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Arginine vasopressin (VP) is neurohypophysial hormone has been implicated in stimulating contractile activity of the male reproductive tract in the testis. Higher levels of VP decrease sperm count and motility. However, very little is known about the involvement of VP in controlling mammalian reproductive process. The goal of this study was to confirm that effect of VP receptor (AVPR2) on sperm function in capacitation condition. Deamino [Cys 1, D-ArgS] vasopressin (dDAVP), an AVPR2 agonist that operates only on AVPR2, was used. Also, Mouse spermatozoa were incubated with various concentrations of dDAVP (10(-11)-10(-5) M) and sperm motility, capacitation status, Protein Kinase A activity (PKA), tyrosine phosphorylation, fertilization, and embryo development were assessed using computer-assisted sperm analysis, Combined Hoechst 33258/chlortetracycline fluorescence, Western blotting, and in vitro fertilization, respectively. AVPR2 was placed on the acrosome region and mid-piece in cauda epididymal spermatozoa, but the caput epididymal spermatozoa was mid-piece only. The high dDAVP treatment (10(-8) and 10(-5) M) significantly decreased sperm motility, intracellular pH and PKA substrates (approximately 55 and 22 kDa) and increased Ca(2+) concentration. The highest concentration treatment significantly decreased PKA substrate (approximately 23 kDa) and tyrosine phosphorylation (approximately 30 kDa). VP detrimentally affected capacitation, acrosome reaction, and embryo development. Treatment with the lowest concentration (10(-11) M) was not significantly different. Our data have shown that VP stimulates ion transport across sperm membrane through interactions with AVPR2. VP has a detrimental effect in sperm function, fertilization, and embryonic development, suggesting its critical role in the acquisition of fertilizing ability of mouse spermatozoa. These research findings will enable further study to determine molecular mechanism associated with fertility in capacitation and fertilization. It is also an important pivotal precondition to the progress of diagnostic test to identify infertility and to apply male contraception.

Alpha-blockers improve lower urinary tract symptoms associated with benign prostatic obstruction. Nocturia, a storage symptom, is a common complaint in men. However, it does not fully respond to α-blocker therapy, likely due to its multifactorial pathophysiology. We evaluated the efficacy and safety of desmopressin as add-on therapy for refractory nocturia in men previously treated with an α-blocker for lower urinary tract symptoms.Eligible patients were men 50 years old or older with lower urinary tract symptoms and persistent nocturia despite α-blocker treatment for a minimum of 4 weeks. The optimum dose of oral desmopressin was determined during a 4-week dose titration period and this dose was maintained for 24 weeks. Flow volume charts, International Prostate Symptom Score total and subscores, uroflowmetry and post-void residual urine volume were assessed.A total of 216 patients were enrolled in the study. Of these patients there were 158 (76%) with nocturnal polyuria, 15 (7.2%) with decreased nocturnal bladder capacity and 35 (16.8%) with nocturia due to both causes. The number of nocturnal voids significantly decreased from a baseline mean of 7.0 to 5.7 episodes for 3 days at the 24-week visit. The average International Prostate Symptom Score total and subscore significantly decreased by 4 weeks and were maintained at 24 weeks. In patients younger than 65 years, International Prostate Symptom Score voiding subscores were significantly improved at 24 weeks compared to those age 65 years or older.Desmopressin add-on therapy for refractory nocturia in men previously treated with an α-blocker for lower urinary tract symptoms improved voiding symptoms as well as nocturia, storage symptoms.

Nocturnal enuresis is characterized by nocturnal urine volumes exceeding bladder capacity and by inability to wake up to the stimulus of a full bladder. Desmopressin (DDAVP) is believed to be efficient in treating nocturnal enuresis by reducing nocturnal urine production. However, clinical observations indicate an additional mode of action since the drug appears to modify sleep architecture, apparently improving the patient's ability to awaken to the stimulus of a full bladder. Because of this, a possible arousing effect of DDAVP was studied.The tentative ability of DDAVP and the endogenous hormone vasopressin (AVP) to produce locomotor stimulation in resting rats after both intracerebroventricular and subcutaneous administration was used as an animal model of arousal. In addition brain monoamine biochemistry was analyzed.The intracerebroventricular injection of AVP (0.1 and 1 microgram.) and the intracerebroventricular (0.1, 1, 10 and 100 microgram.) and subcutaneous (90 and 180 microgram.) injections of DDAVP were both associated with a significant increase in the locomotor activity of the animals compared with controls. The biochemical analysis of cerebral monoamines indicated that DDAVP lowers brain dopamine levels after both types of administration.These results suggest that DDAVP exerts a stimulatory effect in the CNS, which is also observed after peripheral administration. There are also indications for an increase in central dopamine turnover which could explain the registered increase in locomotor activity.

We evaluated the acute effect of indomethacin on renal water and solute handling in children with coexisting monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria, and in healthy controls.A total of 23 subjects were recruited, consisting of 12 children with monosymptomatic nocturnal enuresis and nocturnal polyuria with partial or no response to desmopressin, and 11 age matched controls. Children completed a 48-hour inpatient study protocol consisting of fractional urine collections and blood samples. Sodium and water intake were standardized. During the second night a dose of 50 mg indomethacin was administered orally before bedtime. Diuresis, urine osmolalities, clearances and fractional excretions were calculated for sodium, potassium, urea, osmoles and solute-free water. Renin, angiotensin II, aldosterone and atrial natriuretic peptide were measured in plasma. Prostaglandin E(2) was measured in urine.Indomethacin markedly decreased the nocturnal sodium, urea and osmotic excretion in children with enuresis and controls. The overall effect on nocturnal urine output was inconsistent in the group with enuresis. Subjects in whom nocturnal diuresis was decreased following administration of indomethacin remained dry.Prostaglandin inhibition leads to antidiuresis, reducing the amount of sodium, urea and osmotic excretion in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria. The sodium regulating hormones do not seem to mediate these processes. The overall effect in desmopressin nonresponders with nocturnal polyuria is variable. The extent to which indomethacin can be applied in the treatment of enuresis needs further evaluation.

