Characterization of the pharmacokinetics and pharmacodynamics of a new oral thromboxane A2-receptor antagonist AA-2414 in normal subjects: population analysis.

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Tiagabine therapy for complex partial seizures. A dose-frequency study. The Tiagabine Study Group.

OBJECTIVE: To evaluate the efficacy and safety of 2 regimens of tiagabine as add-on therapy for patients with complex partial seizures (CPSs) that are refractory to other treatment. DESIGN: Randomized, double-blind, placebo-controlled, add-on, parallel-group trial with an 8-week baseline period, 12-week experimental period (4 weeks of dose titration and 8 weeks of fixed-dose therapy), and 4-week termination period. SETTING: Twenty-six centers throughout the United States. PATIENTS: Three hundred fifty-one patients were enrolled, 318 were entered in the double-blind period, and 271 completed the study. INTERVENTIONS: Tiagabine, 16 mg 2 times per day (106 patients); tiagabine, 8 mg 4 times daily (105 patients); and placebo (107 patients). The doses of tiagabine were titrated in 3 steps to the fixed dose. MAIN OUTCOME MEASURE: The median change in the 4-week rate of CPSs from baseline to experimental period. RESULTS: The median change from baseline was -1.6 CPSs per 4 weeks in the group of patients who were given tiagabine 2 times per day, and it was -1.2 CPSs in the group of patients who were given tiagabine 4 time per day (P = .06 and P = .02, respectively, compared with placebo). The 4-week seizure frequency was reduced by 50% or more in 31% of the patients who were given tiagabine 2 times per day and in 27% of the patients who were given tiagabine 4 times per day vs 10% of the placebo-treated patients (P < or = .001 for each tiagabine-treated group compared with the placebo group). The most frequent adverse events involved the central nervous system and occurred in comparable proportions in the 3 treatment groups. Similar proportions of patients discontinued the study prematurely for adverse events. CONCLUSIONS: Tiagabine administered 2 and 4 times daily as add-on pharmacotherapy was effective in reducing CPSs in patients with epilepsy whose conditions were refractory to treatment with other antiepileptic agents, and it was well tolerated.

Pharmacologic effects of A-56234, a new high-ceiling diuretic.

The pharmacokinetic characteristics, the diuretic, saluretic, and uricosuric properties, and the safety of single, rising, oral doses of A-56234, a new high-ceiling diuretic, were evaluated in this double-blind, placebo-controlled, cross-over study. Each of three groups of eight subjects received placebo and three different single doses of the diuretic at 1-week intervals. Doses ranged from 0.5 to 80 mg. Significant, dose-related increases in urine volume and in urinary excretion of sodium and chloride were produced during the 24 hours after administration of 20, 40, 60, and 80 mg of the drug. Uricosuria was not observed at any dose. The drug was rapidly absorbed and displayed linear pharmacokinetics within the dose range studied. The elimination-phase plasma half-life was approximately 6 hours. Hepatic clearance was the main route of excretion in humans; only 2 to 10% of the parent drug was excreted in the urine. The drug was well tolerated and no clinically important adverse events were noted.

Pharmacologic effects of A-49816, a new high-ceiling diuretic.

The pharmacologic effects of A-49816, a high-ceiling, loop diuretic, were evaluated in a single-blind, placebo-controlled, randomized trial. Eighteen (18) normal volunteers aged 19 to 40 years were divided into three groups. The subjects in each group received either placebo or three increasing doses of A-49816 with at least a one-week washout between doses. Nine doses of A-49816 (0.5 to 20 mg) were administered during the entire study. Urine volume and excretion of electrolytes were measured at timed intervals following dosing. A-49816 increased urine volume and excretion of sodium and chloride. Significant saluresis, chloruresis and diuresis were seen in most time periods following administration of the highest doses (12.5, 15 and 20 mg) of A-49816. Kaluresis was not consistently seen at any dose. The mean rates of urine output and sodium and chloride excretion were increased relative to placebo within 2 hours of drug administration. The mean rates of urine formation and sodium and chloride excretion peaked at 2-4 hours and often remained elevated at the 6-12 hour interval.

Carteolol treatment of essential hypertension: a long-term study of safety and efficacy.

The long-term safety and antihypertensive efficacy of carteolol were evaluated in an open-label, multicenter trial of 245 hypertensive patients. For those patients maintained on carteolol monotherapy, three months of treatment with once-daily oral doses of carteolol ranging from 2.5 to 60 mg reduced the mean recumbent blood pressure by 12/14 mm Hg from baseline values of 151/100. Blood pressure reductions observed at three months were maintained throughout the study. The final daily dose of carteolol for most patients was 10 mg or less. Carteolol was shown to be safe and well tolerated by most patients.

Localization and electrical characteristics of a giant synapse in the spinal cord of the lamprey.

