Drugs In Pediatric Patients Research Articles

Contribution of Gag and Protease to HIV-1 Phenotypic Drug Resistance in Pediatric Patients Failing Protease Inhibitor-Based Therapy.

Protease inhibitors (PIs) are used as a first-line regimen in HIV-1-infected children. Here we investigated the phenotypic consequences of amino acid changes in Gag and protease on lopinavir (LPV) and ritonavir (RTV) susceptibility among pediatric patients failing PI therapy. The Gag-protease from isolates from 20 HIV-1 subtype C-infected pediatric patients failing an LPV and/or RTV-based regimen was phenotyped using a nonreplicativein vitroassay. Changes in sensitivity to LPV and RTV relative to that of the matched baseline (pretherapy) sample were calculated. Gag and protease amino acid substitutions associated with PI failure were created in a reference clone by site-directed mutagenesis and assessed. Predicted phenotypes were determined using the Stanford drug resistance algorithm. Phenotypic resistance or reduced susceptibility to RTV and/or LPV was observed in isolates from 10 (50%) patients, all of whom had been treated with RTV. In most cases, this was associated with protease resistance mutations, but substitutions at Gag cleavage and noncleavage sites were also detected. Gag amino acid substitutions were also found in isolates from three patients with reduced drug susceptibilities who had wild-type protease. Site-directed mutagenesis confirmed that some amino acid changes in Gag contributed to PI resistance but only in the presence of major protease resistance-associated substitutions. The isolates from all patients who received LPV exclusively were phenotypically susceptible. Baseline isolates from the 20 patients showed a large (47-fold) range in the 50% effective concentration of LPV, which accounted for most of the discordance seen between the experimentally determined and the predicted phenotypes. Overall, the inclusion of thegaggene and the use of matched baseline samples provided a more comprehensive assessment of the effect of PI-induced amino acid changes on PI resistance. The lack of phenotypic resistance to LPV supports the continued use of this drug in pediatric patients.

Disease-modifying drugs in pediatric patients with multiple sclerosis

The vast majority of therapies are being evaluated and introduced for the treatment of adult multiple sclerosis (MS). A role of these drugs in the management of pediatric MS has yet to be defined both in Russia and in the whole world. Despite the fact that today the study of new drugs in the pediatric population have included in routine practices of the big pharmaceutical agencies, such as FDA and EMA, recommendations for the treatment of pediatric patients with MS are based not so much on a long period of systematic clinical research, but on professional consensus of international expert associations, in particular, the International pediatric multiple sclerosis study group (IPMSSG). The clinical trials include the small number of patients which is not comparable to those conducted in adults. Therefore, there is a need for study designs for assessment of efficacy and safety of the drugs for MS treatment in children and adolescents. The authors present the IPMSSG concept on the treatment of pediatric MS taking into account peculiarities of the Russian legislation and experience of national experts.

Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis.

BackgroundEncephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy.Patients and MethodsCases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed.ResultsDuring the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects.ConclusionsChildren with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy.

Comparison of Drug Utilization Patterns in Observational Data: Antiepileptic Drugs in Pediatric Patients.

Physicians require information on the comparative benefits and harms of medications for optimal treatment decisions. However, this type of data is limited, especially for pediatric patients. Our aim was to use observational data to measure and compare medication utilization patterns in a pediatric patient population. Using pharmacy claims data from a large, national-scale insurance program in the USA, we identified all patients with a diagnosis of epilepsy treated with a first-generation antiepileptic drug (carbamazepine, ethosuximide, phenobarbital, phenytoin, or valproate) or a second-generation antiepileptic drug [carbamazepine extended release (XR), gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, valproate XR, or zonisamide]. Treatment periods were defined on the basis of prescription fill dates and medication days supplied. Medication use was measured for individual antiepileptic drugs and for first-generation and second-generation drugs as groups. There were 2527 patients (54 %) who initiated therapy with first-generation antiepileptics and 2139 patients (46 %) who initiated therapy with second-generation antiepileptics. First- and second-generation drugs had the same 1-year retention rates [26 % (95 % confidence interval (CI) 24-28) and 26 % (95 % CI 25-28), respectively], and 26 % of patients (95 % CI 25-28) and 29 % of patients (95 % CI 27-31) who started on a first- or second-generation antiepileptic medication, respectively, resumed treatment with the initial drug after discontinuation. Overall, 73 % of patients (95 % CI 71-74) were treated with only one antiepileptic drug, with similar rates for patients started on first- and second-generation drugs [71 % (95 % CI 69-73) versus 74 % (95 % CI 72-76)]. Comparing drug utilization patterns in a pediatric population using observational data, we found similar rates of retention and therapeutic changes. These findings are consistent with the available comparative data and demonstrate an approach that could be extended to other drug classes and conditions in pediatric populations to examine drug effectiveness.

