Long-term Therapy In Children Research Articles

Renal Function in Children with β-Thalassemia Major Treated with Iron Chelating Agent

BACKGROUND: Thalassemia is a disorder of inherited blood and inticated by the abnormal hemoglobin. Transfusion and iron chelation are part of thalassemia management. Iron chelating agent reduces complications due to the excess iron as a result of repeated transfusions, hence, increasing the survival rate. However, prolonged intake of iron chelating agent may increase the risk of renal function impairment. To date, evaluation of renal function in children with β-thalassemia in Medan has never been reported. The objective of this study was to evaluate renal function and other factors in children with β-thalassemia.METHODS: Fourty-five children with β-thalassemia was recruited in this study. Renal function, represented by estimated glomerular filtration rate (eGFR)and serum ferritin levels were examined. The measurement of eGFR was using Schwartz method.RESULTS: Decreased eGFR observed in some the children (2 patients) with β-thalassemia major treated with iron chelating agent. None of the factors examined had association with serum creatinine level. Children's age and duration of iron chelating agent intake had positive correlation with their eGFR (r=0.506, p<0.001 and r=0.518, p<0.001, respectively). However, serum ferritin levels was not a predictor for renal function impairment.CONCLUSION: Most of children with β-thalassemia major treated with iron chelating agent have normal renal function, nevertheless, decreased renal function is observed in few children. Highlighted, renal function examinations should be performed routinely as iron chelating agent administration is a long-term therapy in children with β-thalassemia major.KEYWORDS: β-thalassemia major, renal function, serum ferritin levels, iron chelating agent

Duration of Pediatric Clinical Trials Submitted to the US Food and Drug Administration

ImportanceThe increasing prevalence of pediatric chronic disease has resulted in increased exposure to long-term drug therapy in children. The duration of recently completed drug trials that support approval for drug therapy in children with chronic diseases has not been systematically evaluated. Such information is a vital first step in forming safety pharmacovigilance strategies for drugs used for long-term therapy in children.ObjectiveTo characterize the duration of clinical trials submitted to the US Food and Drug Administration (FDA) for pediatric drug approvals, with a focus on drugs used for long-term therapy.Design and SettingA review was performed of all safety and efficacy clinical trials conducted under the Best Pharmaceuticals for Children Act or the Pediatric Research Equity Act and submitted to the FDA from September 1, 2007, to December 31, 2014, to support the approval of drugs frequently used for long-term therapy in children. Statistical analysis was performed from July 1, 2015, to December 31, 2017.Main Outcomes and MeasuresMaximum duration of trials submitted to support FDA approval of drugs for children.ResultsA total of 306 trials supporting 86 drugs intended for long-term use in children were eligible for the primary analysis. The drugs most commonly evaluated were for treatment of neurologic (25 [29%]), pulmonary (16 [19%]), and anti-infective (14 [16%]) indications. The median maximum trial duration by drug was 44 weeks (minimum, 1.1 week; maximum, 364 weeks). For nearly two-thirds of the drugs (52 [61%]), the maximum trial duration was less than 52 weeks. For 10 of the drugs (12%), the maximum trial duration was 3 years or more. Maximum duration of trials did not vary by therapeutic category, minimum age of enrollment, calendar year, or legislative mandate.Conclusions and RelevancePediatric clinical trials designed to sufficiently investigate drug safety and efficacy to support FDA approval are of relatively limited duration. Given the potential long-term exposure of patients to these drugs, the clinical community should consider whether new approaches are needed to better understand the safety associated with long-term use of these drugs.

Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study.

