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.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

An exploratory pilot study with copeptin as a biomarker for individualizing treatment for nocturnal polyuria.

OBJECTIVE: The aim of the present study was to investigate the use of random copeptin concentrations as possible biomarkers for the differential diagnosis of nocturnal polyuria (NP). METHODS: In all, 111 patients with and without nocturia were enrolled in the study. Patients with a neurogenic bladder and/or those who had undergone bladder or urethral surgery were excluded from the study. All patients completed a 72-hour frequency-volume chart and a renal function profile. A random blood sample was obtained during the day for measurement of plasma copeptin concentrations, osmolality, and serum sodium and creatinine concentrations. The effect of the use of different definitions for NP was evaluated. RESULTS: The median age of the study participants was 61 years, and 48% were female. Copeptin was significantly correlated with urinary and plasma osmolality, as well as free water clearance (r=0.43, 0.56 and -0.38 respectively; P < .001 for all). Study participants were divided into 3 groups: controls (n = 51), those with NP (n = 41), and those with global polyuria (n = 19). Copeptin concentrations were significantly lower in subjects with global polyuria than in those with NP and the control group (2.96 vs 3.97 and 3.94 pM, respectively; P = .008 and .005). There was no significant difference in random daytime copeptin concentrations between the NP and control groups (P = .972). The results differed when other definitions for NP were used (e.g. NPi33 or NUP10). CONCLUSIONS: We could not confirm our hypothesis that patients with NP have lower copeptin concentrations, although random blood sampling is not ideal. Further research is required to determine the use of copeptin in NP, perhaps in the identification of the desmopressin response.

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.