Evaluation of safety in exceeding maximum doses of commonly used antiepileptic drugs in pediatric patients (P4.271)

Evaluation of safety in exceeding maximum doses of commonly used antiepileptic drugs in pediatric patients (P4.271)

Hypersensitivity to non-steroidal anti-inflammatory drugs in pediatric patients

Results Medical records of 104 individuals with a history of hypersensitivity to drugs were analyzed. NSAIDs were the primarily suspected drug in 50% of the cases. The mean age was 10.9 years, with a predominance of males (57.7%). All patients had cutaneous manifestations and isolated angioedema was observed in the majority (53.8%); respiratory symptoms were reported in 44% of cases and gastrointestinal manifestations in 7.6%. Most of the patients reported reactions to more than one NSAID (71%) and dipyrone was the main drug reported in this group (34%), as in the group who had reactions to a single NSAID (73%). All reactions occurred in less than 24 hours after the drug use and 69.2% were of moderate severity. The ER was the main site searched for the treatment of the reactions (88%). During diagnostic investigation 38 oral provocation tests were performed, with positive results in 8 (5 ASA, 1 Ibuprofen, 1 Acetaminophen, 1 Dipyrone). Conclusions The reactions to NSAIDs in pediatric patients are more frequent in males. Angioedema alone was the main clinical manifestation and dipyrone the main drug involved in the reactions. The OPT proved to be an important tool to confirm or exclude the diagnosis of hypersensitivity, with the possibility of providing safer alternatives for those patients with proven reaction.

Achieving therapeutic vancomycin levels in pediatric patients.

Vancomycin is widely used to treat infections caused by methicillin-resistant Staphylococcus aureus. Data for dosing and monitoring of this drug in pediatric patients are lacking, and clinicians who are treating children often follow guidelines established for adults. To examine the total daily doses of vancomycin required to reach therapeutic trough levels (i.e., 10-20 mg/L) in infants, children, and adolescents, and to assess the number of pediatric patients in whom therapeutic trough levels are achieved with current empiric doses (40-60 mg/kg daily). This chart review evaluated patients 1 month to 18 years of age for whom vancomycin was prescribed at a single institution between November 2011 and October 2012. Patients' demographic characteristics, vancomycin dosing parameters, and subsequent steady-state trough concentrations were analyzed. Overall, the proportion of patients who reached therapeutic trough levels with current empiric doses was 39% (74 of 188). The mean total daily dose (± standard deviation) required to achieve therapeutic trough levels was 57.8 ± 11.5 mg/kg for patients 1 to 5 months of age, 68.9 ± 15.4 mg/kg for those 6 to 23 months of age, 65.8 ± 13.0 mg/kg for those 2 to 12 years of age, and 55.7 ± 11.8 mg/kg for those 13 to 18 years of age. Common empiric vancomycin dosing regimens (40-60 mg/kg daily) are not high enough to achieve trough levels of 10-20 mg/L in the majority of pediatric patients. Given these data, the authors suggest a starting dose of 60 mg/kg daily for patients 1 to 5 months of age and those 13 to 18 years of age and a starting dose of 70 mg/kg daily for patients 6 months to 12 years of age.

Pharmacological interaction between valproic acid and carbapenem: What about levels in pediatrics?

Valproic acid (VPA) is the most commonly used antiepileptic drug in pediatric patients, but its major drawback is its multiple pharmacological interactions. ObjectiveTo study children who had been simultaneously treated with carbapenems and valproic acid, considering drug levels, pharmacological interactions and clinical follow-up. Material and methodsRetrospective study of children who simultaneously received treatment with VPA and carbapenems between January 2003 and December 2011. Demographic variables, indication of treatment, dose, VPA plasma levels, interactions, clinical manifestations and medical management were analyzed. Results28 children with concomitant treatment with both drugs were included in the study. 64.3% were males. 78.6% of the interactions were observed in the Intensive Care Unit. 60.7% of children had been previously treated VPA and its major indication were generalized seizures. Basal plasma levels of VPA were recorded in 53% and at 24 h after admittance in 60%. “40% of basal VPA levels were below therapeutic range prior to the administration of carbapenem. After the introduction of carbapenem 88% of level determinations were below therapeutic range”. 54.5% of the patients that were chronically receiving VPA and had good control of epilepsy before admission had seizures during the coadministration. One patient that was on VPA before admission but with bad control of epilepsy worsened, and one patient that acutely received VPA did not achieve seizure freedom. In these cases it was necessary to either increase VPA dose or change to a different antiepileptic drug. ConclusionsLittle is known about the mechanism of pharmacologic interactions between carbapenems and VPA, but it leads to a reduction in plasma levels that may cause a loss of seizure control, so simultaneous use of both drugs should be avoided when possible. If not, VPA levels should be monitored.

Tissue Plasminogen Activator for the Treatment of Parapneumonic Effusions in Pediatric Patients

Intrapleural fibrinolysis has been investigated for the treatment of pleural effusion for several decades. Fibrinolytics have the ability to break up fibrin and loculations that characterize complicated pleural effusions, facilitating drainage. Older fibrinolytics such as urokinase and streptokinase have been replaced by tissue plasminogen activator (tPA) for this indication due to product availability and a more favorable safety profile. The literature supports tPA as a treatment approach for this indication in adult patients, and the use of tPA has become a standard management approach in this population. Over the past decade, data on the efficacy of intrapleural fibrinolytic therapy in children have also been generated, which now support the use of fibrinolysis as a treatment alternative to more invasive therapeutic options such as surgical intervention. In this review, we discuss the pathophysiology, diagnosis, and treatment of parapneumonic effusion and empyema, with a focus on intrapleural fibrinolysis, specifically tissue plasminogen activator, in the pediatric population. Recent articles provide sufficient evidence to support the use of this drug in pediatric patients for the management of pleural effusions; however, due to study heterogeneity, questions remain that may be addressed in future studies.

ECG parameters in children and adolescents treated with aripiprazole and risperidone

Atypical antipsychotics (AP) are increasingly being used in children and adolescents for the treatment of psychiatric disorders. Atypical AP may cause QT prolongation on the electrocardiogram (ECG), which predisposes patients to an increased risk of developing threatening ventricular arrhythmias. Although this phenomenon has been exhaustively reported in adults, few studies investigated the safety of these drugs in pediatric patients. We performed an open-label, prospective study to assess the arrhythmic risk of aripiprazole and risperidone in a pediatric population. A total of 60 patients (55 M/5F, mean age 10.2+2.6 years, range 4-15 years), receiving a new prescription of aripiprazole or risperidone in monotherapy underwent a standard ECG before and after two months from the beginning of antipsychotic treatment. Basal and post-treatment ECG parameters, including mean QT (QTc) and QT dispersion (QTd), were compared within treatment groups. Twenty-nine patients were treated with aripiprazole (mean dosage 7.4+3.1mg/day) and 31 with risperidone (mean dosage 1.5+1mg/day). In our series, no patient exhibited pathological values of QTc or QTd before and after treatment for both drugs. However, treatment with risperidone was associated with a slight increase of both mean QTc and QTd values (407.4+11.9 ms vs 411.2+13.0 ms, p<0.05; and 40.0+4.4 ms vs 44.7+5.5 ms, p<0.001, respectively). Treatment with aripiprazole was associated with no changes of mean QTc, even if a small increase of QTd, (40.6+6.5 ms vs 46.3+7.2 ms, p<0.01) was observed. Although our data suggest a slight effect of aripiprazole and risperidone on ventricular repolarization, it is unlikely that such a change results in clinically relevant effects. The treatment with risperidone and aripiprazole in children with psychiatric disorders is not associated with clinically relevant modifications of QT interval. Caution in prescribing these drugs, however, is necessary in patients with family history of a genetic predisposition to arrhythmias in order to warrant a reliable assessment of drug-induced QT prolongation.

