Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders.

The vasopressin type-2 antagonist tolvaptan (TLV) has clinical advantages including amelioration of congestion and normalization of hyponatremia in patients with decompensated heart failure (HF). However, there have been no studies on the cost-effectiveness of TLV therapy. We enrolled 60 consecutive hospitalized patients with stage D HF who received TLV [TLV (+) group], and 60 propensity score-matched HF patients without TLV treatment [TLV (-) group]. We excluded 54 patients who died or received cardiac replacement therapy within 1 year, and finally enrolled 32 patients who received TLV and 34 who did not, who were followed for > 1 year. Among 45 aquaporin-defined responders, whose urine aquaporin-2 relative to plasma arginine vasopressin level was > 1.4 × 10(3) L/g Cre, the TLV (+) group required significantly lower total medical expenses and shorter lengths of stay (LOS) compared with the TLV (-) group [11.2 (1.233.3) versus 31.2 (2.2-71.4) × 10(5) JPY/year, P < 0.001; 30 (0-304) versus 70 (20-221) days, P = 0.030]. In contrast, among the remaining 21 aquaporin-defined non-responders, medical expenses and LOS were comparable irrespective of TLV administration (P = 0.087 and P = 0.407). In conclusion, TLV therapy may reduce total medical expenses in aquaporin-defined responders with stage D HF.

CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia.

BACKGROUND: Assessment of volume status is essential to best manage hyponatremic patients but is not always accurate in clinical practice. The aim of this study was to evaluate the reliability of C-terminal portion of pro-arginine-vasopressin (CT-pro-AVP), a surrogate biomarker of vasopressin release, in assessing intravascular volume (IVV) depletion in hypoosmolar hyponatremic patients. METHODS: Plasma CT-pro-AVP and urea-to-creatinine ratio (Ur/Cr) were performed in 131 hospitalized patients presenting chronic severe hypoosmolar hyponatremia. At hospital discharge, their IVV was evaluated regardless of CT-pro-AVP concentrations. All patients were then classified as decreased or as normal/expanded IVV group. RESULTS: Plasma CT-pro-AVP levels were higher in patients with decreased IVV (34.6 vs. 11.3 pmol/L, p<0.001) and exhibited a reliable performance for assessment of decreased IVV (ROC AUC at 0.717 [95% CI 0.629-0.805]). The combination of CT-pro-AVP and Ur/Cr resulted in an improved ROC AUC up to 0.787 (95% CI 0.709-0.866). CONCLUSIONS: Our findings support the hypothesis that CT-pro-AVP plasma level may reflect IVV and would be a tool for its assessment. This performance has been magnified by its combination with Ur/Cr. A dual-marker strategy may help clinicians to optimize the management of severe hyponatremia especially in case of confusing clinical presentations.

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

Validation of a commercially available enzyme immunoassay for measurement of plasma antidiuretic hormone concentration in healthy dogs and assessment of plasma antidiuretic hormone concentration in dogs with congestive heart failure.

OBJECTIVE: To validate the use of a human enzyme immunoassay (EIA) kit for measurement of plasma antidiuretic hormone (ADH) concentration in dogs and evaluate plasma ADH concentrations in dogs with congestive heart failure (CHF) attributable to acquired cardiac disease, compared with findings in healthy dogs. ANIMALS: 6 healthy dogs and 12 dogs with CHF as a result of chronic degenerative valve disease or dilated cardiomyopathy. PROCEDURES: Plasma samples from the 6 healthy dogs were pooled and used to validate the EIA kit for measurement of plasma ADH concentration in dogs by assessing intra-assay precision, dilutional linearity, and spiking recovery. Following validation, plasma ADH concentrations were measured in the 6 healthy dogs and in the 12 dogs with CHF for comparison. RESULTS: The EIA kit measured ADH concentrations in canine plasma samples with acceptable intra-assay precision, dilutional linearity, and spiking recovery. The intra-assay coefficient of variation was 11%. By use of this assay, the median plasma concentration of ADH in dogs with CHF was 6.15 pg/mL (SD, 3.2 pg/mL; range, 4.18 to 15.47 pg/mL), which was significantly higher than the median concentration in healthy dogs (3.67 pg/mL [SD, 0.93 pg/mL; range, 3.49 to 5.45 pg/mL]). CONCLUSIONS AND CLINICAL RELEVANCE: Plasma ADH concentrations in dogs can be measured with the tested EIA kit. Plasma ADH concentrations were higher in dogs with CHF induced by acquired cardiac disease than in healthy dogs. This observation provides a basis for future studies evaluating circulating ADH concentrations in dogs with developing heart failure.

Vasopressinergic network abnormalities potentiate conditioned anxious state of rats subjected to maternal hyperthyroidism.

We have previously reported that a mild maternal hyperthyroidism in rats impairs stress coping of adult offspring. To assess anxiogenesis in this rat model of stress over-reactivity, we used two behavioural tests for unconditional and conditional anxious states: elevated plus maze test (EPM) and Vogel conflict test (VCT). In the latter one, arginine vasopressin (AVP) release was enhanced due to osmotic stress. With the EPM test no differences were observed between maternal hyperthyroid rats (MH) and controls. However, with the VCT, the MH showed increased anxiety-like behaviour. This behavioural difference was abolished by diazepam. Plasma AVP concentration curve as a function of water deprivation (WD) time showed a marked increase, reaching its maximal levels within half the time of controls and another significant difference after VCT. A general increase in Fos expression in hypothalamic supraoptic and paraventricular nuclei (PVN) was observed during WD and after VCT. There was also a significant increase of AVP immunoreactivity in anterior hypothalamic area. A large number of Herring bodies were observed in the AVP containing fibres of MH hypothalamic-neurohypophysial system. Numerous reciprocal synaptic connections between AVP and corticotropin releasing factor containing neurons in MH ventromedial PVN were observed by electron microscopy. These results suggest that a mild maternal hyperthyroidism could induce an aberrant organization in offspring's hypothalamic stress related regions which could mediate the enhanced anxiety seen in this animal model.

Assessment of autonomic dysfunction of multiple system atrophy with laryngeal abductor paralysis as an early manifestation.

Laryngeal abductor palsy (LAP) is common in the advanced stages of multiple system atrophy (MSA). However, occurrence of LAP in the early stages might make a diagnosis of MSA difficult. To search for a clue to diagnosis of MSA with LAP as an early manifestation, we assessed the clinical features of autonomic dysfunction and the central cardiovascular control circuits in two MSA patients who had LAP as a cardinal symptom in the early stages. Development of autonomic dysfunction was preceded or followed by LAP. The autonomic symptom occurring predominantly in the earliest stages was urinary disturbance rather than orthostatic hypotension. Although screening cardiovascular autonomic function tests did not conclusively indicate a diagnosis of MSA, vasopressin release in response to head-up tilt and growth hormone response to clonidine administration demonstrated inappropriate responses, suggesting that the noradrenergic neurons of the caudal ventrolateral medulla were impaired. Diagnosis of atypical MSA with LAP in the early stages might be accelerated by a detailed investigation focused on urinary symptoms and neuroendocrine approaches.

Bioavailability assessment of arginine-vasopressin (AVP) using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

A novel method of assessing the extent of oral bioavailability of arginine-vasopressin (AVP) from pharmacological data was presented. After intravascular administration (i.v. bolus or short-term infusion) of AVP to rats, the relationship between blood concentrations and its effect on both mean arterial pressure (hemodynamic effect) and urinary sodium concentration (anti-diuretic effect) was described on the basis of an integrated pharmacokinetic-pharmacodynamic (PK-PD) model. A direct model was used for the hemodynamic response, while an indirect response model, rather than a hypothetical link model was used for the anti-diuretic response. A sigmoid Emax model was applied to describe the drug-receptor interaction. Pharmacological responses after intravascular administration of AVP were reasonably described by the PK-PD model. However, PD parameters estimated by the PK-PD analysis suggested that apparent receptor affinity rather than efficacy in i.v. bolus study was significantly higher than that in the short-term infusion study. This fact indicated that PK-PD relationship was influenced by the intravascular input rate of AVP. We then investigated the relationship between plasma concentration and amount of AVP bound to the V2 receptors in the kidney. The result indicated that the amount of AVP bound to the receptors after i.v. bolus injection was always greater than that after short-term infusion. Since the PK-PD relationship after oral administration was almost identical with that after short-term infusion, the PK-PD model obtained in the short-term infusion study was used to assess the extent of oral bioavailability (EBAPp.o.). The EBAp.o. values, estimated from pharmacological effects (hemodynamic effect and anti-diuretic effect) after oral administration of 5 microg/kg of AVP were 0.68% to 0.93% and were almost identical with the actual EBAPp.o. value (0.81%). From these results, we concluded that oral bioavailability of AVP was reasonably predicted by the PK-PD model, provided that appropriate pharmacological effects and appropriate intravascular dosing rate as a reference formulation are available. The method may be an alternative to methods based on plasma concentrations, when drug concentration cannot be measured and when appropriate pharmacological data are available.

Noninvasive assessment of spontaneous baroreflex sensitivity in patients with liver cirrhosis.

