D-arginine Vasopressin Research Articles

Nile blue as reporter dye in salt aggregation based-colorimetric aptasensors for peptide, small molecule and metal ion detection

Herein, we report a novel approach for the design of a colorimetric aptasensor, relying on a Dye Salt Aggregation-based Colorimetric Oligonucleotide assay (DYSACO assay). This method is based on the use of an intercalating agent, Nile Blue (NB), whose aggregation capacities (and thus modification of its absorption spectrum) are drastically amplified by adding salts to the working solution. The presence of an aptamer could protect NB from such aggregation process due to its intercalation into double-stranded DNA and/or interaction with nucleobases. In response to the addition of the specific ligand, the competition between NB and the target for binding to the aptamer occurs, resulting in an increase in the dye salt aggregation and then in the blue-to-blank color change of the solution. The proof-of-principle was demonstrated by employing the anti-l-tyrosinamide aptamer and the assay was successfully applied to the trace enantiomer detection, allowing the detection of an enantiomeric impurity down to approximately 2% in a non-racemic sample. Through a reversed mechanism based on the increased capture of NB by DNA upon analyte binding, the sensing platform was further demonstrated for the Hg(II) detection. Water samples of different origin were spiked with Hg(II) analyte at final range concentrations comprised between (0.5–15 μM). An excellent overall recovery of 122 ± 14%; 105 ± 14%; 99 ± 9%; was respectively obtained from river, tap and mineral water, suggesting that the sensor can be used under real sample conditions. The assay was also shown to work for sensing the ochratoxin A and d-arginine vasopressin compounds, revealing its simplicity and generalizability potentialities.

Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia.

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL−1) and some patients with moderate hemophilia (0.01–0.05 IU mL−1) administer clotting factor concentrates prophylactically. Desmopressin (d-amino d-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or d-amino d-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00936-5) contains supplementary material, which is available to authorized users.

A Novel Quantitative Method for Analyzing Desmopressin in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

Desmopressin (D-amino D-arginine vasopressin: dDAVP) is used for the treatment of patients with hemophilia A and Von Willebrand disease. Studies on the rationale of dosing are scarce and mainly focus on the underlying causes of the vast differences in desmopressin response among individuals. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of desmopressin in human plasma for identifying its pharmacokinetics and its therapeutic effect relationship in patients with bleeding disorder. The method entails solid-phase extraction with ion exchange for sample clean-up, followed by an LC-MS/MS run. The technique has been validated for analytical selectivity as well as specificity, process efficiency, linearity, accuracy, imprecision, and stability. This method showed good selectivity because no significant chromatographic matrix interferences were observed. The determination coefficient (R) of the calibration curves was ≥0.990. Analyte accuracy ranged from 89.2% to 111.8%, and the between- and within-run imprecision was less than 9.3% in a plasma concentration and range from 60 to 3200 pg/mL. Samples were stable during 3 freeze/thaw cycles with an additional 120 hours of storage at room temperature (21°C-24°C) and 96 hours in the autosampler (10°C). The total run time was approximately 5 minutes. The LC-MS/MS method presented enables quantification of desmopressin in human plasma, and it is sensitive, specific, efficient, accurate, and precise. This analytical technique is a valuable and useful tool to study the interpatient variability of pharmacokinetics.

Intranasal desmopressin reduces renal biopsy-related bleeding and serum sodium levels in patients with reduced renal function.

BackgroundThe use of desmopressin in preventing renal biopsy-related bleeding is not established and its effects on serum sodium levels are not well studied. The study aimed to compare the bleeding complication rates between the groups with and without desmopressin use prebiopsy and to observe the effect of desmopressin on postbiopsy serum sodium levels. MethodsIn this single-center, prospective and retrospective interventional study, from June 2018 onwards, patients with serum creatinine >132.6 μmol/L but not on dialysis and undergoing ultrasound-assisted needle-guided renal biopsy received 150 μg of desmopressin (D-amino D-arginine vasopressin (DDAVP)) (Group II). Data from patients from June 2017 to May 2018 were included in Group I in whom desmopressin was not used. Bleeding complications were monitored by clinical and ultrasound surveillance. Serum sodium levels were checked prior to and 24 h following desmopressin in Group II. ResultsA total of 194 patients were included in the study: 105 in Group I and 89 in Group II. Group II had lower overall minor bleeding complications and perinephric hematomas than Group I (15.7% versus 31.4%, 14% versus 27% and 7.8% versus 19% in Group II and Group I, respectively, with P < 0.05). Not using desmopressin and female sex were significant predictors for overall risk of bleeding on multivariate logistic regression. Serum sodium levels fell in 94% of patients in Group II. Lower prebiopsy serum sodium, higher estimated glomerular function rate and higher spot urine sodium values were associated with a greater decrease in serum sodium after desmopressin.ConclusionIntranasal desmopressin reduces bleeding complications during renal biopsies performed in patients with reduced renal function not requiring dialysis, albeit with a risk of developing hyponatremia.

Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey.

Desamino D-arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored. The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients. We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients. DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use. DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients.

Pig‐to‐baboon liver xenoperfusion utilizing GalTKO.hCD46 pigs and glycoprotein Ib blockade

Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7days, survival is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and by subsequent coagulopathy. Porcine von Willebrand's factor (VWF), a glycoprotein that adheres to activated platelets to initiate thrombus formation, has been shown to constitutively activate human platelets via their glycoprotein Ib (GPIb) receptors. Here, we report our pig-to-primate liver xenoperfusion model and evaluate whether targeting the GPIb-VWF axis prevents platelet sequestration. Twelve baboons underwent cross-circulation with the following extracorporeal livers: one allogeneic control with a baboon liver, 4 xenogeneic controls with a GalTKO.hCD46 pig liver, 3 GalTKO.hCD46 pig livers in recipients treated with αGPIb antibody during perfusion, and 4 GalTKO.hCD46 pig livers pre-treated with D-arginine vasopressin (DDAVP) in recipients treated with αGPIb antibody during perfusion. All perfused livers appeared grossly and macroscopically normal and produced bile. Xenograft liver perfusion experiments treated with αGPIb antibody may show less platelet sequestration during the initial 2h of perfusion. Portal venous resistance remained constant in all perfusion experiments. Platelet activation studies demonstrated platelet activation in all xenoperfusions, but not in the allogeneic perfusion. These observations suggest that primate platelet sequestration by porcine liver and the associated thrombocytopenia are multifactorial and perhaps partially mediated by a constitutive interaction between porcine VWF and the primate GPIb receptor. Control of platelet sequestration and consumptive coagulopathy in liver xenotransplantation will likely require a multifaceted approach in our clinically relevant perfusion model.

Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice

Saposin D-deficient (Sap-D(-/-)) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino d-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D(-/-) mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10∼12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-mo-long water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D(-/-) mice.

MP-06.02: Oral desmopressin in the treatment of nocturia in an aging population

Nocturia, defined as excessive urinating at night, is caused by different factors. If pathological causes such as infections, obstructions, etc. are excluded, an important cause in an aging population could be an insufficient level of ADH (D-arginine Vasopressin = DAVP) at night. The primary endpoint of this research was the proportion of patients with 50% or more reduction in nocturnal urine production resp. nocturnal voiding and elevation of urine osmolarity. The secondary endpoint is to prolong sleep duration by reducing nocturnal urine production.

Stiletto stabbing: Penetrating injury to the hypothalamus with hyperacute diabetes insipidus

Diabetes insipidus (DI) is a well documented complication observed after traumatic head injuries. We report a case of hyperacute onset DI in a 19-year-old male who sustained a hypothalamic-pituitary injury when he was stabbed in the head with a 30-cm long thin-bladed knife. At CT, our patient showed significant hemorrhagic contusions of the lower hypothalamus. He developed polydipsia, polyuria, and mild hypernatremia in the Emergency Department. Diagnostic digital subtraction angiography showed a hypervascular congestive pituitary gland with prominent draining veins. On the third day his hypernatremia became severe (183 mEq/L). He was managed with parenteral fluids and a regimen of intranasal DDAVP (1-desamino 8- d-arginine vasopressin), leading to improved plasmatic sodium levels, urine output, and urinary specific gravity. In patients presenting with hyperacute posttraumatic DI, emergency room physicians and neurosurgeons should rule out direct injury to the hypothalamus and/or the posterior lobe of the pituitary, and initiate early pharmacological treatment.

Hypoparathyroidism: Is It Time for Replacement Therapy?