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.

How to Improve the Implementation of Academic Clinical Pediatric Trials Involving Drug Therapy? A Qualitative Study of Multiple Stakeholders

ObjectiveThe need for encouraging pediatric drug research is widely recognized. However, hospital-based clinical trials of drug treatments are extremely time-consuming, and delays in trial implementation are common. The objective of this qualitative study was to collect information on the perceptions and experience of health professionals involved in hospital-based pediatric drug trials.MethodsTwo independent researchers conducted in-depth semi-structured interviews with principal investigators (n = 17), pharmacists (n = 7), sponsor representatives (n = 4), and drug regulatory agency representatives (n = 3) who participated in institutionally sponsored clinical trials of experimental drugs in pediatric patients between 2002 and 2008.ResultsDissatisfaction was reported by 67% (16/24) of principal investigators and pharmacists: all 7 pharmacists felt they were involved too late in the trial implementation process, whereas 11 (65%) principal investigators complained of an excessive regulatory burden and felt they were insufficiently involved in the basic research questions. Both groups perceived clinical trial implementation as burdensome and time-consuming. The sponsor and regulatory agency representatives reported a number of difficulties but were not dissatisfied.ConclusionsThe heavy burden related to regulatory requirements, and suboptimal communication across disciplines involved, seem to be the main reasons for the major delays in pediatric drug trial implementation. The pharmaceutical aspects are intrinsically tied to trial methodology and implementation and must therefore be examined, in particular by involving Clinical Research Pharmacists at early stages of study conception.

US Perspective on Off‐label Use in Pediatrics

JPGN Volume 56, N T he evaluation of off-label use published by Ruiz-Antoran et al (1) in this issue of the Journal of Pediatric Gastroenterology and Nutrition provides an opportunity to discuss evolving US legislative measures to improve available clinical trial–derived pediatric data and provide coherent labeling for pediatric providers in dosing of drugs for children. Dr Ruiz-Antoran et al present findings of frequent off-label use of drugs in a Spanish outpatient pediatric gastroenterology clinic, which appear generally consistent with the use of off-label drugs in the United States (1–4). There are multiple reasons why providers may prescribe drugs off-label. Providers may not be aware that they are prescribing off-label, or may intentionally choose off-label treatments that are supported by widely accepted recommendations or treatment guidelines (1). Providers may also prescribe drugs off-label because other on-label treatments have been ineffective, or because there is an established effect from that class of medications (5). Also, off-label prescribing may be necessary to provide a product in a pediatric-appropriate strength and formulation (6). The potential negative effect of off-label prescribing in pediatric patients has been evaluated, but the direct relation between off-label prescribing and adverse events has not been definitively established, as noted by Ruiz-Antoran et al (1,7). The potential for adverse reactions associated with off-label drug use exists and steps, such as regulation, clinical practice guidelines, and local initiatives, to decrease adverse reactions associated with off-label use of products are described (1). Given the breadth of potential reasons for off-label prescribing, no one approach appears likely to address all the reasons providers may choose off-label prescribing (2,5,8). In the United States, legislation designed to encourage the appropriate use of drugs in pediatric patients may decrease the frequency of adverse

