Characteristics of Children Receiving Proton Pump Inhibitors
Continuously for Up to 11 Years Duration
To characterize those pediatric patients who receive long-term proton pump inhibitors (PPIs) and to determine
the safety of long-term use of PPIs in this population.
Study design
Patient databases were screened for long-term PPI use, defined as more than 9 months of continuous
prescription, between 1989 and 2004.
The median duration of PPI use in the 166 patients in the study group was 3 years (range, 0.75 to 11.25 years). A
total of 80 patients used PPIs for 3 to 11 years duration; 35 of these for more than 5 years, and 15 for more than 8 years. Mean
age at initial prescription was 7.8 years. At least 1 gastroesophageal reflux disease (GERD)-predisposing disorder was present
in 79% of the patients; the major disorders were neuromotor (in 66%) and esophageal atresia (in 14.5%). No GERD-
predisposing disorder was present in 35 patients (21%). Endoscopic findings included hiatal hernia in 39% and histologically
proven Barrett’s esophagus in 4.8%. Omeprazole was used in 90% of the patients; lansoprazole, in 7%. Six adverse reactions
seen in 4 patients were potentially related to PPI (nausea and diarrhea, skin rash, agitation, and irritability).

Children with underlying GERD-predisposing disorders compose the majority of long-term PPI users. Few
adverse reactions to these drugs occur, and discontinuation of the drug is seldom indicated. These preliminary data suggest that
PPIs may be efficacious and safe for continuous use for up to 11 years’ duration in children. (J Pediatr 2007;150:262-7)

(GERD), whereas histamine-2-receptor antagonists (H2RAs) were widely usedfor milder disease. However, both of these modalities have significant short- comings. In children, surgery carries high rates of early failure and other whereas H2RAs are often ineffective in treating severe and their effect dimin-ishes over time, often within just a few weeks of Proton pump inhibitors (PPIs) From the Division of Gastroenterology, BCChildren’s Hospital/University of British Co- have the advantages of higher and faster rates of healing of esophagitis compared with W.K.) and the Gastroenterology andHealth Services Research Sections, Hous- As in adults, in children PPIs are highly efficacious and safe for treating GERD- related signs and symptoms, including the most severe degrees of reflux esophagitis, with cal Center and Baylor College of Medicine, rates of symptom relief and cure of esophagitis exceeding Thus it is not surprising that in children, as in adults, PPIs are increasingly being used not only in the Canada to the University of British Colum- short term for healing, but also for long-term maintenance of remission of GERD.
bia. Dr. El-Serag is a VA HSR&D awardee However, whereas the safety of omeprazole has been shown in adults for up to 11 years’ (RCD 00-013-2). The study sponsor playedno role in data collection, data processing, continuous safety data for prolonged use in children are not yet available. Studies or writing of the report, or in the decision have shown the efficacy and safety of omeprazole or lansoprazole therapy of up to 3 to submit the paper. The first and thirdauthors collaborated in the writing of the months’ duration in However, the longest period for which detailed PPI first draft of the manuscript, with input safety and efficacy data are available in children is for up to 2 years’ continuous use of In addition, there are few data indicating which children require long-term thors received any payment for producingthe manuscript.
Consequently, we aimed to characterize pediatric patients who receive long-term last revision received Jul 5, 2006; accepted treatment at our institution, and to examine the safety of long-term use of PPI in those Reprint requests: Eric Hassall, MD, Division of Gastroenterology, BC Children’s Hospi-tal, 4480 Oak St, Vancouver, BC V6H 3V4,Canada. E-mail: [email protected].
Table I. Patient age at index PPI prescription
In this retrospective cohort study, patient databases Frequency,
Cumulative frequency,
from British Columbia Children’s Hospital (BCCH) were Age, years
screened for long-term PPI use, defined as more than 9months of continuous prescription in patients with follow-up at BCCH. “Index date” was the date on which a PPI was first prescribed, marking the start of data collection. Potential PPI-related adverse drug reactions were identified and re- corded. The final encounter for the purposes of data collectionwas the last recorded visit in the patient’s chart up to August2004.
To identify and characterize a cohort of pediatric pa- were used for the statistical analyses. Descriptive statistics tients who had received long-term PPI therapy at BCCH, were generated. Comparisons between variables were con- clinical databases from January 1989 through August 2004 ducted using ␹2 tests for categorical variables and t-tests and were screened for the diagnosis of GERD and PPI use. These Mann-Whitney tests for continuous variables. Each patient included a database of gastrointestinal (GI) endoscopies per- was identified on the form by a unique study number, and formed, GI Division outpatient records, and BCCH inpatient charts, as well as databases of PPI users from previous clinical The study design was approved by the Clinical Research studies. The primary inclusion criterion was long-term PPI Ethics Board of the University of British Columbia and the use, defined as continuous prescription of drug for 9 months From these patient records, data were extracted and manually entered into a standardized purpose-designed 38- Patients
page data acquisition form. The data collected included pa- A total of 166 patients had a prescription for a PPI for tient demographics, associated medical disorders, signs and more than 9 months. The mean age of these patients at the symptoms of GERD at presentation and at the latest encoun- time of the index PPI prescription on record was 7.8 years ter, laboratory values, and adverse drug reactions. Associated (standard deviation [SD], 4.9) with a range of 4 weeks to 17 medical disorders were categorized as those predisposing to years Approximately 1/3 of the patients were age 5 GERD (specifically neurologic impairment, congenital years or younger, 1/3 were age 6 to 10 years, and the remain- esophageal abnormalities, previous esophageal surgery, cystic fibrosis, and other chronic pulmonary disorders), and thosenot predisposing to GERD (eg, disorders of the liver, heart, GERD-Predisposing and Non–GERD-Predisposing
and kidney and Helicobacter pylori status).
Details of PPI prescription included drug dose and the start and end dates for each PPI course, referred to as an At least 1 GERD-predisposing disorder was present in “episode.” A “PPI episode” referred to a new start of drug 131 of the 166 patients (79%). These GERD-predisposing (including the first), a change of dose, or a change of drug.
disorders included neuromotor impairment in 66% (with ce- “Exposure” to PPI was defined as the duration for which the rebral palsy in 48 [29%]) and other neurologic disorders or patient was prescribed the drug in a continuous fashion, that syndromes, with a major motor component in 62 patients is, total number of episodes or total number of days. For the same drug, a new PPI episode referred to each new start of atresia (with or without fistula) in 24 (14.5%); esophageal drug separated by at least 7 days from the previous episode.
duplication cyst in 1 (0.6%); and chronic lung disorders in 38 Adverse drug reaction information included the occur- (22.9%), including cystic fibrosis in 7 (4.2%) and other rence of new signs or symptoms deemed to be possibly due to chronic pulmonary disorders in 31 (18.7%). Several patients PPI and not to an intercurrent illness. Specifically, these were had multiple disorders from those mentioned above. Non– nausea, headache, diarrhea, vomiting, skin rash, abnormal GERD-predisposing disorders were present in 107 patients hepatic transaminase values, and abnormal serum urea or and included diabetes, chronic liver disease, Asperger’s syn- drome, and cardiac and renal disorders. The group of 131 The data acquisition form was designed using Tele- patients with at least 1 GERD-predisposing disorder and the form, an electronic data capture/management system pilot- 35 patients without any GERD-predisposing disorders are tested for the purpose of this study. An experienced research associate (W.K.) and the senior investigator (E.H.) extractedpatient data from source documentation and completed and Endoscopic Findings
submitted the forms. The data collection forms were subse- Approximately 74.7% of the patients (124/166) under- quently scanned into an Access database designed for the went an upper GI endoscopy on or before their PPI index study. SAS (version 9.1, SAS Institute, Cary, NC) datasets date; the rest underwent endoscopy at a later date. The Characteristics of Children Receiving Proton Pump Inhibitors Continously for Up to 11 Years Duration Table III. Comparison of several demographic, clinical, and PPI prescription features between pediatric
patients with and with GERD-predisposing disorders

GERD-predisposing disorders,
n ؍ 131 (79%)
None, n ؍ 35 (21%)
Median number of presenting symptoms (IQR) Proven histological Barrett’s esophagus, n (%) findings included erosive esophagitis in 81 patients (65.3%), Table IV. Duration of continuous-use exposure to
histological esophagitis in 20 (16.1%), and normal endoscopy and histology in 23 (18.6%). Esophageal stricture was presentin 15 patients (12.1%). Twelve patients (9.7%) had suspected Cumulative
Barrett’s esophagus, which was confirmed histologically in 8 Patients on PPI,
frequency of patients,
patients (4.8%) by the presence of goblet cell metaplasia with Years on PPI
acid mucin. As shown in there were no significant differences in the prevalence of these findings between the 2 groups with and without GERD-predisposing disorders. All but 1 of these 8 patients was age 11 years or older. During upper GI endoscopy, the locations of the major esophagogas- tric landmarks are routinely documented, and hiatal hernia is considered present if the tops of the gastric folds are proximal to the diaphragmatic pinchcock. By this criterion, hiatal her- nia was present in 28% of the patients with GERD-predis- posing disorders and in 11% of those without such disorders.
