However, the majority of the trials
were performed in adults who often already have irreversible lung damage. Data
regarding the antiinflammatory effects of inhaled corticosteroids in children with
CF is limited. Despite the potential benefits, the risk of systemic adverse events
remains a concern. This may be especially true in patients with CF, as high dosages
are needed to facilitate lung penetration. Given the lack of available clinical data,
routine inhaled corticosteroid treatment should be restricted to patients with
concomitant asthma or steroid- responsive wheezing.
Ibuprofen has been evaluated as an alternative to corticosteroids for the
management of CF-related airway inflammation. Ibuprofen inhibits neutrophil
migration and release of lysosomal enzymes that contain elastase. Because the
antiinflammatory effects are concentration dependent, target peak plasma
ibuprofen concentrations of 50- 100 mcg/ml are recommended. Pharmacokinetic
monitoring may be necessary as there is substantial interindividual variability in
ibuprofen pharmacokinetics associated with bioavailability, patient-age (i.e.,
development) and potentially, the CYP2C9 polymorphism. In a placebo- controlled
clinical trial assessing the effects of long-term, high dose ibuprofen in patients with
CF who had mild pulmonary disease, a slower annual rate of change in FEV1 was
seen in the treatment group. There were no significant differences in
hospitalization or adverse events. The greatest benefit of ibuprofen was in the
youngest patients (aged 5-13 yrs) who were compliant. The Cystic Fibrosis
Foundation advocates high-dose ibuprofen for patients aged 5-12 years with an
FEV1 greater than 60% of predicted.
Antiinflammatory therapy in CF patients is controversial, and, although there may
be benefit if instituted early in the course, there is lack of long-term, definitive
trials. The limited risk:benefit ratio may also preclude their use. Conclusive
recommendations regarding antiinflammatory therapy in CF patients await results
of good clinical trials in adults and children.
Kennedy MJ. Inflammation and Cystic Fibrosis Pulmonary Disease. Pharmacotherapy. 2001;
21: 593-603
Current Clinical Research
Phase II pharmacokinetic studies of linezolid (a new antibiotic) in neonates and
children 3 mo-6 years years, MK826 (a new carbapenem) in children 2-23 months ,
FK463 (a new antifungal) in neonates, levofloxacin 3 mo-17 years, and
fexofenadine 3 mo-2 yrs are being conducted. If you are caring for a patient that
may be eligible for enrollment, please contact Clinical Pharmacology (234-3059) or
you may page Mike Venneman, RN (821-9911).
Editors
Jennifer Lowry, M.D.
Mary Jayne Kennedy, Pharm.D.
Martin Behm, M.D.
Gregory L. Kearns, Pharm.D., FCP
Gary S. Wasserman, D.O.