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Pediatric News

Drug Development

Drug Development

Laws Boost Pediatric Clinical Trials, But Report Finds Room for Improvement

LAWS REQUIRING OR ENCOURAGING pharmaceutical companies to conduct pediatric clinical trials of medications are helping clinicians gain useful information, according to a report from the Institute of Medicine (IOM). But the authors also identified the need for improvements, such as greater transparency about trial results and greater clarity about the potential benefits a trial may offer children. Mostdrugshaveneverbeenstudied in children, yet physicians often prescribe products studied in adults to children without thebenefitofclinicalevidenceto supportthesafetyandefficacyoftheproduct for the patient’s age group and without evidence-based information on dosing. Although this off-label use is a legal andacceptedclinicalpractice,itcansometimes have unintended consequences. Physiologicaldifferencesbetweenadults and children may mean that a drug that is safe and effective in adults may not be so in children or that scaling down adult dosingregimensbasedonweightmaynot beappropriate.Forexample, theIOMreport (http://tinyurl.com/6oqk65r)notes that in 1982, 16 premature infants died from respiratory complications after receivingintravenousordilutedmedications containing benzyl alcohol. No signs of harmhadbeenseeninadministeringsuch products to adults or older children. To avoid such tragedies and to increase the availability of evidence on pediatric medication use, Congress passed 2 key laws. The Best Pharmaceuticals for Children Act (BPCA), enacted in 2002, provides such incentives as a 6-month extension on patent exclusivity of a drug if its maker conducts clinical trials of the medication in children. The Pediatric Research Equity Act (PREA), enacted in 2003, requires pediatric studies for certain drugs. The IOM report, which was published in February, was commissioned by Congress to assess whether the laws were working before the acts face reauthorization. To meet this charge, the IOM committee collected data on pediatric studies conducted under the auspices of these 2 laws. It relied on publicly available documents about such studies posted on the US Food and Drug Administration (FDA) website after September 2007, when a law went into effect requiring public posting of certain study results, as well as redacted documents provided by the FDA regarding studies not subject to these disclosure rules. Overall, the authors concluded that the laws seem to be having the desired effect of producing clinically relevant information that either supports the expected clinical benefit of a drug in pediatric patients or reveals an unexpected lack of efficacy in this age group. For example, studies of insulin glulisine led to approval of this product for use in children with type 1 diabetes aged 4 to 17 years, the peak period of onset for the disorder; studies of the HIV drug nevirapine provided dosing information for individuals as young as 15 days of age; and data on adverse effects and studies showing limited efficacy of the asthma medication omalizumab for children aged 6 to 11 years led the FDA to recommend against use of the drug in this age group. Despite such successes, however, the authors of the report did identify some targets for improvement.ThomasF.Boat, MD,chairof the IOMcommitteeandvice president for health affairs at the University of Cincinnati College of Medicine, explained that although the pediatric studiesbeingconductedunder these laws are generally of good quality and have improved continuously over time, some areas require further attention— for instance, making sure studies are conducted in a timely manner; encouraging use of innovative trial designs that might allow smaller samples (because recruiting adequate numbers of children can be difficult); and ensuring that, when appropriate, studies involve newborns or very young children. “Focusing on the needs of neonates and the very young is going to be very important,” he said. Boat and his colleagues also called for greater transparencyof the resultsof trials conducted under BPCA and PREA. Results of studies conducted before 2007 that are not currently public should be released, Boat said, and redactions should be used only in limited circumstances where there is clear reason to protect the

Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein

Organic anion transporters (OAT1 and OAT3) and multidrug resistance-associated proteins (MRP2 and MRP4) play important roles in anionic drug secretion in renal proximal tubules. Changes in the expression of such transporters are considered to affect the tubular secretion of anionic drugs. The purpose of this study was to elucidate the developmental changes in the expression of OAT1, OAT3, MRP2, and MRP4 and their effects on the tubular secretion of drugs. The mRNA level of each transporter was measured by real-time PCR, and the protein expression was evaluated by Western blotting and immunohistochemical analysis. In addition, the tubular secretion of phenolsulfonphthalein (PSP) in infant (postnatal day 14) and adult rats was estimated based on in vivo clearance study. The protein expression of organic anion transporters were very low at postnatal day 0 and gradually increased with age. In postnatal day 14 rats, the expression of OAT1 and OAT3 seemed to be at almost mature levels, while MRP2 and MRP4 seemed to be at immature levels. Immunohistochemical analysis in the kidney of postnatal day 0 rats revealed OATs on the basolateral membrane and MRPs on the brush-border membrane. At postnatal day 0, the distribution of these transporters was restricted to the inner cortical region, while after postnatal day 14, it was identical to that in adult kidney. An in vivo clearance study revealed that the tubular secretion of PSP was significantly lower in postnatal day 14 rats than adult rats. These results indicate that age-dependent changes in organic anion transporter expression affect the tubular secretion of anionic drugs in pediatric patients.