There were no significant differences in these findings be- tween the groups with and without GERD-predisposing dis- Median daily dose was 20 mg (range, 4 to 90 mg); median total dose-exposure per orders Only 7 patients (4.2%) exhibited evidence patient was 22 g (range, 2.2 to 178 g).
of H. pylori at index PPI prescription, all diagnosed by gastricbiopsy.
vomiting, abdominal pain, failure to thrive, and irritability. Ingeneral, symptoms were more frequent in those patients with Presenting Symptoms
Most of the patients (149; 90.9%) had more than 1 pre- Approximately 76% of the patients (n ϭ 126) reported senting symptom In the group with GERD-predis- at least 1 GERD symptom at their last visit; 24% had no posing disorders, significantly greater proportions of patients had symptoms. However, the median number of symptoms sig- Table V. Adverse drug reactions possibly related to PPI use
Time of onset
after index
Age, years
date, days
nificantly declined from 3 (interquartile range [IQR], 2) re- maximum was 4103 days (11.24 years). The daily dose ranged corded on the initial presentation to 1 (IQR, 1) recorded on from 4 to 90 mg; the median daily dose was 20 mg (IQR, 20 mg). Only 2 patients received 90 mg, and 11 received 80 mg.
The duration of follow-up and hence the duration of PPI Antireflux Surgery
exposure was significantly longer in patients with GERD- A total of 32 patients (19.3%) underwent fundoplica- predisposing disorders; however, there were no differences in tion, 23 before the PPI index date and 9 during follow-up.
the dose of PPI between the groups with and without For the 9 patients who underwent fundoplication after the PPI index date, the median time from that date to the surgery For omeprazole, the median number of episodes was 2 was 368 days (range, 97 to 1141 days). In those 9 patients, the (IQR, 3 episodes). The median duration was 897 days (IQR, stated or inferred reasons for fundoplication were poor re- 934 days). The median dose was 1.1 mg/kg (IQR, 0.9 mg/ sponse to PPI therapy in 6 and patient request in 3. Two of kg), and the total daily dose was 20 mg (IQR, 20.0 mg). The the 9 patients returned to PPI therapy during follow-up.
median absolute daily dose was 20 mg (range, 4 to 90 mg).
For lansoprazole, the median number of episodes of use per patient was 1 (IQR, 1), with a minimum of 1 and PPI Prescription
maximum of 3. The median duration of use per patient was The duration of continuous exposure to PPI is shown in 915 days (IQR, 930 days), with a minimum of 80 days and a The median duration of follow-up (between the maximum of 4108 days. The median dose was 1.4 mg/kg presentation date and date of last encounter) was 3.0 years. The (IQR, 1.7 mg/kg), with a minimum of 0.4 and a maximum of patients had PPI exposure for most of this time (median, 2.75 3.7 mg/kg. The median absolute daily dose was 30 mg (IQR, years). PPI prescription during the follow-up period was con- 45.0 mg), with a minimum of 7.5 and a maximum of 90 mg.
tinuous in 21 patients (13%), at least 65% of the time in 104patients (63%), and Ͻ 50% of the time in 31 patients (19%).
Most of the patients (141; 85%) used omeprazole only.