MONOSYMPTOMATIC nocturnal enuresis is one of the most common nocturnal problems in children with an estimated prevalence of approximately 10% among 7-yearolds. 1 Before the 1980s it was considered a benign condition with a chance of spontaneous cure of 15% per year. 2 Insights into the pathophysiology were limited and no research was done. Treatment was mainly based on behavioral methods, wetting alarms and imipramine. A lot has changed over time. Insights into the pathophysiology identified several causes of enuresis including high arousal thresholds, 3 nocturnal polyuria 4 and nocturnal detrusor overactivity. 5 Antidiuretic medication then became available as a new treatment modality. As these new insights into the pathophysiology and new treatments became a reality, the treatment of enuresis evolved into a multidisciplinary approach. These teams of clinicians include not only pediatric urologists, but also pediatricians, pediatric nephrologists, child psychologists and urotherapists. In this issue of The Journal Tauris et al (page 664) review the importance of the measurement of voided volume to predict the response to desmopressin treatment. They concluded that maximum voided volume is a good predictor of response only if first morning voids are considered. The authors describe a greater response in children with higher voided volumes, indicating that bladder storage has a more important role in the pathophysiology of enuresis in nonresponders. This research is in line with other recent literature on this topic in which the focus is on how to evaluate therapy resistance and, thus, predict treatment outcomes. Most research was done on nighttime polyuria because of the interest of the pharmaceutical industry. With these new elements the assessment of enuresis becomes more complex and time-consuming. However, the major question remains whether based on this assessment, treatment outcomes can really be predicted. Patients with nocturnal enuresis should be categorized as those who do vs do not respond tofirst line and evidence based treatment consisting of antidiuretic treatment, alarm treatment and combined treatments. 6,7 More than 50% of patients will be cured after first line treatment. Thus, for the children presenting

We evaluated bladder reservoir function in children with monosymptomatic nocturnal enuresis with and without response to desmopressin, and assessed the importance of first morning voiding when defining maximum voided volume.A total of 238 patients 5 to 15 years old with monosymptomatic nocturnal enuresis completed 2 weeks of enuresis recordings and 4 days of frequency-volume charts. Of the patients 186 completed subsequent home recordings during titration with desmopressin. Maximum voided volumes with and without the first morning void were calculated. Desmopressin response was defined as greater than 50% reduction in wet nights. Maximum voided volume with and without first morning voiding was evaluated as a prognostic factor for desmopressin response.Mean ± SD maximum voided volume without first morning void was comparable between desmopressin responders and nonresponders (230.5 ± 69.3 ml and 219.0 ± 84.8 ml, respectively, p = 0.391). Inclusion of the first morning void demonstrated responders to have significantly larger values than nonresponders (mean ± SD 296.0 ± 94.0 ml vs 233.5 ± 90.0 ml, p0.001). When first morning void was included, desmopressin response was seen in 40% of patients with voided volumes of 65% expected volume for age vs 10% of patients with volumes less than 65% expected volume for age.Maximum voided volume can be used as a predictor of desmopressin response only if first morning voids are taken into consideration. All patients with monosymptomatic nocturnal enuresis should receive clear instructions to include this measure when completing frequency-volume charts.

Purpose: Nocturnal polyuria is a common but often overlooked cause of nocturia. We investigated the proportion of adults with 2 or greater voids nightly who had nocturnal polyuria in 2 cohorts from the United States and Europe. Materials and Methods: Data on nocturnal polyuria were obtained from 3 or 7-day frequency-volume charts completed by patients as part of screening for inclusion in subsequent trials of nocturia therapy. Patients recorded the time and volume of each void. Nocturnal polyuria was defined as nocturnal urine volume greater than 33% of 24-hour volume, including the first morning void. Results: In the first cohort 1,003 patients were screened, of whom 846 provided evaluable diary data, including 641 (76%) with nocturnal polyuria. Of the total screened population of 1,003 patients 641 (64%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. In the second cohort 1,412 patients were screened, of whom 917 provided evaluable diary data, including 806 (88%) with nocturnal polyuria. Of the total screened population of 1,412 patients 806 (57%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. Of 158 patients receiving benign prostatic hyperplasia and/or overactive bladder medication 141 (89%) had nocturnal polyuria. In each cohort the nocturnal polyuria prevalence was high in all ethnic groups (63% or greater). Conclusions: In this large study nocturnal polyuria was present in most patients with nocturia regardless of gender, age, ethnicity, country and concomitant benign prostatic hyperplasia/overactive bladder therapy.

We evaluated the combination of alarm and desmopressin versus alarm monotherapy for the treatment of nocturnal enuresis.A double-blind, placebo controlled study of alarm therapy combined with desmopressin for children with nocturnal enuresis is described. Of 93 patients 47 were randomized to receive alarm therapy and 40 microg. intranasal desmopressin for 3 weeks followed by 20 microg. desmopressin for 3 weeks (group 1) and 46 received alarm therapy and placebo (group 2). After 6 weeks on alarm therapy and medication or placebo, both groups received an additional 3 weeks of alarm monotherapy. A specialized nurse practitioner advised patients and families of the treatment to be given at home and in the outpatient department. Bed-wetting frequency was evaluated before during and 2 weeks and 6 months after treatment.A significantly greater reduction in the number of wet nights was observed after the first 3 weeks of treatment in group 1. However, after long-term followup no significant differences in bed-wetting frequency were noted.There is a temporary, positive effect on enuresis using desmopressin combined with alarm therapy. However, both treatment modalities have a low long-term success rate of 36% to 37%.

