Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - Evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: Study protocol for a randomized controlled trial

Background: Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. Methods/design: The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. Discussion: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. Trial registration: EudractCT, 2014-004897-40. Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012. Registered on 7 September 2017

The research gap in chronic paediatric pain: A systematic review of randomised controlled trials

Background and Objective: Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain. Methods: We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months-18 years) and evaluated the use of pharmacological or non-pharmacological intervention(s) in the context of pain persisting or re-occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool. Results: A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty-five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non-pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co-analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB. Conclusions: Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long-lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them. Significance: There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non-pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long-lasting diseases

Discondroplasia tibial de los pollos parrilleros

La discondroplasia tibial (TD) forma parte de un conjunto de alteraciones esqueléticas de las aves de corral producidas en forma intensiva, que entrañan disminución de la performance del lote, del rendimiento individual y del bienestar animal. Es un desorden del desarrollo, caracterizado por la permanencia de cartílago anormal en el extremo proximal de la tibia. Si bien las lesiones moderadas no impiden que los pollos lleguen al alimento y al agua; el dolor, asociado a las lesiones severas, puede motivarlos a echarse y por consiguiente a disminuir el consumo. Un estudio secuencial llevado a cabo en dos líneas comerciales de distinta predisposición a desarrollar TD sugirió que, en el caso en estudio, la TD estaba relacionada a una predisposición al raquitismo y asociada a bajos niveles del metabolito activo de la vitamina D3 (el 1,25(OH)2vitamina D3) en la circulación sanguínea, en el período de mayor crecimiento de la tibia. En un sentido amplio este desorden del desarrollo está determinado genéticamente e influido por el manejo a través de factores tales como: nivel de actividad, composición de la dieta y método de alimentación. A pesar de las evidencias a favor de un cambio en el manejo, tendiente a disminuir la incidencia de esta afección, aún no se han modificado las condiciones de crianza en lotes comerciales. Este hecho probablemente ocurrirá cuando el consumidor reclame animales criados teniendo en cuenta las normas de Bienestar Animal. Debido a ello, el manejo sanitario se ha limitado a emplear herramientas que contrarresten los efectos negativos de las causales de TD impuestas por la eficiencia productiva. La escasa experiencia en el diagnóstico diferencial de la TD en lotes comerciales de pollos parrilleros, debería estimularnos a realizar estudios de relevamiento de las afecciones esqueléticas en esta explotación, orientados al reconocimiento diferencial de la TD y su cuantificación, para investigar la relación entre su nivel de incidencia y los distintos factores etiológicos destacados por los investigadores citados en esta revisió

Principios tóxicos de Solanum malacoxylon Sendtner. I. Acción de fracción con solventes selectivos sobre el metabolismo fosfo-calcico y tejidos blandos del conejo.

Se separaron seis fracciones químicamente diferentes de Solanum malacoxylon Sendtner por extracción con solventes selectivos, y se ensayó la acción de estas fracciones sobre el metabolismo del calcio y fósforos en conejos

Biosimilar granulocyte-colony-stimulating factor for mobilization of autologous peripheral blood stem cells in pediatric hematology-oncology patients

BACKGROUND: Recently biosimilars of granulocyte-colony-stimulating factor (G-CSF) became available for prophylaxis and treatment of postchemotherapy neutropenia and for mobilization of peripheral blood CD34+ cells for either autologous or allogeneic hematopoietic stem cell transplant. Most of the data on the mobilization efficacy and safety of biosimilar G-CSF are from adult patients, whereas no data are available in pediatric patients. STUDY DESIGN AND METHODS: This was a retrospective study on cases treated at three Italian pediatric transplant centers, from January 2011 to October 2013. Data were collected on all children undergoing first peripheral blood stem cell (PBSC) mobilization after stimulation with biosimilar G-CSF and chemotherapy. The results were compared with a historical control group. RESULTS:Twenty-nine children underwent mobilization with biosimilar G-CSF. Peak peripheral blood CD34+ cell count of 20\u2009 7\u200910(6) /L was achieved in 90% of patients, with a median value of 71\u2009 7\u200910(6) /L. Eighty-three percent reached the desired target (CD34+/kg) dose. The median number of collected CD34+ cells was 10\u2009 7\u200910(6) /kg (range, 4.8\u2009 7\u200910(6) -68.8\u2009 7\u200910(6) /kg). No difference was observed in comparison with historical control group mobilized with originator filgrastim. Moreover, no major and/or unexpected side effects were reported. CONCLUSION:Biosimilar G-CSF resulted as effective and safe as originator filgrastim molecule in mobilizing PBSCs in children, with the advantage of a reduced cost

ABMT for children AML: Italian experience. GITMO-AIEOP Groups.