IntroductionMethotrexate (MTX) is a cornerstone of treatment in a wide variety of inflammatory conditions, including juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM). However, owing to its narrow therapeutic index and the considerable interpatient variability in clinical response, monitoring of adherence to MTX is important. The present study demonstrates the feasibility of using methotrexate polyglutamates (MTXPGs) as a biomarker to measure adherence to MTX treatment in children with JIA and JDM.MethodsData were collected prospectively from a cohort of 48 children (median age 11.5 years) who received oral or subcutaneous (SC) MTX therapy for JIA or JDM. Dried blood spot samples were obtained from children by finger pick at the clinic or via self- or parent-led sampling at home, and they were analysed to determine the variability in MTXPG concentrations and assess adherence to MTX therapy.ResultsWide fluctuations in MTXPG total concentrations (>2.0-fold variations) were found in 17 patients receiving stable weekly doses of MTX, which is indicative of nonadherence or partial adherence to MTX therapy. Age (P = 0.026) and route of administration (P = 0.005) were the most important predictors of nonadherence to MTX treatment. In addition, the study showed that MTX dose and route of administration were significantly associated with variations in the distribution of MTXPG subtypes. Higher doses and SC administration of MTX produced higher levels of total MTXPGs and selective accumulation of longer-chain MTXPGs (P < 0.001 and P < 0.0001, respectively).ConclusionsNonadherence to MTX therapy is a significant problem in children with JIA and JDM. The present study suggests that patients with inadequate adherence and/or intolerance to oral MTX may benefit from SC administration of the drug. The clinical utility of MTXPG levels to monitor and optimise adherence to MTX in children has been demonstrated.Trial registrationISRCTN Registry identifier: ISRCTN93945409. Registered 2 December 2011.

Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

Long-term safety of PEG 4000 in children with chronic functional constipation: A biochemical perspective

PurposeTo evaluate the long-term safety of polyethylene glycol (PEG) 4000 in children with constipation, particularly the biochemical aspects of safety.MethodsMedical records were evaluated, and 100 children, who had been taking PEG 4000 for more than 6 months, and who had been under clinical and biochemical monitoring, were enrolled. Ages; 6.11±3.12 years, Duration of therapy; 16.93±7.02 months, dose of PEG 4000; 0.72±0.21 g/kg/d.ResultsNone of the children complained of clinical adverse effect. The first biochemical test was performed at 8.05 months after beginning of PEG 4000. Serum phosphate (SP) value was high in 10 children, and leucopenia was noted in one child. The second test was performed in 44 children at 7.57 months after the first test. The SP value was high in four children, including the three children whose initial SP value was high and one new child. Six out of 10 children with high initial SP value became normal and one was lost. Hypernatremia was noted in one child. The third test was done in 15 children at 7.5 months after the second test. The SP value of the new child from the second test was high, but became normal after finishing treatment. Two out of 3 children with high SP value at the second test became normal and one was lost. The fourth test was done in 2 children few months after the third test. All of the results were normal. There were no relation between duration of therapy and hyperphosphatemia, or between dose of PEG 4000 and hyperphosphatemia.ConclusionsPEG 4000 is safe for long-term therapy in children with constipation with respect to biochemical parameters.

Treatment of Alport syndrome: beyond animal models

Alport syndrome (AS) is a hereditary glomerulopathy due to abnormal composition of the glomerular basement membrane, leading to end-stage renal disease (ESRD). Studies of animal models of AS have suggested a variety of potentially effective therapies, but none of these has been definitely shown to prevent or delay ESRD in human AS. Studies in Alport mice suggest that angiotensin inhibition not only has antiproteinuric effects but suppresses cytokine and collagen production as well as tubulointerstitial fibrogenesis and inflammation. For these reasons, many Alport patients are treated empirically with angiotensin antagonists. Cyclosporine may reduce proteinuria in AS, but the risk of nephrotoxic side effects complicates long-term therapy in children. Current data on the role of HMG-CoA reductase inhibition are sparse, so therapy should be limited to adults with dyslipoproteinemia. Results of some, but not all, studies suggest that bone marrow-derived cells may ameliorate disease in Alport mice. However, until experimental doubts concerning the superiority of bone-marrow transplantation over other treatments are resolved by additional investigation, human research subjects should not be exposed to cell-based therapies that may carry substantial risks. In summary, all potential therapies are off-label use in children. As a consequence, initial therapeutic trials should focus on the safety and efficiency of medical treatment, as well as the optimal timing of therapy.