We compared the efficacy of desmopressin and enuresis alarm as first and second line treatment options for monosymptomatic nocturnal enuresis.A total of 104 children with monosymptomatic nocturnal enuresis were randomly assigned to either desmopressin (54) or enuresis alarm (50) as first line treatment. Following 12 weeks of first line treatment children with a full response were evaluated for relapse 12 weeks after withdrawal of treatment. Children with partial or no response were switched to the alternative treatment and then evaluated after 12 weeks of crossover treatment. Relapse was defined as more than 1 episode of bedwetting monthly.Following first line treatment 77.8% of the desmopressin group and 82% of the enuresis alarm group achieved a successful result, including full response in 37% and 50% of the groups, respectively (p=0.433). Of the children with a full response 50% in the desmopressin group and 12% in the enuresis alarm group experienced a relapse when treatment stopped (p=0.005). Following second line crossover treatment 71.4% of the enuresis alarm-desmopressin group and 67.8% of the desmopressin-enuresis alarm group achieved a successful result, including full response in 47.6% and 45.2% of the groups, respectively (p=0.961).There was no difference between desmopressin and enuresis alarm during treatment for achieving dryness, but the chance of relapse after treatment stopped was higher following desmopressin. Switching to the alternative treatment following partial or no response provided an additional benefit.

Purpose: Studies of desmopressin in children with primary nocturnal enuresis show a greater than 90% decrease in wet nights in 20% to 30%, a 50% to less than 90% decrease in 20% to 40% and less than a 50% decrease in up to 60%. Insufficient response to desmopressin is attributable to various factors, including differences in the primary nocturnal enuresis definition, underlying bladder dysfunction and/or desmopressin pharmacokinetic characteristics. However, little attention has been given to poor compliance with therapy as a possible explanatory factor. For a drug with an effect duration limited to the night after administration a high degree of compliance is essential to ensure consistent therapeutic effects. Materials and Methods: This was a substudy of an international investigation of treatment for 6 months or less with desmopressin tablets in children with primary nocturnal enuresis. Medication was dispensed at each visit as required and collected at each subsequent visit. Compliance was determined by pill counts by study staff. Results: Compliance data were available on 723 patients. Of the patients 81% to 91% ingested all medication as instructed during the initial run-in phases. However, this decreased to 77% and 71% during the first and second 3-month treatment periods, respectively. Conclusions: Patient motivation and compliance are generally stronger in clinical trials than in clinical practice. However, this study shows that some patients were poorly compliant with medication even at study initiation and only 71% were fully compliant with long-term treatment. Decreased compliance was associated with a lower response rate. Patients should be encouraged to comply fully with treatment to achieve an optimal outcome.

Monosymptomatic nocturnal enuresis is frequently associated with nocturnal polyuria and low urinary osmolality during the night. Initial studies found decreased vasopressin levels associated with low urinary osmolality overnight. Together with the documented desmopressin response, this was suggestive of a primary role for vasopressin in the pathogenesis of enuresis in the absence of bladder dysfunction. Recent studies no longer confirm this primary role of vasopressin. Other pathogenetic factors such as disordered renal sodium handling, hypercalciuria, increased prostaglandins and/or osmotic excretion might have a role. So far, little attention has been given to abnormalities in the circadian rhythm of glomerular filtration rate. We evaluated the circadian rhythm of glomerular filtration rate and diuresis in children with desmopressin resistant monosymptomatic nocturnal enuresis and nocturnal polyuria.We evaluated 15 children (9 boys) 9 to 14 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria resistant to desmopressin treatment. The control group consisted of 25 children (12 boys) 9 to 16 years old with monosymptomatic nocturnal enuresis without nocturnal polyuria.Compared to the control population, children with nocturnal polyuria lost their circadian rhythm not only for diuresis and sodium excretion but also for glomerular filtration rate.Patients with monosymptomatic nocturnal enuresis and nocturnal polyuria lack a normal circadian rhythm for diuresis and sodium excretion, and the circadian rhythm of glomerular filtration rate is absent. This absence of circadian rhythm of glomerular filtration rate and/or sodium handling cannot be explained by a primary role of vasopressin, but rather by a disorder in circadian rhythm of renal glomerular and/or tubular functions.

We assessed the effects of long-term oral desmopressin on serum sodium and baseline antidiuretic hormone secretion in elderly patients with nocturia.A total of 15 elderly male patients with severe nocturia (greater than 3 voids nightly) who did not show hyponatremia within 7 days of administration of 0.2 mg desmopressin were enrolled in this study. Desmopressin (0.2 mg) was administered orally nightly for 1 year. Before and 1 month after the 1-year medication 24-hour circadian studies were performed to monitor changes in antidiuretic hormone. Every 3 months during the 1-year medication serum changes and timed urine chemistry were monitored.Desmopressin significantly decreased nocturnal urine output and the number of nocturia episodes (p0.01). Compared to before treatment desmopressin gradually decreased serum sodium and induced statistically but not clinically significant hyponatremia after 6 months of treatment. After discontinuing desmopressin serum sodium returned to the normal range in all patients. There were no significant differences when baseline and posttreatment endogenous antidiuretic hormone were compared. No serious systemic complications were found during medication.Long-term desmopressin administration gradually decreased the serum concentration and induced significant hyponatremia from 6 months in patients who did not show initial hyponatremia. Long-term administration of desmopressin for 1 year in elderly patients did not affect baseline antidiuretic hormone secretion. For long-term desmopressin administration serum sodium should be assessed regularly, at least every 6 months.