We report data from an Italian survey on ABMT in 93 AML children less than 14 years in 1st or 2nd remission performed in 15 Centers. Different conditioning regimens have been employed: BAVC, an original schedule of chemotherapy; TBI plus Cy and/or other drugs (TBI + CHT); other high dose chemotherapy schedules (HD CHT). 62 patients have been transplanted in 1st CR; 38 have been conditioned with BAVC, 16 with TBI + CHT and 8 with HD CHT. Relapses were 21 in the BAVC group (DFS = 35% at 66 months), 5 in the TBI group (DFS = 61% at 48 months) and 5 in the HD CHT group; overall DFS is 39% at 66 months. 31 patients have been transplanted in 2nd CR; 14 were conditioned with BAVC and 16 with TBI + CHT; 6 patients relapsed in the first group, DFS is 56% at 50 months; in the second group 2 early deaths and 3 relapses occurred, DFS is 65% at 65 months. 1 patient in 2nd CR, conditioned with HD CHT, died during aplasia. Overall DFS is 59% at 65 months. Although no final conclusions concerning ABMT in AML children may be drawn from this retrospective study because of heterogeneity of population and methods, results obtained in 2nd CR are clearly better to those obtained with standard chemotherapy alone, confirming the role of ABMT in this high risk category of patients

Undifferentiated (embryonal) sarcoma of the liver in childhood. The experience of the Italian Cooperative group on Pediatric Soft Tissue Sarcoma

Introduction The undifferentiated (embryonal) sarcoma of the liver (USL) is a rare mesenchymal tumor that occurs mainly in children benveen 5 and 10 years. Prognosis is reputed poor because radical surgery is difficult and the activity of chemotherapy is not well documented. Methods Ten children with USL have been enrolled in the protocols ran by the Italian Cooperative Group from 1979 to 1995. Treatment was similar to the one used for children with rhabdomyosarcoma and provided a conservative radical surgery at diagnosis or after preoperative chemotherapy and eventually radiotherapy. Results Surgery was radical in 5 patients: at diagnosis (one case) or after chemotherapy. Response to initial chemotherapy was evident in 6 out of 7 évaluable cases. Six patients are alive without evidence of disease 5 to 12 years from diagnosis. One child died for surgical complication and ftvo because of the tumor. One more patient is lost to follow up. Conclusions Our results confirm the crucial role of radical resection of the tumor. Chemotherapy may be administered to reduce the tumor size making the mass resection feasible. Improvement in surgical techniques and administration of aggressive chemotherapy, similar to that used for rhabdomyosarcom, has improved the prognosis for these patients

Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation

Busulfan (BU) is an alkylating drug frequently used to prepare patients for bone marrow transplantation (BMT). Several studies have documented that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pathway are capable of influencing BU clearance. We compared the BU pharmacokinetics and pharmacodynamics of 13 patients given BMT and receiving BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients treated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to control patients and patients receiving fluconazole (p < 0.01). Mean BU clearance was 7.653 ± 1.871 l/hr.m2 in the itraconazole patients, 10.103 ± 2.007 l/hr.m2 in the itraconazole group and 9.373 ± 1.702 l/hr.m2 in the control group. In this study itraconazole, but not fluconazole, markedly affected the pharmacokinetics of BU as an increase of BU plasma concentrations was observed. The nature of this interaction has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itraconazole can modulate BU pharmacokinetics, oxidative catabolism is probably a determinant of BU metabolism. This hypothesis should be tested in human metabolic studies

Diamo qualità alla vita: completamento dell'offerta di medicina del dolore e Cure Palliative pediatriche specialistiche in Regione Liguria

il poster dal titolo " Diamo qualità alla vita: completamento dell'offerta di medicina del dolore e Cure Palliative pediatriche specialistiche in Regione Liguria" illustra i risultati ottenuti nella Regione Liguria in materia di cure palliative pediatriche rispetto al quale si colloca la propria attività di consulenza tecnico-scientifica per la realizzazione dell’hospice pediatrico condotta in ambito multidisciplinare attraverso l’accordo tra la Fondazione Maruzza Lefebvre d’Ovidio Onlus e l’Istituto Gaslini