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.

Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group.

PURPOSE: To compare the efficacy and safety of granisetron and ondansetron, serotonin (5-HT3) receptor antagonists shown to be effective in the prevention of chemotherapy-induced emesis. PATIENTS AND METHODS: In a double-blind, randomized, stratified, parallel-group study, the efficacy and safety of granisetron and ondansetron were compared in 987 chemotherapy-naive patients who received cisplatin in doses > or = 60 mg/m2. Granisetron was administered as a single dose of 10 or 40 micrograms/kg before the start of chemotherapy. Ondansetron was administered in doses of 0.15 mg/kg before and 4 and 8 hours after the start of chemotherapy. The three treatment groups were well-matched with respect to demographic characteristics and the dose of cisplatin administered. RESULTS: For all evaluations, single doses of granisetron 10 or 40 micrograms/kg were as effective as three 0.15-mg/kg doses of ondansetron. Total control (no vomiting, no retching, no nausea, and no use of rescue) was attained by 38%, 41%, and 39% of all patients who received granisetron 10 microgram/kg, granisetron 40 micrograms/kg, and ondansetron, respectively. No vomiting or retching and no use of rescue antiemetics were reported in 47%, 48%, and 51% of patients who received granisetron 10 micrograms/kg, granisetron 40 micrograms/kg, and ondansetron, respectively; no nausea and no use of rescue antiemetics were reported in 39%, 42%, and 40% of patients, respectively. CONCLUSION: All three treatment regimens were well-tolerated. The results of this study indicate that a single dose of granisetron 10 or 40 micrograms/kg is as effective as three doses of ondansetron 0.15 mg/kg in the prevention of nausea and vomiting induced by cisplatin chemotherapy.

Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin.

PURPOSE: To assess the antiemetic effects and safety profile of four different doses of granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: One hundred eighty-four chemotherapy-naive patients receiving high-dose cisplatin (81 to 120 mg/m2) were randomized to receive one of four granisetron doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, nausea, vomiting, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. RESULTS: After granisetron doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two vomiting or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no vomiting or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of nausea (P = .0015) and vomiting (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As granisetron dose increased, appetite return increased (P = .040). Headache was the most frequently reported adverse event (20%). CONCLUSION: A single 10-, 20-, or 40-micrograms/kg dose of granisetron was effective in controlling vomiting in 57% to 60% of patients who received cisplatin at doses greater than 81 mg/m2 and totally prevented vomiting in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. Granisetron was well tolerated at all doses.

Nabumetone kinetics in the young and elderly.

Nabumetone, a nonsteroidal anti-inflammatory drug of the naphthylalkanone class, was studied in an open-label fashion to compare the relative single-dose and steady-state kinetics in young healthy male volunteers and in elderly patients with degenerative joint disease. Seventeen healthy male volunteers 21 to 30 years of age and 17 patients 60 to 75 years of age were studied. After a single oral dose of 1,000 mg nabumetone, blood and urine samples were collected over a five-day period. Plasma was assayed for nabumetone and the active metabolite, 6-methoxynaphthylacetic acid, and the urine was assayed for five metabolites. Following this phase, they received daily oral doses of 1,000 mg nabumetone for 14 days. After the final dose, blood and urine samples were again collected for five days for the same assays. These data were fitted to a single compartment model and the derived data are as follows: mean maximal plasma concentration, maximal time concentration, area under the plasma-time curve, elimination rate constant, and elimination half-life in the young group after single dose were 22.9, 8.4, 838, 0.032, and 21.2, respectively, whereas on steady-state, values were 33.6, 4.1, 666, 0.031, and 22.1, respectively. In the elderly group after single dose, these values were 30.2, 10.8, 1,538, 0.024, and 29.2, whereas on steady-state, they were 50.0, 7.2, 1,092, 0.027, and 25.6. The accumulation ratio was 1.6 in the young and 1.8 in the elderly. Side effects in the young were mild and consistent of headaches, epigastric discomfort, nausea, and vomiting, whereas in the elderly they consisted mainly of headaches. No significant changes in complete blood cell count, blood chemistries, or urinalysis were noted. We concluded from these data that the drug does not accumulate if given every 24 hours; therefore, a single daily dose should provide sufficient therapy and that due to a difference in elimination, elderly patients may require a lower dose.

Effects of lesions of the ventral ventral median preoptic nucleus or subfornical organ on drinking and salt appetite after deoxycorticosterone acetate or yohimbine.

Lesions of the ventral ventral median preoptic nucleus (VVMnPO) enhanced daily salt appetite induced by subcutaneous (sc) injections of deoxycorticosterone acetate (DOCA) but did not affect acute salt appetite or water intake after sc injections of 5 mg/kg of the alpha-2-adrenoreceptor blocker yohimbine. Lesions of the subfornical organ (SFO) or its rostral fiber pathways had no effect on fluid intakes during DOCA treatments but significantly reduced water intake after yohimbine. These findings extend those of a previous report (Fitts, Tjepkes, & Bright, 1990) of enhanced DOCA-induced saline intake in VVMnPO-lesioned rats and demonstrate that the effect is specific to lesions of the VVMnPO. The mechanism of the thirst and salt intake elicited by yohimbine is still unclear, but the SFO and its fiber pathways appear to be important for the expression of the water drinking component. Neither lesion reliably affected yohimbine-induced salt appetite.

Ethanol-induced changes in plasma proteins, angiotensin II, and salt appetite in rats.

Sodium depletion in rats elicits a sodium appetite that results from a cerebral action of angiotensin II (ANG II) and aldosterone. Alcohol also activates the renin-angiotensin system, but the mechanism is poorly understood and not related to sodium excretion. In this study, 2.5 g/kg ip ethanol produced a 20% decline in plasma volume and plasma protein concentration in 1-2 hr and elicited salt appetite beginning in 3-4 hr. Blockade of ANG II synthesis in the brain and periphery with the angiotensin-converting enzyme inhibitor captopril eliminated the thirst and salt appetite. Peripheral captopril alone enhanced fluid intake, which indicated that alcohol elevated renin secretion. Ethanol-induced suppression of hepatic plasma protein secretion and the consequent fall in plasma colloid osmotic pressure apparently resulted in hypovolemia and renin secretion, which then produced thirst and salt appetite through an action of ANG II on the brain.

Forebrain sites of action for drinking and salt appetite to angiotensin or captopril.

Three-hour infusions of angiotensin II (ANG II) agonists and antagonists were used to determine the relative sites of action of ANG in producing water drinking and salt appetite. In the first experiment, lateral ventricular (LV) but not fourth ventricular (4V) ANG II elicited water and saline intake, and LV but not 4V sarile, a competitive ANG II receptor blocker, reduced saline intake aroused by ip injections of 10 mg/kg furosemide and 6 mg/kg captopril. In the second experiment, water, but not saline, intake to furosemide-captopril treatment was reduced by sarile infusions into the subfornical organ (SFO). It is concluded that (a) brain ANG receptors for water and saline intakes are more accessible from the forebrain than the hindbrain ventricles and (b) receptors for water drinking, but not saline intake, after captopril reside in part in the SFO. Salt appetite appears to be dependent on ANG II receptors somewhere in the forebrain other than in the SFO.

Subfornical organ connectivity and drinking to captopril or carbachol in rats.

These experiments were conducted to test whether drinking to ip captopril or to intraventricular carbachol requires an intact fiber system from the ventral subfornical organ (SFO). Wire-knife cuts were made through the wall of the third ventricle ventral to the SFO. Control rats had either sham lesions or histologically identified missed cuts. Rats with good cuts (a) drank less than either control group after ip injections of 4 mg/kg captopril, (b) drank normal amounts of 0.3 M NaCl solution when captopril was placed in the drinking water at 0.1 mg/ml, (c) drank less water but a normal amount of saline after 6 mg/kg captopril ip and 10 mg/kg furosemide diuretic ip, and (d) drank normal amounts of water after lateral ventricular injections of 1.2 or 4 nmol of carbachol. The results of the captopril experiments confirm predictions based on studies of SFO lesions and suggest that captopril causes water, but not saline, drinking via an angiotensin-related mechanism acting at the SFO. The carbachol experiment indicates either that the SFO is not a unique receptor site for ventricular carbachol or that the fibers mediating this response do not require the pathways through the ventral pole of the SFO.

Atrial natriuretic peptide in the subfornical organ reduces drinking induced by angiotensin or in response to water deprivation.

Three experiments tested whether the subfornical organ (SFO) could be a site of action for the antidipsogenic effects of atrial natriuretic peptide (ANP) in rats. Pretreatment with 100, 230, or 500 pmol ANP in the SFO reduced drinking induced by 10 pmol angiotensin II in the SFO. Drinking in response to water deprivation was reduced by ANP in rats having cannulas in or near the SFO, but not in rats having cannulas distant from the SFO or in the ventricles. Finally, ANP had no effect on eating or drinking after food deprivation, suggesting that the rats in the other experiments were not acutely incapacitated. The SFO may mediate the central effects of ANP on drinking induced by angiotensin or in response to water deprivation and could play a similar role in the central effects of ANP on salt appetite, diuresis, vasopressin secretion, and blood pressure.

Preoptic angiotensin and salt appetite.

Two experiments were designed to test whether angiotensin (ANG) synthesis or receptor activation in the ventral preoptic region is critical for ANG-induced salt appetite in rats. In Experiment 1, infusions of ANG into the subfornical organ (SFO) produced water drinking without saline intake, but infusions near the organum vasculosum laminae terminalis (OVLT) produced both water and saline drinking. Thus, forebrain areas that support water drinking to ANG do not all support salt appetite. In Experiment 2, rats were given oral captopril (CAP) to enhance daily intake of water and saline solution by increasing ANG II synthesis in the brain. CAP microinjected into the SFO reduced CAP-enhanced water drinking without affecting saline intake, but CAP in the OVLT reduced enhanced saline intake without affecting water drinking. Thus, ANG acting in the OVLT, the most ventral part of the median preoptic nucleus, or other nearby structures is important for ANG-induced salt appetite.

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.

Salt appetite and lesions of the ventral part of the ventral median preoptic nucleus.

Angiotensin receptors in the most ventral part of the ventral median preoptic nucleus (VVMnPO) or organum vasculosum laminae terminalis appear to be important for salt appetite to angiotensin in rats. If so, then small lesions of this region should reduce salt appetite that is dependent on angiotensin. In separate experiments, the lesion greatly reduced salt appetite after treatments with chronic oral captopril or sodium depletion. On the other hand, the VVMnPO lesion actually enhanced salt appetite to deoxycorticosterone acetate. The lesion did not affect water intake to water deprivation, combined food-water deprivation, isoproterenol, or hypertonic saline, and basal plasma osmolality and sodium values were normal. These experiments suggest that VVMnPO lesions selectively affect angiotensin-induced salt appetite without producing the gross hydrational deficits that occur with larger lesions of the ventral forebrain.

Angiotensin-converting enzyme in subfornical organ mediates captopril-induced drinking.

These experiments tested whether angiotensin-converting enzyme (ACE) located within the subfornical organ (SFO) participates in the generation of water intake during peripheral ACE blockade with captopril (CAP). Lesions of the SFO virtually abolished drinking in response to intraperitoneal CAP injection. Intracranially injected CAP suppressed drinking induced by intraperitoneal CAP more completely with direct SFO injection compared with intraventricular or control tissue injections. This central captopril treatment did not alter the drinking response to subcutaneous hypertonic saline. Intraventricular injections of the angiotensin II (ANG II) receptor blocker sarile reduced drinking during oral captopril treatment in rats rehydrating from water deprivation. The results indicate that (a) the SFO mediates drinking caused by peripheral ACE inhibition; (b) the ACE located within the SFO may locally convert ANG I to ANG II, which then stimulates thirst; and (c) central ANG II receptors mediate thirst caused by peripheral ACE inhibition.

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.

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.

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.

Diuresis and reduction of salt appetite by lateral ventricular infusions of atriopeptin II.

Infusions of 60 pmol/h atriopeptin II into the lateral ventricles stimulated urine flow in both normally hydrated and sodium depleted conscious rats without any increase in the excretion of sodium, potassium or total solutes. The urinary sodium concentration and osmolality both declined significantly. In addition to the renal effects, cerebroventricular infusions of 60 pmol/h atropeptin II reduced salt appetite in rats following depletion of sodium by combined treatment with furosemide diuresis and low sodium diet. Neither 60 nor 600 pmol/h doses had any effect on urine volume or concentration during intravenous infusions, so the effects appear to be mediated by the central nervous system (CNS). Atriopeptins may act through the CNS to facilitate reduction of extracellular volume in synergy with peripheral natriuresis: by increasing urine flow independently from natriuresis; and by restricting further expansion of extracellular volume by reducing salt appetite.

Modulation of salt appetite by lateral ventricular infusions of angiotensin II and carbachol during sodium depletion.

Infusions of angiotensin II (AII) or carbachol (CBC) into the lateral ventricles of rats which had been depleted of sodium 4 h previously with either furosemide or polyethylene glycol produced significant changes in salt appetite and sodium and water balances relative to rats infused with saline vehicle. Infusions of AII enhanced the salt appetite and led to rapid retention of both sodium and water. Infusions of CBC abolished the salt appetite and consequently did not produce any increase in sodium balance. Water intake was greater in both AII- and CBC-infused than in vehicle-infused rats and water balances increased during CBC infusion, causing severe dilution of plasma osmolality, sodium and potassium concentrations. Carbachol thus suppressed salt appetite, despite a considerable worsening of the condition of body sodium in these hypovolemic animals. Angiotensin II facilitated the appetite and this enhancement was not secondary to any natriuresis produced by AII infusions.

Fluid intake, distribution, and excretion during lateral ventricular infusions of carbachol in rats.

Infusion of carbachol into the lateral ventricles of rats at rates of 400 or 2000 ng/h for 6 h produced dose-related natriuresis, kaliuresis, and water drinking but no consumption of hypertonic NaCl solution. Electrolyte excretion and water intake were maximal during the first 2 h, and no further increases occurred after 4 h. Sodium losses were estimated as 15-30% of total extracellular sodium. Continuous infusion of 2000 ng/h carbachol for 6 days produced a chronic increase of water intake but no increased consumption of saline. Sodium balances were negative during the first day of infusion, but gradually returned to normal over 6 days. Plasma volume, hematocrit, and plasma sodium and potassium concentrations were normal in carbachol-infused animals on the 6th day. Cholinergic stimulation of the brain thus appeared to interfere with the usual salt appetite following sodium loss.

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.