Understanding Renal Replacement Therapy and Dosing of Drugs in Pediatric Patients with Kidney Disease

Multifaceted factors need to be considered when prescribing renal replacement therapy (RRT) and dosing of drugs in pediatric patients with kidney disease. RRTs in pediatrics such as intermittent hemodialysis, continuous venovenous hemofiltration, continuous venovenous hemodialysis, and continuous venovenous hemodiafiltration affect solute and drug clearance. Drug properties such as molecular weight, molecular charge, volume of distribution, and protein binding affect drug clearance. RRT prescription parameters such as blood flow rate, ultrafiltration rate, membrane size, and pore size can also influence drug clearance. Furthermore, the pediatric patient presents additional concerns because of developmental factors in children that affect both pharmacokinetics of drugs.

Comparative Bioavailability of Propafenone after Administration of a Magistral Suspension vs. Commercial Tablets in Healthy Volunteers

Propafenone (CAS 34183-22-7) is an effective antiarrhythmic drug used in children, although in some countries no specific pediatric formulation is available. The aim of this study is to compare the relative bioavailability of a magistral (MAG) preparation of propafenone versus its commercial (COM) presentation in a group of 16 Mexican healthy volunteers. Bioavailability was determined after crossover administration of the drugs, through a randomized two-phase trial. All volunteers had normal hepatic and renal functions, determined clinically at the beginning of the study, and received 150 mg of either COM (tablets) or MAG (suspension). Blood samples were drawn for a 24-h post-dose analysis by HPLC to measure plasma levels of propafenone. Subjects (mean 25.9 +/- 5.3 years and 66.1 +/- 12.4 kg) had the following pharmacokinetic parameters: Cmax 189.9 +/- 20.92 ng/mL, Tmax 1.5 h, AUC 322.4 +/- 36.28 ng x ml(-1) x h for COM. Values for MAG were Cmax 225.8 +/- 24.38 ng/mL, Tmax 1.7 h and AUC 359.3 +/- 27.90 ng x ml(-1) x h. These values yielded a relative bioavailability of 111.42% for MAG compared with COM. No electrocardiographic changes were recorded in any subject with respect to the baseline value, in both treatment schemes. Therefore, propafenone suspension prepared as a magistral formulation may be used as an alternative drug in pediatric patients.

Reasons for inappropriate prescribing of antibiotics in a high-complexity pediatric hospital

Determine the reasons for inappropriate prescription of antibiotics and identify opportunities to improve prescription of these drugs in pediatric patients hospitalized in intermediate and intensive care units. A prospective, descriptive longitudinal study was conducted of pediatric patients in intermediate and intensive care units who received parenteral administration of antibiotics, with the exception of newborns, burn unit patients, and surgical prophylaxis patients. A univariate analysis and multiple logistic regression were performed. A total of 376 patients with a median of age of 50 months were studied (interquartile range [IQR] 14.5-127 months). Out of the total patients studied, 75% had one or more underlying conditions. A total of 40.6% of these patients had an oncologic pathology and 33.5% had neurological conditions. The remaining 25.9% had other underlying conditions. Antibiotic treatment was inappropriate in 35.6% of the patients studied (N = 134). In 73 (54.4%) of the 134 cases, inappropriate use was due to the type of antibiotic prescribed, the dose administered, or the treatment period. The 61 (45.5%) remaining cases did not require antibiotic treatment. In the multivariate analysis, the risk factors for inappropriate use of antibiotics were: administration of ceftriaxone OR 2 (95% CI, 1.3-3.7; P = 0.02); acute lower respiratory tract infection OR 1.8 (95% CI, 1.1-3.3; P < 0.04); onset of fever of unknown origin in hospital inpatients OR 5.55 (95% CI, 2.5-12; P < 0.0001); and febrile neutropenia OR 0.3 (95% CI, 0.1-0.7; P = 0.009). Inappropriate use of antibiotics was less common in the clinical conditions that were well-characterized. Prescribing practices that could be improved were identified through the preparation and circulation of guidelines for antibiotic use in hospital inpatients.