Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part II. Dose-proportionality and gonadotropin suppression after multiple doses of ganirelix in healthy female volunteers.

OBJECTIVE: To assess the dose-proportionality and pharmacodynamic properties of multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands). DESIGN: Randomized, parallel, pharmacokinetic, and pharmacodynamic study. SETTING: Phase I clinical research unit. PATIENT(S): Three groups of 15 healthy female volunteers of reproductive age. INTERVENTION(S): Subcutaneous injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2 concentrations. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters and hormone suppression. RESULT(S): Steady-state levels were reached between days 2 and 3. Peak concentrations, which occurred approximately 1 hour after dosing, increased in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean values for the area under the curve over one dosing interval (24 hours) were 33 ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25-mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after injection, respectively). Serum hormone levels returned to pretreatment values within 2 days after the last injection. CONCLUSION(S): The pharmacokinetics of ganirelix were dose-proportional within the dose range studied. Multiple injections resulted in immediate suppression of gonadotropins, which was rapidly reversed after treatment discontinuation.

[Suppression by pancuronium and tubocurarine of the afferent discharge of the muscle spindle induced by succinylcholine].

Effect of pancuronium on the increased afferent discharge of the muscle spindle induced by succinylcholine (SCC) (Succinylcholine induced discharge, SID) was studied in the decerebrate cat by recording the discharge of the muscle nerve going to the gastrocnemius muscle. This action of pancuronium was compared with that of tubocurarine and the antagonistic action if any by neostigmine of this action of pancuronium and tubocurarine was also studied. Pancuronium 0.025 or 0.05mg.kg-1 reduced the peak values of SID to 25.2% and 6.8% of the control value respectively. Tubocurarine 0.125mg.kg-1 reduced this to 38.2%. Inhibition of the SID by pancuronium or tubocurarine was not reversed by the administration of neostigmine. Thus pancuronium reduced SID depending on its dose. The ability of pancuronium and tubocurarine to suppress SID is related to their neuromuscular blocking effects, but the failure by neostigmine to reverse this action of pancuronium or tubocurarine might suggest a different type of reaction at the acetylcholine receptor of the intrafusal fiber compared with the one at the acetylcholine receptor of the skeletal muscle.

[Study of neuromuscular transmission with evoked electromyography--11. Comparison between blocks by magnesium and by pancuronium].

Effects of magnesium (Mg) on muscle compound action potentials (CAPs) which were elicited from gastrocunemius muscle by sciatic nerve stimulation in cats were studied, and the results were compared with those of alpha-bungarotoxin (alpha BuTX) and of non-depolarizing relaxants which had been reported previously. Recovery curves (RCs) of CAPs and train-of-four ratios (TOFR) as parameters of neuromuscular blockade were estimated during blocks by Mg as well as the methods described in the previous reports. The following results were obtained. 1) Neuromuscular blocks which were dependent on serum [Mg2+] were observed in accordance with cumulative dosages of MgSO4 solutions. 2) Recovery curves of CAPs showed a pattern which was characterized by extreme potentiations of test responses at shorter intervals of paired stimuli, followed by a slight depression at longer intervals than 500 msec. This pattern of RC was remarkably different from those after alpha BuTX and relaxants. 3) The mechanisms to produce these differences of RCs were discussed, and it is concluded that the notable depression of RCs derived from muscle relaxants may be caused by inhibitory effect on nerve terminals of relaxants which have different mechanism from that by Mg.

The effect of highly diluted agitated thyroxine on the climbing activity of frogs.

We studied the influence of specially prepared highly diluted thyroxine on the spontaneous tendency of juvenile frogs, which were at the end of thyroxine-controlled metamorphosis, to leave the water and climb onto land. The test dilution with a thyroxine concentration beyond Avogadro's value (dilution thyroxine D30) and the reference (dilution water D30) were prepared according to directions from the literature on homeopathy. A few drops of these solutions were added to tap water of basins containing the frogs. The frogs' climbing activities were monitored immediately after adding the solutions. The hypothesis derived from a preliminary study was that there is less climbing activity in frogs treated with dilution thyroxine D30 than in a reference group. This hypothesis was proven. Climbing activity diminished under the influence of dilution thyroxine D30, with statistical significance both in comparison to the effect of the analogously prepared solvent (dilution water D30) as well as in comparison to control observations before the start of treatment. When in a later step of observation the dilution water D30-control group was treated with dilution thyroxine D30, the diminishing effect on activity also occurred.

Plasma cholinesterase levels following pancuronium and vecuronium.

Plasma cholinesterase levels were measured in 52 patients following administration of pancuronium 1 mg/70 kg (10 patients) and 0.1 mg/kg (10 patients) and vecuronium in doses of 1 mg/70 kg (10 patients), 0.1 mg/kg (10 patients) and 0.2 mg/kg (12 patients). Both doses of pancuronium produced a significant (P less than 0.05 - less than 0.005) reduction in the enzyme levels. Vecuronium in a dose of 1 mg/70 kg was without any significant effects but the two higher doses produced a dose-related reduction of about 8 and 16% in the enzyme levels, respectively, which was statistically significant (P less than 0.05 - less than 0.001).

Ventilatory effects of propofol during induction of anaesthesia. Comparison with thiopentone.

The ventilatory effects of induction of anaesthesia with either propofol 2.5 mg/kg or thiopentone 4.0 mg/kg have been observed in patients premedicated with either atropine alone or papaveretum and hyoscine. Induction of anaesthesia with propofol was accompanied by a greater degree of ventilatory depression which was of longer duration than following thiopentone. The effect was accentuated by the opioid premedication.

Modification by ketamine on the neuromuscular actions of magnesium, vecuronium, pancuronium and alpha-bungarotoxin in the primate.

The neuromuscular effects of ketamine, at cumulative doses of 2.5 and 10 mg.kg-1 iv, were studied by electromyographically quantifying the thumb response evoked by ulnar nerve stimulation in 25 monkeys anaesthetized with pentobarbital-N2O-O2. Ketamine alone at these doses had no neuromuscular effects. When the EMG response was maintained at 50% of control by a continuous infusion of magnesium, vecuronium, or pancuronium, ketamine depressed the responses by an additional 13 +/- 3%, 34 +/- 7% and 32.5 +/- 3.3% (mean +/- SEM), respectively, at the highest dose, P less than 0.05. In contrast, ketamine had no effect on the neuromuscular block produced by incremental doses of alpha-bungarotoxin. These results indicate that ketamine does not act on the postjunctional acetylcholine receptor. It plays a secondary role in neuromuscular block, possibly by prejunctional or postjunctional effects independent of receptor occupation.

Ketamine-pancuronium induction in patients with aortic stenosis.

In 15 patients with severe aortic stenosis who were to undergo aortic valve replacement, the induction sequence ketamine followed by pancuronium caused a 25% rise in systolic blood pressure. In a similar series, the induction sequence diazepam + morphine followed by pancuronium caused a 22% fall in systolic blood pressure. This shows that the blood pressure rise caused by ketamine is not blocked by pancuronium, although pancuronium may possibly modify the cardiovascular responses to this drug.

Inhibition of bile salt excretion and bile flow by spasmolytic drugs. An additional therapeutic effect in the treatment of biliary colics?

The influence of the spasmolytic drugs hyoscin-N-butylbromide (HBB, Buscopan) and Extractum opii (E. opii) on bile flow, bile salt and bilirubin excretion is investigated in the cholecystectomized, unanaesthetized pig and compared with the results after acute, quantitative interruption of the enterohepatic circulation (EHC) by biliary drainage. The results demonstrate that HBB and E. opii induce a significant decrease in bile flow and bile salt excretion. A further analysis suggests that this effect is due to an inhibition of intestinal motility and transit time, followed by a delay of the EHC of bile salts with a decrease in biliary bile salt excretion and bile salt dependent bile flow. The results point out a second mechanism that might be responsible for the effectiveness of spasmolytic drugs in the treatment of biliary colics: the lowering of intraluminal pressure by inhibition of bile salt dependent bile flow.

[Incidence of homeopathic treatment with cuprum 4 CH on the intestinal transit of mouse: preliminary study]. / Incidence d'un traitement homéopathique par cuprum 4 CH sur le transit intestinal de la Souris: étude préliminaire.

An homeopathic treatment with cuprum 4 CH, 24 and 5 hours before neostigmine (50 micrograms/kg/IP) administration has been done in the mouse. This treatment significantly reduces (Kruskal-Wallis: p less than 0.02) the faciliting action of neostigmine on intestinal transit.

