Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses

Fahey, Jeanne M.; Grassi, Jeffrey M.; Reddi, Jyoti M.; Greenblatt, David J.

doi:10.1016/j.pbb.2005.12.006

Cited by 17 publications

(5 citation statements)

References 24 publications

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“…One study in rats showed that the number of binding sites for zolpidem was diminished 40 min after zolpidem intake while affinity for the receptor was not changed (Fahey, et al, 2006). It was hypothesised that this decrease in binding sites was due to a degradation of the α1-subtype GABA A receptor or that zolpidem binding induces a substitution of the α1-subtype by one of the other subunits (Fahey, et al, 2006). The time course of these events is compatible with our PK/PD-tolerance model.…”

Section: Discussionsupporting

confidence: 80%

“…Our PK/PD model indicates that zolpidem's PD effects are attenuated from 2 hours post-dose, and this raises the question which tolerance mechanism best fits this relatively slow process. One study in rats showed that the number of binding sites for zolpidem was diminished 40 min after zolpidem intake while affinity for the receptor was not changed (Fahey, et al, 2006). It was hypothesised that this decrease in binding sites was due to a degradation of the α1-subtype GABA A receptor or that zolpidem binding induces a substitution of the α1-subtype by one of the other subunits (Fahey, et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

et al. 2009

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Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

et al. 2009

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“…These derivatives were originally designed to be selective GABA receptor modulators based on their structural analogy with zolpidem, which produces rapid‐onset, short‐duration hypnosis as a consequence of binding to benzodiazepine receptors . Zolpidem induces analgesia at high doses (80 mg/kg), but has the secondary effect of decreasing locomotor activity in mice . Although the mechanisms responsible for zolpidem‐induced analgesia are not yet known, opioid pathway involvement has been suggested…”

Section: Introductionmentioning

confidence: 99%

Antihyperalgesic effects of a novel muscarinic agonist (LASSBio‐873) in spinal nerve ligation in rats

Mendes

Antunes

Trachez

et al. 2013

Clin Exp Pharma Physio

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New chemicals or adjuvants with analgesic effects on chronic pain are needed and clinically relevant due to the limited number of effective compounds that possess these characteristics. LASSBio-873, a pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivative, activates muscarinic cholinergic receptors and has potent analgesic effects on acute and inflammatory pain. The present study evaluated the therapeutic and prophylactic effects of oral administration of LASSBio-873 in a spinal nerve ligation (SNL) model of chronic peripheral nerve injury. LASSBio-873 (100 mg/kg) inhibited the development of thermal hyperalgesia and mechanical allodynia when administered once daily for 7 consecutive days after SNL surgery and reversed these symptoms. LASSBio-873 treatment did not alter rat behaviour in open field testing measured during the first 24 h after administration and again after 7 continuous days administration. The analgesic effect of LASSBio-873 was inhibited by intrathecal methoctramine, an M2 receptor antagonist, implicating the muscarininc M2 receptor signalling pathway in the drug's action. These results reinforce the potential of LASSBio-873 as a possible prototype for the development of more effective alternatives for the treatment of neuropathic pain.

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“…PTZ was infused at a constant rate of 0.5 ml/min using a motor driven infusion pump (Stoelting Co., Wood Dale Illinois, USA). The volume of solution infused before the appearance of full-blown clonic-tonic seizure was recorded (Fahey et al, 2006). The threshold doses of PTZ (mg/kg) required to elicit seizures were calculated from the volume of infusion (ml), concentration of PTZ (mg/ml) and body weight (kg), using the following formula: volume of PTZ (ml) × concentration of PTZ (mg/ml)/body weight (kg).…”

Section: Methodsmentioning

confidence: 99%

Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats

Kovačević

Timić

Tiruveedhula

et al. 2014

Brain Research Bulletin

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Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type.

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Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses

Cited by 17 publications

References 24 publications

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

Antihyperalgesic effects of a novel muscarinic agonist (LASSBio‐873) in spinal nerve ligation in rats

Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats

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