Adverse Drug Reactions
Seven patients (4.2%) used lansoprazole only; 1 used another Only 6 signs or symptoms possibly related to PPI use PPI only; 10 used omeprazole and lansoprazole (not concur- were seen in 4 patients (2.4%). The details of these events and rently); 5 used omeprazole and another PPI; and 2 used omeprazole, lansoprazole, and another PPI. The 166 patients had a total of 452 PPI episodes, of which 423 (93.6%) were of tribution of biochemical test values in the patients who un- more than 30 days’ duration. Omeprazole was prescribed in derwent more than 1 test. For example, of the 112 patients 405 of these episodes (89.6%), lansoprazole in 32 (7.1%), and who had more than 1 aspartate aminotransferase (AST) mea- surement, 80 (71.4%) were normal and 9 (8%) were “always A total of 136 patients (81.9%) had no gaps between abnormal.” Of those 9, none had values greater than twice the PPI episodes; that is, for the periods that they were prescribed upper limit of normal, and all were taking other medications medication, they took it continuously. In the remaining pa- concurrently with a PPI. Tests for hepatitis B and C were tients, the median duration of gaps in PPI episodes was 108 negative in the 5 patients tested. Three patients had AST days (IQR, 290 days). The median number of PPI episodes levels that went from normal at the first measurement to per patient was 2 (range, 1 to 8). The median duration of PPI abnormal at the last measurement, 3 had alanine aminotrans- prescription per patient was 916 days, approximately 2.5 years ferase (ALT) levels that did the same, and 1 had AST and (IQR, 923 days). The minimum was 273 days, and the ALT levels that did the same. Again, no patient had an Characteristics of Children Receiving Proton Pump Inhibitors Continously for Up to 11 Years Duration enzyme level higher than twice the upper limit of normal, and tomatic responses to PPI, and thus it is likely that most took tests for hepatitis B and C were negative in all 3 of the 7 patients tested. Use of other medications concurrently with a Of the 166 patients, 48% took a PPI for 3 to 11 years; PPI was common in this group; these medications included most (66%) were started on the drug at age 6 years or older.
anticonvulsant agents known to affect hepatic transaminase Although this reflects our approach over the period analyzed values. In the 2 patients in whom creatinine levels went from (January 1989 through August 2004), it does not necessarily normal to abnormal, the abnormal levels were only negligibly reflect our current practice; with more data and experience, we elevated (by Ͻ 5% above the upper limit of normal), and in have become increasingly comfortable starting PPI therapy in the 2 patients in whom creatinine levels were “always abnor- younger children, and not only for failures of H2RA. In the mal,” primary renal disease was present. There were no sig- present study, 14 patients were started on a PPI before age 1 nificant differences among the patients with abnormalities in year, but most of these patients were referred to us while creatinine, AST, or ALT in PPI type, dose, or duration, or in already receiving a PPI. This age group is under study for PPI the presence or type of comorbid disorders.
pharmacokinetic and safety parameters. Nevertheless, under 1year of age, we prescribe PPIs in only very carefully selected patients, as there are relatively few indications for PPI use in Some have alleged that long-term PPI therapy is over- used in For example, in various series, reported Although 76% of patients took a PPI for at least 2/3 of indications for PPI therapy were nonulcer dyspepsia in 6% to the time monitored, the patients with GERD-predisposing 21%, uninvestigated dyspepsia in 7% to 33%, and use of disorders had a significantly greater degree of exposure to nonsteroidal anti-inflammatory drugs (mostly uninvestigated) PPIs, indicating that they were less likely or able to withdraw in 5% to 42%; in 1 series, only 27% of the patients on from PPI therapy. Most of the documented experience in this study is with omeprazole. This is partly for historical reasons, though it is possible that the same trends might also apply because we started using it in children in 1989 and it was the children, there are no data supporting this, and in the present first PPI for which efficacy, dosing, and safety data were series, all children had GERD documented by investigation, available for children.The other PPI for which considerable including endoscopy. Therefore, our series focuses only on the pediatric data are now available is lansoprazole; the consider- severe end of the spectrum of GERD, those needing treat- able shorter-term data available suggest that efficacy and safety rates for this drug are similar to those for omepra- In this study, we identified and characterized a cohort of 166 children with GERD who were prescribed a PPI con- That PPIs are efficacious in even the most severely tinuously for a long duration. As is well recognized, certain affected children is confirmed by symptom resolution or disorders predispose persons to the most severe and chronic significant decrease in symptom frequency from presenta- tion to final visit. This was previously shown in shorter children—who often respond poorly to antireflux surgery— follow-up Along the same lines, it is not who stand to especially benefit from long-term PPI therapy.
