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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).

ABSTRACT Purpose: Approximately one-third of the children with primary monosymptomatic enuresis (PMNE) do not respond to first-line treatment. We aimed to investigate the short-term and six-month effectiveness of combining desmopressin acetate with parasacral transcutaneous electrical nerve stimulation (PTENS) in these children and adolescents. Materials and Methods: Participants aged six–17 years with PMNE were randomly assigned to receive desmopressin acetate with active or sham PTENS. Both groups participated in weekly 30-minute electrotherapy sessions for 15 weeks. The intervention group (IG) received electrotherapy at a frequency of 10 Hz and pulse width of 700 μs. A dry and wet nights calendar assessed the frequency of wet nights in the short term and six months after the intervention ended. Results: Of 66 participants, 34 were randomized to the IG. The median age was 10.3 years (8.8 – 12), and 53% were male. Intention-to-treat analysis showed a significant reduction in the frequency of wet nights after the interventions (p <0.001) in both groups, with the IG demonstrating significant improvement, immediately after the interventions (p=0.005) and after six months (p<0.001) compared to the placebo group (PG). The Kaplan-Meier survival analysis showed improvement in the IG that became more pronounced from the 15th week onwards (log-rank test, p < 0.01). Conclusions: A 15-week treatment with desmopressin acetate and PTENS significantly reduced wet nights in children and adolescents with PMNE, and this improvement was maintained six months after the interventions.

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.

Renal colic is a prevalent cause of abdominal pain in the emergency department. Although non-steroidal anti-inflammatory drugs and opioids are used for the treatment of renal colic, some adverse effects have been reported. Therefore, desmopressin -a synthetic analogue of vasopressin- has been proposed as another treatment choice. In the present study, indomethacin in combination with nasal desmopressin was compared with indomethacin alone in the management of renal colic. Included in the study were 124 patients with initial diagnosis of renal colic and randomized to receive indomethacin suppository (100 mg) with either desmopressin intranasal spray (4 puffs, total dose of 40 micrograms) and or placebo intranasal spray. All the included patients were finally diagnosed with renal colic. There was no difference between the two groups in pain at the baseline (p = 0.4) and both treatments reduced pain successfully (p < 0.001). There was no significant difference between the two groups in pain reduction (p = 0.35). While there was significant pain reduction in both patients groups, pain reduction of NSAIDs (e.g. indomethacin) in renal colic, does not significantly improve when given in combination with desmopressin.

Background Few studies manage patients with isolated monosymptomatic enuresis (MNE) with multidisciplinary evaluation and pre- and long-term post-intervention monitoring. Methods This was a prospective study of MNE patients, aged 6–16 years, diagnosed by multidisciplinary assessment. Of the 140 initial applicants (58.6%) with MNE, 82 were included in the study and randomized for therapeutic intervention in three treatment groups, namely: alarm, desmopressin and alarm + desmopressin. Therapeutic response was evaluated 12 months after treatment withdrawal. Results Of the 82 patients [mean age 9.5 (SD ± 2.6) years, n = 62 males (75.6%)], 91.1% had a family history of nocturnal enuresis (NE) in first-/second-degree relatives, 81.7% had constipation and 40.7% had mild-to-moderate apnea. Prior to randomization, management of constipation and urotherapy led to remission in seven of the 82 patients; 75 patients were randomized to intervention. There were 14/75 (18.7%) dropouts during the intervention, especially in the alarm group ( p  = 0.00). Initial complete/partial response was achieved in 56.6% of the alarm group, 70% of the desmopressin group and 64% in the combined group ( p  = 0.26). Continued success occurred in 70% of the alarm group, 84.2% of the desmopressin group and 100% of the combined group ( p  = 0.21). Recurrence occurred in 3/20 (15%) patients in the alarm group and 1/19 (5.2 %) patients of the desmopressin group. Post-intervention Child Behavior Checklist (CBCL) and PedsQL 4.0 scores showed significant improvement. Conclusions The three therapeutic modalities were effective in managing MNE with low relapse rates; the alarm group showed the highest dropout rate. Therapeutic success was associated with improvement of behavioral problems and quality of life scores.

