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Background Nocturnal enuresis (NE), or ‘bedwetting’, is a form of night-time urinary incontinence occurring in younger children. A diagnosis of NE can be socially disruptive and psychologically stressful for a child. The most common strategies used by parents to manage NE are waking the child during the night to use the bathroom and limiting the child’s water intake before going to bed. Behavioural or educational therapies for NE such as urotherapy or bladder retraining are widely accepted and considered as a mainstream treatment option for non-neurogenic lower urinary tract dysfunction in children. Pharmacotherapy also plays an ancillary role. However, there is no gold standard therapy or intervention to effectively manage NE. Methods This study aims to determine the efficacy of a herbal combination in the treatment of NE in children. The target population for this study is 80 children aged between 6 and 14 years old (males and females) who have primary nocturnal enuresis ≥3 per week (wet nights). The active group will receive one or two capsules per day containing 420 mg of a proprietary blend of Urox® (Seipel Group, Brisbane, Australia) containing Cratevox™ ( Crataeva nurvala L; Capparidaceae; Varuna) stem bark extract standardised for 1.5% lupeol: non-standardised Equisetum arvense L. (Equisetaceae; Horsetail) stem extract; and, non-standardised Lindera aggregata Sims. The primary outcome for this study is the frequency of nocturia. Secondary outcomes include safety, quality of life, and daytime incontinence. Each participation will be involved in the trial for 32 weeks including contact with the research team every 2 weeks for the first 8 weeks and then every 8 weeks until trial completion. Discussion This study examines a novel treatment for an under-researched health condition affecting many children. Despite the availability of several therapies for NE, there is insufficient evidence to support the use of any one intervention and as such this randomised placebo-controlled phase II trial will be an important contribution to understanding potential new treatments for this condition. Trial registration Australian and New Zealand Clinical Trials Registration Number: 12618000288224 . Protocol: 23 February 2018, version 1.1.

Background We aimed to investigate if there was any relationship between screen time (ST) and the severity of primary monosymptomatic nocturnal enuresis (PMNE) and treatment success. Methods This study was conducted in urology and child and adolescent phsychiatry clinic in Afyonkarahisar Health Sciences University Hospital. After diagnosis patients were seperated by the ST for exploring causation. Group 1 > 120, Group 2 < 120 (min/day). For the the treatment response, patients were grouped again. Group 3 patients were administered 120 mcg Desmopressin Melt (DeM) and were requested < 60 min ST. Patients in Group 4 were given 120 mcg DeM solely. Results The first stage of the study included 71 patients. The ages of the patients ranged from 6 to 13. Group 1 comprised 47 patients, 26 males and 21 females. Group 2 comprised 24 patients,11 males and 13 famales. Median age was 7 years in both groups. The groups were similar in respect of age and gender ( p  = 0.670, p  = 0.449, respectively). A significant relationship was determined between ST and PMNE severity. Severe symptoms were seen at the rate of 42.6% in the Group 1, and at 16.7% in the Group 2 ( p  = 0.033). 44 patients completed the second stage of the study. Group 3 comprised 21 patients, 11 males and 10 females. Group 4 comprised 23 patients,11 males and 12 famales. Median age was 7 years in both groups. The groups were similar in respect of age and gender ( p  = 0.708, p  = 0.765, respectively). Response to treatment was determined as full response in 70% (14/20) in Group 3 and in 31% (5/16) in Group 4 ( p  = 0.021). Failure was determined in 5% (1/21) in Group 3 and in 30% (7/23) in Group 4 ( p  = 0.048). Recurrence was determined at a lower rate in Group 3 where ST was restricted (7% vs. 60%, p  = 0.037). Conclusion High screen exposure may be a factor for PMNE aetiology. And also reducing ST to a normal range can be an easy and beneficial method for treatment of PMNE. Trial Registration ISRCTN15760867( www.isrctn.com ). Date of registration: 23/05/2022. This trial was registered retrospectively.