Increased calcium excretion due to desmopressin has been reported in children with nocturnal enuresis. Desmopressin is often used to treat adult patients with nocturnal polyuria. However, data on the effect of desmopressin on water/electrolyte excretion in adults are scarce. We present the short-term effects of desmopressin on water and electrolyte excretion in adult patients with nocturnal polyuria.A total of 16 male patients with nocturnal polyuria, mean age 76.3 years, received 0.1 or 0.2 mg desmopressin before sleep. Frequency volume chart was recorded, and daytime and nighttime urine samples were collected separately before and after desmopressin administration. Urinary excretions of sodium, potassium and calcium were determined, and compared before and after treatment with desmopressin.Desmopressin significantly increased urine osmolality, decreased nocturnal total urine volume, reduced the ratio of nocturnal urine volume-to-whole day urine volume and decreased nocturnal voiding frequency. Nocturnal urinary excretion of calcium (mean 0.137 vs 0.169 mg/kg body weight per hour, p = 0.004) and whole day excretion of calcium (mean 165.9 vs 200.0 mg per day, p = 0.012) were increased after desmopressin treatment. Nocturnal urinary potassium excretion (mean 0.030 vs 0.025 mEq/kg body weight per hour, p = 0.030) and whole day potassium excretion (mean 40.7 vs 36.1 mEq per day, p = 0.017) were decreased by desmopressin treatment. However, desmopressin treatment did not significantly change urinary secretion of sodium and chloride at nighttime or for the whole day.Desmopressin reduces nocturnal urine volume and nocturnal voiding frequency in male patients with nocturnal polyuria. However, increased calcium and decreased potassium excretion following desmopressin treatment deserve attention particularly when it is used on a long-term basis.

We evaluated combination treatment with desmopressin and oxybutynin in patients with enuresis who did not respond to desmopressin monotherapy. Furthermore, we compared 2 methods of estimating bladder capacity and evaluated the ability of these methods to predict the response to desmopressin and oxybutynin.A total of 60 children with a mean age +/- SD of 10.6 +/- 3.0 years who had monosymptomatic nocturnal enuresis completed the study. After a 2-week observation period maximal voided volume during free access to fluid intake was determined by a 2-day frequency-volume chart and maximal voided volume after water load was determined on a separate day. Patients then received 20 mug desmopressin intranasally at bedtime during 2 weeks. In nonresponders to desmopressin with less than a 50% decrease in wet nights 5 mg oxybutynin twice daily was added for another 2 weeks.Of the patients 41 (68%) showed more than 50% decrease in wet nights during the 2-week desmopressin treatment period (4.6 +/- 1.6 to 0.7 +/- 0.8, p0.001). In desmopressin nonresponders combined treatment with desmopressin and oxybutynin resulted in a further decrease in wet nights (4.0 +/- 1.2 to 1.7 +/- 1.4, p0.001). Maximal voided volume during free access to fluid intake was significantly higher in desmopressin responders than in nonresponders (244 +/- 111 vs 160 +/- 65 ml, p0.001). In contrast, maximal voided volume after water load was not significantly different between desmopressin responders and nonresponders.The study indicates a role for oxybutynin in combination with desmopressin in children who are not responding to desmopressin monotherapy. Maximal voided volume during free access to fluid intake is a clinically useful predictor of the response to desmopressin but not to oxybutynin.

Since antidiuretic treatment with desmopressin in the evening has proven effective against enuresis, it would not be surprising if diuretic treatment in the afternoon would have similar effects. We are currently testing this in an open pilot investigation.A total of 33 children including 12 girls with a mean age +/-SD of 7.6 +/- 2.3 years with monosymptomatic enuresis were recruited from an outpatient primary care setting. Wet and dry nights were recorded for 2 weeks without medication, 2 weeks with 0.4 mg desmopressin orally at night and 2 weeks with 1 mg/kg furosemide 4 to 5 hours before bedtime.The mean number of wet nights +/-SD during the 3 periods was 10.2 +/- 3.0, 6.7 +/- 4.7 and 7.8 +/- 4.5, respectively. The effects of desmopressin and of furosemide were statistically significant (p0.0001 and p = 0.001), although the 2 treatments did not differ (p = 0.08). Only 6 children had a complete response (ie greater than 90% reduction in wet nights) to desmopressin and 5 responded to furosemide. Interestingly, 2 children had a clearly better response on furosemide than on desmopressin.The treatment of enuresis with diuretic medication in the afternoon may be beneficial but needs to be tested in randomized controlled trials.

We determined in older adults whether frequent nighttime voiding is associated with urine overproduction at night or nocturnal polyuria (NP) and whether NP is associated with abnormalities of arginine vasopressin (AVP) blood levels and/or renal responsiveness to AVP.We used a convenience sample of adults 65 years and older in home and general clinical research center settings. A total of 45 participants completed the 3-day general clinical research center stay. We used 7-day voiding diaries to determine which participants had 2 or greater nighttime voids and NP, defined as 35% or greater of 24-hour urine output at night. Abnormalities in AVP release and secretion were determined by water deprivation testing and by twice daily blood AVP measurement.There was a strong positive association between the number of nighttime voids and the proportion of urine produced at night (r = 0.6, p0.001). There was no association between NP and AVP blood levels or action. Participants with and without NP had similar maximum urine osmolality following water deprivation and exogenous AVP administration (mean 549 mOsm, range 422 to 713 and 547 mOsm, range 353 to 692, respectively).We found no association between NP and AVP abnormalities in this sample of older adults. Study participants had low maximal urine osmolality in response to fluid deprivation and exogenous vasopressin administration irrespective of whether they were identified as having NP.

Desmopressin acetate, most commonly used to treat nocturnal enuresis in children, is also used to correct bleeding disorders and as prophylaxis for surgical bleeding in patients with certain bleeding diatheses. However, desmopressin also has a potent antidiuretic effect, impairing free water resorption by the kidney. Consequently, retention of free water and hyponatremia can ensue. We report on a patient who, after treatment with desmopressin as prophylaxis for surgical bleeding secondary to von Willebrand disease, experienced complications of hyponatremia and seizures secondary to water intoxication following laparoscopic radical nephrectomy.

