Renato Tambucci

Anti-viral therapy for congenital cytomegalovirus infection: pharmacokinetics, efficacy and side effects

Abstract Congenital cytomegalovirus (CMV) infection is the most common congenital infection in the world with approximately 0.5–2% of all live born infants, and can cause early or late severe neurological and neurisensorial damage. Although no drug has been licensed for therapy of congenital CMV infection, ganciclovir (GCV) and its oral pro-drug, valganciclovir (val-GCV), is increasingly being administrated to symptomatic infants, to improve neurodevelopmental and auditory outcome. Other potentially efficacious for therapy of congenital CMV disease are foscarnet and cidofovir, which have only been administered in few cases. A literature search was performed to look for evidence based or scientific articles evaluating pharmacokinetics, efficacy, and side effects of GCV/val-GCVand the other two anti-viral drugs.

Update on the role of eslicarbazepine acetate in the treatment of partial-onset epilepsy

Eslicarbazepine acetate (ESL) is a once daily new third generation antiepileptic drug that shares the basic chemical structure of carbamazepine and oxcarbazepine – a dibenzazepine nucleus with the 5-carboxamide substituent, but is structurally different at the 10,11-position. ESL is a pro-drug metabolized to its major active metabolite eslicarbazepine. Despite the fact that the exact mechanism of action has not been fully elucidated, it is thought to involve inhibition of voltage-gated sodium channels (VGSC). ESL inhibits sodium currents in a voltage-dependent way by an interaction predominantly with the inactivated state of the VGSC, thus selectively reducing the activity of rapidly firing (epileptic) neurons. ESL reduces VGSC availability through enhancement of slow inactivation. In Phase III studies, adjunctive therapy with ESL 800 or 1,200 mg/day leads to a significant decrease in the seizure frequency in adults with refractory partial onset epilepsy. Based on these results, ESL has been approved in Europe (by the European Medicines Agency) and in the United States (by the US Food and Drug Administration) as add-on therapy. Data on efficacy and safety have been confirmed by 1-year extension and real life observational studies. Recently, based on results from two randomized, double-blind, historical control Phase III trials, ESL received US Food and Drug Administration approval also as a monotherapy for patients with partial onset epilepsy. In the pediatric setting, encouraging results have been obtained suggesting its potential role in the management of epileptic children. Overall ESL was generally well tolerated. The most common adverse events were dizziness, somnolence, headache, nausea, diplopia, and vomiting. Adverse events can be minimized by appropriate titration. In conclusion, ESL seems to overcome some drawbacks of the previous antiepileptic drugs, suggesting a major role of ESL in the management of focal onset epilepsy for both new onset and refractory cases, either as monotherapy or as adjunctive treatment.

Clinical relevance of esophageal baseline impedance measurement: just an innocent bystander.

Objective: The clinical relevance of esophageal baseline impedance (BI) remains to be determined. In the present study, we explored the impact of gastroesophageal reflux disease (GERD) and esophageal dysmotility on BI. Methods: A total of 18 children with esophageal atresia, 26 children with GERD, and 17 controls prospectively underwent esophagogastroduodenoscopy and pH–impedance monitoring. BI was measured in both proximal and distal esophagus. Gastroesophageal reflux (GER) and bolus transit indicators were defined according to published criteria. Results: Patients with esophageal atresia showed significantly lower proximal and distal BI values (952 [716–1811] &OHgr;; 895 [284–1189] &OHgr;; respectively) compared with those with GERD (3015 [2368–3975] &OHgr;; 2231 [1770–3032] &OHgr;, P < 0.001 and <0.001, respectively) and controls (3699 [3194–4358] &OHgr;; 3522 [2927–3994] &OHgr;, P < 0.001 and <0.001, respectively). Using linear regression, proximal BI strongly correlated with total bolus transit time (r2 = 0.61, P < 0.001) and bolus presence time (BPT; r2 = 0.63, P < 0.001). Distal BI weakly correlated with acid exposure time (r2 = 0.16, P < 0.01) and longstanding reflux episodes (r2 = 0.17, P < 0.01), and strongly correlated with total bolus transit time (r2 = 0.53, P < 0.001) and BPT (r2 = 0.58, P < 0.001). By logistic regression, BPT predicted low proximal BI values (odds ratio [OR] 1.052; P < 0.05), whereas both GER indicators (acid exposure time: OR 1.56, P < 0.05; longstanding reflux episodes: OR 2.8, P < 0.05) and BPT (OR 1.66, P < 0.01) predicted low distal BI values. Conclusions: Along the length of esophagus, both bolus transit variables and GER significantly affect BI. This suggests that BI may merely mirror phenomena occurring within the esophageal lumen or wall, limiting its value as a discrete clinical entity to replace variables already used for assessing both GERD and esophageal dysmotility.

