Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia.

OBJECTIVE: To explore risk factors for desmopressin-induced hyponatraemia and evaluate the impact of a serum sodium monitoring plan. SUBJECTS AND METHODS: This was a meta-analysis of data from three clinical trials of desmopressin in nocturia. Patients received placebo or desmopressin orally disintegrating tablet (ODT; 10-100 µg). The incidence of serum sodium <130 mmol/L was recorded by age, sex and dose. Potential predictors of clinically significant hyponatraemia were identified using multivariate analysis in a Cox proportional hazards model. RESULTS: Dose, age, baseline serum sodium level and kidney function, according to estimated GFR clearance, were significant risk factors for hyponatraemia in both sexes; similar to the known risk factors associated with hyponatraemia in the general population. In men, arthritis and use of drugs for bone disease were also predictive of hyponatraemia, while in women, raised monocytes and absence of lipid-modifying drugs increased the risk of hyponatraemia. Use of the proposed monitoring scheme and the minimum effective dose would have omitted all patients with clinically significant hyponatraemia from further treatment. CONCLUSIONS: The incidence of hyponatraemia can be reduced by using minimum effective gender-specific dosing with the ODT formulation of desmopressin (25 µg in women, 50 µg in men). A sodium monitoring plan is proposed whereby baseline sodium must be ≥135 mmol/L (especially important in the elderly), with additional monitoring at week 1 and month 1 for those at elevated risk because they are aged ≥65 years or receiving concomitant medication associated with hyponatraemia. This monitoring plan would help to prevent some at-risk patients developing hyponatraemia; retrospective application of the monitoring plan showed that, once at-risk patients were appropriately screened out, only mild, non-clinically significant hyponatraemia was observed, within ranges of other drugs associated with hyponatraemia and similar to the background prevalence in the treatment population.

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors.

The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine concentrating mechanism through the AVP/V2 type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongly support the existence of an extrarenal V2R. The clinical importance of the extrarenal V2R spans widely from stimulation of coagulation factor in the endothelium to as yet untested potential therapeutic targets. These include V2R-regulated membranous fluid turnover in the inner ear, V2R-regulated mitogensis and apoptosis in certain tumor tissues, and numerous other cell types where the physiological role of V2Rs still requires further research. Here, we review current evidence on the physiological and pathophysiological functions of renal and extrarenal V2Rs. These functions of V2R are important, not only in rare diseases with loss or gain of function of V2R but also in relation to the recent use of nonpeptide V2R antagonists to treat hyponatremia and possibly retard the growth of cysts and development of renal failure in autosomal dominant polycystic kidney disease. The main functions of V2R in principal cells of the collecting duct are water, salt, and urea transport by modifying the trafficking of aquaporin 2, epithelial Na(+) channels, and urea transporters and vasodilation and stimulation of coagulation factor properties, mainly seen with pharmacological doses of 1-desamino-8-D-AVP. The AVPR2 gene is located on the X chromosome, in a region with high probability of escape from inactivation; this may lead to phenotypic sex differences, with females expressing higher levels of transcript than males.

Potential clinical applications of current and future oral forms of desmopressin (Review).

Desmopressin is a synthetic analogue of vasopressin and a selective vasopressin receptor 2 agonist. It was first synthesised in 1967 and utilised for its antidiuretic properties. It is also used in bleeding disorders to enhance clotting. Other potential uses of the drug have been reported. The present review aims to provide a broad overview of the literature on potential further uses of oral forms of desmopressin. Key therapeutic areas of interest were identified based on known physiological activities/targets of desmopressin or reports of an effect of desmopressin in the literature. The feasibility of adequate dosing with oral forms of the drug was also considered. Systematic literature searches were carried out using the silvi.ai software for the identified areas, and summaries of available papers were included in tables and discussed. The results of the searches showed that desmopressin has been investigated for its efficacy in a number of areas, including bleeding control, renal colic, the central nervous system and oncology. Evidence suggests that oral desmopressin may have the potential to be of clinical benefit for renal colic and bleeding control in particular. However, further research is needed to clarify its effect in these areas, including randomised controlled studies and studies specifically of oral formulations (and doses). Further research may also yield findings for cancer, cognition and overactive bladder.

Temporal delays and individual variation in antidiuretic response to desmopressin.

This study aimed to estimate the relationship between pharmacokinetics and the antidiuretic effect of desmopressin. In the investigator-blind, randomized, parallel group study, 5 dose groups and 1 placebo group, each consisting of 12 healthy, overhydrated, nonsmoking male subjects 18-55 yr of age were infused intravenously over 2 h with placebo or 30, 60, 125, 250, and 500 ng desmopressin in 50 ml of normal saline. Plasma desmopressin and urine osmolality rose by variable amounts during the infusions of 60, 125, 250, and 500 ng desmopressin. Plotting mean urine osmolality against the concurrent mean plasma desmopressin yielded a temporal delay between pharmacokinetic (PK) and -dynamic (PD) responses in all dose groups. Using simulation from the indirect-response model, assuming a constant (4 ng/ml) desmopressin concentration, this delay between PK and PD was estimated at 4 h (10th-90th percentile: 1.8-8.1). Within each group, however, there were large individual variations (2- to 10-fold) in the magnitude and duration of the antidiuretic effect. The antidiuretic effect of intravenous desmopressin in water-loaded healthy adults varies considerably due largely to factors other than individual differences in pharmacokinetics. The antidiuretic effect is time as well as dose dependent and may be self-amplifying. The most likely explanation for these findings is that the time required for a given level of plasma desmopressin to exert its maximum antidiuretic effect varies markedly from person to person due to individual differences in the kinetics of one or more of the intracellular mechanisms that promote the reabsorption of solute-free water by principal cells in renal collecting tubules.

Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Desmopressin orally disintegrating tablet (ODT) 60-240 µg has proved an effective and well-tolerated antidiuretic treatment in male and female patients with nocturia. The main adverse event is hyponatraemia. Recent studies suggest that female patients are more sensitive to desmopressin ODT, achieving the same efficacy at lower doses than male patients. The study demonstrates the efficacy of desmopressin ODT in male and female Japanese patients with nocturia. It provides further evidence that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males. Tailoring the dose according to gender provides an improved therapeutic window with the benefits of a decreased risk of hyponatraemia without compromising efficacy. OBJECTIVES: To establish the dose-response efficacy of desmopressin in a Japanese patient population for the treatment of nocturia. To explore gender differences in sensitivity to desmopressin in Japanese patients with nocturia. PATIENTS AND METHODS: A phase II multicentre, randomized, placebo-controlled, double-blind, parallel-group, comparative clinical trial was conducted. Subjects aged 55-75 years, with a mean of ≥2 voids per night, were included and randomized to receive placebo or one of four doses of desmopressin orally disintegrating tablet (ODT): 10 µg, 25 µg, 50 µg or 100 µg. The dose-response relationship of pharmacodynamic variables measured after a single dose of desmopressin administered to water-loaded subjects (treatment period 1) was compared with the primary clinical endpoint of change from baseline in mean number of nocturnal voids, after 28 days of desmopressin treatment (treatment period 2). RESULTS: A total of 116 patients were treated in treatment period 1 of whom 113 qualified for treatment period 2, and 111 completed the study. In treatment period 1 a dose-response relationship was observed, both overall and in each gender group. Overall, the duration of antidiuretic action (DOA; time with urine osmolality >200 mOsm/kg) for the 25, 50 and 100 µg doses was 2 h (P = 0.010), 3.45 h (P < 0.001) and 5.74 h (P < 0.001), respectively; all statistically significant compared with placebo. Female patients were found to be more sensitive to desmopressin; DOA in female patients was longer than in male patients after desmopressin 25 and 50 µg. Extrapolation suggests that male patients require ∼58 µg to achieve similar DOA to females receiving 25 µg. A dose-response relationship was also seen in treatment period 2 for the group overall with a greater reduction in mean number of nocturnal voids from baseline to day 28 at higher doses, and with significant reductions in the 25- (P = 0.015) 50- (P < 0.001) and 100-µg (P = 0.001) dose groups compared with placebo. Similar dose-response relationships were also seen when the data were analysed by gender. Desmopressin ODT was well tolerated with no serious or severe adverse events. CONCLUSIONS: A dose-response relationship for desmopressin ODT was shown in a population of Japanese patients with nocturia. The study suggests that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males, indicating a gender-specific therapeutic window with a decreased risk of hyponatraemia without compromising efficacy on reduction of nocturnal voids. Further dose-finding studies are planned to confirm the recommended dose for the treatment of nocturia in a Japanese patient population.

Long-term durability of the response to desmopressin in female and male nocturia patients.

AIMS: To explore the durability of efficacy and gender differences during chronic administration of desmopressin in nocturia. METHODS: This pooled analysis of three short-term efficacy studies, with extensions, of desmopressin administered as orally disintegrating tablet (ODT) or solid tablet in nocturia treatment, comprised 351 patients completing 40-56 weeks' treatment. Efficacy endpoints of change in number of nocturnal voids and duration of initial undisturbed sleep period from baseline were analyzed to determine response durability and gender differences. RESULTS: The mean decrease in number of nocturnal voids during short-term treatment was maintained and further reduced during the long term. At 52 weeks, the mean decrease in number of nocturnal voids from baseline reached 1.4-2.1 voids for desmopressin ODT 25-100 µg. Following 40-week tablet treatment, the decrease in number of nocturnal voids was 0.8-1.5 for desmopressin 100-400 µg. The mean decrease in nocturnal voids (25-50 µg ODT) was greater for females than males. For females, the improvement in initial period of undisturbed sleep was 2.5-3 hr for desmopressin ODT 25-100 µg, compared with 1.3-2.6 hr for males. No gender difference in efficacy was seen in the tablet studies. CONCLUSIONS: The decrease in nocturnal voids and improvement in sleep with short-term desmopressin treatment were maintained throughout long-term treatment. A durable gender difference in efficacy in favor of females was observed with desmopressin ODT 25 µg. Further, large-scale long-term trials are needed to confirm the durability of efficacy with gender-specific doses of desmopressin.

Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis.

UNLABELLED: 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.

Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study.

Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.

Nocturia Think Tank: focus on nocturnal polyuria: ICI-RS 2011.

The following is a report of the proceedings of the Nocturia Think Tank sessions of the annual International Consultation on Incontinence-Research Society, which took place June 13-15, 2011 in Bristol, UK. The report is organized into sections pertaining to the main topics of discussions having occurred at that meeting, centering on the relationship of nocturnal polyuria (NP) and nocturia but also synthesizing more current evidence advancing our knowledge of the diagnosis and management of nocturia. This article is not meant to be a comprehensive review on the subject of nocturia, a number of which are available in the recent literature. All authors were physically present during, or in a preliminary session just prior to, the meeting in Bristol.

Gender difference in antidiuretic response to desmopressin.

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 µg than for men. The ED(50) for men was modeled to be 43.2 µg and 16.1 µg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 µg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-µg melt is an efficacious and safe dose, while for women a dose of 25 µg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.

Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria.

BACKGROUND: Clinical benefit has not been evaluated much in patients with nocturia. OBJECTIVE: To assess the clinical benefit of desmopressin orally disintegrating tablet (ODT) in women (25µg) and men (50µg) with nocturia due to nocturnal polyuria (NP). DESIGN, SETTING, AND PATIENTS: Patients with NP from two randomised, placebo-controlled trials in men (CS41) and women (CS40) with two or more nocturnal voids per night were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline in nocturnal voids, 33% and 50% responder status (average reduction of ≤33% and ≤50%, respectively, in the mean number of nocturnal voids vs baseline), and percentage of nights with at most one void or no voids (ie, complete response) during 3-mo treatment period were assessed for clinical benefit. Two-sided test (5% significance level) was used for all endpoints. RESULTS AND LIMITATIONS: Demographics and baseline characteristics of patients in CS41 (N=230) and CS40 (N=232) were similar. A greater reduction in the mean number of nocturnal voids was seen with desmopressin ODT in men (treatment difference [TD]: -0.37 voids) compared with women (TD: -0.29 voids). For 33% and 50% responder status, TD with ODT versus placebo were 21% and 12%, respectively, in men, and 12% and 17%, respectively, in women. For the number of nights with at most one void, TDs were 11% and 13% (p<0.009 for both) for men and women, respectively. For complete response, TD was significant in men (TD: 9%, p<0.001). Limitations inherent in this analysis were evident as the data for cotreatments (baseline) and quality of life were not collected. CONCLUSIONS: A stronger treatment effect with desmopressin ODT versus placebo and the magnitude of differences are indicative of clinical benefit in patients with NP. PATIENT SUMMARY: We looked at the clinical benefit of desmopressin ODT in patients with nocturnal polyuria. We conclude that clinical benefit was observed with desmopressin ODT in these patients.

A Danish population-based cohort study of desmopressin use in adults with nocturia or nocturnal enuresis.

OBJECTIVE: This study investigated how desmopressin is prescribed to adults in Denmark. METHODS: All adult users of desmopressin over an 8-year period were identified from the Danish National Prescription Registry. Adult patients with nocturia or nocturnal enuresis (NE) were identified by indication codes for "frequent nocturnal voiding" or "involuntary nocturnal voiding", respectively. Patient demographics, desmopressin formulation and dose, and concomitant medication were investigated. RESULTS: In all, 13 871 adults with nocturia and 2872 adults with chronic (i.e. >10 prescriptions) NE were given 102 547 and 43 712 desmopressin prescriptions, respectively. Across the entire patient cohort, 57% were women and mean patient age was 62 years. Over 40% of prescriptions were to elderly patients (≥65 years), and desmopressin use for adult enuresis increased with age. Orally disintegrating tablets were the most frequently used formulation (57%-65% of prescriptions), and a greater proportion of women than men used low-dose desmopressin (60 µg). Concomitant use of painkillers (opioids: 18%-26.7% of prescriptions; non-steroidal anti-inflammatory drugs: 14.2%-16.4% of prescriptions) and antidepressants (14.4%-18.1% of prescriptions) was common in both conditions, and 5.4%-9.2% of concomitant prescriptions were for overactive bladder medications. CONCLUSIONS: This study provides insights into desmopressin use among Danish adults. Nearly half the prescriptions were to patients aged ≥65 years, despite historical manufacturer recommendations that desmopressin be restricted to patients <65 years of age. NE is considered a childhood condition, but desmopressin use for adult NE increased with age. A greater proportion of desmopressin prescriptions to women than men were for the lowest dose, consistent with greater sensitivity to desmopressin in women.

Recent advances in managing and understanding enuresis.

Enuresis, particularly in children during sleep, can be a debilitating condition, affecting the quality of life of the child and his or her family. The pathophysiology of nocturnal enuresis, though not clear, revolves around the inter-related mechanisms of overactive bladder, excessive nocturnal urine production, and sleep fragmentation. The first mechanism is more related to isolated nocturnal voiding, whereas the latter two are more related to nocturnal enuresis, in which circadian variations in arginine vasopressin hormone play a key role. A successful treatment would depend upon appropriately addressing the key factors precipitating nocturnal enuresis, necessitating an accurate diagnosis. Thus, advancements in diagnostic tools and treatment options play a key role in achieving overall success. This review summarizes recent advances in understanding the pathophysiology of nocturnal enuresis, diagnostic tools, and treatment options which can be explored in the future.

The analgesic action of desmopressin in renal colic.

Urolithiasis is a frequent problem causing a significant clinical, psychological and socio-economic burden. Analgesia remains the most important element in the medical treatment of renal colic. Nonetheless, both NSAIDs and opiates have a side effect profile which can cause further complications. As such, the use of desmopressin for renal colic has received increased attention in the last two decades. This paper provides an overview of current evidence on the use of desmopressin as an analgesic strategy in renal colic.

Delaying time to first nocturnal void may have beneficial effects on reducing blood glucose levels.

Experimental studies disrupting sleep and epidemiologic studies of short sleep durations indicate the importance of deeper and longer sleep for cardiometabolic health. We examined the potential beneficial effects of lengthening the first uninterrupted sleep period (FUSP) on blood glucose. Long-term data (≥3 months of treatment) were derived from three clinical trials, testing low-dose (10-100 µg) melt formulations of desmopressin in 841 male and female nocturia patients (90 % of which had nocturnal polyuria). We performed post hoc multiple regression with non-fasting blood glucose as dependent variable and the following potential covariates/factors: time-averaged change of FUSP since baseline, age, gender, race, ethnicity, baseline glucose, baseline weight, change in weight, patient metabolic status (normal, metabolic syndrome, type II diabetes), dose, follow-up interval, and time of random glucose sampling. Increases in FUSP resulted in statistically significant reductions in blood glucose (p = 0.0131), even after controlling for all remaining covariates. Per hour increase in time to first void was associated with glucose decreases of 1.6 mg/dL. This association was more pronounced in patients with increased baseline glucose levels (test of baseline glucose by FUSP change interaction: p < 0.0001). Next to FUSP change, other statistically significant confounding factors/covariates also associated with glucose changes were gender, ethnicity, metabolic subgroup, and baseline glucose. These analyses indicate that delaying time to first void may have beneficial effects on reducing blood glucose in nocturia patients. These data are among the first to suggest that improving sleep may have salutary effects on a cardiometabolic measure.

Desmopressin in treatment of haematological disorders and in prevention of surgical bleeding.

Stimulation with the vasopressin analogue desmopressin (DDAVP) of extrarenal arginine vasopressin (AVP) V2-receptors in endothelial cells and possible in platelets increases the circulating levels of coagulation factor VIII (FVIII), von Willebrand factor (VWF) and tissue plasminogen activator (t-PA). The purpose of this paper is to provide an updated review of current information on the efficacy and safety of DDAVP in the treatment of haemophilia, von Willebrand disease (VWD), uremia, liver cirrhosis, and in congenital or drug-induced platelet dysfunction--under surgical or non-surgical conditions. In summary, desmopressin is an effective haemostatic drug that when administered i.v., s.c. or intranasally increases plasma levels of FVIII and VWF 2-6 times and improves platelet function. It has a proven haemostatic efficacy in mild haemophilia A and VWD as well as in uremia, liver cirrhosis and in congenital and acquired, drug induced platelet dysfunction. Desmopressin has few side effects but observation is advised in small children and elderly.

Clinical review: Treatment of neurohypophyseal diabetes insipidus.