surprising that the cohort maintained on PPI included a Most patients in this study had GERD-predisposing disor- significant proportion (14%) who had failed at least 1 ders and exhibited significantly more symptoms at presenta- antireflux procedure. The high failure rates of open and tion, a higher prevalence of failure to thrive, and a lower laparoscopic antireflux surgery in children are well recog- prevalence of nausea than those without underlying disorders and in our center, the number of new antireflux This profile is consistent with the nature of many surgery procedures has fallen from approximately 50 per of the underlying disorders themselves; children with neuro- year to 5 per year today. In our series, 9 patients (5%) on logic impairment and syndromes often are unable to report long-term PPI therapy were referred for surgery at the symptoms. Thus in this group, there should be a high degree physician’s or patient’s instigation, but 2 of these returned of suspicion for GERD based on observed physical signs as well as reported symptoms. Although only 21% of all our The endoscopic findings are of particular interest.
patients had no major underlying disorder, this study provides Hiatal hernia was found on at least 1 endoscopy in 39% of new information on the safety of PPI use in this group of the patients; this is a higher prevalence than reported patients, which is becoming increasingly more recognized and GERD-predisposing patients is not surprising— children There is no standard definition of what constitutes with neurologic disorders, repaired esophageal atresia, and “long-term” PPI We adopted an arbitrary definition of chronic lung disease have many reasons to develop at least 9 months of continuous prescription to avoid captur- But even in the absence of these disorders, hernias tend to be ing data on patients taking short courses of PPIs. Although our methodology does not allow us to determine compliance, Of the 12 patients (15%) with suspected Barrett’s our patients attended regularly for follow-up and prescription esophagus on endoscopy, 8 (5%) were documented. This is a renewal, were severely affected with GERD, and had symp- higher percentage than reported previously and suggests in children with severe GERD, Barrett’s esophagus may be more Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in prevalent than previously considered. However, this group of the treatment of erosive esophagitis: a meta-analysis. World J Gastroenterol2005;11:4067-77.
patients with severe GERD is highly selected, and thus the Huang JQ, Hunt RH. pH, healing rate, and symptom relief in patients with findings may not be generalizable to other settings.
GERD. Yale J Biol Med 1999;72:181-94.
The adverse drug reactions considered associated with Hyman PE, Garvey TQ 3rd, Abrams CE. Tolerance to intravenous ranitidine.
PPI therapy were nausea, vomiting, diarrhea, skin rash, and Hyman P, Hassall E: Marked basal gastric acid hypersecretion and peptic ulcer irritability. These occurred in only 4 patients. Although the disease: medical management with combination H2-histamine receptor antagonist and incidence of reactions was very low (6/528 patient-years), our anticholinergic. J Pediatr Gastroenterol Nutr 1988;7:57-63.
Nwokolo CU, Smith JT, Gavey C, Sawyer A, Pounder RE. Tolerance during 29 retrospective analysis likely underestimates their true inci- days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine.
dence. Nevertheless, it does appear that no serious reactions Aliment Pharmacol Ther 1990;4(suppl 1):29-45.
occurred, and that those that possibly may be attributable to Wilder-Smith CH, Ernst T, Gennoni M, Zeyen B, Halter F, Merki HS. Toler- PPIs were of sufficient discomfort or inconvenience so as to ance to H2-receptor antagonists. Dig Dis Sci 1990;35:976-83.
Gunasekaran TS, Hassall E. Efficacy and safety of omeprazole for severe gastro- cause permanent discontinuation of the drug in only 3 of the esophageal reflux in children. J Pediatr 1993;123:148-54.
