The relationship between the anticonvulsant properties of SC-13504 and its plasma levels, measured by polarography, in baboons with photosensitive epilepsy.

SC-13504 was given intravenously to baboons with photosensitive epilepsy, Papio papio, with and without prior administration of allylglycine. Plasma levels of the drug were determined by differential pulse polarography and correlated with behavioural changes and the anticonvulsant action of the drug. Protection against photically induced seizures or self-sustaining myoclonic responses was seen 30 to 120 min after SC-13504, 4-8 mg/kg (when plasma levels were 1 mug/ml or greater). EEG and neurological signs of toxicity were seen after SC-13504 8 mg/kg but not after 4-6 mg/kg.

The ability of RX 77368 - a stabilised analogue of TRH - to provoke the secretion of prolactin and TSH in vivo.

RX 77368, a stabilised analogue of TRH, has been evaluated for its ability to provoke the release of TSH and prolactin in vivo after intravenous administration to rats and human volunteers. The analogue caused a dose-related release of TSH in both species. In rats the compound caused release of prolactin but the dose-response relationship was bi-phasic, so that large doses caused only a diminished response. The prolactin response in human volunteers was equivocal and further experiments will be necessary to define the effect. Despite its greater biological stability the potency, efficacy and duration of effect with RX 77368 was similar to that of TRH in both species. The manner in which further endocrine investigations may aid the clinical development of RX 77368 is discussed.

The influence of dosage form on aspirin kinetics: implications for acute cardiovascular use.

In this study, the pharmacokinetics of several formulations of aspirin were examined: soluble aspirin, mouth-dispersible aspirin, plain aspirin and enteric-coated aspirin granules. Blood samples were taken at frequent intervals for 24 hours after single dosing in 12 healthy volunteers and Tmax, Cmax and t1/2 measured. Cmax was significantly higher for soluble aspirin than for the other formulations and the t1/2 was shorter. The results show the rapid absorption of aspirin from a soluble formulation compared with that from plain aspirin or enteric-coated aspirin granules. Recommendations to treat patients suspected of having a heart attack as soon as possible with aspirin are now widely accepted and the present study would suggest that soluble aspirin should be the aspirin of choice in this situation.

Nasogastric intubation technique for bile sampling in the baboon (Papio ursinus).

A duodenal tube was introduced into the duodenum of the fasted baboon via the nasal passage. After the application of vacuum for several minutes, the baboon received an intravenous injection of pancreozymin and cholecystokinin which caused contraction of the gall bladder. Aspiration of the bile sample was carried out via the duodenal tube.

Reversal of clonidine induced miosis by the alpha 2-adrenoreceptor antagonist RX 781094.

Clonidine given i.v. at a dose of 0.1 mg and 0.2 mg was found to cause miosis in a placebo controlled double-blind study in six healthy volunteers. In a further single-blind placebo controlled study in three of these volunteers, the alpha 2-adrenoreceptor antagonist RX 781094 at a dose of 0.1 mg/kg i.v. reversed the miosis induced by i.v. clonidine 0.2 mg. At a dose of 0.05 mg/kg the miosis was partially reversed.

The pharmacokinetics after intravenous and oral administration in man of the alpha 2-adrenoreceptor antagonist idazoxan (RX781094).

A high performance liquid chromatographic method was developed for the quantitative determination of idazoxan in plasma. The assay was used to study the disposition of the drug after intravenous infusion and oral administration to five normal subjects. After i.v. administration the kinetics could be described by a two compartment model with a mean elimination half life of 4.20 h. The mean calculated volume of distribution during the elimination phase was 3.20 l/kg-1 and the mean plasma clearance was 824 ml min-1. After oral administration a lag period before onset of absorption was observed in all five volunteers, the plasma levels declining monoexponentially from the peak concentration with a mean elimination half life of 5.58 h. The absolute availability varied between 26% and 41% with a mean value of 34%. In-vitro measurements produced a blood/plasma ratio of 1.3 for idazoxan.

Pharmacokinetics of intravenous and oral tolmesoxide.

A high pressure liquid chromatographic assay was developed for simultaneous measurement of the plasma levels of tolmesoxide and its principal metabolite, RX71112. The assay was used to study the disposition of intravenous and oral tolmesoxide in ten normotensive subjects. Two exponential terms were required to describe the disposition of the drug following intravenous administration, whilst a single exponential term sufficed to account for the decay in the plasma concentration after oral administration. The bioavailability of oral tolmesoxide from capsules averaged 84.5% and was independent of dose. The mean half-life after i.v. dosing was 2.6 h (+/- 0.3 SEM) compared to values of 1.9 h (+/- 0.1 SEM) and 2.7 h (+/- 0.5 SEM) following 200 and 400 mg oral doses respectively. In all subjects RX71112 appeared in plasma shortly after tolmesoxide following both routes of administration. The terminal half-life of the metabolite was significantly longer than tolmesoxide with a mean value of 4.9 h (+/- 0.9 SEM) following the 200 mg oral dose of tolmesoxide. The binding of tolmesoxide and RX71112 at therapeutic plasma concentration was 36.8% (+/- 0.5 SEM) and 58.5% (+/- 0.3 SEM) and this remained unchanged at higher concentrations.

The use of ex vivo platelet aggregation to confirm the in vivo alpha 2-adrenoreceptor antagonist effect of idazoxan in man.

The aggregation of human platelets induced by adrenaline has been used as a test system to investigate the in vivo effect of the alpha 2-adrenoreceptor antagonist idazoxan during initial intravenous studies with increasing doses. The inhibitory effect of idazoxan in vitro was confirmed; addition of idazoxan to platelet suspensions prior to adrenaline caused a competitive inhibition of the aggregatory response by specific antagonism of the platelet alpha 2-adrenoreceptor. Following intravenous infusions of increasing doses of idazoxan to volunteers, a dose-dependent inhibition of the ex vivo aggregatory response to adrenaline was observed in isolated platelet suspensions compared to predose values. The inhibitory effects of idazoxan in vivo declined in a biphasic manner with a more rapid fall over the first hour. This reflects the kinetics of the drug in plasma and the semilogarithmic nature of the concentration-response line observed in vitro. Intravenous doses of 100 and 300 micrograms/kg were demonstrated to be effective antagonist doses of the platelet alpha 2-adrenoreceptor in healthy volunteers.

Naloxone suppresses buprenorphine stimulation of plasma prolactin.

The effects of parenterally-administered buprenorphine and simultaneous injection of naloxone was evaluated in six healthy adult males. Each subject was studied on six occasions, an average of 10 days apart, and received either two simultaneous intramuscular injections of saline, buprenorphine 0.3 mg and saline, or buprenorphine 0.3 mg and 0.6 mg, 0.45 mg, 0.3 mg, or 0.15 mg of naloxone. Simultaneous injection of buprenorphine 0.3 mg and saline resulted in an average increase in plasma prolactin above baseline levels of approximately 10 and 25 ng/ml, 30 and 55 minutes after injection. Buprenorphine-induced stimulation of plasma prolactin levels was statistically significantly greater than basal prolactin values (p less than 0.01). When 0.6 mg of naloxone was simultaneously injected with 0.3 mg buprenorphine, peak plasma prolactin levels were significantly lower (p less than 0.05) than prolactin values after administration of 0.3 mg buprenorphine and saline. Simultaneous injection of 0.45 mg naloxone and 0.3 mg buprenorphine also resulted in a significant attenuation (p less than 0.05) of buprenorphine-stimulated prolactin levels. Injection of 0.3 mg or 0.15 mg of naloxone did not inhibit prolactin stimulation produced by buprenorphine 0.3 mg. These findings demonstrate a dose-effect relationship between naloxone concentration and suppression of the increase in plasma prolactin levels produced by administration of buprenorphine 0.3 mg. As prolactin stimulation occurs shortly after opioid agonist administration and is temporally concordant with the rapid induction of pharmacologic reinforcement associated with opiate abuse, naloxone added to buprenorphine parenteral preparations may reduce the abuse potential of buprenorphine.