Eltanolone: 50 years on and still looking for steroid hypnotic agents!

Sear, J.W.

doi:10.1111/j.0265-0215.1998.00268.x

Cited by 6 publications

(3 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is well-established that neurosteroids such as (3α,5α)-3-hydroxypregnan-20-one ( 1 ) and (3α,5α)-3,21-dihydroxypregnan-20-one ( 2 ) and neuroactive steroids such as (3α,5β)-3-hydroxypregnan-20-one (pregnanolone, 3 ) modulate γ-aminobutyric acid A (GABA A ) receptor function . γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmittter within the CNS (central nervous system), and steroids that potentiate the effects of GABA at GABA A receptors have therapeutic potential as anticonvulsants, anxiolytics, sedatives, and hypnotics . In addition to the above endogenous steroids, a number of synthetic analogues including alfaxalone ( 4 ) have been shown to modulate GABA A receptors allosterically .…”

Section: Introductionmentioning

confidence: 99%

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Anderson¹,

Boyd²,

Clark³

et al. 2000

J. Med. Chem.

View full text Add to dashboard Cite

Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.

show abstract

Section: Introductionmentioning

confidence: 99%

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Anderson¹,

Boyd²,

Clark³

et al. 2000

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Neuroactive steroids have long been known to produce anesthesia (Seyle, 1942), but the clinical development of neuroactive steroid anesthetics has been hampered by side effects that are in part related to the pharmaceutical formulation required for the intravenous administration (Anderson et al, 1997;Sear, 1998). At present, there is a renewed interest in the efficacy of neuroactive steroids for the management of epilepsy, anxiety, insomnia, migraine, drug dependence, depression, stress, and premenstrual syndrome (Gasior et al, 1997;Rupprecht and Holsboer, 1999).…”

mentioning

confidence: 99%

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Visser¹,

Gladdines²,

Graaf³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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, 2␤-3␣-5␣-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2␤-3␣-5␣-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 Ϯ 16 ng ⅐ ml Ϫ1 for pregnanolone, 221 Ϯ 83 ng ⅐ ml Ϫ1 for ORG 20599, and 483 Ϯ 42 ng ⅐ ml Ϫ1 for alphaxalone to 1619 Ϯ 208 ng ⅐ ml Ϫ1 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 ϭ 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.

show abstract

“…Pyrogens and fever may also suppress hepatic clearance of drugs, [23][24][25] which could enhance and prolong the effects of alfentanil given over longer periods of time. 28,29 Some of this variability could in theory be due to postoperative fever and pyrogen release. 28,29 Some of this variability could in theory be due to postoperative fever and pyrogen release.…”

mentioning

confidence: 99%

Influence of Escherichia coli Endotoxin on the Pharmacokinetics and Respiratory Depressant Effect of Alfentanil in Rabbits

Björkman

Redke

1996

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Postoperative fever occurs in many surgical patients, due to release of pyrogens into the circulation. Pyrogens and fever may influence the pharmacokinetics and effects of drugs. The aim of this study was to investigate the interactions of a pyrogen with the opioid analgesic alfentanil in an animal model. Alfentanil was infused over 10 min into 17 conscious rabbits and over 120 min in another 12 animals. Some of them had been randomized to pretreatment with Escherichia coli endotoxin. Arterial plasma concentrations of alfentanil were determined repeatedly, and arterial blood gas values were recorded. Endotoxin antagonized the respiratory depressant effect of the 10-min infusion of alfentanil by increasing drug distribution clearance during the infusion. In addition, endotoxin raised the total volume of distribution of alfentanil from 0.70 to 1.4 L/kg. Plasma protein binding and elimination clearance were not affected. The increase in volume of distribution and the lack of effect of endotoxin on elimination clearance were confirmed in the 120-min infusion experiments. Apparent concentration-effect relationships for the actions of alfentanil on arterial CO2, O2, and pH were not influenced by the endotoxin. Circulating pyrogens can thus influence the pharmacokinetics and, indirectly, the effects of alfentanil.

show abstract

Eltanolone: 50 years on and still looking for steroid hypnotic agents!

Cited by 6 publications

References 32 publications

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Influence of Escherichia coli Endotoxin on the Pharmacokinetics and Respiratory Depressant Effect of Alfentanil in Rabbits

Contact Info

Product

Resources

About

Eltanolone: 50 years on and still looking for steroid hypnotic agents!

Cited by 6 publications

References 32 publications

Conformationally Constrained Anesthetic Steroids That Modulate GABAA Receptors

Conformationally Constrained Anesthetic Steroids That Modulate GABAA Receptors

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABAAReceptor in Vivo

Influence of Escherichia coli Endotoxin on the Pharmacokinetics and Respiratory Depressant Effect of Alfentanil in Rabbits

Contact Info

Product

Resources

About

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Conformationally Constrained Anesthetic Steroids That Modulate GABA_A Receptors

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo