scholarly journals Effectiveness of Vasopressin V2 Receptor Antagonists OPC-31260 and OPC-41061 on Polycystic Kidney Disease Development in the PCK Rat

2005 ◽  
Vol 16 (4) ◽  
pp. 846-851 ◽  
Author(s):  
Xiaofang Wang ◽  
Vincent Gattone ◽  
Peter C. Harris ◽  
Vicente E. Torres
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Disease Development ◽  
Polycystic Kidney ◽  
Receptor Antagonists ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor

TOLVAPTAN USE IN SEVERE NEONATAL AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): THE PHARMACEUTICAL CHALLENGE

2016 ◽  
Vol 101 (9) ◽  
pp. e2.58-e2 ◽  
Author(s):  
Kazeem Olalekan ◽  
Andy Fox ◽  
Rodney Gilbert
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Hospital Pharmacist ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor ◽  
Paediatric Formulation

BackgroundUnlicensed medications are used all the time in the management of diseases in childhood. Tolvaptan (Jinarc®) is a vasopressin V2-receptor antagonist licensed for use to slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1 to 3 with evidence of rapidly progressing disease. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its messenger cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduce the cyst burden and protect kidney function1 A Phase 3 trial showed that Tolvaptan, as compared with placebo, slowed down the increase in total kidney volume and decline in kidney function in adults (average 39 yrs) with ADPKD over a 3-year period.2 ADPKD is the most common form of polycystic kidney disease (PKD) typically late in onset and results from mutation of either of two genes: PKD1 and PKD2. Autosomal recessive polycystic kidney (ARPKD), the other form of PKD, is 20 times less common, presents primarily in infancy and childhood, is typically more severe, and commonly associated with hypertension. ARPKD results from mutation of PKHD1. In spite of these differences, there is growing evidence to suggest that ADPKD and ARPKD are more related than previously suspected.3 Bilineal inheritance of PKD1 abnormalities has been reported to cause extremely severe disease resembling ARPKD.4 The use of Tolvaptan in the management of PKD in children is therefore expected to become more important.AimTo describe the first known UK use of Tolvaptan in a neonate with severe ADPKD and the role of the hospital pharmacist in facilitating the use.MethodThe role descriptor of hospital pharmacists produced by the World Health Organisation (WHO) was adapted and used to map the pharmaceutical challenges of using Tolvaptan in this child. The descriptor include: (i) Promotion of rational prescribing of drugs, (ii) Use of specialist pharmacists networks to gain greater expertise; (iii) Monitor compliance and therapeutic response and report adverse drug reactions; (iv) ensure supply of high quality products; (v) partake in planning and implementation of clinical trials.ResultsThe use of Tolvaptan for indication other than hyponatraemia and other endocrine uses are not routinely commissioned by NHS England. In view of the exceptionality of this case – a severe neonatal form of ADPKD with estimated prevalence of the order of 1 in tens of millions, an Individual Funding Request (IFR) application was made and was approved. The application was supported by financial information provided by the hospital pharmacist who facilitated the application process. Using available information and formulation knowledge, a suspension was eventually recommended and was well tolerated. This resulted in approximately 85% reduction in the cost of treatment over six months. Tolvaptan produced the expected aquaresis and blood pressure reduction. Initial dose of 0.1 mg/kg/day was used and increased according to weight and clinical response. Initial monitoring parameters, which included 4 hourly blood pressure, urine and electrolytes and hepatic function, were recommended. Electrolyte supplements were adjusted accordingly. At 2-month review point, there was no oedema of leg and face but the kidneys were still enlarged. The long term effect on cyst burden and kidney function is being evaluated and will feed into the IFR process.ConclusionThe use of unlicensed medications in children poses a number of pharmaceutical challenges and can be managed through a multidisciplinary approach to treatment intervention. It also re-enforce the paediatric formulation challenge to pharmaceutical companies in which formulation needs are prioritised and existing data are better used to facilitate paediatric formulation development.

scholarly journals Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

2019 ◽  
Vol 49 (6) ◽  
pp. 487-493 ◽  
Author(s):  
Xiaofang Wang ◽  
Megan M. Constans ◽  
Fouad T. Chebib ◽  
Vicente E. Torres ◽  
Lorenzo Pellegrini
Keyword(s):  
Kidney Disease ◽  
Serum Creatinine ◽  
Polycystic Kidney Disease ◽  
Urine Output ◽  
Low Dose ◽  
High Dose ◽  
Polycystic Kidney ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor ◽  
Camp Levels

Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

scholarly journals Polycystic Kidney Disease and the Vasopressin Pathway

2017 ◽  
Vol 70 (Suppl. 1) ◽  
pp. 43-50 ◽  
Author(s):  
Maatje D.A. van Gastel ◽  
Vicente E. Torres
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Polycystic Kidney Disease ◽  
Experimental Studies ◽  
Lifestyle Changes ◽  
Current Evidence ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor

Vasopressin, also known as arginine vasopressin or antidiuretic hormone, plays a pivotal role in maintaining body homeostasis. Increased vasopressin concentrations, measured by its surrogate copeptin, have been associated with disease severity as well as disease progression in polycystic kidney disease (PKD), and in experimental studies vasopressin has been shown to directly regulate cyst growth. Blocking vasopressin effects on the kidney via the vasopressin V2-receptor and lower circulating vasopressin concentration are potential treatment opportunities that have been the subject of study in PKD in recent years. Treatment with vasopressin V2-receptor antagonist tolvaptan has been shown to inhibit disease progression in experimental studies, as well as in a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD, lowering total kidney volume growth from 5.5 to 2.8%, and the slope of the reciprocal of the serum creatinine level from -3.81 to -2.61 mg per mL-1/year. Alternatively, lowering circulating vasopressin could delay disease progression. Vasopressin is secreted in response to an increased plasma osmolality, which in turn is caused by a low fluid or high osmolar intake. Other lifestyle factors, like smoking, increase vasopressin concentration. Here, we provide a comprehensive review of the physiology as well as pathophysiology of vasopressin in PKD, the promising effects of tolvaptan treatment, and potential synergistic or additive treatments in combination with tolvaptan. In this study, we also review current evidence regarding the effect of influencing disease progression in PKD by lifestyle changes, especially by fluid intake.

scholarly journals Treatment of autosomal recessive and autosomal dominant polycystic kidney disease

2019 ◽  
Vol 64 (2) ◽  
pp. 22-29
Author(s):  
E. F. Andreeva ◽  
N. D. Savenkova
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Mtor Inhibitors ◽  
Somatostatin Analogues ◽  
Polycystic Kidney ◽  
V2 Receptor ◽  
Autosomal Dominant Polycystic Kidney

The article reflects the genetic variants of polycystic kidney disease, describes the modern strategy for the treatment of polycystic kidney disease in children and adults. The authors present the results of clinical trials of vasopressin V2 receptor antagonists (tolvaptan, liksivaptan), a multi-kinase inhibitor (tezevatinib), somatostatin analogues (lankreotide, octreotide), statins (pravastatin), mTOR inhibitors (everolimus, sirolimus), metformin in patients with autosomal recessive and autosomal polycystic kidney disease. The authors discuss the factors determining the prognosis and outcome of these diseases.

scholarly journals Effects of hydration in rats and mice with polycystic kidney disease

2015 ◽  
Vol 308 (3) ◽  
pp. F261-F266 ◽  
Author(s):  
Katharina Hopp ◽  
Xiaofang Wang ◽  
Hong Ye ◽  
María V. Irazabal ◽  
Peter C. Harris ◽  
...  
Keyword(s):  
Drinking Water ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Water Intake ◽  
High Water ◽  
Polycystic Kidney ◽  
Vasopressin Release ◽  
V2 Receptor ◽  
Camp Levels

Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C ( Pkd1RC/RC) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-d-arginine vasopressin, as previously shown for Pkd1RC/RC mice and confirmed here in Pkd2WS25/− mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models.

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