127Archivio Italiano di Urologia e Andrologia 2018; 90, 2 ORIGINAL PAPER Desmopressin 120 mcg, 180 mcg, 240 mcg: The right treatment for the right patient Pietro Ferrara 1, 2, Ester Del Vescovo 2, Francesca Ianniello 1, Giulia Franceschini 2, Luciana Romaniello 3, Alberto Verrotti 4 1 Institute of Pediatrics, Catholic University Medical School, Rome, Italy; 2 Campus Bio-Medico University, Rome, Italy; 3 San Carlo Hospital, Potenza, Italy; 4 Department of Pediatrics, University of L’Aquila, L’Aquila, Italy. Background: The first-line drug therapy for patients with nocturnal enuresis (NE) associ- ated with nocturnal polyuria and normal bladder function is desmopressin (dDAVP). Objective: To evaluate if increasing dose of oral desmopressin lyophilisate (MELT) can improve response rates to dDAVP and is useful in enuretic children. Materials and methods: We enrolled a total of 260 children all diagnosed with NE. Enuretic children were treated with increasing MELT at a dose of 120, 180 and 240 mcg a day. Results. We included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 ± 2.52 years). Of the 237 patients enrolled in the study and treated with MELT 120 mcg, a full response was achieved in 135 (56.9%). A partial response was achieved in 21 (8.9%) patients, therefore the dose was increased up to 180 mcg, with further improving symptoms (14.3%) or full response (9.5%), and up to 240 mcg, without usefulness. Conclusions: MELT at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects. KEY WORDS: Desmopressin; Nocturnal enuresis. Submitted 14 February 2018; Accepted 16 March 2018 Summary No conflict of interest declared. ated with nocturnal polyuria and normal bladder func- tion is desmopressin (dDAVP) for a period of 3 months following by withdrawal. dDAVP is associated with a response rate of about 40-60%, however its effect may not be maintained on discontinuing treatment, and symptoms have been found to recur in about 50-80% after stopping treatment (3). The different formulations of dDAVP are an intranasal solution, an oral tablet formulation and the recent oral sublingual lyophilisate (MELT). The aim of this study is to evaluate if increasing dose of MELT (120, 180, 240 mcg/day) can improve response rates to dDAVP in enuretic children. MATERIALS AND METHODS We enrolled a total of 260 children all diagnosed with NE, between April 2014 and April 2017, at the Paediatric Service of Campus Bio-Medico Hospital in Rome. Inclusion criteria were: age > 5 years and a diagnosis of primary MNE (PMNE) without NE treatment in the last 3 months. Exclusion criteria were the presence of sec- ondary NE, any provided story of urinary infection, nephrogenic diabetes or congenital genitourinary anom- alies. The children and their families were asked to par- ticipate in the study. This study was conducted in accor- dance with the regulatory standards of Good Clinical Practice and the Declaration of Helsinki. We carefully evaluated each patients with medical histo- ry and physical examination, including monitoring blood pressure, possible sign of spinal dysraphism or polythelia, neurological reflexes and genital examination. During the period of treatment, all patients and their parents were asked to keep a NE calendar depicting the wet and the dry nights and in addition, we educated both child and parents with dietary advices (4). During the follow-up, families were called to verify their adherence and responses to the therapy and dietary rec- ommendations. Enuretic children were initially treated for a period of 3 weeks with MELT (Minirin®) at a dose of 120 mcg a day and after this observation period, the responders or full responders continued treatment up to three months, the DOI: 10.4081/aiua.2018.2.127 INTRODUCTION Nocturnal enuresis (NE) is a very common pediatric disor- der. According to recent International Children’s Continence Society (ICCS), NE is defined as intermittent incontinence occurs exclusively during sleeping periods. NE should not be used to refer to daytime incontinence (1). In children without any other lower urinary tract symp- toms and without a history of bladder dysfunction is defined as mono-symptomatic NE (MNE). NE is a multifactorial disorder. It has 3 main pathophys- iological determinants that are nocturnal polyuria, detru- sor overactivity and failure to awaken in response to bladder sensations. When organic disease is not suspect- ed and children suffer from MNE that causes a significant problem, it should be treated (2). The first-line drug therapy for patients with MNE associ- Ferrara_Stesura Seveso 28/06/18 16:38 Pagina 127 Archivio Italiano di Urologia e Andrologia 2018; 90, 2 P. Ferrara, E. Del Vescovo, F. Ianniello, G. Franceschini, L. Romaniello, A. Verrotti 128 partial responders increased MELT at a dose of 180 mcg and non responders were excluded. Patients