Botulinum toxin type A treatment in neurogenetic syndromes

Purpose: To review the use of therapeutic botulinum toxin type A (BoNT-A) treatments in uncommon neurogenetic syndromes.

Method: A retrospective questionnaire and interview study of a selected case series to assess the efficacy and safety following initial BoNT-A treatment (50–400 units per subject) was conducted to determine the response of families to treatment. Twelve male and six female subjects with ages from 2–19 years were included. The reasons for treatments were based on both patient-related and caregiver-related objectives. Satisfaction with achievement of stated goals was assessed by follow-up interviews.

Results: Beneficial effects were reported in 56%, some effects in 22% and no to minimal effects in 22%. The duration of effect ranged from 10 days to 12 months with an average of 3.16 months. Ten families would repeat the injections as needed, four would not and four were not sure. Unanticipated effects of BoNT-A treatments were reported by some families. Adverse effects did not occur with the doses that were used.

Conclusions: The results suggest that obtaining family input may be useful when treating spasticity in unusual circumstances. The use of BTX-A in uncommon neurogenetic syndromes was supported by the majority of families interviewed.     

Modified constraint-induced therapy for children with hemiplegic cerebral palsy: A feasibility study

Purpose: To determine the feasibility of family-focused, modified constraint-induced therapy with children with hemiplegic cerebral palsy and test study procedures in preparation for a randomized controlled trial.

Design: Prospective pre–post feasibility study.

Methods and procedures: Ten children (median age: 3 years 6 months) were assessed at baseline, at completion of intervention and at 6 months post-baseline. Intervention consisted of a mitt worn on the unaffected hand for 2?hours per day for 8 weeks. Targeted adjunct therapy was provided during the time the mitt was worn. Primary assessments included the Canadian Occupational Performance Measure, Goal Attainment Scaling, Assisting Hand Assessment and the Melbourne Assessment of Unilateral Upper Limb Function.

Outcomes: Modified constraint-induced therapy as implemented in this study was acceptable to participants. Over the intervention period, participants experienced improvements in the performance of important daily activities as determined by the primary outcome measures.

Conclusions: Modified constraint-induced therapy which targets participant-identified goals and which is family-focused warrants further investigation utilizing randomized trial methodology.

Propósito: Determinar la viabilidad de la terapia modificada de inducción de restricción enfocada en la familia en niños con parálisis cerebral hemipléjica, y evaluar procedimientos de estudio en la preparación de una prueba controlada aleatorizada. Diseño: Estudio prospectivo pre-post viabilidad. Métodos y procedimientos: Se evaluaron a diez niños (edades medias: 3años 6 meses) en una etapa inicial, al completar el tratamiento y a los seis meses después de la evaluación inicial. La intervención consistió del uso de un guante en la mano no afectada durante 2 horas al día por 8 semanas. La terapia adjunta fue proporcionada durante el periodo de tiempo en que el guante fue usado. Los instrumentos de evaluación primaria incluyeron: Canadian Occupational Performance Measure, Goal Attainment Scaling, Assisting Hand Assessment y the Melbourne Assessment of Unilateral Upper Limb Function. Resultados: La terapia de inducción de restricción modificada fue aceptada por los participantes de la forma en que fue implementada en este estudio. Los participantes experimentaron mejoría en el desempaño de las actividades de la vida diaria durante el periodo de tratamiento, siendo determinado esto por los resultados de las mediciones primarias. Conclusiones: El hecho de que las terapias de inducción de restricción modificada tengan como objetivo metas identificadas por los pacientes y un enfoque familiar, sienta precedente para la realización de investigaciones futuras que utilicen una metodología de pruebas aleatorizadas. Palabras clave: Terapia de inducción restringida modificada, parálisis cerebral, función del miembro superior, pediátrica, enfocado en la familia, hemiplejia     

Application of a physiologically‐based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.     

Covariate effects and population pharmacokinetics of lamivudine in HIV-infected children

Aim

Lamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and C_max).

Methods

Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building.

Results

A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h⁻¹ and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg⁻¹ ranged from 4.44 mg l⁻¹ h for children <14 kg to 7.25 mg l⁻¹ h for children >30 kg.

Conclusions

The use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered.