The present experiments were designed to study the effect extracellular hyponatraemia on aldosterone secretion. Hyperaldosteronism was induced by peritoneal dialysis with 5% glucose solution in dexamethasone-pretreated rats. In the narrow physiological range of 135-142 mmol/l, as well as in the whole range of the study (122-142 mmol/l), the plasma concentration of sodium showed a close negative correlation with the serum concentration of aldosterone (r = -0.71 and -0.83, respectively). Plasma renin activity increased after peritoneal dialysis; however, no close correlation was observed either between sodium concentration and plasma renin activity or plasma renin activity and serum aldosterone concentration within the dialysed group. The ratio of serum concentration of aldosterone to plasma renin activity showed no considerable change between 132 and 142 mmol/l but rose steeply below 132 mmol sodium/l suggesting that a factor(s) other than angiotensin may also contribute to the induction of hyperaldosteronism.U
In a single dose, randomized, cross-over study, with one week of wash-out period, the relative bioavailability of Dopegyt tablets containing 250 mg alpha-methyldopa (AMD) and Presinol film tablets with identical active ingredient content was examined in 24 healthy volunteers. Since technologically two completely different preparations (a film-tablet and a non-film-tablet) having significantly different in vitro dissolution were to be compared, both preparations were compared to a third one, AMD solution (Dopegyt solution) with 250 mg/50 ml concentration. Plasma concentrations of the drug were measured for 24 hours post-dose, applying HPLC with fluorometric detection. Pharmacokinetic parameters calculated from individual data (AUC0-infinity, AUC0-t, Cmax, Cmax/AUC0-infinity, t(max)) were evaluated statistically. Wilcoxon's nonparametric test and the four-way variance analysis could not detect any significant difference at the usual a=95% probability level in these pharmacokinetic parameters of the two tablet preparations. For AUC0-infinity at the 90% probability level, the confidence interval was 0.883-1.237 (with an estimated geometric mean of 1.045), for the test/reference ratio of Dopegyt and Presinol tablets, thus the two preparations proved to be bioequivalent. The relative bioavailability of Dopegyt (test preparation) and Presinol (reference preparation) calculated from the AUC0-infinity values was 116.7+/-56.7% that also confirmed bioequivalence. The results of all the applied statistical tests suggest that Dopegyt and Presinol can be considered as bioequivalent preparations.
AMG 114 is a novel, hyperglycosylated erythropoiesis-stimulating agent. In preclinical studies, AMG 114 demonstrated increased potency and longer half-life than darbepoetin alfa and epoetin alfa. This phase I/II, randomised, double-blind, placebo-controlled, dose-escalation study evaluated safety, pharmacokinetics, and efficacy of AMG 114 in patients with non-myeloid malignancies and chemotherapy-induced anaemia. Patients were randomised (1:5) to receive subcutaneous placebo or AMG 114 Q3W for 6 weeks in 3 dose cohorts of 15 μg (cohort A1), 50 μg (cohort A2), or 200 μg (cohort A3). Safety endpoints included incidence of adverse events and dose-limiting toxicities (DLTs). The PK profile of AMG 114 was evaluated. Efficacy was assessed by change in haemoglobin from baseline to end of treatment. Forty-eight patients enrolled: 8 received placebo, 40 received AMG 114. No DLTs were observed; adverse events were consistent with underlying malignancies. The PK profile was dose-proportional over the dose range tested; terminal half-life of AMG 114 was approximately 130 h. Mean change (range) in haemoglobin from baseline in AMG 114-treated patients was -0.16 (-1.8 to 1.3), 0.21 (-1.5 to 3.4), and 0.76 (-1.0 to 2.9) g/dl in cohorts A1, A2, and A3, respectively. AMG 114 appeared to be well tolerated, but the study was halted, in part because of modest efficacy.
8626 Background: In treating chemotherapy-induced anemia (CIA), erythropoiesis-stimulating agents (ESAs) that can be administered every 3 wks (Q3W), a common chemotherapy schedule, are convenient for patients (pts) and minimize resource utilization. AMG114 is a hyperglycosylated analog of recombinant human erythropoietin, with 4 additional N-linked carbohydrates and 10-amino acid difference from human erythropoietin. In vitro and in vivo animal data for AMG114 predict increased biological activity and prolonged half-life compared with commercially available ESAs. Methods: This multicenter, randomized, double-blind, placebo-controlled, dose-finding, phase 1 study evaluated safety, pharmacokinetics (PK), and efficacy of AMG114 administered subcutaneously Q3W in anemic pts (hemoglobin [Hb] ≥ 8.5 and ≤ 10.5 g/dL) with nonmyeloid malignancies receiving nonplatinum chemotherapy. Patients received AMG114 or placebo for 6 wks (ie, 3 administrations), followed by 3 wks of observation. Efficacy was assessed by Hb change from baseline. Results: Three doses were tested in sequential dose escalation cohorts (including pts receiving placebo): 15 (n=10), 50 (n=18), and 200 (n=20) mcg. Tumor types were: breast (33.3%), non-Hodgkin’s lymphoma, pancreatic, and colorectal (12.5% each). Consistent with animal PK models, the 200-mcg cohort had adequate levels of AMG114 for evaluation of prespecified endpoints (Table). The safety profile of AMG114 was similar to placebo and expected for this population. Antibodies to AMG114 were not detected. Conclusions: AMG114, a novel ESA with an extended 131-hour half-life, appears to be safe and effective at stimulating erythropoiesis and raising Hb levels using 200 mcg Q3W. Although the need for new longer-acting ESAs in the CIA setting may be limited as it is possible to synchronize anemia therapy with most chemotherapy schedules using currently available ESAs, AMG114 may hold promise in other settings. [Table: see text] [Table: see text]
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