Flurazepam hydrochloride

Greenblatt, David J.; Shader, Richard I.; Koch‐Weser, Jan

doi:10.1002/cpt19751711

Cited by 62 publications

(16 citation statements)

References 15 publications

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“…The only metabolite of flurazepam detected in serum was desalkylflurazepam, also a principal metabolite of flurazepam in humans [1,2,20,21], Other identified metabolic products of flurazepam were not measured in dog serum. As in humans [20,21], desalkylflurazepam is eliminated more slowly than the parent compound.…”

Section: Discussionmentioning

confidence: 94%

“…Flurazepam hydrochloride is a benzodiazepin derivative that is extensively used as a hypnotic agent throughout the world [1][2][3], Previous studies have demonstrated that the rate and extent of benzodiazepine up take from systemic blood into the central nervous system are important determinants of the time-course and intensity of clinical action [4][5][6][7][8][9][10]. The present study evaluated the pharmacokinetics of intravenous flurazepam in dogs and the rate and extent of flu razepam entry into cerebrospinal fluid (CSF).…”

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confidence: 99%

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Pharmacokinetics and CSF Entry of Flurazepam in Dogs

et al. 1988

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Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 1/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

et al. 1988

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“…Since the model refers to the α1β2γ2 sub-type whose main effects are sedation, ataxia and anterograde amnesia [11,12] drugs belonging to G1, with exception of 1.a, presents more pronounced effects on sedation [9] and sideeffects as hypnotic, anxiolitic and myorelaxants. In fact, with regard to their primary pharmacological action diazepam 1.a has a markedly anxiolytic action, being a full agonist of BZs receptors, while flurazepam 1.b has a hypnotic action [25,26]. In the group of 7-NO2-benzodiazepines the pharmacological effects are more dispersed: nitrazepam acts as the anticonvulsant, clonazepam as antiepileptic [27] and is used as an aid on treatment of depressive disorders [28].…”

Section: Resultsmentioning

confidence: 99%

“…In the group of 7-NO2-benzodiazepines the pharmacological effects are more dispersed: nitrazepam acts as the anticonvulsant, clonazepam as antiepileptic [27] and is used as an aid on treatment of depressive disorders [28]. Nevertheless compounds with C2'-F substitution such as flurazepam [26] 1.b and flunitrazepam [29] 2.b are mainly hypnotic-sedatives. The compounds with -NO2 groups on C7 and -Cl at C2' present anticonvulsant activities and may have more affinity for another subtype receptor, such as the α3β2γ2 receptor [8,10,30].…”

Section: Resultsmentioning

confidence: 99%

Structural and electronic effects of the C2’ substituent in 1,4–benzodiazepines

Gomes¹,

Santos²,

Beleza³

et al. 2011

Eur. J. Chem.

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KEYWORDSBenzodiazepines are drugs used for treatment of several central nervous system disorders, such as anxiety and sleep. In spite of their wide and popular usage in clinics, the mechanism explaining why a certain pharmacological activity is superimposed onto another for a given benzodiazepine remains unclear. The knowledge of the conformation of benzodiazepines and their electronic charge distribution at molecular surfaces may give new insights into the pharmaco-benzodiazepine receptor interactions, contributing to the improvement of the existing models. In the present study, the solid state geometric and conformational parameters of the available X-ray benzodiazepine structures were analyzed and reviewed. The electronic features of two groups of benzodiazepines with different substituents at C7 and C2' positions were studied by DFT quantum chemical calculations. The conformations of the molecules with optimized geometry were also analyzed. The relative charge distribution around the benzodiazepinic rings and electrostatic potential mapped on electronic density surfaces were obtained. The ring geometric parameters for the diazepine moiety in 1,4-benzodiazepines, do not vary significantly except for a few compounds in which steric and/or intermolecular interactions play a part. The benzodiazepine ring assumes a pseudosymmetrical boat conformation and the torsion angle around the C5-Ph bond varies depending on the nature of the substituent on C2'. Also, the presence of the nitro or chloride substituent on the C7 position and the presence of a fluorine atom on the C2' position significantly alter the relative charge distributions at the attached carbon atoms and the topology of the surface electrostatic potential.Benzodiazepine DFT Structure characterization X-ray Fluoro Isoelectronic potential surfaces

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“…Since its introduction in 1970, the use of flurazepam has become very extensive, and clinical trials of most other hypnotic agents utilize flurazepam as the ref erence standard for comparison [6,7].…”

Section: Flurazepammentioning

confidence: 99%

Pharmacokinetics of Benzodiazepine Hypnotics

et al. 1983

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Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10–20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5–5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.

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Flurazepam hydrochloride

Abstract: Flurazepam (Dalmane, Ro 5‐6901) was introduced in 1970 in the United States as an hypnotic. Its popularity has increased rapidly. In 1973 more than 6.5 million prescriptions for flurazepam were filled at American retail pharmacies, at a total expenditure exceeding 8 million dollars.

Cited by 62 publications

References 15 publications

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Pharmacokinetics and CSF Entry of Flurazepam in Dogs

Structural and electronic effects of the C2’ substituent in 1,4–benzodiazepines

Pharmacokinetics of Benzodiazepine Hypnotics

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