Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency.

OBJECTIVE: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). DESIGN: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. METHODS: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). RESULTS: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. CONCLUSIONS: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Conditioned taste aversion and c-Fos expression in cholestatic rats.

Rats in which a ligation of the bile duct (BDL) was paired with a saccharin taste developed a persistent conditioned taste aversion in both preference and taste reactivity tests. All BDL animals regardless of pairing had increased c-Fos-like immunoreactivity (FLI) in the area postrema and the nucleus of the solitary tract. This FLI may reflect the illness associated with BDL, but there was no evidence of conditioned FLI.

Influence of the subfornical organ on meal-associated drinking in rats.

A lesion of the subfornical organ (SFO) may disrupt drinking after a meal of dry chow as it does drinking after intragastric administration of hypertonic saline. Food and water intakes of SFO-lesioned (SFOX) and sham-lesioned rats were measured during 90-min tests following various lengths of food deprivation. During the tests, all rats began eating before they began drinking. After 20-24 h of food deprivation, latency to begin drinking after eating had started was longer for SFOX than for sham-lesioned rats. Plasma osmolality was elevated by 2-3% in both lesion groups at 12 min, the latency for sham-lesioned rats to drink, but SFOX rats nevertheless continued eating and delayed drinking. Eating after shorter 4-h food deprivations and ad libitum feeding produced more variable drinking latencies and less consistent effects of SFO lesion. During 24 h of water deprivation, SFO lesion had no effect on the suppression of food intake and did not affect food or water intakes during the first 2 h of subsequent rehydration. These findings indicate that the SFO is involved in initiating water intake during eating and in determining drinking patterns and the amount of water ingested during a meal.

Effects of SFO lesions on salt appetite during multiple sodium depletions.

A depletion of sodium may increase sodium intake by increasing the synthesis of angiotensin (ANG) II in the blood and by stimulating ANG II receptors in the subfornical organ (SFO) of the rat. Lesions of SFO reportedly reduce these intakes. The present experiments tested the effects of SFO lesions on salt appetite after three successive depletions. After a furosemide-induced natriuresis, Long-Evans rats had free access to water- and sodium-deficient diet for 22 h. Water and 0.3 M NaCl were given for 2 h, and then the rats received regular chow, water, and 0.3 M NaCl until the next injection 5 or 7 days later. SFO lesions reduced water intake 1-2 h after each furosemide injection but not during the overnight periods. The lesions did not affect salt appetite the next day, 24-26 h after furosemide, but they did prevent the expected increase in the chronic daily 0.3 M NaCl intake after repeated depletions. The second experiment was similar to the first except that three subcutaneous injections of 100 mg/kg captopril were given at 1, 18, and 20 h after furosemide for the second depletion only. After the first depletion, the results were similar to those of the same condition of the first experiment. After the second depletion, captopril greatly reduced water intake and salt appetite in all rats including those with SFO lesions. Thus, we found that the lesion reduced chronic intake, but we did not replicate results showing large effects of SFO lesions on acute salt appetite. This residual acute appetite after SFO lesion remains dependent on the synthesis of ANG II.

Circumventricular organs and ANG II-induced salt appetite: blood pressure and connectivity.

A lesion of the subfornical organ (SFO) may reduce sodium depletion-induced salt appetite, which is largely dependent on ANG II, and yet ANG II infusions directly into SFO do not provoke salt appetite. Two experiments were designed to address this apparent contradiction. In experiment 1 sustained infusions of ANG II into SFO did not produce a sustained elevation of blood pressure, and neither a reduction of blood pressure alone with minoxidil and captopril nor a reduction of both blood pressure and volume with furosemide and captopril enhanced salt appetite. Infusions of ANG II in the organum vasculosum laminae terminalis (OVLT) did evoke salt appetite without raising blood pressure. In experiment 2 knife cuts of the afferent and efferent fibers of the rostroventral pole of the SFO abolished water intake during an infusion of ANG II into the femoral vein but failed to reduce salt appetite during an infusion of ANG II into the OVLT. We conclude that 1) hypertension does not account for the failure of infusions of ANG II in the SFO to generate salt appetite and 2) the OVLT does not depend on its connectivity with the SFO to generate salt appetite during ANG II infusions.

An overview of NASA ISS human engineering and habitability: past, present, and future.

The International Space Station (ISS) is the first major NASA project to provide human engineering an equal system engineering an equal system engineering status to other disciplines. The incorporation and verification of hundreds of human engineering requirements applied across-the-board to the ISS has provided for a notably more habitable environment to support long duration spaceflight missions than might otherwise have been the case. As the ISS begins to be inhabited and become operational, much work remains in monitoring the effectiveness of the Station's built environment in supporting the range of activities required of a long-duration vehicle. With international partner participation, NASA's ISS Operational Habitability Assessment intends to carry human engineering and habitability considerations into the next phase of the ISS Program with constant attention to opportunities for cost-effective improvements that need to be and can be made to the on-orbit facility. Too, during its operations the ISS must be effectively used as an on-orbit laboratory to promote and expand human engineering/habitability awareness and knowledge to support the international space faring community with the data needed to develop future space vehicles for long-duration missions. As future space mission duration increases, the rise in importance of habitation issues make it imperative that lessons are captured from the experience of human engineering's incorporation into the ISS Program and applied to future NASA programmatic processes.

The induction of c-Fos in the NTS after taste aversion learning is not correlated with measures of conditioned fear.

The induction of c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) has been shown to be correlated with behavioral expression of a conditioned taste aversion (CTA). However, because this cellular response is also dependent on an intact amygdala, it may represent the activation of a stress-related autonomic response. The present experiments addressed this possibility by evaluating the correlation between c-FLI in the intermediate division of the NTS (iNTS) and 2 measures of conditioned fear: freezing and changes in mean arterial pressure (MAP) and heart rate (HR). Exposure to the taste conditioned stimulus (CS) resulted in a marked induction of c-FLI in the iNTS, whereas exposure to a fear CS did not. Further, exposure to a taste CS did not selectively lead to increases in MAP or HR. Results suggest that induction of c-FLI in the iNTS may reflect the activation of a cell population whose function is unique to the CTA paradigm.

Effects of bile duct ligation and captopril on salt appetite and renin-aldosterone axis in rats.

A ligation of the common bile duct (BDL) produces cholestasis and hypotension and increases the daily ingestion of sodium chloride solutions in rats. Low-dose captopril (CAP) treatment also modifies the ingestion of water and sodium in naive rats, and may do so in cholestatic rats. This study examined whether the elevated ingestion of saline by Long-Evans rats after BDL is associated with increased plasma renin activity (PRA), and whether treatment with a low dose of the angiotensin converting-enzyme inhibitor CAP further exacerbates fluid intake and PRA after BDL. In these experiments water and 0.3 M saline intake and PRA and plasma aldosterone (PA) were measured in naive and CAP-treated BDL and sham-ligated rats. We found that BDL elevated rats' daily saline intake 2 weeks after the ligation procedure but had no effect on PRA. CAP (0.1 mg/mL) placed in the drinking water of some BDL rats further increased saline intake. Both PA and hematocrits tended to be reduced in BDL rats, whereas PRA was elevated in both BDL and sham-ligated rats receiving CAP in the drinking water or by gavage (0.1 mg/mL in 10 mL/kg). The data suggest that the ingestion of saline by rats can be modified by BDL and CAP administration, but that exaggerated saline intake in BDL rats is not associated with excessive renin secretion.

Drinking and blood pressure during sodium depletion or ANG II infusion in chronic cholestatic rats.