Endocrine diseases caused by hormone deficiencies are commonly treated by replacement of the deficient hormones. For example, Addison’s disease is treated with oral glucocorticoids, autoimmune hypothyroidism with oral thyroxine, and premature ovarian failure with oral estrogen and progesterone. The availability of orally deliverable drugs makes this straightforward. However, when the deficient hormone in question is a protein, oral treatment presents problems because proteins are generally degraded by proteolytic digestive enzymes when delivered orally. This obstacle commonly is circumvented by sc injection of the peptide hormone in question (i.e. GH, insulin, 1-desamino--D-arginine vasopressin). So what is different abouthypoparathyroidism,whichalsoresultsfromdeficiencyof PTH, a protein hormone? Why is this disorder not routinely treated by replacement of PTH? This is the subject of a series of reportsbyWineretal.(1–4),themostrecentofwhichisincluded in this month’s Journal (4). Hypoparathyroidism results from deficiency of PTH (5–9). This may be a congenital abnormality resulting in failure of the parathyroid glands to form, as exemplified by the DiGeorge syndrome, or may result from inactivating mutations in the parathyroid-specific transcription factor, glial-cell missing B. It may result from mutations in the PTH gene itself. A functional, congenital form of hypoparathyroidism results fromactivatingmutationsinthecalcium-sensingreceptorthat

Perioperative desmopressin prolongs survival in surgically treated bitches with mammary gland tumours: A pilot study

Desmopressin (1-deamino-8- d-arginine vasopressin, also known as DDAVP) is a safe haemostatic compound capable of inhibiting lymph node and lung metastasis in a mouse model of mammary tumour manipulation and surgical excision. The aim of this study was to test the efficacy and safety of perioperative DDAVP (1 μg/kg) in surgically treated bitches with mammary gland tumours (MGT). Twenty-one, otherwise healthy, intact bitches, with malignant MGT stage III or IV were randomly allocated to DDAVP ( n = 11) or placebo ( n = 10) groups. En bloc mastectomy of the affected gland/s was performed. DDAVP had a significant beneficial effect on disease-free period ( P < 0.01) and overall survival time ( P < 0.05). No side effects were seen in any of the cases. Whatever the mechanism of action, it seems that DDAVP may have a novel use in cancer surgery to minimise spread or survival of residual malignant cells. Additional, large scale controlled trials are required to fully evaluate this adjuvant pharmacological protocol.

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino- d-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.

Pax Transactivation-Domain Interacting Protein Is Required for Urine Concentration and Osmotolerance in Collecting Duct Epithelia

Pax transactivation-domain interacting protein (PTIP) is a widely expressed nuclear protein that is essential for early embryonic development. PTIP was first identified on the basis of its interactions with the developmental regulator Pax2 but can also bind to other nuclear transcription factors. The Pax2 protein is essential for development of the renal epithelia and for regulating the response of mature collecting ducts to hyperosmotic stress. For determination of whether PTIP also functions in more differentiated cell types, the Cre-LoxP system was used to delete the ptip gene in the renal collecting ducts using Ksp-Cre driver mice. Collecting duct-specific ptip knockout mice were viable with little discernible phenotype under normal physiologic conditions. However, collecting duct-specific ptip mutants were unable to concentrate urine after the treatment of desamino-cis, D-arginine vasopressin, an antidiuretic hormone. Furthermore, aquaporin-2 (AQP2) expression in the inner medulla of the ptip knockout mice was decreased approximately 10-fold compared with that of wild-type littermates. Expression level of tonicity responsive enhancer binding protein, a transcription factor of AQP2, is not altered in the mutant mice, but its nuclear localization in the inner medulla is unresponsive after treatment with vasopressin agonists. This was due, at least in part, to decreased expression of the arginine vasopressin receptor 2 in ptip mutants. Furthermore, ptip null inner medullary collecting duct cells were sensitive to hyperosmolality in vitro. Thus, ptip is required for the urine concentration mechanism by modulating arginine vasopressin receptor 2 and AQP2 expression in the inner medulla. The data suggest an essential role for ptip in regulating urine concentration and in controlling survival of collecting duct epithelial cells in high osmolality.

Effect of 1-deamino 8- d-arginine vasopressin spray on nasal cytology and mucociliary clearance in patients with nocturnal enuresis

To determine any possible adverse effect of 1-deamino 8-D-arginine vasopressin (DDAVP) spray on nasal cytology and mucociliary clearance in patients with nocturnal enuresis. Twenty-two children aged 6-16 enrolled in the study. Epithelial surface cells samples were taken from the nasal mucosa and mucociliary clearance time was calculated before and 1 and 6 months after administration of DDAVP spray. No qualitative changes in the epithelial surface cells and mucociliary clearance time were observed at 1 and 6 months after therapy. Based on the findings of the present study, DDAVP spray can be used for 6 months in children without apparent risk of damage to the epithelial surface cells and mucociliary clearance time.

Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity

In antidiuresis, vasopressin (AVP) occupation of V2 receptors in renal collecting ducts activates adenylyl cyclase, resulting in increased intracellular cAMP levels, which activates protein kinase A (PKA). PKA phosphorylates both the cAMP responsive element binding protein, which induces aquaporin-2 (AQP2) transcription, and AQP2, which then is translocated to the apical membrane, allowing urine concentration. Lithium treatment often causes nephrogenic diabetes insipidus (NDI), which coincides with decreased AQP2 expression and which generally is ascribed to reduced adenylyl cyclase activity. However, the underlying mechanism by which lithium causes NDI is poorly understood. This study demonstrated that the mouse cortical collecting duct mpkCCD(c14) cells are a good model; the deamino-8 D-arginine vasopressin (dDAVP)-induced endogenous AQP2 expression and plasma membrane localization was time-dependently reduced by treatment with clinically relevant lithium concentrations. Lithium did not affect AQP2 stability but decreased its mRNA levels. Surprising, the effect of lithium was cAMP independent; it did not alter AVP-stimulated cAMP production or PKA-dependent phosphorylation of AQP2 or cAMP responsive element binding protein. In vivo, kidney tissue of rats with lithium-induced NDI indeed generated less dDAVP-induced cAMP than that of controls, but this could be due to elevated blood AVP levels in rats with lithium-induced NDI. Indeed, Brattleboro rats, which lack endogenous AVP, with clamped blood dDAVP levels, showed no difference in dDAVP-generated cAMP generation between kidneys of rats with lithium-induced NDI and control rats. In conclusion, the first proper cell model to study lithium-induced NDI was developed, and it was demonstrated that the lithium-induced downregulation of AQP2 and development of NDI occur independent of adenylyl cyclase activity in vitro and in vivo.

Increased aquaporin-1 expression in choroid plexus epithelium after systemic hyponatremia

The expression of aquaporin-1 (AQP1) protein, a water channel, in the choroid plexus epithelium was examined in the rat to determine the role of AQP1 in the pathophysiology of systemic hyponatremia. Systemic hyponatremia was produced by coadministration of 30 ml hypotonic dextrose solution (140 mM) intraperitoneally and 3 μg 1-deamino-8- d-arginine vasopressin (dDAVP) subcutaneously. This hydration protocol produced severe systemic hyponatremia: 2 h after drug administration, normonatremic serum osmolarity and Na + concentration (296 ± 5 mOsm/L and 140 ± 5 mM) were reduced to 252 ± 5 mOsm/L and 117 ± 2 mM, respectively. AQP1 expression in the third ventricle choroid plexus epithelium was determined by using immunohistochemistry and quantitative immunoblot analysis. After 2 h of systemic hyponatremia, AQP1 expression was significantly increased by 28.2 ± 2.7% ( n = 6, P < 0.05), whereas it was attenuated to 15.7 ± 2.2% ( n = 6, P < 0.05) after 6 h of systemic hyponatremia. In addition, TUNEL staining revealed apoptotic granule cells in the dentate gyrus (DG) adjacent to the third ventricle with a peak measured 2 h after the start of the systemic hyponatremia protocol, while virtually no apoptotic granule cells left 6 h after the start of the hyponatremic treatment. These findings suggest that AQP1-mediated excessive water influx into the brain through the blood-cerebrospinal fluid barrier during systemic hyponatremia may elevate the intracranial pressure and result in the apoptotic brain cell death. Thus, AQP1 in the choroid plexus may play an important role in the pathogenesis of systemic hyponatremia.