Intravenous daclizumab for recalcitrant ocular inflammatory disease

To evaluate outcomes of patients with recalcitrant ocular inflammation treated with intravenous daclizumab. Retrospective case-series. Seventeen patients (33 eyes) with ocular inflammation who had failed several previous systemic immunomodulatory therapies were included in this study. Daclizumab was infused intravenously at a dose of 1 mg per kilogram every 2 weeks. The dose and intervals were adjusted according to control of inflammation off systemic and/or topical corticosteroid therapy. Control of ocular inflammation without corticosteroid therapy was the primary efficacy end point. The mean patient age at the commencement of daclizumab therapy was 34.8(range 8-64 years). Three patients were less than 16 years of age at the initiation of therapy. The duration of drug use was 23.6 +/- 15.7 months (range 8-68 months), and the time to control inflammation was 9.8 +/- 11.3 weeks, which was achieved in 15 patients (88.2%). Flare-up rate was 44 per 100 person-years follow-up. Fifteen of 33 eyes (45%) had an improvement in the visual acuity, 13 eyes (39.3%) had stable acuities, and five eyes (15%) had a worsening of their acuities. Two patients (14%) exhibited worsening of ocular inflammation, and were declared as treatment failures. Side effects associated with daclizumab included nausea, fatigue and muscle aches. Daclizumab is effective in controlling inflammation in patients with stubborn non-infectious ocular inflammation. It has a corticosteroid-sparing effect, can be used as long-term therapy in children and adults, and is capable of inducing durable remission.

Review: Antiphospholipid antibodies in pediatric systemic lupus erythematosus and the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is recognized increasingly as the most common acquired hypercoagulation state of autoimmune etiology and may occur as an isolated clinical entity (primary APS) or in association with an underlying systemic disease, particularly systemic lupus erythematosus (SLE). The major differences between pediatric and adult APS include absence of common acquired risk factors for thrombosis, absence of pregnancy-related morbidity, increased incidence of infection-induced antibodies, differences in cut-off values for determination of aPL and specific factors regarding long-term therapy in children. APS in children has been largely reported in patients with arterial or venous thromboses and less frequently in association with neurological or hematological manifestations. The presence of aPL in pediatric SLE can modify the disease expression and may be an important predictor of the development of irreversible organ damage. Two recently established international registries of neonates and children with APS provide a good opportunity to conduct large, prospective studies on the clinical significance of aPL and long-term outcome of pediatric APS.

THE EFFECTS OF INTRAVENOUS(IV), SUBCUTANEOUS (SC) AND INTRANASAL (IN) ADMINISTRATION OF 6H-RH(1–44)MH2 ON GROWTH-HORMONE SECRETION IN NORMAL MEN: DOSE-RESPONSE RELATIONSHIPS

To compare its effectiveness in stimulating growth-hormone (GH) release, GH-RH (1-44) NH2 was given intravenously (80 mcg; n=16), subcutaneously (2.1; 4.2, 8.4; 12 b; 168 and 21 mcg/kg; n=16) and intranasally (1.4, 3.6; 7; 14.21 and 28 mcg/kg; n=16) to normal male volunteers. GH stimulation occured in a dose-responsive manner after SC and after IN routes of administration. Although the degree of GH stimulation terms of GH peak and GH integrated concentration, was variable among subjects, the greatest amount of stimulation occured with the highest doses. If maximal observed concentration of GH is used as an indicator of responsiveness to the various doses and routes of administration, approximately a 15 fold higher SC dose and a 25 fold higher IN dose were required to stimulate a comparable amount of GH secretion as compared with IV administration. Stimulation of GH secretion occured within 30 minutes of IV and SC administration and within 45 minutes of IN 6R-RH(1-44)NH2 administration. It is concluded that optimisation of IN administration of GH-RH(1-44) NH2 is necessary before using it for long-term therapy in children with GH deficiency.

Pemoline pharmacokinetics and long term therapy in children with attention deficit disorder and hyperactivity.

The pharmacokinetic behaviour of pemoline was studied in 28 children, aged 5 to 12 years, diagnosed as having the attention deficit disorder with hyperactivity. The mean elimination half-life of pemoline in these children was approximately 7 hours, which is considerably shorter than the half-life of 11 to 13 hours previously reported in adults. The tendency of the half-life to increase with age may be explained by the statistically significant decrease in total body clearance with age. The increasing half-life of pemoline with age should be considered during long term drug therapy. In this study no tolerance to the beneficial effects of pemoline was observed over 6 months. The apparent therapeutic serum concentration range for these children was attained after doses of 37.5 to 131.25 mg pemoline daily. Since the optimum serum concentration shows wide variation, the dosing regimen must be determined individually. Routine monitoring of the pemoline serum concentrations is not useful because of this apparent variation in optimum serum concentration and because of the linear relationship between dose and concentration.