After a chronic ligation of the common bile duct (BDL), Long-Evans rats are hypotensive and have elevated saline intake during both sodium-depleted and nondepleted conditions. We tested whether BDL rats have exaggerated hypotension during sodium depletion or an elevated dipsogenic response to angiotensin II (ANG II) that might help to explain the saline intake. After 4 wk of BDL, rats were hypotensive at baseline and developed exaggerated hypotension during acute furosemide-induced diuresis. Without saline to drink, BDL rats increased water intake during depletion equal to sham-ligated rats. However, with saline solution available at 22 h after sodium depletion, the BDL rats drank more water and saline than did sham-ligated rats. This rapid intake temporarily increased their mean arterial pressure to equal that of sham-ligated rats. Intravenous infusion of ANG II induced equal drinking responses despite reduced pressor responses in the BDL rats relative to sham-ligated rats during both ad libitum and sodium-depleted conditions. Thus BDL rats have exaggerated hypotension during diuresis, and their hypotension is corrected by drinking an exaggerated volume of saline, but they do not have an increased drinking response to ANG II.

Effects of SFO lesion or captopril on drinking induced by intragastric hypertonic saline.

This study examined the hypothesis that the subfornical organ (SFO), a circumventricular organ with both osmosensitive elements and dipsogenic receptors for circulating angiotensin (ANG) II, is important for the water drinking response that follows an intragastric (ig) load of hypertonic NaCl. A 2-ml saline load was administered ig at 300, 900, or 1200 mOsm/kg to rats with sham lesions or lesions of the SFO, and intake was measured periodically for 2 h. Hypertonic loads caused sham-lesioned rats, but not SFO-lesioned rats, to drink earlier in the test or to drink more water than did the isotonic load. Inhibition of ANG II synthesis in unoperated rats with 100 mg/kg of captopril reduced water intake only during the initial 15 min after a gavage of 1200 mOsm/kg saline. Loads of 900 and 1200 mOsm/kg both increased plasma osmolality and sodium concentration by 15 min after gavage without greatly affecting hematocrit or plasma protein concentration. Thus, the SFO is important for the osmotically-induced water drinking response after acute ig administration of hypertonic saline. With the possible exception of the first 15 min, this drinking response is independent of the peripheral synthesis of ANG II.

Induced preference or conditioned aversion for sodium chloride in rats with chronic bile duct ligation.

We examined whether a learned aversion to saline could account for the reduction in saline intake produced by bile duct ligation (BDL) in rats and whether increased saline intake by BDL rats was associated with hypotension. In three experiments, rats were given continuous access to water in choice with saline after surgery. In Experiment 1, rats were deprived of food and fluid for 24 h and then given 2-h access to either 0.15 or 0.3 M saline. Rats received a BDL or sham-ligation immediately (paired) or 48 h after (nonpaired) the 2-h bout of saline ingestion. The results show that nonpaired BDL rats increased their daily saline intake relative to nonpaired sham-ligated or paired BDL rats approximately 1-4 weeks after surgery. In Experiment 2, when water and either cherry or grape Kool-Aid (0.05% w/v) dissolved in 0.15 M saline to distinguish the flavor of the solution was offered prior to surgery, BDL rats reduced their ingestion of grape-flavored saline after surgery regardless of whether they were exposed to grape- or cherry-flavored saline prior to surgery. In Experiment 3, when rats were offered water and 0.3 M saline 48 h after surgery, BDL rats ligated for 4 weeks increased their saline intake relative to sham-ligated controls and this elevation in saline intake by BDL rats was associated with hypotension. The results suggest that the symptoms associated with the BDL surgery can serve as effective unconditioned stimuli in the acquisition of learned flavor aversions, and that hypotension may play a role in the elevated intake of saline by BDL rats.

Efficacy of intravenous granisetron to control nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.

