Kristian Vinter Juul

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.

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.

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.

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. Neurourol. Urodynam. 31:330–339, 2012.

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

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.

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

To explore the durability of efficacy and gender differences during chronic administration of desmopressin in nocturia.

National Surveillance of Central Diabetes Insipidus (CDI) in Denmark: Results From 5 Years Registration of 9309 Prescriptions of Desmopressin to 1285 CDI Patients

CONTEXT Epidemiological data for central diabetes insipidus (CDI) are sparse. OBJECTIVE The purpose of this study was to provide accurate epidemiological data on CDI on a national level. DESIGN AND SETTING This was a drug utilization and patient registry study during a 5-year period from 2007 to 2011. METHODS We used the Danish National Prescription Registry data linked with the Danish National Patient Registry to study the epidemiology of CDI using waiting time distribution and other pharmacoepidemiological methods. PATIENTS A total of 1285 patients with CDI were recorded in the observation period and given 9309 prescriptions for desmopressin in the nasal formulation, orodispersible tablet, or conventional tablet. RESULTS The period prevalence rate of CDI in Denmark over the 5-year period investigated was 23 CDI patients per 100 000 inhabitants, with a higher prevalence in children and older adults (>80 years of age). The 1-year period prevalence rate of CDI decreased in Denmark over the 5 years from approximately 10 to 7 CDI patients per 100 000 inhabitants. The yearly incidence rate of new cases of CDI was found to be 3 to 4 patients per 100 000. The incidence of (presumable) congenital CDI was found to be 2 infants per 100 000 infants. Half of the patients with CDI prescribed as oral treatment were provided dosing instructions to only administer the drug before bedtime, and one third of the CDI patients either had no specific instructions or were instructed to use the drug as needed. Hospital admissions due to severe hyponatremia occurred in 0.9% of patients over a 5-year period, predominantly in females with an incidence ratio of women to men of 1.8:1. CONCLUSION Half of the cases of CDI are acquired later in life. At least half of the patients with CDI are instructed to prevent nocturnal polyuria, but it is not clear whether their CDI remains uncontrolled during the daytime or, alternatively, whether they use desmopressin only as needed. Female patients with CDI had approximately twice the number of hospital admissions due to severe hyponatremia than male patients with CDI.

Management of nocturia: The role of antidiuretic pharmacotherapy

Strategies to manage nocturia include lifestyle modifications and treatment with alpha‐blockers, antimuscarinic therapies, and antidiuretics. The concept of achieving success should not be limited to reduction of nighttime voids; it should ideally include proof of improvement of conditions generally associated with nocturia, such as falls, quality of life, and overall health. Few studies have looked specifically at parameters other than nocturnal voids, such as sleep latency, first undisturbed sleep period (FUSP), and total sleep time, including their clinical relevance to patient well‐being. Lifestyle modifications, such as voiding before bedtime, limiting caffeine and alcohol, and adjusting medication timing, may be initially effective in mild cases of nocturia. Statistically significant reductions in voiding have been reported with antimuscarinic agents and alpha‐blockers as initial therapy, but these reductions generally are not clinically relevant. The antidiuretic therapy desmopressin acetate, a selective vasopressin receptor 2 agonist, is effective in adults with nocturia associated with nocturnal polyuria; however, hyponatremia can occur. The newest formulation—desmopressin orally disintegrating sublingual tablet (ODST)—has greater bioavailability; thus, lower doses can be used, potentially reducing hyponatremia risk. A phase 3 study demonstrated statistically significant reductions in nocturnal voids for desmopressin ODST 50 and 100 µg versus placebo (−1.18 and −1.43 vs. −0.86; P = 0.02 and P < 0.0001, respectively) in patients with nocturia. Treatment was well‐tolerated, and low‐dose desmopressin ODST was associated with statistically significant increases in duration of FUSP. Development of a validated composite endpoint may help clinicians identify and compare strategies for treating nocturia. Neurourol. Urodynam. 33:S19–S24, 2014.

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.

Nocturia Is Associated With Loss of Deep Sleep Independently From Sleep Apnea

Sleep apnea is a well-acknowledged reversible cause of nocturia, but little is known about how nocturia disrupts normal sleep architecture. We report here that, among patients with nocturia without sleep apnea, nocturnal voiding is related to deficits in slow wave (i.e., N3 or ‘‘deep’’) sleep across the entire night Patients (13 females; two males; mean [SD] age1⁄4 46 [9.9]) documented to have frequent nocturnal urination at least three times nightly for three consecutive nights as confirmed via a home voiding diary were studied polysomnographically in the sleep laboratory for a single night during baseline measurements for a randomized clinical trial. During the diary phase, all patients kept 24hr urine volumes, which documented nocturnal polyuria, defined as a nocturnal polyuria index of >33% over 24hr. When in the laboratory, mean (SD) recording duration was 496 (44.2) (range 429–560)min. Patients were audio monitored and allowed to void at will by signaling to the technologist whenever they felt the need to use the bathroom. The average number of voids per patient on the lab night was 2.4 (SD1⁄40.83; range 1–4). We quantified sleep stages for the entire lab night following standard procedures. Sleep apnea was not present in these patients (mean [SD] Apnea/Hypopnea Index1⁄4 0.3 [0.8] events per hour). Of the 15 patients, two had one void, six had two voids, six had three voids and one had four voids during the laboratory night. Comparisons between those patients with one or two voids versus those with three or four voids showed a trend for higher amounts of N3 sleep (expressed as a percentage of total sleep) in the former, relative to the latter (X [SD] for one/two voids1⁄422.6% [8.0] versus three/four voids1⁄4 13.4% [11.3], t1⁄4 1.84, P< 0.09) and significantly lower N1 sleep (9.1% [5.3] versus 16.5% [7.2], t1⁄4 2.30, P< 0.04) without differences in age between the voiding groups (t1⁄4 0.41, NS). These data indicated that nocturnal voiding had negative effects across the entire night of sleep. We also examined the time to first void, sometimes called the first uninterrupted sleep period, whichwas significantly longer in the group with one/two voids (150.4 [104.9]min) versus those with three/four voids (57.4 [34.1]min) (t1⁄42.37, P< 0.05). These data demonstrate that nocturnal voiding can adversely affect the occurrence of N3 sleep, often considered the most restorative stage of sleep. N3 sleep is typically subject to homeostatic control, such that when disrupted early in the night, the time of its greatest propensity, the brain typically compensates by shifting its occurrence to later in the night. Experimental evidence suggests, however, that such overnight compensation may not be complete. When voiding at night occurs frequently, our data imply that a redistribution of N3 across the entire night may not occur in nocturia. Long-term loss of N3 sleep as occurs in nocturia could have potentially deleterious impact on daytime alertness, health and wellbeing.