Mariana Catapano

Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey

The aim of this Delphi survey is to develop common definitions for unlicensed and off-label drug use in children to be used for research and regulatory purposes. After a literature review on the current status of unlicensed/off-label definitions, a two-stage, web-based Delphi survey was conducted among experts in Europe. Their opinion on concerns, rules and scenarios regarding the unlicensed and off-label use of medicines were obtained. Results were then consulted with the European Medicines Agency (EMEA) before the final proposal was circulated to participants. Eighty-four experts were invited to participate (scientists, health professionals, pharmaceutical companies, regulatory agencies), 34 responded to the first round questionnaire and participated in subsequent rounds. Consensus was reached for the majority of questions. The lowest level of consensus reached was for questions related to a different formulation or if a drug was given although contraindicated. At the final step, 85% of the responding experts agreed on the proposed definition for off-label (use of a drug already covered by a Marketing Authorisation, in an unapproved way) and 80% on the definition for unlicensed (use of a drug not covered by a Marketing Authorisation as medicinal for human use), respectively. Results will facilitate the conduct of pharmacoepidemiological studies and allow comparison between different countries. The Delphi panel agreed that the definitions should be circulated within the scientific community and recommended to be adopted by relevant regulatory authorities.

Challenges in prescribing drugs for children with cancer

Paediatric oncology has achieved high cure rates despite the limited availability of drugs that have been specifically studied for use in children with cancer. Efficacy of these drugs has received more attention than their safety, but permanent side-effects in growing children need to be considered. An absence of pharmacokinetic data, dose-defining studies, schedules defined by age, and appropriate formulations can lead to underdosing or overdosing in specific age groups, resulting in a potential lack of benefit, development of resistance, and increased adverse drug reactions. These major clinical concerns have promoted initiatives in Europe since 2003 regarding the need for a Paediatric Regulation, aimed at improving the risk-benefit ratio of such drugs in children and providing the legal framework to overcome the limitations of the past. However, to undertake the appropriate studies of these drugs in this setting, financial support is essential. Europe is now showing its commitment to overcome the present difficulties of drug prescribing for children with cancer by introducing measures that will encourage new public-private partnerships. All those involved, including researchers, paediatric oncologists, learned societies, regulatory agencies, national agencies, and pharmaceutical companies, need to become more familiar with the opportunities opened up by the new regulation, which is aimed at providing an increased cooperation between researchers and drug developers for the benefit of children.

Peripheral plasma amino acid abnormalities in rehabilitation patients with severe brain injury

OBJECTIVE Acute severe brain injury causes an increased mobilization of amino acids from tissue. The plasma amino acid profile of patients undergoing rehabilitation after brain injury is unknown. This study was aimed at delineating the plasma amino acid profile of rehabilitation patients with brain injury. DESIGN Peripheral plasma aminogram, lactate, pyruvate, glycerol, ketone body, and carnitine concentrations were determined in 11 patients with brain injury (34.6+/-15 years old, 60+/-16.8 days after injury) and in 8 controls. Resting energy expenditure and nitrogen balance were also determined. RESULTS (1) All essential amino acids and about 50% of nonessential amino acids were significantly lower in brain injury patients than in controls (p < .05). (2) Plasma amino acids were lower irrespective of either energy and protein intake or nitrogen balance. (3) Total carnitine concentration and esterified/free carnitine ratio were higher in brain injury patients than in controls (p < .05). CONCLUSIONS Rehabilitation patients with brain injury may have an important reduction of their plasma aminogram. Muscle tissue depletion and the persistence of a hypercatabolic state caused by subclinical infections, pressure sores, and immobility may contribute to this reduction.

Altered Muscle Energy Metabolism in Post-absorptive Patients with Chronic Renal Failure

Skeletal muscle biopsies were performed on 12 healthy sedentary subjects and on 22 non-dyalized chronic renal failure patients (CRF) on a free diet and after overnight fasting. Parathormone, glucagon and insulin were determined at the same time of biopsies. CRF patients showed significantly low ATP and creatine phosphate levels. Regarding enzyme activities, a high hexokinase Vmax was found, while the pyruvate kinase activity was lower than in the control group. For the tricarboxylic acid cycle, citrate synthase, succinate dehydrogenase and malate dehydrogenase activities were higher; total NADH cytochrome c reductase activity was also high, while cytochrome oxidase activity was slightly lower. Both alanine aminotransferase and aspartate aminotransferase activities were considerably high in comparison with the control group. In conclusion, our study revealed a hypermetabolic TCA cycle, but impaired oxidative phosphorylation, which partly explained the reduced ATP concentration. Excessive protein intake and hormonal derangements may play a role in these metabolic changes.