We determined the prevalence of positive family history of nocturnal enuresis in relation to response to desmopressin.A total of 328 children with nocturnal enuresis and 53 normal children were interviewed to determine the presence of family history of nocturnal enuresis. Response to desmopressin was confirmed in some cases by home recordings of enuresis episodes during 2 baseline weeks and 2 weeks of 20 to 40 microg. desmopressin intranasally.Significantly more patients than normal children (75% versus 38%, p0.001) reported a positive family history of enuresis (any relative). The high prevalence of a positive family history of nocturnal enuresis was present in severe/nonsevere or primary/secondary types of enuresis. Of the patients 141 completed 4 weeks of home recordings including 20 with a complete response (greater than 90% reduction in wet nights week), 25 with a partial response (50% to 90% reduction) and 96 with no response (less than 50% reduction). The prevalence of a positive family history (any relative) was no different among the response groups (80%, 84% and 78%, respectively). Similarly, family history, as defined by first order relatives only, showed no relation to treatment response.A positive family history of nocturnal enuresis is more prevalent in patients with enuresis than in normal children regardless of the nature of the nocturnal enuresis. In contrast to previous reports, a positive family history failed to predict a good response to desmopressin treatment. Hereditary factors are important to consider in desmopressin responding and desmopressin resistant cases.

We confirmed findings that oral desmopressin safely decreases the number of wet nights in children with enuresis and identified doses at which acceptable responses can be obtained.We evaluated the safety and efficacy of oral desmopressin in a double-blind, placebo controlled, parallel group, randomized, multicenter trial of 193 children 6 to 16 years old with documented primary nocturnal enuresis. The study was conducted in 2 phases: 1) a 2-week dose ranging phase in which children received desmopressin (0.2, 0.4 or 0.6 mg.) or placebo at bedtime and 2) an 8-week dose titration phase that followed a 2-week placebo washout. Patients received 0.2 mg. desmopressin or placebo for the first 2 weeks and then the dose was increased in 0.2 mg. increments at 2-week intervals until the patient was completely dry or was receiving 0.6 mg. Patients were instructed to limit fluid intake. Mean decrease from baseline in the number of wet nights, percentage of responding patients and safety were assessed at 2-week intervals.There was a statistically significant linear response to oral desmopressin at doses from 0.2 to 0.6 mg. during the dose ranging phase (por =0.05). The decrease in wet nights after 2 weeks of treatment with desmopressin was 27%, 30% and 40% at 0.2, 0.4 and 0.6 mg. doses, respectively, compared to 10% with placebo. All doses were statistically significantly different from placebo (por =0.05). During the dose titration phase all placebo treated and 87% of desmopressin treated patients were receiving the maximum dose of 3 tablets nightly because they had not been completely dry in the previous 2 weeks. Nevertheless, 44% of desmopressin treated patients had achieved at least a 50% reduction from baseline in the number of wet nights per 2 weeks at the lower doses of 0.2 and 0.4 mg. Most adverse events (rhinitis, pharyngitis, headache and increased cough) were mild to moderate in severity, unrelated to treatment and resolved before the study was completed.Oral desmopressin administered at bedtime to children with primary nocturnal enuresis was significantly better than placebo for decreasing episodes of bed-wetting (p0.05). A linear dose-response relationship was observed (p0.05). An acceptable response to treatment (50% or greater reduction from baseline in wet nights per 2 weeks) was seen at all doses of desmopressin. Oral desmopressin, up to 0.6 mg. for 8 weeks, was well tolerated.

The use of desmopressin in patients with primary nocturnal enuresis is based on the hypothesis of a nocturnal lack of endogenous arginine vasopressin. However, in addition to the kidney, other targets of desmopressin are known. Therefore, we examined whether the administration of desmopressin influences central nervous function in children with primary nocturnal enuresis.Our prospective, randomized, double-blind, placebo controlled cross-over study was performed on 40 children with nocturnal enuresis. Patients were randomly assigned to receive either 20 microg. desmopressin intranasally or 0.9% saline solution. Each group comprised 19 and 21 to children, respectively. After 2 weeks the groups were switched. The children were tested for short-term memory and reaction time to both treatments. Statistical analysis was done using the Wilcoxon matched pairs test.Median patient age was 8.0 years (range 6 to 13). During desmopressin treatment children in both groups had a significant decrease of wet nights (5.3 to 3.2 per week). In contrast to reaction time, short-term memory was significantly different between both groups (p0.05).Our results demonstrate an increase in short-term memory after desmopressin treatment in children with nocturnal enuresis. This finding indicates the central nervous system as a target involved in the pathogenesis of nocturnal enuresis as well as the therapeutic benefit of desmopressin treatment.

We compared bladder volume and renal concentrating capacity in dry children and 2 distinct groups of children with enuresis to hypothesize about the pathogenesis of various types of enuresis.A total of 55 dry children and 100 with enuresis underwent an overnight thirst provocation test to assess renal concentrating capacity and completed a 2-day voiding chart to assess functional bladder capacity. The enuretic children were subdivided into 27 desmopressin responders and 73 desmopressin nonresponders before study inclusion.The desmopressin responder group had lower average renal concentrating capacity +/-1 standard deviation than dry children and desmopressin responders (856 +/- 158 mOsm./kg. versus 939 +/- 147 and 962 +/- 151, respectively, p0.05). Analogously average daytime urine production in the desmopressin responder group was greater than in dry children and desmopressin responders (22.2 +/- 10.2 ml./kg. body weight versus 15.4 +/- 7.3 and 15.3 +/- 7.2, respectively, p0.01). Average functional bladder capacity expected for age was less in desmopressin nonresponders than in dry children and responders (52.2% +/- 19.9% versus 79.2% +/- 30.4% and 69.5% +/- 25.7%, respectively, p0.001).Desmopressin responders produced larger amounts of less concentrated urine than the other children, while desmopressin nonresponders had smaller bladder capacity than the other groups. These results support the idea that enuretic children who respond favorably to desmopressin treatment have polyuria, whereas children with therapy resistant enuresis have detrusor hyperactivity.

