Philip D. Walson

Ibuprofen, acetaminophen, and placebo treatment of febrile children

A double‐blind, parallel‐group, triple‐dummy‐designed, single‐oral‐dose study compared the efficacy, tolerability, safety, and dose‐response of 5 mg/kg (n = 32) and 10 mg/kg (n = 28) ibuprofen suspension, 10 mg/kg acetaminophen elixir (n = 33), and placebo liquids (n = 34) in 127 children (2 to 11 years of age) with fever (101° to 104° F). Blood samples, oral temperatures, pulse, blood pressure, and respiration were obtained before and ½, 1, 2, 3, 4, 5, 6, and 8 hours after the dose was administered. The study was terminated early if oral temperature was > 104° F or if it increased 1° F above baseline. All agents were well tolerated and more effective than placebo (p < 0.05) for fever control. Ibuprofen, 10 mg/kg, was favored over 10 mg/kg acetaminophen (p < 0.05). For temperatures > 102.5° F, a dose‐response relationship for 5 and 10 mg/kg ibuprofen was demonstrated in terms of percentage of fever reduction and in terms of the initial 2‐hour rate of decrease in temperature. Antipyretic efficacy for temperatures > 102.5° F was 10 mg/kg ibuprofen > 5 mg/kg ibuprofen > 10 mg/kg acetaminophen > placebo. All treatments were well tolerated. No significant clinical or laboratory abnormalities were noted. Ibuprofen suspension may be a safe and effective antipyretic in children.

Pharmacokinetics of Common Analgesics, Anti-Inflammatories and Antipyretics in Children

SummaryNon-steroidal anti-inflammatory drugs (NSAIDs) are a major component of paediatric therapeutics. This paper summarises the clinical pharmacology and pharmacokinetics of some commonly used NSAIDs as well as paracetamol (acetaminophen), which has very weak anti-inflammatory activity. Available information is reviewed in an attempt to evaluate the basis for paediatric dosing recommendations and to underline known or likely differences in drug disposition that result from diseases and changes in developmental physiology. Clinically important general considerations are stressed, including areas in which age-appropriate pharmacological information is needed but unavailable. The review is not exhaustive, as only the following selected drugs are surveyed: paracetamol, ibuprofen, indomethacin, diclofenac, naproxen and sulindac. Some compounds of interest, including salicylates (e.g. aspirin, salsalate), recently introduced drugs (e.g. ketoprofen, nimesulide) and those withdrawn (e.g. zomepirac, benoxaprofen), are not included. Non-NSAID analgesics (e.g. dextropropoxyphene, narcotics) are also not included.

Measurement of Acetaminophen‐Protein Adducts in Children and Adolescents with Acetaminophen Overdoses

Acetaminophen‐protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen‐induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen‐protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time ofrou‐ tine blood sampling for clinical monitoring. Six subjects developed “severe” hepatotoxicity (transaminase elevation > 1000IU/L), and 6 subjects had transaminase elevation of 100 to 1000 IU/L. Acetaminophen‐protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6000 IU/L) and high riskforthe development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen‐protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Carbamazepine age-dose ratio relationship in children.

Summary: Steady-state plasma carbamazepine (CBZ) concentrations were measured in 196 pediatric inpatients taking CBZ alone or CBZ combined with other drugs. The steady-state CBZ concentrations divided by the daily administered dose (dose ratio, reciprocal of apparent clearance) increased significantly (r = 0.183, p > 0.01) with age. The correlation between dose and CBZ concentration, while significant (r = 0.265, p = 0.023), was weak because of wide interindividual differences in dose ratio. There was a negative correlation between CBZ daily dose and CBZ dose ratio. This negative correlation was significant in children 4–6 (r2 = 0.481, p > 0.01), 7–11 (r2 = 0.399, p > 0.01), and < 11 years of age (r2 = 0.401, p > 0.01), but not in children > 4 years of age (r2 = 0.172, p < 0.1). The CBZ dose ratio was significantly (p > 0.001) lower in patients taking CBZ in combination with more than one other antiepileptic drug compared with those on CBZ monotherapy. No significant (p < 0.1) difference in CBZ dose ratio was found between male and female patients. These findings suggest that CBZ clearance was influenced by age, dose, and comedication with more than one other antiepileptic drug but not sex. The concentration necessary for efficacy is a clinical, not an analytical decision. However, the dose-concentration relationships show that recommended pediatric CBZ doses of 10–30 mg/kg/day are not enough to attain published therapeutic CBZ concentrations in many children. Increases in CBZ doses to<30 mg/kg/day may be required even in children on monotherapy. However, prospective studies of the efficacy and toxicity of this regimen are required before it can be recommended.