Objective To compare the efficacy of desmopressin plus tolterodine (D+T) with desmopressin plus indomethacin (D+I) for treating enuresis in children. Design Open-label randomized controlled trial. Setting Bandar Abbas Children’s Hospital, a tertiary care children’s hospital in Iran, from March 21, 2018, to March 21, 2019. Participants 40 children older than five years with monosymptomatic and non-monosymptomatic primary enuresis resistant to desmopressin monotherapy. Intervention Patients were randomized to receive either D+T (60 µg sublingual desmopressin and 2 mg tolterodine) or D+I (60 µg sublingual desmopressin and 50 mg indomethacin) every night before bedtime for five months. Outcome Reduction in the frequency of enuresis was evaluated at one, three, and five months, and response to treatment at five months. Drug reactions and complications were also noted. Results After adjustment for age, consistent incontinence from toilet training, and non-monosymptomatic enuresis, D+T was significantly more efficacious than D+I; mean (SD) percent in nocturnal enuresis reduction at 1 [58.86 (7.27)% vs 31.18 (3.85) %; P <0.001], 3 [69.78 (5.99)% vs 38.56 (3.31)%; P <0.000], and 5 [84.84(6.21)% vs 39.14 (3.63)%; P <0.001] months showing a large effect. At 5 months, complete response to treatment was only observed with D+T, while treatment failure was significantly higher with D+I (50% vs 20%; P =0.047). None of the patients in either group developed cutaneous drug reactions or central nervous system symptoms. Conclusion Desmopressin plus tolterodine appears to be superior to desmopressin plus indomethacin for treating pediatric enuresis resistant to desmopressin.

PurposeFor a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, “children are not small adults,” and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication.MethodsPopulation pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis.ResultsThe half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-μg lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-μg tablet, even when the same exposure is achieved.ConclusionsA new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation.

Introduction Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations—a tablet and a lyophilisate—in both fasted and fed children. Methods Previously published data from two studies (one in 22 children aged 6–16 years, and the other in 25 children aged 6–13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect. Results The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant. Conclusion Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.

Introduction The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age. Methods Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies. Results The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects. Conclusions Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed. Clinical Trial Registration This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).

ObjectiveEvidence about the negative caffeine effect on enuresis in children remains understudied or poorly understood. The study aimed to investigate the effect of caffeine restriction on the improvement and severity of primary monosymptomatic nocturnal enuresis (PMNE).DesignRandomised clinical trial.SettingTwo referral hospitals in Tehran, Iran, from 2021 to 2023.PatientsFive hundred and thirty-four PMNE children aged 6–15 years (each group 267).InterventionsAmount of caffeine consumption was recorded by the feed frequency questionnaire and was estimated by Nutrition 4 software. Caffeine consumption per day in the intervention group was <30 mg, and in the control group, 80–110 mg. All children were asked to return 1 month later to check the recorded data. The ordinal logistic regression analysis was used to assay the effects of caffeine restriction on PMNE by relative risk (RR) at a 95% CI.Main outcome measuresThe effect of limited caffeine consumption on the improvement and severity of PMNE.ResultsThe mean age of the intervention and control groups was 10.9±2.3 and 10.5±2.5 years, respectively. The mean number of bed-wetting before caffeine restriction in the intervention and control group was 3.5 (SD 1.7) times/week and 3.4 (SD 1.9) times/week (p=0.91) and 1 month after intervention were 2.3 (SD 1.8) times/week and 3.2 (SD 1.9) times/week, respectively (p=0.001). Caffeine restriction significantly reduced the severity of enuresis in the intervention group. Fifty-four children (20.2%) improved (dry at night) in caffeine restriction and 18 children (6.7%) in the control group with RR 0.615 at 95% CI 0.521 to 0.726, p=0.001. The caffeine restriction significantly reduced the enuresis in children with a number-needed-to-treat benefit 7.417. It means you must treat 7.417 PMNE children with caffeine limitation to improve one child with enuresis (become dry).ConclusionCaffeine restriction can be helpful in reducing PMNE or its severity. Constructive limitation of caffeine is suggested as one of the first-line treatments in the management of PMNE.Trial registration numberIRCT20180401039167N3.

