Entry of lorazepam into cerebrospinal fluid [letter]

Ochs, HR; Busse, J; Dj, Greenblatt; Allen, Matthew R.

doi:10.1111/j.1365-2125.1980.tb01778.x

Cited by 14 publications

(4 citation statements)

References 6 publications

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“…The ESB1609 CSF:plasma ratio in both rat and human studies is approximately an order of magnitude lower than those reported for other highly protein‐bound compounds, 29,30,32–34 and this likely reflects a higher level of protein binding of ESB1609 in plasma (>98% for ESB1609 vs 80%–96%). Unbound ESB1609 CSF:plasma ratio in the rat studies approximated free fraction of ESB1609 in plasma similar to that reported for other compounds 32,33 . Plasma ESB1609 free fraction was not measured in the phase 1 study; however, the CSF:plasma ratios observed likely reflect the unbound ESB1609 in plasma.…”

Section: Discussionmentioning

confidence: 58%

“…ESB1609 CSF:plasma ratio for AUC 0-24 and C max ratios consistently ranged between ≈0.04% and 0.07% across dose levels in humans, similar to that seen in the rodent microdialysis study. The ESB1609 CSF:plasma ratio in both rat and human studies is approximately an order of magnitude lower than those reported for other highly protein-bound compounds, 29,30,[32][33][34] and this likely reflects a higher level of protein binding of ESB1609 in plasma (>98% for ESB1609 vs 80%-96%). Unbound ESB1609 CSF:plasma ratio in the rat studies approximated free fraction of ESB1609 in plasma similar to that reported for other compounds.…”

Section: Discussionmentioning

confidence: 59%

“…Unbound ESB1609 CSF:plasma ratio in the rat studies approximated free fraction of ESB1609 in plasma similar to that reported for other compounds. 32,33 Plasma ESB1609 free fraction was not measured in the phase 1 study; however, the CSF:plasma ratios observed likely reflect the unbound ESB1609 in plasma. These data will also be important in the design of a dosing strategy in future studies in patients.…”

Section: Discussionmentioning

confidence: 96%

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A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5

France,

Rubino,

Safir

et al. 2023

Clinical Pharm in Drug Dev

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ESB1609 is a small‐molecule sphingosine‐1‐phosphate‐5 receptor–selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine‐1‐phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax) were reached by 4–5 hours and 6–10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein‐bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half‐lives ranged from 20.2 to 26.8 hours. The effect of either a high‐fat or standard meal increased maximum plasma concentration and area under the concentration‐time curve from time 0 to infinity compared to the fasted state by 2.42–4.34‐fold higher, but tmax and half‐life remained the same irrespective of fed state. ESB1609 crosses the blood‐brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 96%

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A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5

France,

Rubino,

Safir

et al. 2023

Clinical Pharm in Drug Dev

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“…In another group the mean percentage level in CSF was 23.5 k 13 per cent and in yet another group 16.7 f 3.1 per cent. A similar percentage for the relationships between CSF and serum concentrations has been found after lorazepam (Ochs, 1980). BZD with a short distribution phase are used mainly as hypnotics (flunitrazepam, diazepam), while those with a longer distribution phase are employed mainly as anxiolytics (bromazepam, chlordiazeoxide) .…”

Section: Determinants Of Activity After Single Dosesmentioning

confidence: 69%

Recent advances in the clinical pharmacology of benzodiazepines part I: Pharmacokinetics

Saletu

Pakesch

1987

Human Psychopharmacology

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Tranquillizers, and specifically benzodiazepines (BZD), have become one of the most widely used group of drugs in the world; some have suggested too widely used. Interest in these drugs is still extremely high, both from the scientific and sociological point of view. This is best documented by the fact that the present review is based on more than 700 articles published between 1981 and 1984 covering various aspects of clinical pharmacology. Pharmacokinetic studies dealing with absorption, metabolism and elimination after acute and chronic administration demonstrate that the onset and duration of action of BZD after single oral doses depend largely on absorption rate and the rate and extent of distribution. The rate and extent of accumulation during multiple dosage depend on the elimination half-life and clearance. A framework is proposed for classification of BZD according to the elimination half-life. Various factors -such as age, sex, disease state and drug interactioninfluence the pharmacokinetic properties of BZD. Pharmacodynamic studies are mostly concerned with effects of the drug on the central nervous system (CNS), as well as on behaviour and neuroendocrine functions. The former include computer-assisted quantitative analyses of the scalp-recorded wake electroencephalogram (EEG), based on which it seems possible to determine if, how, when and at what dose a newly developed compound affects the human brain. Sleep investigations are now concerned not only with the effect of the drug on the all-night sleep, but also on the quality of awakening and early morning behaviour as well as with residual effects during daytime, affecting mnestic and cognitive functions, psychomotor performance (specifically in regard to driving ability), as well as mood and affectivity. Finally, for almost a decade increasing concern has been expressed about the widespread use of tranquillizers in society. Scientific evidence concering this issue will be reviewed so that an appropriate medical decision may be reached for the treatment of the individual patients after consideration of the beneficial effects as well as undesirable side-effects.

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Benzodiazepines used Primarily for Emergency Treatment (Diazepam, Lorazepam and Midazolam)

Trinka

2009

The Treatment of Epilepsy

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Entry of lorazepam into cerebrospinal fluid [letter]

Cited by 14 publications

References 6 publications

A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5

A Phase 1 First‐in‐Human Single‐Ascending‐Dose Trial With ESB1609, a Selective Agonist to the Sphingosine‐1‐Phosphate Receptor 5

Recent advances in the clinical pharmacology of benzodiazepines part I: Pharmacokinetics

Benzodiazepines used Primarily for Emergency Treatment (Diazepam, Lorazepam and Midazolam)

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