Ventilatory effects of a propofol infusion using a method to rapidly achieve steady-state equilibrium.

The ventilatory effects of a propofol infusion were studied in 10 females premedicated with atropine and nine with papaveretum and atropine. The infusion, at a rate of 20 mg kg-1 h-1 for 5 min, reducing to 12 mg kg-1 h-1 for 10 min and then 6 mg kg-1 h-1 thereafter, was known to produce a steady-state plasma propofol concentration for 20-25 min after 25 min from commencement. Minute ventilation, tidal volume, frequency and response to breathing carbon dioxide were measured before the infusion and during the steady-state period. Propofol decreased minute ventilation to 56% and 46% (P less than 0.01) of their mean control values in the atropine and papaveretum groups, respectively. Mean tidal volume was decreased to 41-44% (P less than 0.02) by propofol, but a tachypnoea observed in the atropine group during the infusion was absent in the papaveretum group. Propofol alone had no effect on the slopes of the carbon dioxide response curves but did produce a shift to the right (P less than 0.05). Following papaveretum premedication the minute ventilation-carbon dioxide response curve slope, was decreased to 55% of its mean control volume value by the infusion, but this failed to reach statistical significance.

Thiopentone reduces the haemodynamic response to induction of high-dose fentanyl-pancuronium anaesthesia in coronary artery surgical patients.

Thirty-three coronary artery bypass graft patients anaesthetized with high-dose fentanyl (50 micrograms/kg)-pancuronium-oxygen were divided into one control group receiving additional saline and two groups receiving additional 1 mg/kg or 2.5 mg/kg of thiopentone before laryngoscopy and intubation. During laryngoscopy and intubation, systemic arterial pressures, heart rate and rate-pressure-product remained at considerably elevated levels caused by pancuronium in the control group. Both doses of thiopentone reduced these haemodynamic values close to their initial levels. Cardiac index and left ventricular stroke work index were significantly decreased, especially by the higher thiopentone dose, as compared with the control group. However, there were no statistical differences between the haemodynamic changes produced by the two doses of thiopentone. Sedative or hypnotic supplementation of high-dose fentanyl anaesthesia seems to be necessary if pancuronium is used as a muscle relaxant. A small increment of thiopentone, 1 mg/kg, was enough to return haemodynamic parameters almost to their initial levels, whereas the effect of 2.5 mg/kg of thiopentone was unnecessarily strong.

The effects of hypercarbia and hypocarbia on pancuronium and vecuronium neuromuscular blockades in anesthetized humans.

To determine the effects of hypercarbia and hypocarbia on a pancuronium or vecuronium neuromuscular blockade, 54 patients were anesthetized with halothane and 60% nitrous oxide in oxygen. In 30 patients, end-tidal PCO2 was maintained at either 25 mmHg (3.5 kPa, N = 10), 41 mmHg (5.5 kPa, N = 10), or 56 mmHg (7.5 kPa, N = 10). Five patients in each group then were given pancuronium or vecuronium 0.022 mg/kg iv. Neither maximal depressions of twitch tension nor recovery indexes (time for spontaneous recovery of twitch tension from 25 to 75% of control) were altered by hypercarbia or hypocarbia. The remaining 24 patients were divided into three equal groups. Either pancuronium (N = 8) or vecuronium (N = 8) was administered iv as continuous infusion at a rate sufficient to produce a 50% depression of twitch tension. In the remaining eight patients, no muscle relaxant was given. After twitch tension was stable, half of the patients in each group had hypercarbia induced, which depressed twitch tension in all three groups. The patients who received vecuronium had a significantly larger decrease in twitch tension than those who received pancuronium or no muscle relaxant. Conversely, in the remaining patients, hypocarbia produced a significant increase in twitch tension. There was no difference in the magnitude of the increases in twitch tension among the three groups. The authors conclude that pre-muscle relaxant administration-induced hypercarbia or hypocarbia has no effect on a subsequent neuromuscular blockade from pancuronium or vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)

The respiratory depressant effects of nalbuphine and papaveretum as intramuscular premedication.

Forty-four patients scheduled for routine gynaecological surgery through a Pfannenstiel incision were given either nalbuphine or papaveretum as premedication, with hyoscine. Respiratory depression was measured by carbon dioxide rebreathing before and one hour after premedication. Both combinations produced significant respiratory depression as measured by the rebreathing test but no significant difference could be shown between the drugs in this respect.

