Paediatric drugs
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Review Comparative Study
Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol.
Nonsteroidal anti-inflammatory drugs (NSAIDs) possess antipyretic, analgesic and anti-inflammatory effects. They are frequently used in children and have numerous therapeutic indications, the most common ones being fever, postoperative pain and inflammatory disorders, such as juvenile idiopathic arthritis (JIA) and Kawasaki disease. Their major mechanism of action is through inhibition of prostaglandin biosynthesis by blockade of cyclo-oxygenase (COX). ⋯ Pharmacokinetic studies are needed to characterise the disposition of NSAIDs in very young infants in order to use them rationally. To date, no studies have been published on the disposition, tolerability and efficacy of specific COX-2 inhibitors in children. Further clinical experience with these agents in adults is warranted before undergoing trials with specific COX-2 inhibitors in children.
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Apnoea of prematurity is a common condition in neonates born at less than 37 weeks' gestational age; it affects approximately 90% of premature neonates weighing under 1000 g at birth, and 25% of infants with a birthweight of less than 2500 g. Caffeine, a methylxanthine which occurs naturally in many plants, has been used for over 20 years to treat apnoea of prematurity. In a recent double-blind, placebo-controlled trial, apnoea was eliminated or reduced by at least 50% in significantly more neonates receiving caffeine citrate as first-line treatment than those receiving placebo. In a nonblind trial, caffeine citrate was more effective at reducing apnoeic episodes when compared with neonates receiving no treatment. Caffeine as first-line treatment demonstrated similar efficacy to theophylline or aminophylline (theophylline ethylenediamine) in 4 small randomised studies. Caffeine citrate was generally well tolerated in short term clinical trials, with very few adverse events reported. Caffeine was associated with fewer adverse events than theophylline in randomised trials. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo in a double-blind, randomised trial. Long term tolerability data are not yet available. ⋯ Caffeine citrate was generally well tolerated by neonates in clinical trials and it decreased the incidence of apnoea of prematurity compared with placebo. It has demonstrated similar efficacy to theophylline, but is generally better tolerated and has a wider therapeutic index. Caffeine citrate should, therefore, be considered the drug of choice when pharmacological treatment of apnoea of prematurity is required.
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Review Comparative Study
Ondansetron: a review of its use as an antiemetic in children.
Ondansetron, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT3 receptor antagonist, is an antiemetic agent available for use in adults and children. In children receiving ondansetron (multiple 5 mg/m2 or 0.15 mg/kg intravenous and/or oral doses) in addition to chemotherapy in 2 large (n > 100) non-comparative analyses, < or =2 emetic episodes were observed in 33 and 40% of cisplatin recipients, 48 and 68% of ifosfamide recipients, and 70 and 72% of patients receiving other chemotherapeutic regimens. In comparative trials, ondansetron was significantly more effective at reducing nausea and vomiting than metoclopramide or chlorpromazine (both combined with dexamethasone), although the incidence of delayed symptoms were similar between children receiving ondansetron and metoclopramide. In addition, dexamethasone significantly improved the antiemetic efficacy of ondansetron in 1 randomised trial. When used in children undergoing conditioning therapy (including total body irradiation) prior to bone marrow transplantation, ondansetron was significantly better at controlling nausea and vomiting than combined perphenazine and diphenhydramine therapy. In dose-ranging and large placebo-controlled trials, intravenous (0.075 to 0.15 mg/kg) or oral (0.1 mg/kg) ondansetron was significantly more effective than placebo in preventing emesis in children undergoing surgery associated with a high risk of postoperative nausea and vomiting (PONV) including tonsillectomy or strabismus repair. In comparative studies, intravenous administration of ondansetron 0.1 to 0.15 mg/kg was significantly superior to droperidol 0.02 to 0.075 mg/kg or metoclopramide 0.2 to 0.25 mg/kg in preventing emesis in children undergoing various surgical procedures. In comparison with other antiemetics, including prochlorperazine and dimenhydrinate, ondansetron generally showed greater prophylactic antiemetic efficacy. Ondansetron combined with dexamethasone was significantly more effective than ondansetron or dexamethasone alone, as was the combination of ondansetron with a propofol-based anaesthetic compared with either agent alone. Ondansetron is generally well tolerated in children, rarely necessitating treatment withdrawal. The most frequently reported adverse events were mild to moderate headache, constipation and diarrhoea in patients receiving chemotherapy. Wound problems, anxiety, headache, drowsiness and pyrexia were reported most frequently in patients postsurgery. ⋯ Ondansetron has shown good efficacy in the prevention of acute nausea and vomiting in children receiving moderately or highly emetogenic chemotherapy and/or irradiation, particularly when combined with dexamethasone. In the chemotherapy setting, ondansetron is significantly better than metoclopramide and chlorpromazine and has a more favourable tolerability profile. In children undergoing surgery, ondansetron demonstrated superior prophylactic antiemetic efficacy compared with placebo, droperidol and metoclopramide, and was relatively free of adverse events. Ondansetron is thus an effective first-line antiemetic in children undergoing chemotherapy, radiotherapy and surgery.
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Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels). In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related. Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day. Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a > or =50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a > or =50% reduction in seizures was maintained in 7 of 11 children. Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing studies. ⋯ Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjuntive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children.
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Sepsis and septic shock constitute an important cause of morbidity and mortality in critically ill children. Thus, the systemic response to infection and its management remains a major challenge in clinical medicine. Apart from antibiotic administration, the majority of available therapies are limited to supportive strategies, although considerable efforts are being undertaken to devise innovative approaches that modulate host inflammatory responses. ⋯ Metabolic support may include glucose support, extraction of ammonia from the body and recognition of liver dysfunction. Nutritional support may modify the inflammatory host response, and early enteral feeding can improve outcome in critical illness. To date, glucocorticoid and non-glucocorticoid anti-inflammatory agents have not shown significant benefit in septic patients.