166 patients. No significant effect on liver or renal function 10. Hassall E, Israel DM, Shepherd R, Radke M, Dalväg A, Sköld B, and the
International Pediatric Omeprazole Study Group. Omeprazole for treatment of chronicerosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and In conclusion, in the present study, most of the children dose requirements. J Pediatr 2000;137:800-7.
on long-term PPI therapy had an underlying systemic disor- 11. Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of
der that predisposed them to severe reflux. These children had lansoprazole in the treatment of gastroesophageal reflux disease in children. J PediatrGastroenterol Nutr 2002;35:S308-18.
more symptoms than those without such GERD-predispos- 12. Gunasekaran T, Gupta S, Gremse D, Karol M, Pan W-J, Chiu Y-L, et al.
ing conditions, but both groups experienced significant symp- Lansoprazole in adolescents with gastroesophageal reflux disease: pharmacokinetics, tomatic improvement from long-term PPI therapy. There pharmacodynamics, symptom relief efficacy and tolerability. J Pediatric Gastroenterol were no serious adverse drug reactions, and it was very seldom Nutr 2002;35(suppl 4):S327-35.
13. Fiedorek S, Tolia V, Huang B, Stolle J, Lee C, Gremse D. Efficacy and safety of
necessary to discontinue PPI therapy because of an adverse lansoprazole in adolescents with gastroesophageal reflux disease. J Pediatric Gastroen- reaction. Although prospective studies are needed to deter- mine the true prevalence of PPI-attributable reactions, this 14. Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, et al.
Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy,
preliminary study suggests that in children, long-term use of safety, and influence on gastric mucosa. Gastroenterology 2000;118:661-9.
PPIs is efficacious and may be safe for periods up to 11 years.
15. Hassall E, for the International Pediatric Omeprazole Study Group. Omeprazole
Although these findings should provide some reassurance to for maintenance therapy of erosive esophagitis in children [abstract]. Gastroenterology2000;118:A658.
pediatric prescribers and families, an important caveat is that 16. Raghunath AS, O’Morain C, McLoughlin RC. The long-term use of proton-
gastric acid has many important physiological functions, and pump inhibitors. Aliment Pharmacol Ther 2005;22(suppl):55-63.
the goal in healing should not be to make patients achlorhy- 17. Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastro-
dric. Further analysis of other parameters over time is needed, esophageal reflux disease. J Pediatr Gastroenterol Nutr 2002;35:119-36.
18. Hassall E. Co-morbidities in childhood Barrett’s esophagus. J Pediatr Gastroen-
such as gastric histology, vitamin B12 levels, and other nutri- 19. Hassall E. Mistaking ‘life’ (as we know it) for ‘disease’ [letter]. Am J Gastroenterol
20. Kassem NY, Groen JJ, Fraenkel M. Spinal deformities and oesophageal hiatus
Hassall E. Outcomes of fundoplication: causes for concern, newer options. Arch 21. Darling DB, Fisher JH, Gellis SS. Hiatal hernia and gastroesophageal reflux in
infants and children: analysis of the incidence in North American children. Pediatrics Marks RD, Richter JE, Rizzo J, Koehler RE, Spenney JG, Mills TP, et al.
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Characteristics of Children Receiving Proton Pump Inhibitors Continously for Up to 11 Years Duration Table II. Underlying neuromotor impairments
Table VI. Comparison of first and last recorded
laboratory values during an approximate 3-year

Syndromes with a major motor componentء
follow-up of 166 pediatric patients with GERD
Number of
First lab result
Last lab result
patients (%)
MicrocephalyMitochondrial disorderRett syndromeTrisomy 21VACTERL associationX-linked mental retardation Neurologic disorders without syndromes†
Autism with motor componentBrainstem dysfunction NYDCerebral palsy, etiology unknownCentral nervous system lupusGlobal delay NYDPerinatal hypoxiaPostencephalitisPosttraumaticPrematurity *Some disorders were present in more than 1 patient; for example, 2 patients had Downsyndrome, and 3 had mitochondrial disorder.
†Many of these diagnoses were present in more than 1 patient; for example, several hadcerebral palsy-etiology unknown, and 3 had neuromotor impairment postencephalitis.


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D O I 1 0 . 1 1 1 1 / j . 1 3 6 5 - 2 1 3 3 . 2 0 0 7 . 0 8 2 8 6 . xEfficacy of tetracyclines in the treatment of acne vulgaris:a reviewT. Simonart, M. Dramaix* and V. De Maertelaer Department of Dermatology, Erasme University Hospital, 808 Route de Lennik, B-1070 Brussels, Belgium*Department of Biostatistics, School of Public Health, Universite´ Libre de Bruxelles, Brussels, Belgium Depart

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