Eosinophilic esophagitis: is it also a surgical disease?

BACKGROUND Eosinophilic esophagitis (EoE) is a chronic immune/antigen-mediated disease with esophageal dysfunction and eosinophil-predominant inflammation. An association between EoE and gastro-esophageal reflux disease (GERD) has not been well established. AIMS The aim was to evaluate patients with EoE who underwent pH-Multichannel Intraluminal Impedance (pH-MII), investigating proton-pump-inhibitors (PPI) therapy/anti-reflux surgery requirement. METHODS Twenty-five patients [mean age 7.6 (range 1-17 years)] with EoE underwent pH-MII. The children were then divided into Group 1 (pathological pH-MII) and Group 2 (normal pH-MII). PPI was administered for two months in Group 1 and in those children in Group 2 unresponsive to standard EoE therapy (diet and corticosteroids). All patients underwent endoscopy and clinical follow-up. Data are described as mean (range). RESULTS Group 1 (n=16, M:F=14:2) had mean reflux index (RI) 13.9% (0.8%-53.4%) with a mean number of total reflux episodes (RE) of 65.8 (14-341). Group 2 (n=9, M:F=6:3) had a mean RI 1.2% (0.2%-2.7%) with a mean number of total RE of 27.4 (14-39). There was a histological response to repeated cycles of PPI in 11/16 (69%) children in Group 1 and 4/9 (44%) children in Group 2. Fundoplication, because of dependence on PPI, was required in 4/11 PPI-responders in Group 1, allowing discontinuation without relapse of EoE. CONCLUSIONS The use of PPI is suggested in EoE at time of diagnosis in addition to standard treatment and may even have benefit in children who do not appear to have significant GERD but are unresponsive to standard therapy.

Role of non-acid gastro-esophageal reflux in children with respiratory symptoms

Respiratory symptoms are a possible atypical clinical picture of gastro‐esophageal reflux disease (GERD). However, a significant number of patients with GERD‐related respiratory symptoms do not report improvement despite aggressive acid‐suppressive therapy. Some of these refractory cases may be due to the recently appreciated entity of non‐acid or weakly acidic reflux. The aim of our study is to assess the pH‐impedance features of GER inducing airway symptoms, compared with GER inducing typical gastro‐intestinal (GI) symptoms.

OP-24 ESOPHAGEAL BASELINE IMPEDANCE IN NEUROLOGICALLY IMPAIRED CHILDREN.

Introduction: Dysphagia, feeding difficulties and gastro-oesophageal reflux (GORD) are common complaints in neurologically impaired children. Motor pattern generators localised in the brain stem and CNS reflexes play a key role on controlling oesophageal peristalsis and lower oesophageal sphincter activity. Thus, it is not surprising that brain abnormalities may result in significant oesophageal motor dysfunction. In this prospective study we evaluated the differences in multichannel intraluminal impedance-pH monitoring (MII-pH monitoring) pattern between children with cerebral palsy (CP) and 2 groups of neurologically normal children with normal and abnormal MII-pH monitoring. We mainly focused our attention on oesophageal baseline impedance (BI), which has been proposed as useful parameter in predicting GORD severity. Methods: Twenty children with CP and 40 neurologically normal children with suspected GORD underwent MII-pH impedance. Classical MII-pH impedance parameters as well as BI values in both proximal and distal oesophagus were analysed. MII-pH monitoring was considered abnormal if acid exposure time (AET) was >5% and/or SAP was >95%. Results: Nine CP children had a diagnosis of GORD. Of neurologically normal children, 20 had an abnormal (GR-A) and 20 a normal MII-pH monitoring (GR-B). A significant difference in the proportion of children with abnormal AET was found between CP and GR-A (9/20 vs 17/20; p < 0.05). GR-A showed a significantly greater percentage of AET (15.97 [6.4–34.9]) than both CP (8.21 [0–31.9], p < 0.05) and GR-B (1.4, [0–4.5], p < 0.0001), whereas between the latter groups CP showed a greater AET (p < 0.05). Proximal BI values were significantly lower in CP (1759 [691–3133]&OHgr;) than GR-A (2396 [1080–3850]&OHgr;, p < 0.05) and GR-B (3385 [2249–4817]&OHgr;, p < 0.0001). No difference in distal BI was found between in CP (1106 [279–3098]&OHgr;) and GR-A (1152 [246–2526]&OHgr;), while was lower in CP than in GR-B (2965 [1986–3984]&OHgr;, p < 0.001). Considering all patients as a whole group, an inverse correlation was found between distal BI and AET (r-0.66; p < 0.001), whereas within groups an inverse correlation was only confirmed in GR-A pts (r-0.67; p < 0.001). Conclusions: Although an abnormal pH-impedance monitoring was detected in almost half of children with CP, no correlation was found between the AET and BI values, suggesting that the latter cannot be used as predictor of reflux severity in this group of patients. The presence of low impedance values in both proximal and distal oesophagus in children with CP supports the view that in neurologically impaired children BI mainly reflects oesophageal motor abnormalities, which have been previously reported.

