NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience.

NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor. NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA/glycine-induced increases in cytosolic calcium in cultured rat cerebellar granule cells (IC50 = 476nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664nM).

Mixed-effects modeling of the pharmacodynamic response to the calcimimetic agent R-568.

OBJECTIVE: The parathyroid cell calcium receptor is a novel drug target for affecting parathyroid hormone (PTH) secretion and for treating hyperparathyroidism. R-568 is a calcium receptor agonist that inhibits PTH secretion and increases calcitonin release in preclinical studies. The objective of this study was to evaluate the effect of R-568 on PTH plasma concentrations in humans. METHODS: Eighteen healthy postmenopausal women were included in the study. Single ascending oral doses of 10 to 400 mg were administered in a randomized, placebo-controlled double-blind trial. PTH plasma concentrations were measured for up to 120 hours after each dose. RESULTS: R-568 caused a dose-dependent decrease in plasma PTH, with peak effect observed within 1/2 to 2 hours after dosing. The maximum effect did not increase beyond doses from 80 to 160 mg, but duration of response increased at higher doses. An indirect-response model was developed to estimate the rates of input and output of the active moiety(ies), the inhibitory effect on PTH secretion, and the circadian variability in PTH. Population parameter estimates were 3.02 hour-1 and 0.49 hour-1 for rates of input and output of the active moiety(ies), respectively, IA50 (the unscaled amount of R-568 associated with 50% of Emax) was 16.3 mg, Emax (the maximum effect caused by R-568 expressed as a fraction of the rate of PTH secretion in the absence of any drug effect) was 89%, CPTH(baseline) (the baseline PTH plasma concentration in the absence of any drug effect) was 34.6 pg/mL, KePTH (the elimination rate constant for PTH) was 1.73 hour-1, amplitude of the circadian variability in PTH secretion was 5.8%, and the time of peak PTH secretion occurred at about 6 PM. Intersubject variability in parameter estimates ranged from 7% to 121%, and residual variability was 22%. CONCLUSION: The model correctly described the onset, extent, and duration of effect on PTH after a wide range of doses of R-568.

NPS 1506, a novel NMDA receptor antagonist and neuroprotectant. Review of preclinical and clinical studies.

NPS 1506 is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NPS 1506 is neuroprotective in rodent models of ischemic stroke, hemorrhagic stroke, and head trauma, with a 2-hr window of opportunity. Neuroprotectant doses of NPS 1506 ranged from approximately 0.1-1.0 mg/kg, with peak plasma concentrations ranging from 8-80 ng/mL. Even at doses producing behavioral toxicity, NPS 1506 did not elicit MK-801-like behaviors, did not generalize to phencyclidine (PCP), and did not elicit neuronal vacuolization. In a Phase I study, intravenous (i.v.) doses of NPS 1506 from 5-100 mg were well tolerated and provided plasma concentrations in excess of those required for neuroprotection in rodents. Adverse events at the 100-mg dose included mild dizziness and lightheadedness, and mild to moderate ataxia. Neither PCP-like psychotomimetic effects nor cardiovascular effects were noted. The long plasma half-life of NPS 1506 (approximately 60 hr) suggests that a single i.v. dose will provide prolonged neuroprotection in humans.

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Comparative bioavailability of suprofen after coadministration with food or milk.

Suprofen is a nonsteroidal analgesic with demonstrated efficacy in the treatment of mild to moderate pain associated with a variety of clinical conditions. Because nonsteroidal analgesic agents may cause gastrointestinal side effects, they are frequently prescribed with food or milk. The purpose of this study was to evaluate the effects of a standard meal and milk alone on the rate and extent of absorption of suprofen. In a randomized three-way cross-over study, 24 healthy volunteers each received a single 200-mg oral dose of suprofen in the fasted state half an hour after a standard meal or half an hour after an 8-ounce glass of milk. The influence of food and milk was greater on the rate than on the extent of absorption of suprofen as illustrated by a more pronounced effect on Cmax than on AUC. In addition, food had a greater influence on the bioavailability of suprofen than milk. Food decreased the mean Cmax to 44% and the mean AUC to 81% relative to the fasted state, whereas milk decreased the mean Cmax to 74% and the mean AUC to only 87% of the respective parameters in the fasted state. Symmetrical confidence intervals demonstrated that the mean AUCmilk was within only 19% and the mean AUCfood was within only 25% of the mean AUC in the fasted state, with 95% confidence.

Clinical pharmacokinetics of etintidine.

The pharmacokinetics of etintidine (E), a potent H2 blocker, were studied in 12 normal, fasted subjects. The subjects received five ascending doses of E HCl in capsules at 72-h intervals. Blood and urine samples were collected and the plasma and urine levels of E were determined by HPLC. Following oral administration, plasma E levels showed double peaks in half of the subjects. Mean Cmax (0.42, 2.11, 3.82, 4.50, and 7.15 micrograms ml-1), AUC0-infinity (0.96, 4.94, 11.3, 17.5, and 24.5 h micrograms ml-1), and the amount of E excreted unchanged in 72 h (20, 54.8, 170, 320, and 371 mg) were determined. These parameters indicate the amount of E absorbed increased linearly with dose for each individual. Renal clearance was independent of the dose and the mean value (16.6 lh-1) was about twice that of the creatinine clearance (which did not significantly change as a result of E treatment), indicating that E is actively secreted into the renal tubules. As E was eliminated rapidly from the body (t1/2 less than 2 h), no substantial accumulation of E is expected after multiple dose treatment.

The effect of food or milk on the bioavailability of etintidine in healthy subjects.

A three-way crossover study was conducted in 24 normal, male volunteers to compare the bioavailability of etintidine from capsules (2 X 200 mg) taken under fasting conditions, with food and with milk. Blood samples were collected prior to and at various times after each treatment and plasma levels of etintidine were determined by high performance liquid chromatography. Statistical analysis of the plasma etintidine concentration data indicated that while neither food nor milk had an apparent effect (p greater than 0.05) on the rate of etintidine absorption, both food alone and milk alone slightly decreased the extent of etintidine absorption. Mean bioavailability parameters of etintidine obtained following the administration of etintidine with food, milk or under fasting conditions are 5.28, 5.26 and 5.88 micrograms.h/ml, respectively (for AUC) and 1.75, 2.18 and 2.59 micrograms/ml, respectively (for Cmax), and 1.23, 1.01 and 0.91 h, respectively (for tmax). Symmetrical 95% confidence interval analyses showed that the observed decreases of less than 11% in the AUC values of etintidine following the concomitant administration of food or milk were within 17% of the fasting value and, therefore, may not be of clinical significance.

Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers.

The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H2 receptor antagonist etintidine in healthy volunteers. Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p greater than 0.05) in the mean values of Cmax, tmax, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.

Pharmacokinetics and bioavailability of etintidine in beagle dogs: effects of routes of administration, doses, dosage forms, and chronic dosing.

Etintidine HCl is an H2 receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are: 1. Plasma levels of etintidine after i.v. administration of 200 mg of E followed a 3-exponential decay with a terminal t1/2 of 1.7h. 2. Following oral administration of 200 mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first-pass elimination. 3. A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg-1 and this relationship did not change with repeated dosing. 4. Some accumulation of etintidine took place during the 52 weeks of chronic dosing.

Etintidine-propranolol interaction study in humans.

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC0-infinity values (573.5 vs. 146.4 ng.hr/ml, p = 0.0001) and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropranolol indicates that etintidine also increased the AUC0-24 values (43.8 vs. 16.4 ng.hr/ml, p = 0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.

Etintidine-theophylline interaction study in humans.

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of theophylline was investigated in 10 male volunteers. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of theophylline elixir (5 mg/kg) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 h following the administration of theophylline. Plasma theophylline levels were analysed by HPLC. Theophylline was rapidly absorbed following oral administration of the theophylline elixir to both the placebo and etintidine treatment groups. Comparison of the pharmacokinetic parameters of theophylline between the etintidine and the placebo groups indicates that while etintidine did not significantly (p greater than 0.05) affect the apparent Cmax (11.1 vs 10.0 micrograms ml-1) and Tmax (1.7 vs 1.4 h) values of theophylline, etintidine significantly reduced the oral clearance (0.0200 vs 0.0564 l kg-1 h-1, p = 0.000006) and prolonged the elimination half-life (16.8 vs 6.0 h) of theophylline. The data indicate that etintidine, like cimetidine, extended the elimination of theophylline in humans.

A high-performance liquid chromatographic microassay employing a liquid-solid extraction technique for etintidine in plasma.

This paper describes a new, rapid solid extraction method for the determination of etintidine in plasma. The method employs a semiautomatic sample preparation system. Plasma samples and the internal standard (cimetidine) were applied onto octyl-bonded silica extraction columns. The extraction columns were then subjected to Tris buffer and water wash and were subsequently loaded onto an automatic sample injection system. The contents of the extraction columns were eluted on-line with a mobile phase of acetonitrile:methanol:0.1% ammonium hydroxide (85:10:5, by volume) onto a silica analytical column and detected by UV absorption at 229 nm. The chromatographic condition separates etintidine from some of its metabolites and other endogenous components in plasma. The detection limit for etintidine was 0.02-0.05 microgram/ml when 0.2 ml of plasma was used. This method has been used for the determination of plasma etintidine levels in humans and mice after oral administration of etintidine and was found to be suitable for pharmacokinetic/bioavailability studies of etintidine in humans and animals. The method can also be used for the quantitative determination of cimetidine and certain metabolites of etintidine.

Photoelectron microscopy: a new approach to mapping organic and biological surfaces.

A general method of imaging organic and biological surfaces based on the photoelectric effect is reported. For the experiments, a photoelectron emission microscope was constructed. It is an ultrahigh vacuum instrument using electrostatic electron lenses, microchannel plate image intensifier, cold stage, hydrogen excitation source, and magnesium fluoride optics. The organic surfaces examined were grid patterns of acridine orange, fluorescein, and benzo(a)pyrene on a Butvar surface. A biological sample, sectioned rat epididymis, was also imaged by the new photoelectron microscope. Good contrast was obtained in these initial low magnification experiments. These data demonstrate the feasibility of mapping biological surfaces according to differences in ionization potentials of exposed molecules. A number of technical difficulties, such as the intensity of the excitation source, must be solved before high resolution experiments are practical. However, it is probable that this approach can be useful, even at low magnifications, in determination of the properties of organic and biological surfaces.