Chelation Therapy for Childhood Lead Poisoning: The Changing Scene in the 1990s

chelation therapy prevents or reverses Pb neurotoxicity or that it is superior to removing the child from the Pb source. However, few will disagree that chelation is indicated for BPb levels of 45 J.1gj dL (2.172 J.1mol/L) or higher, which is the BPb level consistent with the FDA-approved indication for the oral chelator succimer. These authors, however, agree with a recent recommendation to use 40

Role of therapeutic drug monitoring (TDM) in pediatric anti-convulsant drug dosing

The role of therapeutic drug monitoring (TDM) in patient care has grown rapidly since its introduction three decades ago. The role of a TDM service in establishing proper pediatric anti-epileptic drug (AED) use is described. A number of studies are reviewed which identified proper pediatric dosage regimens for phenobarbital, carbamazepine, valproic acid, phenytoin and clonazepam. Finally, the potential role of TDM in the use of new AEDs is mentioned. These studies are given as examples of how professionals knowledgeable in clinical epilepsy management, clinical pharmacology and pharmacokinetics, can use TDM to design individualized dosage regimens, as well as assess compliance, toxicity and drug interactions.

Valproic Acid Dosages Necessary to Maintain Therapeutic Concentrations in Children

Summary Steady-state plasma valproic acid (VPA) concentrations were measured in 118 pediatric inpatients taking VPA. There was a significant (p<0.0001) inverse correlation between the daily VPA dosage and the VPA dose ratio (concentration/dose or 1/clearance). The VPA dose ratio was significantly lower in patients taking VPA in combination with phenobarbital (p<0.01), carbamazepine (p<0.05), or multiple other antiepileptic drugs (p<0.0001), compared with those on VPA monotherapy. Neither age nor sex had any influence on VPA dose ratios. No significant (p > 0.1) correlation was found between VPA doses and concentrations in children on monotherapy. The distribution of VPA dose concentrations suggests that children, especially those on VPA polytherapy, require higher than recommended pediatric VPA maintenance doses (>60 mg/kg/day) to maintain concentrations >50 mg/L. Results also indicate that at higher concentrations (>80 mg/L), increasing doses may produce less than proportional increases in total VPA concentration.

Principles of Drug Prescribing in Infants and Children: A Practical Guide

SummaryPaediatric prescribing is much more complicated than prescribing for adults. The specific and general aspects of paediatric patients, the limitations of commercially available dosage formulations, the vagaries of administering medicines, the general inadequacy of clinical pharmacology training, and the dearth of information about drug use in children all add to the difficulties facing the practitioner who treats infants and children.For these reasons practitioners should prescribe judiciously, select carefully the safest dosage regimen available, and educate their patients, caregivers and staff about their choices and expected positive and negative effects. Practitioners should also have available and use written, electronic, as well as human sources of expert advice. They should write all prescriptions legibly and carefully, document their therapeutic decisions and plans, and carefully monitor their patients’ responses to therapy. Careful attention to the principles of clinical pharmacology can do much to improve the efficacy of paediatric prescribing and decrease its costs and risks.

Influence of levodopa/carbidopa on body temperature in children

Abstract In a multidisciplinary study of the efficacy and tolerability of levodopa/carbidopa in a pediatric population, oral body temperature was measured during two 7-week longitudinal dosing studies. In study 1, 15 children received 0.55/0.14 mg/kg of body weight of levodopa/carbidopa three times daily; in study 2, 13 children received 1.02/0.25 mg/kg. Eight children participated in both studies, and follow-up measurements of body temperature were obtained 4 to 6 weeks after the termination of dosing. The results revealed that, from baseline to the end of the 7-week dosing regimen, mean oral body temperature was unchanged in the 0.55/0.14 mg/kg group but significantly (F = 5.06, P

Safety of Paracetamol and Ibuprofen in Febrile Children

SummaryThe increasing use of ibuprofen for the treatment of fever in children has caused concern about possible toxic effects. In susceptible adults ibuprofen has caused kidney dysfunction. While it is unlikely that a child with known kidney disease would be given ibuprofen, many children with febrile illnesses are dehydrated. This report presents an analysis of pre- and poststudy observations from 2 clinical trials that compared the antipyretic effects of ibuprofen and paracetamol in 180 otherwise healthy febrile children.In the first trial, 119 febrile children received a single oral dose of either placebo, paracetamol or one of 2 doses of ibuprofen. In the second trial, 61 children received either paracetamol or one of 3 doses of ibuprofen orally every 6 hours for between 24 and 48 hours. Pre- and poststudy blood chemistries, urine and vital signs were analysed.Liberal statistical analyses identified few adverse effects and no clinically significant adverse effects. Statistically significant changes were all consistent with poststudy haemodilution (rehydration) except for blood urea nitrogen (BUN). Poststudy BUN concentrations were statistically significantly greater than prestudy values for paracetamol- and ibuprofen-treated patients. However, none of the BUN results were abnormal or clinically important.Although this study found no clinically significant adverse effects, much larger studies are necessary to establish safety in the general population.