Factors affecting train-of-four fade.

The characteristics of the train-of-four response during neuromuscular blockade with two agents, atracurium and vecuronium, have been compared. During onset of blockade, at 75% depression of the initial twitch, atracurium was associated with significantly more fade than was vecuronium, and larger doses of atracurium were associated with less fade than smaller doses of the same agent. In addition, with both agents, the degree of fade at a given amount of initial twitch depression was significantly less during onset than during spontaneous offset of action. The degree of train-of-four fade bears no fixed relationship to depression of the initial twitch.

Plasma levels of progesterone and oestrogens in women treated with an oral contraceptive of low oestrogen content (Ovostat 1375).

The plasma levels of progesterone and oestrogens were measured during treatment with an oral contraceptive containing 37.5 mug of ethinyl oestradiol and 1 mg of lynestrenol (= 3-desoxy-17alpha-ethinyl-19-nortestosterone) (Ovostat 1375, Organon, Oss, Holland). Blood samples were taken every day during 9 complete cycles in 5 healthy women. The plasma levels of progesterone were in the range of those found during the early follicular phase of the normal women. No ovulation seemed to have occurred. The mean plasma levels of oestrogens (oestradiol and oestrone) during treatment were below those found during early follicular phase of 34 normal cycles although overlapping of values occurred. The ratio between oestradiol and oestrone during treatment was 1:2 vs. 1:1 during the early follicular phase of the normal cycles. In two cycles treatment was started during the midcyclic rise of oestrogens. No rise of progesterone indicating corpus luteum formation was found. Despite the low amount of oestrogen in the drug the ovaries appeared to secrete minimal amounts of sex steroids. The lynestrenol content is likely to be partly responsible for the inhibition of ovulation and the additional suppression of steroidogenesis.

Pretreatment with d-tubocurarine, vecuronium, and pancuronium attenuates succinylcholine-induced increases in plasma norepinephrine concentrations in humans.

We studied in patients the effect of d-tubocurarine, which has sympathetic ganglion blocking action, on succinylcholine-induced increases in plasma levels of catecholamines, and compared it with the effects of vecuronium and pancuronium, which have little sympathetic ganglion blocking action. Thirty-two patients were divided into five groups: seven were given 3 mL saline; seven received 1 mg/kg succinylcholine; and six, seven, and five patients were given 0.08 mg/kg d-tubocurarine, 0.01 mg/kg vecuronium, and 0.01 mg/kg pancuronium, respectively, all of which were injected 5 min before 1 mg/kg succinylcholine. Succinylcholine alone significantly increased plasma norepinephrine concentrations, systolic blood pressure, and heart rate from 187 +/- 39 pg/mL (mean +/- SEM), 93 +/- 2 mm Hg, and 77 +/- 4 beats/min to 429 +/- 61 pg/mL, 120 +/- 7 mm Hg, and 102 +/- 6 beats/min, respectively, with onset of fasciculations. Pretreatment with d-tubocurarine, vecuronium, and pancuronium significantly and equally attenuated both the fasciculations and the cardiovascular responses to succinylcholine. These results suggest that the sympathetic ganglion blocking action of neuromuscular relaxants when given before succinylcholine is not an important factor in attenuation of succinylcholine-induced increases in plasma levels of catecholamines.

Bradycardia during antagonism of pancuronium-induced neuromuscular block.

Heart rate was compared in matched patients during antagonism of neuromuscular block induced by tubocurarine, pancuronium or alcuronium with neostigmine 0.03 mg kg-1 preceded by atropine 0.015 mg kg-1. The frequency of bradycardia was greater during antagonism of pancuronium compared with alcuronium. Although there was a difference between the group receiving pancuronium and that receiving tubocurarine, it was not statistically significant. The decrease in heart rate was more rapid and profound in the pancuronium group; seven of the 15 patients who received pancuronium required an additional dose of atropine as compared with only one patient who received tubocurarine. However, the difference in heart rate between those who received pancuronium and those receiving tubocurarine was short-lasting, whereas the heart rate of those who received alcuronium was higher than that in the other groups during the entire 60-min period of observation. The findings with pancuronium may be a result of its inhibitory effect on serum cholinesterase.