AIMS/BACKGROUND: An impairment of baroreceptor sensitivity has been found in liver cirrhosis. Noninvasive and spontaneous estimates of baroreflex sensitivity are obtained from beat-to-beat blood pressure and heart rate recordings by means of cross-spectrum analysis and calculation of alpha-index (as a measure of baroreflex gain). The aim of the present study was to investigate the function of the spontaneous baroreflex sensitivity related to clinical Child score in liver cirrhosis. METHODS: The alpha-index was evaluated in 40 cirrhotic patients (18 with and 22 without ascites) and 17 healthy subjects by analysing finger arterial pressure recorded noninvasively with the Portapres device. RESULTS: Baroreflex sensitivity was significantly lower in cirrhotic patients with and without ascites compared with healthy subjects (p<0.01). Furthermore, in patients with ascites the baroreflex gain was significantly related to plasma sodium (p<0.01). A significant inverse relationship was present between baroreflex gain and grade of Child score and the severity of ascites (p<0.01). There were no significant relationships between hormonal parameters (catecholamines, renin, aldosterone, arginine-vasopressin, atrial natriuretic peptide and nitric oxide) and baroreflex gain. No significant differences were found between healthy subjects and cirrhotic patients with respect to systolic and diastolic blood pressure total variability in a supine position, whilst it was lower in cirrhotic patients with ascites in a tilted position (p<0.05). CONCLUSION: Our findings showed that baroreflex sensitivity was significantly impaired in cirrhotic patients when compared with healthy subjects. In addition, there was a significant trend toward lower baroreflex sensitivity values with the grade score of Child class (p<0.01). Spectral analysis of the alpha-index provides viable alternatives to the pharmacological approach for estimation of baroreflex sensitivity and may represent a prognostic tool to identify cirrhotic patients at increased risk of adverse events.

Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure.

Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL-6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 micrograms/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 h after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-microgram/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-microgram/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 h. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 micrograms/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 micrograms/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.

[Clinical assessment of posterior pituitary function by direct measurement of plasma vasopressin levels during hypertonic saline infusion].

Clinical usefulness of a radioimmunoassay of plasma arginine vasopressin concentration (AVP) during hypertonic saline infusion for the assessment of posterior pituitary function was studied in comparison with the conventional water deprivation test. Infusion of 5% saline at a rate of 0.05 ml/kg/min for 120 min in 15 normal subjects induced an elevation of plasma osmolality (Posm) from 290.3 +/- 0.7 to 307.5 +/- 2.1 mOsm/kg with a resultant increase in AVP from 2.4 +/- 0.4 to 9.9 +/- 2.2 pg/ml. During the infusion, a highly significant correlation between AVP and Posm was observed with a regression line expressed as AVP = 0.40 (Posm - 283.0). In 22 polyuric patients, on the other hand, the infusion induced a marked elevation of Posm from 302.6 +/- 2.5 to 321.3 +/- 2.9 mOsm/kg, but caused a slight (less than 5.8 pg/ml) or no increase in AVP from the basal levels (0.5 +/- 0.1 pg/ml). A conventional water deprivation test was carried out in ten patients with neurogenic diabetes insipidus, including one who had coincidental nephrogenic diabetes insipidus. As would be expected, urine osmolality (Uosm) did not rise beyond Posm in seven of them. However, two of three other patients, who had a complete lack of AVP response to the hypertonic saline, were able to concentrate their urine with a maximal Uosm/Posm of 1.3 and 1.1 respectively. The concurrent decrease in creatinine clearance to 49 and 57% of the initial values, respectively, indicated that a marked reduction in glomerular filtration rate due to severe dehydration was responsible for the unexpected concentration of urine in the patients with totally impaired AVP secretion. Based on these results, we conclude that the direct measurement of AVP during hypertonic saline infusion is an essential procedure for the accurate evaluation of posterior pituitary function.

Assessment of hormonal disorders of water metabolism.

Clinical disorders of water regulation are relatively common and occur with severity ranging from profound and easily recognizable disturbance of body water balance to mild and often clinically inapparent. The development of sensitive and specific radioimmunoassay procedures capable of quantitating the level of AVP in plasma and urine has allowed elucidation of the pathophysiology of many of the disorders whether due to deficiency of ADH secretion and action or to excessive or persistent hormone release. In turn, the understanding of the factors regulating ADH release and action has led to establishment and validation of a variety of procedures that by indirect means allow estimation of extent of hormone action. These procedures based on physiologic influences that stimulate or inhibit ADH release or action are simple, readily available, and relatively inexpensive, and are capable of making an accurate diagnosis of a water-losing or water-retaining disorder. Properly performed and interpreted, such tests as water deprivation, saline infusion, comparison of urine and serum osmolality, and water loading can obviate the need for AVP immunoassays in evaluating most clinical disorders of water regulation. The immunoassay of AVP, although a valuable tool for the study of normal and pathologic physiology of ADH, is rarely necessary to firmly establish a clinical diagnosis and may itself be the source of misleading conclusions if its limitations are not fully appreciated.