N-Trimethyl chitosan chloride as absorption enhancer in oral peptide drug delivery. Development and characterization of minitablet and granule formulations

In this study, minitablet and granule formulations were developed as solid oral dosage forms for the delivery of peptide drugs with the absorption enhancer N-trimethyl chitosan chloride (TMC). Minitablets were deemed suitable as a dosage form due to their ability, as components of multiple unit dosage forms (MUDFs), to disperse from each other, before disintegration, effectively increasing the area in which the polymer can assert its absorption-enhancing effect. The polymer should be released from the dosage forms prior to the release of the peptide, which was, together with achieving maximum release of both ingredients, the main focus of this study. Desmopressin (1-(3-mercaptopropionic acid)-8- d-arginine vasopressin monoacetate (DDAVP) was used as model peptide drug. The optimized minitablet formulation consisted of two types of granules, namely DDAVP and TMC granules. DDAVP granules, containing tetraglycerol pentastearate (TGPS), were specifically aimed at delaying the release of the peptide from the dosage form. Burst release of TMC was attempted with TMC granules. Both these granule types were included in the granule formulation. Release profiles for both the optimized minitablet formulation as well as the granule formulation showed that the release of DDAVP was effectively delayed from the formulation compared to the formulation where no attempt at delaying the release was made. In comparison, more TMC was released, and at a faster rate, from the granule formulation than the optimized minitablet formulations. Both the optimized minitablet formulation and the granule formulation show suitable release profiles for the delivery of peptide drugs with TMC as absorption enhancer in solid oral dosage forms.

Adenotonsillectomy in children with von Willebrand's disease: how and when. A case report with review of the literature

The presence of coagulation pathology in children who are candidates for adenotonsillectomy (AT) is a challenge to the otolaryngologist. von Willebrand's disease (vWD) is the most common hereditary coagulopathy and is due to a quantitative and/or qualitative deficiency of von Willebrand's factor (vWF). In recent years, the administration of 1-deamino-8- d-arginine vasopressin (DDAVP) has been recommended as coadjuvant therapy for surgical procedure. This synthetic hormone promotes the release of vWF and factor VIII from endothelial cells. In this report, the authors describe the history of a child with vWD undergoing successful AT after administration of DDAVP. Furthermore, a review of the literature with particular emphasis on the use of DDAVP is made.

The nasal mucosa of children with nocturnal enuresis before and after treatment with 1-deamino 8- d-arginine vasopressin spray

Intranasal administration of 1-deamino 8- d-arginine vasopressin (DDVAP) used for treatment of nocturnal enuresis (NE), might be expected to have various effects on the nasal mucosa, e.g. altering the clearance by the mucociliary apparatus. We evaluated two samples (brushes) of epithelial surface cells from the nasal mucosa, one from each nostril, of 18 children (ten males and eight females) with a mean age of 7.7 years (range: 5–13 years) who were affected by primary NE. Samples were taken before and 1 and 6 months after administration of DDVAP spray. No qualitative changes in the epithelial surface cells from nasal mucosa were recognized and only non-statistically significant increases in percentages of goblet, ciliated, basal and unciliated cells at 1 and 6 months after therapy were observed. Thus, it appears that DDVAP spray can be used for at least 6 months in children without apparent risk of damage to the epithelial surface cells from the nasal mucosa.

Evidence that atypical vasopressin V 2 receptor in inner medulla of kidney is V 1B receptor

Vasopressin V 2 receptors at high-density and V 1B receptors are candidates for the V 2-like receptor, which evokes an increase in [Ca 2+] i when stimulated by the vasopressin V 2 receptor agonist 1-desamino-8- d-arginine vasopressin (dDAVP) in kidney inner medullary collecting duct. We compared the pharmacological characteristics of vasopressin V 2 and V 1B receptors in Chinese hamster ovary (CHO) cells to those of vasopressin V 2-like receptors in rat inner medullary collecting duct cells. The vasopressin V 1B receptor-selective agonist [deamino-Cys 1, d-3-(Pyridyl)-Ala 2, Arg 8]vasopressin (D3PVP) did not stimulate the [Ca 2+] i increase in high-density vasopressin V 2 receptor-expressing CHO cells, but did in inner medullary collecting duct cells. Moreover, the vasopressin V 1A/V 2 receptor dual antagonist 4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5- d][1] benzazepin-6-yl)carbonyl] 2-phenylbenzanilide (YM087), which has no effect on vasopressin V 1B receptors, did not block the [Ca 2+] i increase in inner medullary collecting duct cells when stimulated by dDAVP and D3PVP. On reverse transcription-polymerase chain reaction (RT-PCR) analysis of kidney, vasopressin V 1B receptor mRNA was detected only in the medulla. We propose that the true nature of the vasopressin V 2-like receptor in the inner medullary collecting duct is the vasopressin V 1B receptor, rather than the vasopressin V 2 receptor expressed at high-density.