The safety and efficacy of granisetron (10 micrograms/kg and 40 micrograms/kg) were evaluated during a second (n = 393) and third (n = 200) cycle of chemotherapy in this multicenter, double-blind, randomized, parallel-group study. Granisetron was administered as a single intravenous dose before the start of cisplatin chemotherapy (> or = 60 mg/m2). Total control (no vomiting, no retching, no nausea, and no use of antiemetic rescue medication) after the first 24 hr following chemotherapy was achieved in 40% and 49% of patients in Cycles 2 and 3, respectively, for the 10 micrograms/kg group, and in 42% and 38% of patients in Cycles 2 and 3, respectively, for the 40 micrograms/kg group. Both dose levels of granisetron were well tolerated. The results demonstrate comparable efficacy between the 10 micrograms/kg and 40 micrograms/kg doses of granisetron in preventing nausea and vomiting during repeat cycles of high-dose cisplatin-based chemotherapy. The results of this study show that granisetron 10 micrograms/kg is safe and well tolerated, and remains effective with repeat cycle use.

Influence of salt intake, ANG II synthesis and SFO lesion on thirst and blood pressure during sodium depletion. Subfornical organ.

Water intake was elevated in sodium-depleted rats during a daytime salt appetite test, but other rats drank a similar amount of water when saline was not available for drinking during the test. This water intake stimulated by sodium depletion was blocked by an inhibition of angiotensin (ANG) II synthesis with a high dose of captopril (100 mg/kg, sc). Captopril did not reduce water intake by causing hypotensive shock or uremia, because water and saline intakes were increased rather than decreased after a low dose of captopril (5 mg/kg) that also reduced blood pressure and elevated blood urea nitrogen. The water intake, but not salt appetite, induced by sodium depletion was greatly reduced by a lesion of the subfornical organ (SFO) in one-bottle tests, and this was not clearly related to any effects of the lesion on blood pressure. A physiological role for ANG II in water intake induced by sodium depletion has recently been disputed, but the simplest explanation for the data remains that elevated levels of circulating ANG II bind to receptors in the SFO to generate daytime water drinking during sodium depletion.

Drinking in sodium-depleted rats with bile duct, vena cava or portal vein obstruction.

The authors investigated whether a depletion of sodium with furosemide enhanced the water and 0.3 M NaCl intakes of rats with experimental cholestasis, portal hypertension or congestive heart failure. These were induced, respectively, by bile duct ligation (BDL), portal vein constriction or vena cava constriction. BDL alone increased daily saline intake. In BDL rats, but not in sham-ligated controls, experience with a prior depletion of sodium enhanced the 2-h saline intake and the retention of water and sodium after a subsequent depletion. Chronic cava constriction, but not portal constriction, enhanced sodium intake and retention after sodium depletion during a 2-h test and enhanced water intake overnight after the test. The results suggest that the ingestion of sodium by BDL and cava-constricted rats may share a common mechanism.

Ethanol preference, metabolism, blood pressure, and conditioned taste aversion in experimental cholestasis.

The effect of a ligation of the common bile duct (BDL) on the chronic free-selection intake of ethanol was investigated. Rats were given a choice between water and a solution of either 6% (v/v) ethanol, 0.06% (w/v) sodium saccharin, or a mixture of both ethanol and saccharin. In different experiments, solutions were first presented either 3 weeks before surgery, about the time of surgery, or 2 weeks after surgery. Reductions in ethanol or saccharin intake were observed in BDL rats whenever the solutions were first presented either 3 weeks before or shortly after the surgery. No differences attributable to BDL were seen when ethanol solutions were first presented 2 weeks after surgery. The contingent nature of the effect suggests that the reduction results from a conditioned taste aversion rather than from differences in ethanol metabolism, sensitivity, or neurohormones such as angiotensin. The findings urge caution in the monitoring of the dietary habits of patients with a rapidly developing biliary obstruction.

Interaction of hydration and subfornical organ lesions in sodium-depletion induced salt appetite.

The authors tested whether the level of hydration after furosemide diuresis and 22 hr of sodium depletion affects the amount of water or 0.3 M NaCl solution consumed by rats with intact brains or with lesions of the subfornical organ (SFO). Rats received 2 (underhydrated) or 10 (euhydrated) ml/kg water by gavage as the only fluid input 2, 4, and 20 hr after 10 mg/kg furosemide. These hydration treatments had little or no effect on the amount of saline consumed in 2 hr by intact rats. SFO lesions reduced water intake regardless of hydration condition. Euhydrated, SFO-lesioned rats drank a normal amount of saline, but underhydrated, lesioned rats drank less saline than any other group. Thus, euhydration may facilitate salt appetite in SFO-lesioned rats, and the deficits in salt appetite noted in SFO-lesioned rats may result from deficits in water ingestion rather than from a destruction of angiotensin II receptor sites that directly provoke salt appetite.

Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced emesis.

The purpose of this study was to evaluate the efficacy and safety of four different doses of granisetron when administered as a single intravenous (i.v.) dose for prophylaxis of cisplatin-induced emesis in a multicenter, randomized, parallel-group, double-blind investigation. A total of 353 chemotherapy-naive patients were enrolled, stratified according to cisplatin dose (moderate dose: 50-80 mg/m2, n = 169; high dose: 81-120 mg/m2, n = 184) and randomized to one of four granisetron doses: 5, 10, 20, or 40 micrograms/kg. Control of emesis was evaluated by the percentages of patients attaining complete response (no vomiting or retching, and no rescue medication) and major response (< or = 2 episodes of vomiting or retching, and no rescue medication). Patients were assessed on an inpatient basis for 18-24 h. Safety analyses consisted of adverse events and laboratory parameter changes. Complete response rates over 24 h after chemotherapy were 23%, 48%, 48%, and 44% for granisetron doses of 5, 10, 20, and 40 micrograms/kg, respectively, in the combined patient population (P = 0.011 for linear trend); 29%, 56%, 58%, and 41%, respectively, in the moderate-dose cisplatin stratum (P = 0.278 for linear trend); and 18%, 41%, 40%, and 47%, respectively, in the high-dose cisplatin stratum (P = 0.011 for linear trend). Transient headache was the most frequently reported adverse event (19%). There was no evidence of association between increased dose and headache. A single 10-, 20- or 40-micrograms/kg dose of granisetron is comparably effective in controlling nausea and vomiting associated with moderate or high-dose cisplatin chemotherapy. Granisetron was safe and well tolerated at all doses.

A double-blind comparison of the efficacy of two dose regimens of oral granisetron in preventing acute emesis in patients receiving moderately emetogenic chemotherapy.

BACKGROUND: The purpose of this study was to define an optimal administration schedule of granisetron for patients receiving moderately emetogenic chemotherapy by comparing the antiemetic efficacy and safety of 2 mg of the drug administrated orally. METHODS: In this double-blind, randomized, parallel study, 2-dose regimens of oral granisetron were evaluated in 697 adult cancer patients. Patients were stratified by gender and randomized to receive 2 mg oral granisetron, either as a divided dose given 1 hour prior to chemotherapy and 12 hours after the start of chemotherapy, or as a single dose 1 hour prior to chemotherapy at Cycle 1. The primary efficacy endpoints assessed were the percentage of patients with complete response (no nausea, no emesis, and no additional antiemetic medication during the 24-hour post-chemotherapy interval) and the incidence of emesis and nausea. Following completion of Cycle 1, patients were given the opportunity to receive open-label granisetron (2 mg once daily) on the first day of each remaining cycle of chemotherapy. RESULTS: No statistically significant differences in any of the endpoints were observed between the two treatment groups. Approximately 50% of patients in both treatment groups achieved complete response. The proportion of patients with no episodes of emesis occurred with similar frequency in the two treatment groups. Approximately 52% of patients in either treatment group were free of nausea during the postchemotherapy period. There was no difference between treatment groups regarding the use of antiemetic rescue medication. Finally, the incidence of adverse experiences was similar for both treatment groups. CONCLUSIONS: Both dose regimens of oral granisetron were similarly effective in controlling nausea and vomiting in the 24-hour interval following chemotherapy. Granisetron was well tolerated with few adverse events attributable to the study drug.