Effects of hypoxia on enzyme activities in skeletal muscle of rats of different ages. An attempt at pharmacological treatment

The activities of enzymes related to energy metabolism in the gastrocnemius and soleus muscles in young-adult (4 months), mature (12 months) and senescent (24 months) rats were compared after 72 h of continuous exposure to normobaric hypoxia or normoxia after alpha-adrenergic antagonist nicergoline or saline solution had been given intraperitoneally for 30 consecutive days. The maximum rates (Vmax) of the following enzyme activities in the crude extract and/or the mitochondrial fraction of each muscle specimen were evaluated: (1) for the anaerobic glycolytic pathway: hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase; (2) for the tricarboxylic acid cycle; citrate synthase and malate dehydrogenase; (3) for the electron transfer chain; cytochrome oxidase; and (4) for the NAD+/NADH redox state: total NADH cytochrome c reductase. The significant differences between the enzyme activities at different ages or under different experimental conditions in the two tissue preparations of the two muscles were determined by ANOVA. MCA and ETA were used to evaluate the net effects of the experimental conditions. Ageing did not seem to affect the soleus and gastrocnemius muscles in the same way. Changes were seen only in the glycolytic pathway enzymes in the crude extract from the gastrocnemius muscle. In the soleus muscle changes in enzyme activities as a function of ageing were also found in the mitochondrial fraction. We also found that hypoxia caused greater changes in 12-month-old rats than in those of other ages (especially in the enzyme activities of the gastrocnemius muscle). Finally out data show that only in certain cases was the pharmacological treatment able to modify the influence of hypoxic conditions on the levels of enzyme activities, regardless of the age of animals.

Pediatric Drug Safety Signal Detection: A New Drug–Event Reference Set for Performance Testing of Data-Mining Methods and Systems

BackgroundBetter evidence regarding drug safety in the pediatric population might be generated from existing data sources such as spontaneous reporting systems and electronic healthcare records. The Global Research in Paediatrics (GRiP)–Network of Excellence aims to develop pediatric-specific methods that can be applied to these data sources. A reference set of positive and negative drug–event associations is required.ObjectiveThe aim of this study was to develop a pediatric-specific reference set of positive and negative drug–event associations.MethodsConsidering user patterns and expert opinion, 16 drugs that are used in individuals aged 0–18 years were selected and evaluated against 16 events, regarded as important safety outcomes. A cross-table of unique drug–event pairs was created. Each pair was classified as potential positive or negative control based on information from the drug’s Summary of Product Characteristics and Micromedex. If both information sources consistently listed the event as an adverse event, the combination was reviewed as potential positive control. If both did not, the combination was evaluated as potential negative control. Further evaluation was based on published literature.ResultsSelected drugs include ibuprofen, flucloxacillin, domperidone, methylphenidate, montelukast, quinine, and cyproterone/ethinylestradiol. Selected events include bullous eruption, aplastic anemia, ventricular arrhythmia, sudden death, acute kidney injury, psychosis, and seizure. Altogether, 256 unique combinations were reviewed, yielding 37 positive (17 with evidence from the pediatric population and 20 with evidence from adults only) and 90 negative control pairs, with the remainder being unclassifiable.ConclusionWe propose a drug–event reference set that can be used to compare different signal detection methods in the pediatric population.

Biochemical evaluations in skeletal muscles of primates with MPTP parkinson-like syndrome

The toxic effects of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in primates can be exploited for investigating the physiopathology of Parkinsons disease which may also cause functional alterations of skeletal muscles, whose biochemical modifications have been studied very little. Some enzyme activities related to energy transduction in skeletal muscles were evaluated (gastrocnemius, soleus and biceps) from MPTP-treated monkeys. Systemically administered MPTP altered the enzyme activities related to: (i) the anaerobic glycolytic pathway (decrease in hexokinase and phosphofructokinase activities; increase in lactate dehydrogenase activity); (ii) the tricarboxylic acid cycle (decrease in malate dehydrogenase activity); (iii) the electron transfer chain (decrease in cytochrome oxidase activity related to complex IV). No alteration in mitochondrial Complex I was observed. Treatment with an ergot alkaloid derivative (dihydroergocryptine) modified some alterations in the muscle enzyme activities and reduced the rigidity and some autonomic dysfunction.

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

The lack or incompleteness of evidence of the efficacy and safety of drugs used in children has been a growing concern in the recent past. The great majority of drugs prescribed to children are often given either on an unlicensed or an “off label” basis simply by extrapolating data for adults and without conducting any paediatric clinical, pharmacokinetics, dose finding, or formulation studies in the paediatric population. The paediatric pharmaceutical repertoire therefore comprised pills too large to swallow and extemporaneous formulations containing excipients unsafe or unpalatable to children. Diseases in children, however, are often different from their adult equivalents, and the processes underlying growth and development might lead to a different effect or an adverse drug reaction unseen in adults. The health and, therefore, quality of life of the children in Europe suffer from a lack of testing and authorisation of medicines for their use. It means that children are “orphans” of appropriate medicinal products and children continue to be exposed to risks, and at the same time miss out on therapeutic advances. This is particularly ironic considering that our modern system of medicines regulation, that ensures the high standards of safety, quality and efficacy of medicinal products for use in adults, was developed primarily in response to therapeutic disasters, or “drug catastrophes”, that occurred in children in the past ( such as the numerous cases of icterus induced by sulphanilamide which occurred in 1937 and the well-known phocomelia caused by thalidomide in the 1960s).