CONTEXT: In recent years, there have been several improvements in the treatment of neurohypophyseal diabetes insipidus (DI). They include new formulations of the vasopressin analog, desmopressin; a better understanding of the effect of fluid intake on dosing; and more information about treatments of infants, children, and pregnant women who present special challenges. This review aims to summarize past and current information relative to the safety and efficacy of treatments for the types of DI caused by a primary deficiency of vasopressin. EVIDENCE ACQUISITION: The review is based on publications identified primarily by a PubMed search of the international literature without limitations of date. EVIDENCE SYNTHESIS: In acute settings where fluid intake is determined by factors other than thirst, desmopressin should be given iv in doses that have a short duration of action and can be adjusted quickly in accordance with changes in hydration as indicated by plasma sodium. In ambulatory patients, the oral formulations (tablet or melt) are preferred for their convenience. If fluid intake is regulated normally by the thirst mechanism, the tablets or melt can be taken safely 1 to 3 times a day in doses sufficient to completely eliminate the polyuria. However, if fluid intake consistently exceeds replacement needs as evidenced by the development of hyponatremia, the dose should be reduced to allow higher than normal rates of urine output or intermittent breakthrough diuresis. This regimen is often indicated in infants or children because their rate of fluid intake tends to be greater than in adults. In all cases, the appropriate dose should be determined by titration, owing to considerable interindividual differences in bioavailability and antidiuretic effect. CONCLUSIONS: Desmopressin can provide effective and safe therapy for all patients with neurohypophyseal or gestational DI if given in doses and by a route that takes into account the determinants of fluid intake.

The evolutionary origin of the vasopressin/V2-type receptor/aquaporin axis and the urine-concentrating mechanism.

In this mini-review, current evidence for how the vasopressin/V2-type receptor/aquaporin axis developed co-evolutionary as a crucial part of the urine-concentrating mechanism will be presented. The present-day human kidney, allowing the concentration of urine up to a maximal osmolality around 1200 mosmol kg(-1)-or urine to plasma osmolality ratio around 4-with essentially no sodium secreted is the result of up to 3 billion years evolution. Moving from aquatic to terrestrial habitats required profound changes in kidney morphology, most notable the loops of Henle modifying the kidneys from basically a water excretory system to a water conserving system. Vasopressin-like molecules has during the evolution played a significant role in body fluid homeostasis, more specifically, the osmolality of body liquids by controlling the elimination/reabsorption of fluid trough stimulating V2-type receptors to mobilize aquaporin water channels in the renal collector tubules. Recent evidence supports that all components of the vasopressin/V2-type receptor/aquaporin axis can be traced back to early precursors in evolutionary history. The potential clinical and pharmacological implications of a better phylogenetic understanding of these biological systems so essential for body fluid homeostasis relates to any pathological aspects of the urine-concentrating mechanism, in particular deficiencies of any part of the vasopressin-V2R-AQP2 axis causing central or nephrogenic diabetes insipidus-and for broader patient populations also in preventing and treating disturbances in human circadian regulation of urine volume and osmolality that may lead to enuresis and nocturia.

Desmopressin duration of antidiuretic action in patients with central diabetes insipidus.

The key question answered by this study is whether it is possible to deliver a pharmacokinetic and pharmacodynamic duration of antidiuretic action long enough to ensure adequate antidiuresis with two daily administrations of desmopressin in patients with central diabetes insipidus (CDI). We studied the efficacy and safety of desmopressin i.v. in 13 CDI patients using two 3-way crossover designs, in the doses 30, 60, 125 ng, and 125, 250 and 500 ng. Duration of action, minimum output rate, max osmolality and average osmolality during action (AUC osmolality) were measured every 30 min for the first 2 h during the infusion, and then every hour or every second hour until the urine output rate was greater than 2 ml/kg/30 min. The duration of antidiuretic action was 4, 8 and 11 h, respectively, for 125, 250, and 500 ng, increasing from 250 to 500 ng but for the remaining secondary dynamic efficacy parameters no difference could be detected based on descriptive statistics between the doses 250 and 500 ng, indicating that the upper plateau region of the dose-response curve had been reached. All treatment emergent adverse events were classified as unrelated or unlikely related to trial medication. No serious adverse events occurred. Data on duration of action indicates that it is possible to achieve antidiuretic control with 500 ng i.v. corresponding to 160 µg orodispersible tablets twice daily in CDI patients. Today, the Minirin Melt label recommends the majority of CDI patients a dose of 60 to 120 µg t.i.d.