Topic
ORG-21465
About: ORG-21465 is a research topic. Over the lifetime, 3 publications have been published within this topic receiving 46 citations.
Papers
TL;DR: The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABAA receptor in vivo, and it is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuro active steroids in vivo effects.
Abstract: The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2β-3α-5α-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2β-3α-5α-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation ( e PD ) were similar for the different neuroactive steroids but values of the potency estimate ( K PD ) ranged from 157 ± 16 ng · ml −1 for pregnanolone, 221 ± 83 ng · ml −1 for ORG 20599, and 483 ± 42 ng · ml −1 for alphaxalone to 1619 ± 208 ng · ml −1 for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC 50 in an in vitro [ 35 S] t -butylbicyclophosphorothionate binding assay ( r = 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA A receptor in vivo.
22 citations
TL;DR: Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase, and the relationship between sedation, anaesthesia, excitation and plasma drug concentrations was explored.
Abstract: ORG 21465 has been found to possess anaesthetic properties in humans and its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define its pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentrations. A water soluble preparation of ORG 21465 was administered to six male volunteers as a series of three 15-min computer-controlled, pharmacokinetic model-driven infusions targeting three exponentially increasing plasma concentrations: 0.5, 1 and 2 micrograms ml-1. The clinical characteristics of the resultant sedation and anaesthesia were observed. Plasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect compartment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia with ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml-1 depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-response curve was 1.42 and the equilibration rate constant of the biophase was 0.112 min-1. Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase.
15 citations
TL;DR: It is found that ORG 21465 was an effective anaesthetic in humans and the relationship between sedation, anaesthesia and excitation requires further exploration.
Abstract: Ten male volunteers received a 1-min i.v. infusion of a new water soluble steroid anaesthetic agent, ORG 21465. Individuals received doses ranging from 0.8 to 1.8 mg kg-1. All subjects experienced venous pain at the site of injection; those receiving 1.0 mg kg-1 or more became anaesthetized. There was no evidence of histamine release and apnoea did not occur. Excitatory phenomena were observed in all subjects and were dose related; no spikes were seen on the EEG. Pharmacokinetic analysis supported a three-compartment (non-weight-related) model with compartmental volumes V1, V2 and V3 of 4.31, 14.2 and 89.4 litre, respectively. Clearance from the central compartment V1 was 1.55 litre min-1. Inter-compartmental clearances Q1 and Q2 were 2.54 and 1.79 litre min-1. We found that ORG 21465 was an effective anaesthetic in humans. The relationship between sedation, anaesthesia and excitation requires further exploration.
12 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2002 | 1 |
| 1997 | 2 |