1. Physiological and morphological experiments were carried out to determine the characteristics of a giant synapse in the lamprey spinal cord. The presynaptic element is a Müller fibre, running the length of the spinal cord, and the post-synaptic element is a lateral interneurone. 2. Injection of the interneurone with fluorescent dye revealed several dendritic processes extending into the region of the Müller fibres and spreading over a longitudinal distance of about 150 mum. Electron microscopic examination of the Müller fibres confirmed that they do not send out processes to form synapses. Thus, the synapse is between the cylindrical fibre and one or more dendritic branches of the interneurone. 3. Measurements with intracellular electrodes showed the Müller fibres to have input resistances of about 1 Momega and space constants of 1-0-1-7 mm. The space constant was larger for hyperpolarizing pulses than for depolarizing pulses because of delayed recitification. The interneurones had input resistances of about 6 Momega. 4. The neurones were electrically as well as chemically coupled. When a current-passing electrode was placed in the fibre and hyperpolarizing pulses applied, the amplitude of the electrical coupling potential recorded from the interneurone was maximal at one position of the current-passing electrode and decreased as the electrode was moved away from the optimal position. The decrease in amplitude with electrode displacement indicated that the region of synaptic contact was very restricted. 5. The electrical synapse was highly rectifying, the forward resistance being about nine-times smaller than the backward resistance.

Synaptic transfer at a vertebrate central nervous system synapse.

1. The relation between presynaptic depolarization and transmitter release was examined at a synapse between a Müller axon and a lateral interneurone in the spinal cord of the lamprey. Two micro-electrodes, one for passing current and the other for recording the resulting voltage change, were placed in the presynaptic axon; a single electrode for recording the post-synaptic potential produced by release of transmitter was placed in the post-synaptic cell. 2. When action potentials were blocked with tetrodotoxin, brief depolarizing pulses in the presynaptic fibre were as effective as the action potential had been in producing transmitter release. 3. The release process had an apparent threshold depolarization of 40-50 mV and saturated at presynaptic depolarizations of the order of 100 mV. Increasing the duration of the presynaptic pulse increased the maximum level of release. 4. Displacing the presynaptic voltage recording electrode from the position of synaptic contact toward the current passing electrode increased the apparent depolarization required to produce a given level of transmitter release. This shift in the input-output relation was consistent in magnitude with the voltage attenuation between the presynaptic recording electrode and the synapse expected from the space constant of the fibre. 5. The effect of conditioning hyperpolarization and depolarization of the presynaptic fibre on subsequent transmitter release by brief depolarizing pulses was examined. No effect was observed when the presynaptic recording electrode was in the region of synaptic contact. When the presynaptic electrode was not so positioned, conditioning effects were observed which depended on electode position and could be attributed to changes in the space constant of the presynaptic fibre. No conditioning effects were observed on transmitter release by the action potential.

The effects of oral doses of lansoprazole and omeprazole on gastric pH.

We compared gastric pH values after therapeutic doses of lansoprazole and omeprazole in 17 healthy adult men. The pharmacokinetics of the two drugs were studied. A three-way crossover design compared the effects on gastric pH of 15 and 30 mg lansoprazole and 20 mg omeprazole--each given once daily for 5 days. Ambulatory 24-h intragastric pH levels were measured before dosing, after the first and fifth doses in each period, and 15 days after each dosing period. A positive relationship between the lansoprazole or omeprazole area under the curve (AUCs) and the 24-h mean pH values was found for each regimen. No differences in maximum concentration (Cmax) and AUC were noted from day 1 to day 5 for the two lansoprazole doses. With omeprazole, both Cmax and AUC levels were greater on day 5 than on day 1. All three regimens increased 24-h mean gastric pH, although 30 mg lansoprazole had the most significant effect. The percentage of time that gastric pH was >3, >4, and >5 was also significantly higher with 30 mg lansoprazole. All three regimens were associated with reversible elevations of serum gastrin, which more than doubled at some points. No clinically significant adverse events were documented.

Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome.

Lansoprazole, a new substituted benzimidazole H+,K(+)-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion was defined as the dose required to reduce acid secretion to < 10 meq/hr in the last hour before the next dose. Doses were adjusted upwards until effective control was achieved. Patients not controlled with 120 mg once daily were placed on twice daily lansoprazole. Most patients (90%) required lansoprazole once daily. During long-term follow-up (mean 18.5 months), 25% of patients required upward dose adjustments and 25% of patients required twice daily lansoprazole. Following cessation of therapy, the mean time for gastric acid output to reach half basal acid output was 39.1 hr. Lansoprazole was well-tolerated without side effects. Clinical chemistry and hematological studies were unchanged, and no gastric carcinoids developed. These results demonstrate that lansoprazole is a safe and effective inhibitor of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Because it has a long duration of action, lansoprazole can be used to control gastric acid hypersecretion in most patients with Zollinger-Ellison syndrome using a once daily dosing schedule.