Drug Therapy of Childhood Obesity

Over the last decades obesity prevalence among children and adolescents has increased dramatically and coincidentally the well-established comorbidities associated with the excess body weight have become a major health challenge worldwide. Despite intensive lifestyle modifications, patients severely obese might warrant adjunctive interventions. Although, antiobesity pharmacotherapy is emerging as a promising adjunctive strategy for adults who fail to respond to behavioral strategies, most of agents are not licensed for the treatment of obesity in children and adolescents. The aim of this narrative review is to discuss possible mechanisms by which drugs lead to weight loss and to summarize data concerning FDA-approved anti-obesity focusing on relatively small body of evidence concerning pharmacological options for managing pediatric obesity. Lifestyle and behavioral interventions remain the mainstream of the obesity treatment in children, but adjunctive pharmacotherapy may be beneficial in some patients. Although well-designed clinical trials are needed to properly evaluate safety and efficacy of anti-obesity drugs in children and adolescents, pediatricians dealing with obesity should know what drugs are available. Early identification, during childhood, of individuals who most likely respond favorably to a specific anti-obesity agent will be possibly more efficacious in addressing the global obesity epidemic, than pharmacotherapies started in older ages.

Gastroenterology: Focus on Children with Gastrointestinal Problems

Gastrointestinal imaging tests are a cornerstone of the gastroenterologist’s diagnostic armamentarium. Over the last decades, nuclear medicine has gained increasing importance for the assessment of the digestive system disorders.

An uncommon cause of abdominal pain in a child: Meckel diverticulum

Meckel diverticulum, a common congenital anomaly of the small intestine, can be responsible of several complications due to the presence of ectopic gastric mucosa and represents a challenge for diagnosis. We present the case of a 11-year boy suffering from intestinal pain and bleeding in which radiological examinations unexpectedly raised the suspicion of Meckel diverticulum. The diagnosis was confirmed using 99mTc-pertechnetate scintigraphy. At surgery, a fistulous tract between Meckel diverticulum and an inflamed appendix was found. The authors discuss the role of medical nuclear imaging which, notwithstanding its limitations, is of fundamental importance to achieve a correct and timely diagnosis. This is of particular relevance in unusual cases, as the one presented, in which Meckel diverticulum is found concurrently with other intestinal abnormalities.

Diagnostic Tests in Pediatric Constipation

ABSTRACT Constipation is one of the most common gastrointestinal symptoms in children. With a median reported prevalence of 12%, it accounts for about 25% of all pediatric gastroenterology consultations. The majority of children experiences functional constipation and do not usually require any diagnostic testing. For those children not responding to conventional medical treatment or in the presence of a more significant clinical picture, however, an accurate instrumental assessment is usually recommended to evaluate either the underlying pathophysiologic mechanisms or a possible organic etiology. The present review analyzes the possible diagnostic investigations for severely constipated children, focusing on their actual indications and their utility in clinical practice. During the last decade, there has been a remarkable increase in our knowledge of normal and abnormal colonic and anorectal motility in children, and a number of different techniques to measure transit and motility have been developed and are discussed in this narrative review.