Objective: To determine the extent of use in children in hospital of drugs that are not specifically licensed for use in children (unlicensed) and of drugs that are used outside the terms of their product licence that apply to indication, age, dose, or route of administration (off label). Design: Prospective study of drugs administered on paediatric medical and surgical wards for 13 weeks. Setting: Regional children's hospital. Subjects: Paediatric inpatients in medical and surgical wards. Main outcome measures:Comparison of the use of each drug with its product licence to determine whether the drug was used in an unlicensed or off label manner. Results: 2013 courses of drugs were administered to 609 paediatric patients in 707 admissions. 506 (25%) of the drug courses (prescriptions) were either unlicensed (139) or off label (367) uses. In 256 (36%) of the 707 admissions patients received one or more courses of an unlicensed or off label treatment in hospital. Conclusions: Use of drugs in an off label or unlicensed manner to treat children is widespread. Drugs are more likely to be used in an off label manner than in an unlicensed manner.

To determine the incidence of adverse drug reactions (ADRs) to unlicensed and off‐label drugs used in paediatric inpatients, we carried out prospective surveillance on five different paediatric wards in a regional children's hospital for 13 wk. Comparison of the use of each drug with its summary of product characteristics was made to determine whether the drug was used in an unlicensed or off‐label manner. The presence of an ADR was determined using previously defined criteria. In total, 4455 courses of drugs were administered to 936 patients in 1046 admissions. In 507 (48%) of the 1046 admissions, patients received one or more unlicensed or off‐label drugs. ADRs occurred in 116 (11%) of the 1046 patient admissions. ADRs were associated with 112 (3.9%) of the 2881 licensed drug prescriptions and 95 (6%) of the 1574 unlicensed or off‐label drug prescriptions. Use of drugs in an off‐label or unlicensed manner to treat children is widespread. ADRs are a significant problem following unlicensed or off‐label drug prescriptions. □Adverse drug reactions, children, off‐label, unlicensed

Symbiotic relationships between neurons and glia must adapt to structures, functions, and metabolic roles of the tissues they are in. We show here that Müller glia in retinas have specific enzyme deficiencies that can enhance their ability to synthesize Gln. The metabolic cost of these deficiencies is that they impair the Müller cell's ability to metabolize Glc. We show here that the cells can compensate for this deficiency by using metabolites produced by neurons. Müller glia are deficient for pyruvate kinase (PK) and for aspartate/glutamate carrier 1 (AGC1), a key component of the malate-aspartate shuttle. In contrast, photoreceptor neurons express AGC1 and the M2 isoform of pyruvate kinase, which is commonly associated with aerobic glycolysis in tumors, proliferating cells, and some other cell types. Our findings reveal a previously unidentified type of metabolic relationship between neurons and glia. Müller glia compensate for their unique metabolic adaptations by using lactate and aspartate from neurons as surrogates for their missing PK and AGC1.glutamine metabolism | aerobic glycolysis | retina | Müller glia | photoreceptors A erobic glycolysis is a metabolic adaptation that proliferating cells use to meet anabolic demands (1, 2). In tumors, it is called the "Warburg effect." Tumors convert ∼90% of Glc they consume to lactate (Lac). The brain converts only 2-25% of the Glc it uses to Lac (3).In retinas of vertebrate animals, energy is produced in a way that resembles tumor metabolism more than brain metabolism. Aerobic glycolysis accounts for 80-96% of Glc used by retinas (4-7). Retinas are made up of neurons and glia (8). The outermost layer is occupied by photoreceptors (PRs). The inner layers are a diverse collection of signal processing neurons. Müller glia spans the thickness of the retina. The site of aerobic glycolysis in retina has not been established.Exchange of fuels is an important part of the relationship between neurons and glia (9-12). Transfer of metabolites between intracellular compartments also is important. Glycolysis is supported by reoxidation of cytosolic NADH, which can be catalyzed by lactate dehydrogenase (LDH) or by the malate-aspartate shuttle (MAS). PRs and other neurons in retinas express aspartate/glutamate carrier 1 (AGC1; also known as "Aralar") (13), a mitochondrial aspartate/glutamate carrier that has a key role in the MAS. However, Müller cells (MCs) are AGC1-deficient (13). The significance of the distribution of AGC1 has been enigmatic.Aerobic metabolism in tumors is linked to expression of the M2 isoform of pyruvate kinase, PKM2 (14, 15). Pyruvate kinase (PK) catalyzes the final step in glycolysis, synthesis of Pyr (16). Liver (PKL) and erythrocyte (PKR) isoforms are splice variants of the PKLR gene, and PKM1 and PKM2 are splice variants of the PKM gene. A unique feature of PKM2 is that it is responsive to allosteric and posttranslational regulators (16). PKM2 expression in cancer cells correlates with reduced yield of ATP from Glc and accumulation of glycolytic inte...

To determine the incidence of adverse drug reactions (ADRs) to unlicensed and off-label drugs used in paediatric inpatients, we carried out prospective surveillance on five different paediatric wards in a regional children's hospital for 13 wk. Comparison of the use of each drug with its summary of product characteristics was made to determine whether the drug was used in an unlicensed or off-label manner. The presence of an ADR was determined using previously defined criteria. In total, 4455 courses of drugs were administered to 936 patients in 1046 admissions. In 507 (48%) of the 1046 admissions, patients received one or more unlicensed or off-label drugs. ADRs occurred in 116 (11%) of the 1046 patient admissions. ADRs were associated with 112 (3.9%) of the 2881 licensed drug prescriptions and 95 (6%) of the 1574 unlicensed or off-label drug prescriptions. Use of drugs in an off-label or unlicensed manner to treat children is widespread. ADRs are a significant problem following unlicensed or off-label drug prescriptions.