who had increased the dose to 180 were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months, the partial responders increased MELT at a dose of 240 mcg and non responders were excluded. Finally patients treated with MELT 240 mcg were observed for 3 weeks and even in this observation period, the responders or full responders continued treatment up to three months and non responders were excluded. According to the ICCS classification for initial success, the children were classified as non-responders if there was no or less than 50% decrease in wet nights com- pared to baseline; partial responders if there was 50% or more, but less than 90% decrease in wet nights com- pared to baseline; responders if there was a 90% or more decrease in wet nights compared to baseline; full respon- ders if there was a 100% decrease or less than 1 symp- tom occurrence monthly. RESULTS We enrolled 260 children with PNE. Of these, 23 were excluded for the following reasons: 15 had undergone therapy with MELT, 5 were lost to the follow up, 3 because of a further period of observation. We included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 ± 2.52 years). Of the 237 patients enrolled in the study and treated with MELT 120 mcg, a full response was achieved in 135 (56.9%), a partial response was achieved in 21 (8.9%) and 81 (34.2%) had no response in terms of a decreased number of wet nights, reflecting values in the literature. When the 21 partial responders increased MELT at a dose of 180 mcg, 16/21 (76.2%) had no further improvement and a mild improved response was achieved in 3/21 (14.3%); in these patients in which MELT dosage was increased to 240 mcg/day, a response or full response was achieved only in 2/21 (9.5%). They were evaluated again after 3 weeks of pharmaco- logical therapy combined with dietary advices. Of the 3 patients that increased the dosage to 240 mcg/day, no one had response in terms of a decreased number of wet nights. DISCUSSION In our study we would like to highlight the importance of appropriate dDAVP administration and to clarify best practice in the use of this medication. Reported response rates vary, only 41% of patients achieved ≥ 50% reduction in wet nights in the study by Lottman et al. (5), but 77% achieved > 90% reduction in the study by Onol et al. (6). It depends on the type of patients selected, suboptimal adherence rates, adminis- tration methods and doses and formulations used (7). Several studies have demonstrated decreased secretion of ADH and a reduced response to antidiuretic hormone in children affected. Moreover, NE may be present with sev- eral comorbidities such as sleep disorders, psychological problems, parasomnias, left-handedness, polythelia, lan- guage disorders and testicular pathology (8-10). Various formulations of dDAVP are available (tablets, nasal spray) and many studies also showed that the dosage for MELT is more predictable due to the signifi- cantly smaller variance, however there is only limited information on the response to dDAVP in children rela- tive to the dose required to produce an antidiuretic effect for the entire night. In a previous dose-ranging study, dDAVP tablets of up to 600 mcg at bedtime did not appear to reach a maximum effect (11, 12). In our study only a small percentage of patients who had increased the dose of MELT to 180 mcg have further improved symptoms (14.3%) or was full responders (9.5%). No patient treated with 240 mcg had usefulness. It can suggests the importance of selecting the right treat- ment for the right patients. Patients must be properly evaluated and diagnosed, and therapy must be used appropriately for the treatment to be successful. Data show that proper patient screening can predict treatment response, as well as failure rates. A recent study, in fact, suggests that also the use of blad- der diaries is highly recommended wherever possible (13). Therefore, it is essential that the treating physician rec- ognize that dDAVP will not work for all patients, and increasing dosage is not helpful if we do not use some tools to predict response. It is important that the most appropriate treatment strategy is selected as quickly as possible in order to minimize distress and difficulty for the patient and family. MELT at the dose of 120 mcg resulted efficacy and safe- ty; the increased dose up to 180 mcg resulted poorly effi- cacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects. REFERENCES 1. Austin PF, Bauer SB, Bower W, et al. 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Rome, Italy Ester Del Vescovo, MD Giulia Franceschini, MD Campus Bio-Medico University, Rome, Italy Luciana Romaniello, MD San Carlo Hospital, Potenza, Italy Alberto Verrotti, MD Department of Pediatrics, University of L’Aquila, L’Aquila, Italy Ferrara_Stesura Seveso 28/06/18 16:38 Pagina 129