[Assessment of the efficacy and tolerance of a benzodiazepine antagonist (Ro 15-1788)]. / Evaluation de l'efficacité et de la tolérance d'un antagoniste des benzodiazépines (Ro 15-1788).

The aim of this study was to evaluate the efficacy and the tolerance of Ro 15-1788, a specific benzodiazepine antagonist, in reversing the effects of midazolam. Six healthy male volunteers (mean age 32 +/- 3 years; mean weight 75.5 +/- 5 kg) took part in this study. Two of the three following drugs: midazolam (0.15 mg X kg-1), Ro 15-1788 (0.1 mg X kg-1) or placebo, diluted in 10 ml isotonic saline, were injected intravenously in 15 s at 5 min intervals in a double-blind manner in each subject during six randomized sessions: midazolam-placebo; Ro-placebo; placebo-midazolam; placebo-Ro; midazolam-Ro; Ro-midazolam. At least four days were allowed between each session for each subject. The evaluation of the effects on the central nervous system was as follows. At the time of injection of the first drug and, if possible, at the time of injection of the second drug, the subject was asked to count aloud to 150. The following variables were timed: start of dysarthria, cessation of counting, abolition and duration of absence of the ciliary reflex and duration of induced sleep. Retrograde and anterograde amnesia were evaluated by the recall of a playing card and a number. Haemodynamic effects (variations of systolic and diastolic pressures and pulses rate) as well as respiratory ones (apnoea) were also studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium and lanthanum on phosphate efflux from nonmyelinated nerve fibers.

Phosphate efflux was measured as the fractional rate of loss of radioactivity from rabbit vagus loaded with radiophosphate. The effects of changes in extracellular calcium and of lanthanum have been investigated. In Locke solution with normal, 0.9 mM, calcium and without phosphate, the fractional rate of loss was 1.62 X 10(-3) min-1 at 120 min after the beginning of the washing period and fell slowly (9% hr-1) during washing from 2 to 6 hr. Addition of calcium to the Locke solution produced a transient increase followed by a reversible maintained increase in phosphate efflux. The latter was 40 and 75% above efflux in normal calcium for 20 and 50 mM calcium, respectively. Removal of calcium, with or without addition of EGTA, produced only a transient increase in phosphate efflux, with no subsequent maintained change. Addition of low concentrations of lanthanum produced a reversible inhibition of phosphate efflux. Half-maximal inhibition was at 3.5 micro M lanthanum and appeared to be due to binding of lanthanum to more than one, probably two, sites. Measurements of inhibition by lanthanum at different calcium concentrations did not indicate any competition between calcium and lanthanum. It is suggested that a least a part of phosphate efflux depends on internal calcium and that lanthanum acts by preventing release of phosphate from the phosphate transport mechanism.

Efflux of inorganic phosphate from mammalian non-myelinated nerve fibres.

1. Uptake and release of radiophosphate were measured in desheathed rabbit vagus nerve. 2. During incubation in Locke containing 0.2 mM-[32P]phosphate a slow labelling of water soluble compounds of the nerve was found; the labelling of the non water soluble compounds was much smaller. During washing with inactive Locke, the label was almost entirely released from the water soluble compounds; the radioactivity of these compounds was therefore used as the basis for the calculation of the efflux rate constants. 3. The efflux of radiophosphate increased with increasing phosphate concentration of the washing fluid. 4. A similar effect of external phosphate on the efflux of radiophosphate was seen when the phosphate concentration was suddenly changed. The rate constants were in 0.2 mM-phosphate 1.29 X 10(-3) min-1, in 0.2 mM 1.95 X 10(-3) min-1, and in 2 mM 3.21 X 10(-3) min-1 at 37 degrees C. After changing the external solution the efflux reached a new level with a time constant of about 9 min. 5. Addition of arsenate also increased the efflux of radiophosphate; on a molar basis the effect of arsenate was slightly smaller than the effect of phosphate. 6. Addition of malate or malonate did not affect the efflux of radiophosphate. 7. When the Na of the Locke was replaced by Tris, the efflux of radiophosphate was lowered by 76%, the new level was reached with a time constant of 7.7 min. In Tris-Locke changes in external phosphate did not affect the phosphate efflux. 8. A lowering of the phosphate efflux by 52% was found in Li-Locke; the efflux was then no longer affected by the external phosphate concentration. 9. The effect of external phosphate on the efflux and in the radiophosphate was also measured at intermediate Na concentrations. At different Na concentrations the ratio between the Na dependent effluxes in 2 and 0.2 mM-phosphate was approximately equal to the ratio between the Na dependent influxes in 2 and 0.2 mM-phosphate. 10. The efflux of 22Na had a rate constant of 0.050 min-1 in Locke and 0.046 min-1 in Tris-Locke. 11. It is concluded that part of the efflux of phosphate is mediated by a Na-dependent transport system; the system appears to be able to exchange phosphate between the inside and the outside and to mediate net movements of phosphate in both directions.