Overview of systematic reviews of therapeutic ranges : methodologies and recommendations for practice

BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges. METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed. RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed. CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols

Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15–18 weeks' gestation, or chorionic villus cells obtained at about 10–12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments

Uso de suplementos vitamínicos e/ou minerais por crianças menores de seis meses no interior do estado de Pernambuco Use of vitamin and/or mineral supplies by infants under six months of age in the interior of Pernambuco State

OBJETIVOS: descrever o uso de suplementos vitamínicos e/ou minerais em crianças, do nascimento até o sexto mês de vida, bem como avaliar a associação entre o uso dos suplementos e características socioeconômicas, biológicas, padrões alimentares e de assistência à saúde. MÉTODOS: o estudo compreendeu uma sub-amostra de 399 crianças que pertenciam a um estudo coorte, realizado no interior de Pernambuco. RESULTADOS: a proporção de crianças que recebeu vitaminas e/ou minerais foi de 18,8%. O uso desses suplementos aumentava com a idade da criança, OR=4,38 com 17 semanas e OR=9,82 com 26 semanas de vida, quando comparadas com as crianças na idade de quatro semanas. O maior uso de suplementos foi observado naquelas crianças de melhor renda e entre aquelas que não compartilhavam o domicílio com outras menores de cinco anos. As mães com idade igual ou superior a 25 anos recorreram mais à suplementação para seus filhos do que aquelas mais jovens. A duração mediana do aleitamento materno esteve associada à suplementação de vitaminas e/ou minerais, sendo menor entre as crianças que utilizaram esses medicamentos. CONCLUSÕES: verificou-se a utilização do recurso medicamentoso como via de ingestão de vitaminas e/ou minerais em lactentes cujas necessidades nutricionais poderiam ser atendidas através do aleitamento materno exclusivo.<br>OBJECTIVES: to describe the use of vitamin and or minerals supplements in children from birth to six months of age, as well as to assess the association between supplements use and social, economic, biological features, nutrition standards and healthcare. METHODS: the study comprised a sub-sample of 399 children in a cohort study performed in the interior of Pernambuco. RESULTS: the proportion of children receiving vitamin and/or minerals supplements was of 18.8%. The use of these supplements increased with the child's age, OR=4.38 with 17 weeks and OR=9.82 with 26 weeks of age when compared with four weeks old infants. The increased use of supplements was determined in children of low income families and among the ones not sharing the home with other children under five years old. Twenty five year old or older mothers used more supplements than younger mothers. The average time for breastfeeding was associated to vitamins and/or minerals supplements use, being shorter among children using these supplements. CONCLUSIONS: the use of supplements as a means for vitamins and/or minerals offer in babies whose nutritional needs could be met through exclusive breastfeeding, was determined