Primary nocturnal enuresis is a prevalent childhood condition that can persist into adulthood. Desmopressin is an antidiuretic available as orally disintegrating lyophilisate (melt) or solid tablet. Recent findings suggesting different food interactions and clinical characteristics, including compliance, between desmopressin melt and tablet motivated a post hoc analysis of a previously reported randomised, crossover study. The efficacy of desmopressin melt compared with tablet was evaluated using the International Children’s Continence Society (ICCS) responder definitions. Compliance was further analysed using detailed criteria, and the association between efficacy and compliance was examined. In total, 221 patients aged 5–15 years, already receiving desmopressin tablets were randomised to the treatment sequence melt (120/240 μg)/tablet (0.2/0.4 mg) or tablet/melt in two consecutive 3-week periods. The probability of being a responder (partial or full) during either period was significantly more likely with desmopressin melt compared with tablet (odds ratio, 2.0; confidence intervals, 1.07–3.73; p  = 0.03). There was no period effect on compliance in the tablet/melt sequence and no difference in the number of completely compliant patients in each formulation group; however, more patients were >75 % compliant in period 1 compared with period 2 in the melt/tablet sequence. Increased compliance was associated with greater reductions in the number of wet nights for both formulations. Conclusions: Desmopressin melt, compared with tablet, improves the probability of being a responder. Switching from tablet to melt formulation increased patient compliance. Increased compliance was associated with increased efficacy. Switching to desmopressin melt may benefit patients with suboptimal responses to desmopressin tablet.

Introduction. Nocturnal enuresis is a condition, which can affectthe quality of life in children. The present study was designed toinvestigate the efficacy of low-dose imipramine combined withdesmopressin on treatment of patients with primary nocturnalenuresis who were defined as desmopressin non-responders.Methods. A randomized clinical trial was carried out on patientswith primary nocturnal enuresis. Forty children with enuresisranging from 5 to 12 years old were randomly divided into theintervention (n = 20) and control groups (n = 20). The subjects inthe intervention group were treated with desmopressin combinedwith 5 mg imipramine at bedtime, and those in the control groupwere given desmopressin alone. The patients were followed upweekly for one month. The number of wet nights was recorded.Results. Two individuals in the intervention and three individualsin the control group were excluded from the study. Our findingsindicated that the age and gender showed no significant difference.Furthermore, a significant better recovery in the enuresis wasobserved in 18 of 20 patients who were treated with combinationtherapy after 1 month (P < .05). In addition, the frequency ofrecovery was significantly higher (83.3%) in the intervention group,compared with the control group (29.4%).Conclusion. The analysis showed that low-dose imipramine is welltolerated in clinical practice and may represent a good short-termtreatment option in combination therapy where desmopressinalone is not efficient enough.

Background We investigated the effect of combining indomethacin and desmopressin in treating children with monosymptomatic nocturnal enuresis (MNE) and desmopressin-resistant nocturnal polyuria. Methods Twenty-three children with MNE, nocturnal polyuria, and partial or no response to desmopressin were recruited from incontinence clinics of our tertiary referral center. We used a randomized single-arm crossover placebo-controlled study design consisting of two 3-week treatment periods with a combination of desmopressin (0.4 mg) and indomethacin (50 mg) or desmopressin and placebo at bedtime. Home recordings at baseline and for the final 2 weeks of each treatment period were performed and included nocturnal urine output measurements. The number of dry nights achieved and reduction in the nocturnal urine output were the main effect parameters. Student’s t test and Pearson’s correlation coefficient were used for statistical analysis. Results The addition of indomethacin to desmopressin significantly reduced nocturnal urine output (from 324 ± 14 ml to 258 ± 13 ml, p  < 0.001). This did not lead to more dry nights in all children, and we found no statistically significant reduction in enuresis frequency (from 68 % ± 0.1 to 56 % ± 0.1, p  = 0.24). Conclusions Addition of indomethacin to desmopressin can further reduce nocturnal urine output in children with MNE and desmopressin-resistant nocturnal polyuria. The combination treatment does not, however, improve outcome in terms of frequency of nights with enuresis. The dissociation of antidiuretic and antienuretic effect may reflect nocturnal bladder reservoir dysfunction in children who present with normal daytime bladder function.