although blood-sparing properties of tranexamic acid (TA) and desmopressin (Desmo) have been well described following various surgical procedures, few studies have compared the effect of Desmo to that of TA in total knee arthroplasty (TKA). The purpose of our study was to compare the effectiveness of TA and Desmo in reducing perioperative bleeding during TKA. we conducted a prospective double-blind study including patients undergoing TKA under spinal anesthesia, randomized into 2 groups: the Desmo group (patients received 0.3 μg/kg of Desmo in 100 ml of saline over 30 minutes before incision, followed by a saline infusion of 30 ml/kg over 12 hours) and the TA group (patients received 20 mg/kg of TA in 100 ml of saline over 30 minutes before incision, followed by 10 mg/kg of TA in 30 ml/kg of saline over 12 hours). The endpoints were perioperative bleeding, transfusion requirement and postoperative complications. the study included 55 patients divided into 2 groups: TA group (28 patients) and Desmo group (27 patients). Blood accumulation in the jar during the procedure was significantly higher in the TA group (339±40 ml) than in the Desmo group (295±77 ml) (p=0.038). During the first 12 postoperative hours, additional blood accumulation in the redon was significantly higher in the Desmo group (h6: 288±55ml, H12: 383±63ml) compared to the TA group (h6: 188±42ml, h12: 287±60ml) with at H6: p= 0.001 and at H 12: p= 0.009. After 12 hours postoperatively, blood volume in the redon became similar in the 2 groups. From the time of discharge from the post-interventional monitoring room (PICU) to 2 days postoperatively, hemoglobin and hematocrit levels were similar in the 2 groups. Platelet count (PLT) was significantly higher in the Desmo group than in the TA group upon leaving the PICU (Pq desmo: 193929±25000 vs Pq AT: 157370±24300; p< 0.001) and on postoperative day 1 (Pq desmo: 178929±26200 vs Pq AT: 168929±25100; p= 0.048). By postoperative day 2, platelet counts became similar in the 2 groups. During the postoperative period, only one patient in the Desmo group required an allogeneic blood transfusion. No postoperative thromboembolic events were noted in our patients. both TA and desmopressin are comparably effective in reducing perioperative blood loss during TKA under spinal anesthesia.

Purpose To evaluate the efficacy and safety of adding a low-dose oral desmopressin to tamsulosin therapy for treatment of nocturia in patients with benign prostatic hyperplasia (BPH). Methods Eligible patients with BPH and nocturia ≥2/night were randomly allocated to two treatment groups; the first of which received 3-month treatment scheme of daily oral dose of tamsulosin OCAS 0.4 mg and desmopressin MELT 60 mcg (D/T group), while the second one received tamsulosin OCAS 0.4 mg only (T group). Patients were followed on monthly basis and changes in the parameters from baseline to 3 months after treatment were assessed on I-PSS/QoL questionnaire, 7-day voiding diary, urinalysis, serum sodium, abdominal ultrasonography and uroflowmetry. Results A total of 248 patients were included within the study; 123 patients in the combined D/T group and 125 patients in T group. The frequencies of night voids decreased by 64.3 % in D/T group compared to 44.6 % in T group. The first sleep period, significantly increased from 82.1 to 160.0 min and from 83.2 to 123.8 min in D/T and T group, respectively; and significant differences between both groups were observed at the end of study ( p  < 0.001). I-PSS, QoL score, post-void residual urine volume and Q max were significantly improved with no statistical difference between both groups. No serious adverse effects were reported in both groups. Conclusion The addition of low-dose oral desmopressin therapy to an α-blocker tamsulosin provides effective treatment for nocturia in patients with LUTS/BPH.

IntroductionIntracerebral haemorrhage (ICH) can be devastating and is a common cause of death and disability worldwide. Pre-ICH antiplatelet drug use is associated with a 27% relative increase in 1 month case fatality compared with patients not using antithrombotic drugs. We aim to assess the feasibility of conducting a randomised controlled testing the safety and efficacy of desmopressin for patients with antiplatelet-associated ICH.Methods and analysisWe aim to include 50 patients within 24 hours of spontaneous ICH onset, associated with oral antiplatelet drug(s) use in at least the preceding 7 days. Patients will be randomised (1:1) to receive intravenous desmopressin 20 µg in 50 mL sodium chloride 0.9% infused over 20 min or matching placebo. We will mask participants, relatives and outcome assessors to treatment allocation. Feasibility outcomes include proportion of patients approached being randomised, number of patients receiving allocated treatment, rate of recruitment and adherence to treatment and follow-up. Secondary outcomes include change in ICH volume at 24 hours; hyponatraemia at 24 hours, length of hospital stay, discharge destination, early death less than 28 days, death or dependency at day 90, death up to day 90, serious adverse events (including thromboembolic events) up to day 90; disability (Barthel index, day 90), quality of life (EuroQol 5D (EQ-5D), day 90), cognition (telephone mini-mental state examination day 90) and health economic assessment (EQ-5D).Ethics and disseminationThe Desmopressin for reversal of Antiplatelet drugs in Stroke due to Haemorrhage (DASH) trial received ethical approval from the East Midlands—Nottingham 2 research ethics committee (18/EM/0184). The DASH trial is funded by National Institute for Health and Care Research RfPB grant: PB-PG-0816-20011. Trial results will be published in a peer reviewed academic journal and disseminated through academic conferences and through patient stroke support groups. Reporting will be in compliance with Consolidated Standards of Reporting Trials recommendations.Trial registration numbersNCT03696121; ISRCTN67038373; EudraCT 2018-001904-12.

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.

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.