Eugene J. Segre

Pharmacokinetics of naproxen overdoses

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subjects without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of J, 2, 3, or 4 gm (up to eight times the clinically e.ffective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

Correlation of flunisolide plasma levels to eosinopenic response in humans

Abstract Plasma levels of flunisolide were measured in healthy male volunteers after the administration of single doses of the drug by the intravenous, oral, intranasal, and bronchial inhalation routes. The systemic availability of a 1-mg dose orally was only 21%. After a single dose of approximately 0.117 mg intranasally plasma levels ranged up to 1 ng/ml. When 1 mg was administered by bronchial inhalation, peak or near peak plasma levels were recorded at 2 min and remained near this level throughout the first hour before declining at a rate similar to that observed after flunisolide intravenously (plasma t12=1.6 to 2 hr). Gargling with an alcoholic mouthwash immediately after inhalation reduced plasma levels at 30 and 60 min but not earlier, suggesting rate-limiting dissolution of flunisolide in bronchial fluids or rate-limiting diffusion across the mucociliary blanket or pulmonary membrane. The systemic availabilities of the inhaled-mouthwash and inhaled-no mouthwash doses were 32% and 39%, respectively. Systemic potency of flunisolide, measured by eosinopenic response, was oral

Effects of Enovid on cortisol metabolism

Abstract Cortisol metabolism of 4 patients on cyclic Enovid (10 mg. daily) therapy for from 5 to 8½ years was compared to 4 controls. The metabolic clearance rate, as determined by the continuous infusion technique using tracer amounts of isotopic cortisol, was markedly decreased in treated subjects. The plasma concentration of cortisol was significantly elevated in the Enovidtreated women. These changes were also evident in a single patient who was treated for only 10 days. The production rate of cortisol was not significantly different between the two groups. It is unlikely, therefore, that adrenocortical function is depressed by such treatment. The changes in the MCR and plasma cortisol are most probably the result of increased cortisol binding by transcortin under the stimulation of the estrogenic activity of Enovid.

Effects of cloprednol and other corticosteroids on hypothalamic-pituitary-adrenal axis function.

The effects of cloprednol and other synthetic corticosteroids on hypothalamic-pituitary-adrenal (HPA) function were studied in healthy subjects after administration of a single oral dose of corticosteroid at 6 a.m. or 6 p.m., and after daily 6 a.m. administration of corticosteroids at various doses for seven days. The degree of HPA suppression was assessed by metyrapone tests (METP), insulin hypoglycaemia tests (IHT) and 6 a.m. fasting plasma Cortisol concentrations. Regardless of the corticosteroid tested, 6 p.m. dosing was at least four-fold more suppressive of METP response than 6 a.m. administration. At therapeutically equivalent doses, single doses of triamcinolone and dexamethasone were more suppressive of HPA-axis function than cloprednol, hydrocortisone or prednisolone. After 6 a.m. administration for seven days, 12·5 mg of cloprednol did not impair the Cortisol response to IHT or interfere with the METP response. The clinically equivalent dose of prednisolone (25 mg) resulted in slightly greater HPA-axis suppression. All doses of dexamethasone (0·5, 3·75 and 6·0 mg) and of betamethasone (2·0, 4·0 and 6·5 mg) were more suppressive of HPA-axis function than either cloprednol or prednisolone. These results suggest that at equipotent anti-inflammatory doses, cloprednol is slightly less suppressive of HPA-axis function than prednisolone, and both cloprednol and prednisolone are much less suppressive than dexamethasone or betamethasone.

Metabolic Effects of Cloprednol—A New Systemic Corticosteroid

The short-term metabolic effects of cloprednol, a new short-acting synthetic corticosteroid, were evaluated in four normal subjects. Cloprednol, 12.5 mg/day, in one subject had no appreciable effect on urinary excretion of sodium, potassium, nitrogen, or calcium. Cloprednol, 20 mg/day, in three subjects had no significant effect on mean daily urinary sodium and potassium excretion, although mild, transient sodium retention and kaliuresis were observed. One subject had increased nitrogen excretion and all three had a small increase in calcium excretion. Prednisolone, 40 mg/day, a dose with antiinflammatory potency equivalent to 20 mg/day cloprednol, given subsequently to two subjects under identical conditions resulted in sodium and potassium excretion results similar to those of cloprednol, 20 mg/day, but produced a much greater increase in nitrogen and calcium excretion. These results suggest that, like prednisolone, cloprednol lacks the sodium-retaining properties of hydrocortisone and raise the possibility that cloprednol has less of a deleterious effect on nitrogen and calcium excretion than prednisolone.

The uterine effects of vaginally administered prostaglandin E2

Abstract A group of 15 women with normal menstrual cycles was treated with prostaglandin E 2 (PGE 2 ) during the luteal phase of the cycle (day 20 to 22). A solution of PGE 2 in normal saline or polyethylene glycol was applied vaginally in amounts ranging from 25 mcg to 2 mg, either as a single dose or as a series of repeated doses, and uterine activity was monitored. A single dose of 1 mg distinctly increased uterine activity; 8 to 10 mg given in divided doses within 45 minutes changed the pattern of luteal phase uterine activity into intensive and regular contractions. The uterine effects of PGE 2 were manifest in 20 to 40 minutes after administration; the effect lasted for 2 to 4 hours. The systemic reactions and side effects which occur during intravenous infusion of PGE 2 were absent.