Jens Peter Nørgaard

Diurnal Anti-Diuretic-Hormone Levels in Enuretics

The diurnal antidiuretic hormone levels were studied in eleven enuretics and related to urine production and functional bladder capacity. A fluid deprivation test monitoring antidiuretic hormone levels was undertaken in four patients. The study suggests that the normal increase in nighttime antidiuretic hormone levels is absent in enuretics, who show a stable hormone level both day and night. Consequently the volume of night urine production approximates day urine production per hour. The functional bladder capacity was clearly exceeded at night in eight of eleven patients. The fluid deprivation test showed a normal response to fluid deprivation. In conclusion, the study adds further evidence that bladder capacity is a major factor in enuresis. Urine volumes that exceed bladder capacity at night may be caused by a lack of diurnal rhythmicity in antidiuretic hormone levels.

NOCTURNAL POLYURIA AND NATRIURESIS IN MALE PATIENTS WITH NOCTURIA AND LOWER URINARY TRACT SYMPTOMS

PURPOSE We investigated the circadian variation in urine output, plasma angiotensin II, aldosterone, atrial natriuretic peptide, arginine vasopressin and blood pressure. MATERIALS AND METHODS We studied 17 elderly men with nocturia and lower urinary tract symptoms, and 10 age matched controls without nocturia. RESULTS Of the 17 patients studied 11 had a lack of diurnal variation in urine output and increased nocturnal urine production associated with increased nocturnal sodium excretion, and 6 had a diurnal variation in urine output comparable to controls. CONCLUSIONS Nocturia in a large proportion of elderly men with lower urinary tract symptoms is caused by nocturnal polyuria and natriuresis.

Association of Nocturia and Mortality: Results From the Third National Health and Nutrition Examination Survey

PURPOSE Nocturia, a common problem in men and women, has been associated with chronic illnesses such as heart disease and hypertension. Using data from the Third National Health and Nutrition Examination Survey we investigated the association of nocturia with subsequent mortality risk. MATERIALS AND METHODS NHANES III is a national probability survey of the United States between 1988 and 1994. Mortality data were obtained by linkage of NHANES III to the National Death Index. Cox proportional hazards regression models were used to assess the association between nocturia and all cause mortality, controlling for potential confounders in a sample of 15,988 men and women 20 years old or older. RESULTS The prevalence of nocturia, defined as 2 or more voiding episodes nightly, was 15.5% in men and 20.9% in women. Multivariate analyses showed a statistically significant trend of increased mortality risk with increased number of voiding episodes in men and women. The magnitude of the nocturia and mortality association was greater in those younger than 65 years with attenuated associations in the 65 years old or older age group. CONCLUSIONS Nocturia is a strong predictor of mortality, more so in younger men and women than in the elderly, with a dose-response pattern in increased mortality risk with increasing number of voiding episodes nightly. Potential underlying mechanisms of the observed association of nocturia and increased mortality risk include sleep disruption and subsequent development of related comorbid conditions.

Desmopressin 30 Years in Clinical Use: A Safety Review

Desmopressin acetate is the synthetic analogue of the antidiuretic hormone arginine vasopressin. It has been employed clinically for >30 years in a range of formulations: intranasal solution (since 1972), injectable solution (since 1981), tablets (since 1987), and most recently, an oral lyophilisate (since 2005). The antidiuretic properties of desmopressin have led to its use in polyuric conditions including primary nocturnal enuresis, nocturia, and diabetes insipidus. While a large body of clinical data is available for desmopressin, and despite its widespread use, comprehensive reviews of the safety of desmopressin are lacking (although some case series have attempted to correlate patient and/or dosing characteristics with the occurrence of adverse reactions). The purpose of this paper is to review the safety of desmopressin, based on analyses of both published data (MedLine) and of adverse reactions reported to Ferring Pharmaceuticals, the major manufacturer of desmopressin. Based on the findings, suggested strategies to reduce the risk of adverse reactions are proposed. Treatment with intranasal and oral formulations of desmopressin is generally well tolerated, and side effects are usually minor. The risk of hyponatraemia, although small, can be reduced by adhering to the indications, dosing recommendations and precautions when prescribing desmopressin.

Desmopressin orally disintegrating tablet effectively reduces nocturia: Results of a randomized, double‐blind, placebo‐controlled trial

The primary objective was to investigate the efficacy of desmopressin orally disintegrating tablet versus placebo in patients with nocturia. Pharmacodynamics, safety and patient‐reported quality of life (QoL) outcomes were also evaluated. One of several benefits of the new formulation is increased bioavailability. Exploring lower doses allows for a better evaluation of therapeutic effect versus tolerability.

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.

Nocturia and associated morbidity in a community-dwelling elderly population

To investigate the association between nocturia and selected concomitant diseases and medications in a community‐dwelling elderly population.

Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia.

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.

29-Week Doxazosin Treatment in Patients with Symptomatic Benign Prostatic Hyperplasia: A Double-Blind Placebo-Controlled Study

In a placebo-controlled study, the safety and efficacy of the selective alpha 1-adrenoceptor-blocking agent doxazosin 4 mg once daily in the symptomatic treatment of benign prostatic hyperplasia (BPH) were evaluated. One hundred patients were primarily included in a 9-weeks study, and after this 75 patients accepted to continue in the present 20 weeks extension. Of the patients in the doxazosin-group (DG) 61% reported overall improvement against 53% in the placebo-group (PG)--(p = 0.56). In the DG, 49% of obstructive symptoms were improved compared to 27% in the PG (p < 0.01), and a reduction of 60% of irritative symptoms was found in the DG against 36% in the PG (p < 0.01). Daytime frequency was reduced by median 1.5 in the DG and remained unchanged in the PG (p < 0.01). Nocturia was reduced by median 1 and 0.5 respectively (p = 0.06). Maximum urinary flow rate (MFR) was improved by median 1.5 ml/s in the DG, while it deteriorated by median 0.5 ml/s in the PG (p < 0.05), Considering postvoid residual urine volume, cystometry variables (first sensation and bladder capacity), changes in sexual function and adverse events there was no difference between the two groups. In conclusion, doxazosin 4 mg once daily in long-term treatment of patients with BPH reduces both obstructive and irritative symptoms, daytime voiding frequency and although only slightly, significantly augments MFR without interference with sexual function and without other serious adverse effects.

A new fast-melting oral formulation of desmopressin: a pharmacodynamic study in children with primary nocturnal enuresis

To determine the pharmacodynamic properties of a new oral lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 µg) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night‐time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population.