We performed a crossover study to determine the relative pharmacokinetic bioavailability and antidiuretic activity of desmopressin in 16 orally hydrated, healthy human subjects.The investigation included 5 study periods with 1 period used to establish baseline diuresis in the absence of desmopressin and the remaining 4 randomized to a single 0.6 mg. oral dose of desmopressin administered as whole, crushed or chewed tablets, or as an oral solution. Serial plasma samples were collected for 12 hours for desmopressin pharmacokinetic analysis. Pharmacodynamics were assessed by measuring changes in urine volume and osmolality from baseline. Standard bioequivalence metrics were used to compare the pharmacokinetics and pharmacodynamics of crushed and chewed tablets, and oral solution to that of swallowing whole tablets.The 90% confidence interval analysis of log transformed plasma desmopressin area under the plasma concentration-time curve from time 0 to infinity and maximum plasma drug concentration showed that crushed and chewed tablet treatments were bioequivalent to swallowing whole tablets. The 90% confidence interval analysis for the decrease in urine volume and increase in urine osmolality demonstrated that crushed and chewed tablets, and oral solution treatments were equivalent to whole tablet treatment in the area under curve from time 0 to the last sampling time point and maximum drug effect.The results of this study imply that desmopressin administered orally as crushed or chewed tablets, or as an oral solution has the same net effect on decreasing urine volume and increasing urine osmolality as swallowing tablets whole.

We tested the role of the bladder in the pathogenesis of desmopressin resistant enuresis by evaluating the influence of urine production on the timing of the enuretic event and the response to anticholinergic medication.We gave 33 children with monosymptomatic nocturnal enuresis resistant to the standard 0.4 mg. oral dose of desmopressin 0.4 and 0.8 mg. desmopressin and placebo tablets for 5 nights each in a double-blind crossover fashion. The time of enuresis or nocturia was documented. All 9 children who had at least 1 dry treatment period during the randomized portion of the study then received open label treatment with 0.8 mg. desmopressin. Nonresponders to this regimen and the remainder of the children were offered anticholinergic treatment.Average time between bedtime and voiding was 5.0, 5.6 and 5.0 hours during the nights with placebo, and 0.4 and 0.8 mg. desmopressin, respectively (p = 0.12). Of the 9 children subsequently treated with 0.8 mg. desmopressin 5 became completely dry. Of the remaining 28 children given anticholinergic treatment 20 responded.Antidiuresis does not delay the enuretic event in children with desmopressin resistant enuresis. This finding and the favorable response to anticholinergic medication favor the hypothesis that these children have nocturnal bladder instability. A subgroup of enuretic children responds to high but not normal doses of desmopressin.

We studied bladder dysfunction in children with significant primary nocturnal enuresis refractory to treatment.We evaluated 33 Chinese boys and 8 girls with a mean age of 10.4 years, who had significant monosymptomatic primary nocturnal enuresis (3 or more wet nights weekly) after desmopressin treatment with or without an enuretic alarm failed. Daytime cystometry, continuous nighttime cystometry and electroencephalography monitoring during sleep, and detailed recording of daytime and nighttime urinary output were performed.We recognized 5 patterns of bladder dysfunction and its association with sleep-arousal status. Pattern 1 was normal daytime urodynamics with significant bladder instability at night with normal volume voiding precipitated by unstable detrusor contractions in 14 boys (34%). Pattern 2 was normal daytime urodynamics with frequent small volume voiding at night, probably representing latent bladder instability, in 4 boys (10%). Pattern 3 involved abnormal daytime urodynamics with small bladder capacity, a discoordinated daytime voiding pattern and marked nighttime bladder instability associated with poor sleep in 6 boys (15%). Pattern 4 was abnormal daytime urodynamics with an obstructive pattern, and marked daytime and nighttime detrusor hypercontractility (mean maximum detrusor pressure 178 cm. water) in 8 boys (20%). Pattern 5 was abnormal daytime urodynamics with a dysfunctional daytime voiding pattern and frequent small volume nighttime voiding in 8 girls and 1 boy (22%). In all patients functional bladder capacity was smaller than expected for age and the majority had no nocturnal polyuria. Despite underlying bladder dysfunction a 4-week course of 400 microg. desmopressin orally at bedtime still produced a significant response with a greater than 50% decrease in the number of wet nights during treatment in 47% of the patients, although enuretic symptoms immediately relapsed on cessation of therapy in all. Notably cystourethroscopy in 7 of the 8 boys with pattern 4 dysfunction revealed bladder trabeculations and abnormal urethral lesions, including congenital obstructive posterior urethral membranes in 4, Moormann's ring in 2 and irregular scarring at the bulbous urethra in 1.Abnormal bladder function, including small functional capacity, instability during sleep and marked detrusor hypercontractility, was common in our enuretic children in whom treatment failed. More importantly, nocturnal enuresis may be the only presenting symptom and there may be a response to desmopressin with a decreased number of wet nights even in cases of significant underlying bladder dysfunction. These findings may have important implications for our management strategy for monosymptomatic primary nocturnal enuresis.

We evaluate the therapeutic effectiveness of treating monosymptomatic primary nocturnal enuresis (PNE) that has persisted into adulthood.Patients older than 18 years with persistent monosymptomatic primary nocturnal enuresis were treated with 20 to 40 microg. desmopressin (DDAVP) nightly for 6 months. If the patients remained incontinent on maximal pharmacotherapy or if they became incontinent after cessation of DDAVP we initiated treatment with an enuretic alarm for 6 months. Patients not responsive to DDAVP or the enuresis alarm were given a trial of 50 mg. imipramine nightly. All patients were reassessed for continence 18 months after initiation of the treatment protocol.We treated 29 patients of a median age of 20 years (range 18 to 33) who were enuretic more than 4 nights per week. With the initial DDAVP treatment 19 (66%) became continent (enuresis 0 or 1 night a month) but after discontinuation of DDAVP only 2 (7%) remained continent. Of the 27 patients subsequently treated with an enuretic alarm 9 (33%) became continent and 18 had persistent enuresis. Of these 18 patients 11 resumed DDAVP and became dry, while 7 nonresponsive to DDAVP were given imipramine and 2 (29%) are continent.Overall, 83% of patients (24 of 29) achieved continence, including 38% (11 of 29) who are continent off all treatment modalities and 45% (13 of 29) who are currently continent on pharmacotherapy (11 on DDAVP and 2 on imipramine). The remaining 17% of patients (5 of 29) have persistent primary nocturnal enuresis recalcitrant to all therapeutic attempts.

We report our experience with the use of desmopressin in the spina bifida population that is dry during the day but wet at night.From 1994 to 1996, 18 patients with myelodysplasia were treated with desmopressin for persistent nocturnal enuresis. Initial dose was 40 mcg. before bedtime, decreased by intervals of 10 mcg. every 3 weeks. Patients were kept on the minimum dose required to keep them dry. We reviewed morning catheterized volumes, side effects and dosages needed to stay dry, and compared augmented patients with nonaugmented patients.Of 18 patients 14 (78%) reported marked improvement in nocturnal enuresis. Of 6 augmented patients 5 (83%) are dry compared to 9 of 12 nonaugmented patients (75%). There were no adverse side effects from the use of desmopressin. Average dose to stay dry was 20 mcg. for augmented and 30 mcg. for nonaugmented patients. Of the 4 patients who had persistent nocturnal incontinence despite desmopressin 3 (75%) became dry with a single catheterization in the middle of the night.Desmopressin is successful in treating nocturnal enuresis in the spina bifida patient with diurnal continence.

Desmopressin nasal spray has proved to be efficacious treatment of primary nocturnal enuresis. Oral desmopressin tablets would be a more easily used, convenient vehicle for our patients and their parents. We evaluated the effectiveness of oral desmopressin in decreasing the number of wet nights in patients with primary nocturnal enuresis.We performed a double-blind, placebo controlled, parallel group trial of oral desmopressin in 141 children 5 to 17 years old with documented primary nocturnal enuresis at 14 sites. Patients were screened for number of wet nights for 2 weeks before study entry. A minimum of 3 wet nights weekly for 2 consecutive weeks was required for study entry. Patients were randomized to receive 200, 400 or 600 mcg. desmopressin or placebo before bedtime. Fluids were restricted 2 hours before bedtime based on body weight. The primary efficacy variable was mean decrease in the number of wet nights recorded during the last 2-week treatment period. The percentage of responding patients and mean decrease from baseline in number of wet nights at 2, 4 and 6 weeks were also assessed.The decrease in wet nights was 9, 20, 30 and 36% for placebo, and 200, 400, and 600 mcg. desmopressin orally per day, respectively. The 600 mcg. dose of oral desmopressin daily was statistically significantly different (p0.05) from placebo in decreasing wet nights. A complete or near complete response (0 to 2 wet nights) was noted in 3, 18, 33 and 24% of the patients who received placebo, and 200, 400 and 600 mcg. oral desmopressin daily, respectively. The 400 and 600 mcg. treatment groups were statistically significantly different (p0.05) from placebo. A less than 50% decrease in wet nights was noted in 83, 79, 64 and 61% of the patients who received placebo, and 200, 400 and 600 mcg. oral desmopressin daily, respectively. Oral desmopressin exhibited a dose response in the treatment of primary nocturnal enuresis. The linear trend for the decrease in wet nights was statistically significant (p0.05).A dose of 600 mcg. oral desmopressin daily significantly decreased the mean number of wet nights when administered for 6 weeks. A higher dose may be necessary for an improved response.

We report on a girl with the Prader-Willi syndrome who received desmopressin for nocturnal enuresis, and water intoxication developed after she ingested a large amount of fluid.The patient received 10 mg. desmopressin at bedtime for enuresis. She was hospitalized when a major motor seizure and coma (Glasgow coma scale 8) occurred after ingesting 48 ounces of fluid. Treatment included 3% saline, followed by 5% dextrose in water and sodium chloride given intravenously.Serum sodium increased to 128 mEq./l. and serum glucose remained normal. Computerized tomography and magnetic resonance imaging of the head were normal and revealed no evidence of cerebral pontine myelinosis. Patient consciousness returned to normal by day 5 after the seizure.In patients treated with desmopressin the risk of a seizure or altered level of consciousness can be minimized by not ingesting large quantities of fluid. We recommend that patients drink no more than 8 ounces of fluid on any evening that desmopressin is administered.

We evaluated the efficacy and safety of 2 oral doses of desmopressin compared to 20 micrograms. nasal spray and baseline values in the treatment of primary nocturnal enuresis.A multicenter study was done comparing oral dosages (200 and 400 micrograms.) of desmopressin (4-week, randomized, double-blind phase followed by 12 weeks of open label treatment with 400 micrograms.) to 20 micrograms. nasal spray in 66 adults and adolescents 12 to 45 years old with primary nocturnal enuresis.No significant differences were found between the 2 doses of desmopressin tablets or between the tablets and 20 micrograms. nasal spray during the double-blind phase. However, patients who initially received 200 micrograms. desmopressin tablets experienced fewer wet nights after they completed 12 weeks of open label treatment when the dose was escalated to 400 micrograms. tablets. Those who received 400 micrograms. tablets initially maintained response during this phase. Desmopressin tablets were well tolerated at both dose levels: 96% of patients and 94% of physicians rated the tolerability as excellent.Desmopressin tablets are an effective and safe alternative for treatment of nocturnal enuresis.

Patients with primary nocturnal enuresis were entered into 4 treatment groups: observation, imipramine, desmopressin acetate or alarm therapy. Patients were weaned from therapy 6 months after inclusion in the study and were evaluated for continence at 3, 6, 9 and 12 months after beginning the study protocol. Of the 50 patients under observation 6% were continent at 6 months and 16% were continent within 12 months. Of 44 patients treated with imipramine 36% were continent at 6 months on medication; however, only 16% were continent at 12 months, off medication. Similarly, of the 88 patients treated with desmopressin acetate 68% were continent at 6 months but only 10% were continent at 12 months. Of the 79 patients treated with alarm therapy 63% were continent at 6 months and 56% were dry at 12 months. Although each form of therapy improved continence over observation alone (p0.01), only the bed-wetting alarm system demonstrated persistent effectiveness (p0.001).

The prevalence of enuresis and management options for this condition were studied in our population of sickle cell patients. A total of 91 active patients (6 to 21 years old) followed at our regional sickle cell center was surveyed for the symptoms of primary nocturnal enuresis. Of the 91 patients 27 (29.6%) had primary nocturnal enuresis. Of those with enuresis 17 had homozygous sickle cell anemia, 5 had hemoglobin sickle cell disease, 4 had sickle cell beta + thalassemia and 1 had sickle cell beta zero-thalassemia. Of 10 patients who elected to receive intranasal desmopressin acetate 6 (60%) had complete or partial resolution of nocturnal enuresis. Our data confirm the high prevalence of nocturnal enuresis in patients with sickle cell disease and support the role of desmopressin acetate in the treatment of these patients.

The pharmacokinetics of desmopressin (1-desamino-8-D-arginine vasopressin) were investigated in 8 patients with nocturnal enuresis, of whom 4 were known to respond completely to desmopressin and 4 were nonresponders. A decrease in urine production was confirmed in responders after the administration of desmopressin while the drug did not cause antidiuresis in nonresponders. Absorption and excretion of desmopressin were identical in each group. Results indicate at least 2 pathophysiological mechanisms in nocturnal enuresis, including insufficient nocturnal production of arginine vasopressin and impaired renal sensitivity to arginine vasopressin and desmopressin. Each type results in high nocturnal urine production.

The response to desmopressin in 71 children with nocturnal enuresis was evaluated to determine whether a family history of nocturnal enuresis could be helpful in predicting which patients would respond. The overall response rate to desmopressin (53 of 71 patients, 75%) was comparable to previous studies. A poor response was associated with a negative family history of nocturnal enuresis (1 of 14 patients, 7%), whereas the response in those with a positive family history was excellent (52 of 57 patients, 91%). We conclude from this preliminary retrospective study that a high rate of success may be predicted when desmopressin is used in patients with familial nocturnal enuresis, whereas less optimism is warranted when no family history of nocturnal enuresis can be elicited. This observation should be validated in a larger, prospective clinical study.

The effect of intranasal desmopressin on primary nocturnal enuresis was investigated in a study divided into 2 parts in which the first part was a randomized, double-blind, placebo-controlled cross-over study of 52 Finnish school children 5 to 13 years old. A variety of approaches had previously been attempted in most children, including water deprivation, night awakenings, enuresis alarm and imipramine, without success. The patients were randomized to 4 periods of 3 weeks each: 2 periods on placebo and 2 periods on 20 micrograms. desmopressin spray. The entire 12-week treatment period was preceded and followed by control periods (without treatment). The number of dry nights, measured as calculated averages per week, increased significantly (p less than 0.01) from 0.6 dry nights during pre-treatment to 4.3 and 4.6 dry nights per week during the 2 desmopressin treatment periods, respectively. The placebo responses were 2.1 and 2.4 dry nights per week, respectively. The second part of the study was an open dose-finding and drug safety study of a further 3 months in duration. The aim was to evaluate the efficacy and tolerance of 20, 30 and 40 micrograms. doses. All 47 patients who relapsed during the post-treatment period in part 1 were included. During this period 53% of the patients responded fully, 19% were intermediate responders and 28% did not respond. As reported in other studies most patients suffered relapse after treatment. During continued treatment for 3 months at doses between 20 and 40 micrograms. desmopressin was well tolerated, had no effect on body weight or blood pressure and did not cause any adverse reactions.

The systemic and renal effects of high partial ureteral obstruction were investigated in a new model of experimental hydronephrosis. The test group comprised 12 contralaterally nephrectomized growing male New Zealand rabbits. As compared to the pyelographic findings in 6 unilaterally nephrectomized control animals, the test group could be divided into partially obstructed but non-hydronephrotic and obstructed-hydronephrotic subgroups. Animals of all 3 groups were capable of increasing their weight during the first 2 postoperative months. The mean plasma creatinine concentration remained normal in the obstructed group and even hydronephrosis was compatible with a normal serum creatinine level. As studied during forced hypotonic expansion, the renal response to a vasopressin analogue was significantly different in all 3 animal groups. Reciprocal but less marked differences were noted in the animals' ability to retain water during this test. We conclude that in this experimental model the magnitude of the antidiuretic response is inversely related to the radiologically defined degree of obstruction.

Maximal renal concentrating capacity was determined with the aid of intranasal desaminocysteine-D-arginine vasopressin, a derivative of natural vasopressin, in 9 infants and 2 children with congenital or acquired pelvioureteral or vesicoureteral stenosis. Urinary tract infection was present in some but not all cases. Immediately postoperatively all 13 renal units displayed rather subnormal maximal renal concentration capacity (355 plus or minus 81 mosm. per kg. or mean plus or minus 1 standard deviation), which was corrected to some extent at the time of removal of the ureteral splint 5 to 10 days later (455 plus or minus 129 mosm. per kg.). Between 5 and 15 months postoperatively all but 1 renal unit displayed further significant increment in maximal renal concentration capacity. This single unit, operated on initially for vesicoureteral reflux secondary to neurogenic bladder, was found to be stenotic at the level of the ureterovesical junction. Routine determination of maximal renal concentration capacity at the time of operation could enable one to judge the kidney drainage postoperatively.

Desmopressin has been used as a hemostatic agent in numerous hematological and nonhematological diseases. We report a case of surgical hemorrhage secondary to prolonged bleeding time of unexplained origin controlled with desmopressin.

The intranasal DDAVP (1-deamino-8-D-arginine vasopressin) test is a safe and feasible method for the study of renal concentrating ability in children. This study describes a simplification of the test. Sixty randomly selected children were tested for urine osmolality at different hours after intranasal administration of DDAVP. No fluid restriction was prescribed. Optimal concentrating ability was attained after 3 and 5 hours. Without impairing the validity of the DDAVP test, it can be performed in a simpler way than previously recommended.