Rate of entrance of benzodiazepines into the brain determined by eye movement recording.

Tedeschi, Gioacchino; Smith, Andrew T.; Dhillon, Soraya; Richens, A.

doi:10.1111/j.1365-2125.1983.tb01471.x

Cited by 45 publications

(14 citation statements)

References 17 publications

(18 reference statements)

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“…The systemic administration of diazepam used in the present study does not allow the exact location of its action to be pinpointed, although evidence demonstrating that diazepam crosses the blood–brain barrier (Tedeschi et al . ) supports the idea that it acts within the brainstem. However, Wang et al .…”

Section: Discussionsupporting

confidence: 69%

GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

Teixeira

Fernandes

Vianna

2019

The Journal of Physiology

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Key points The activation of the group III/IV skeletal muscle afferents is one of the principal mediators of cardiovascular responses to exercise; however, the neuronal circuitry mechanisms that are involved during the activation of group III/IV muscle afferents in humans remain unknown. Recently, we showed that GABAergic mechanisms are involved in the cardiac vagal withdrawal during the activation of mechanically sensitive (predominantly mediated by group III fibres) skeletal muscle afferents in humans. In the present study, we found that increases in muscle sympathetic nerve activity and mean blood pressure during isometric handgrip exercise and postexercise ischaemia were significantly greater after the oral administration of diazepam, a benzodiazepine that increases GABAA activity, but not after placebo administration in young healthy subjects. These findings indicate for the first time that GABAA receptors modulate sympathetic vasomotor outflow and the pressor responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. Abstract Animal studies have indicated that GABAA receptors are involved in the neuronal circuitry of the group III/IV skeletal muscle afferent activation‐induced neurocardiovascular responses to exercise. In the present study, we aimed to determine whether GABAA receptors modulate the neurocardiovascular responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. In a randomized, double‐blinded, placebo‐controlled and cross‐over design, 17 healthy subjects (eight women) performed 2 min of ischaemic isometric handgrip exercise at 30% of the maximal voluntary contraction followed by 2 min of postexercise ischaemia (PEI). Muscle sympathetic nerve activity (MSNA), blood pressure (BP) and heart rate (HR) were continuously measured and trials were conducted before and 60 min after the oral administration of either placebo or diazepam (10 mg), a benzodiazepine that enhances GABAA activity. At rest, MSNA was reduced, whereas HR and BP did not change after diazepam administration. During ischaemic isometric handgrip, greater MSNA (pre: ∆13 ± 9 bursts min−1 vs. post: ∆29 ± 15 bursts min−1, P < 0.001), HR (pre: ∆23 ± 11 beats min−1 vs. post: ∆31 ± 17 beats min−1, P < 0.01) and mean BP (pre: ∆33 ± 12 mmHg vs. post: ∆37 ± 12 mmHg, P < 0.01) responses were observed after diazepam. During PEI, MSNA and mean BP remained elevated from baseline before diazepam (∆10 ± 8 bursts min−1 and ∆25 ± 14 mmHg, respectively) and these elevations were increased after diazepam (∆17 ± 12 bursts min−1 and ∆28 ± 13 mmHg, respectively) (P ≤ 0.05). Importantly, placebo pill had no effect on neural, cardiac and pressor responses. These findings demonstrate for the first time that GABAA receptors modulate MSNA and the pressor responses to skeletal muscle metaboreflex activation in humans.

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Section: Discussionsupporting

confidence: 69%

GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

Teixeira

Fernandes

Vianna

2019

The Journal of Physiology

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“…This approach has been previously reported (Bittencourt et al, 1981, Tedeschi et al, 1983. Into this framework, specific tasks of cognitive and psychomotor performance have been fitted to provide a more detailed insight into the nature of the induced sedation.…”

Section: Introductionmentioning

confidence: 99%

Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.

Griffiths¹,

Jones²,

Richens³

1986

Brit J Clinical Pharma

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1 The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo. 2 The performance tests selected (stroop task, five choice serial reaction time, memory span, logical reasoning, mood and saccadic eye movement analysis) were thought to reflect aspects of normal daily activity. 3 The tests demonstrated a clear reduction of performance for all active treatments. No drug emerged as the most potent sedative overall, as each of the tests was affected to a different degree by each drug. 4 Drug effects were not qualitatively different between active treatments so that zopiclone was indistinguishable from the three benzodiazepines with which it was compared.

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“…Examples of development of acute tolerance to diazepam (Ellinwood & Nikaido 1987) and alcohol (Vogel-Sprott 1979) have been repeated. Since the penetration of hydroxylated benzodiazepines into the CNS is not very rapid (Tedeschi et al 1983), the orally ingested soft gelatine formulation may be slightly faster than standard tablet in this respect. This in turn might lead to a development of acute tolerance.…”

Section: Discussionmentioning

confidence: 99%

A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

Tuomainen

1989

Pharmacology & Toxicology

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In a double-blind and cross-over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one-week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half-lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tablet form.

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Rate of entrance of benzodiazepines into the brain determined by eye movement recording.

Cited by 45 publications

References 17 publications

GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.

A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

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Rate of entrance of benzodiazepines into the brain determined by eye movement recording.

Cited by 45 publications

References 17 publications

GABAA receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

GABAA receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam.

A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

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GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans

GABA_A receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans