Interaction of triazolobenzodiazepines with benzodiazepine receptors

Sethy, Vimala H.; Russell, Roland R.; Daenzer, Carol L.

doi:10.1111/j.2042-7158.1983.tb04825.x

Cited by 19 publications

(10 citation statements)

References 2 publications

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“…Whereas [3Hl-labeled triazolobenzodiazepines show similar in vitro biochemical and autoradiographic receptor binding as classical benzodiazepines (Kochman and Hirsch, 1982;Sethy et al, 1983;Upjohn Co., personal communication;VonVoigtlander and Straw, 1985), they have been reported to show some marked differences from the classical benzodiazepines in in vitro tests of stimulated C1-flux (Obata and Yamamura, 1988). Whereas in vitro Sinding of the triazolobenzodiazepines to benzodiazepine receptors is similar to that of the classical benzodizepines, Miller et al (1987a) reported that low doses of alprazolam (0.02-0.05 mgkg) in rats increase brain concentrations of benzodizepine receptors as defined by displacement of previously administered [3Hl-Ro15-1788 from brain tissues by unlabeled benzodiazepines (e.g., alprazolam) (Miller et al, 1987b).…”

Section: Discussionmentioning

confidence: 99%

Acute effects of alprazolam and adinazolam on the concentrations of corticotropin‐releasing factor in the rat brain

Owens

Bissette

Nemeroff

1989

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Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis. However, considerable evidence indicates that CRF may be responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress as well. In addition, clinical studies indicate that CRF of both hypothalamic and extrahypothalamic origin may be hypersecreted in major depression as well as other psychiatric disorders. These findings, taken together, led to the hypothesis that the efficacy of antidepressant and/or anxiolytic drugs may be related to their actions on CRF-containing neural pathways in the central nervous system (CNS). Therefore, alterations of CRF concentrations in 18 rat brain regions were studied after acute administration of a tricyclic antidepressant (imipramine) or one of two triazolobenzodiazepines (alprazolam or adinazolam) that possess anxiolytic properties typical of benzodiazepines, as well as purported antidepressant activity unique to these compounds. Treatment with alprazolam or adinazolam increased hypothalamic CRF concentrations, which was associated with lower plasma ACTH concentrations. In contrast, the concentration of CRF was markedly reduced in the locus coeruleus, amygdala, and several cortical regions by either triazalobenzodiazepine. Acute treatment with imipramine was without effect on CRF concentrations in any brain region studied. Of particular interest is the finding that the two triazolobenzodiazepines exert effects on CRF concentrations in the locus coeruleus and hypothalamus that are opposite to CRF changes seen after stress.

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Section: Discussionmentioning

confidence: 99%

Acute effects of alprazolam and adinazolam on the concentrations of corticotropin‐releasing factor in the rat brain

Owens

Bissette

Nemeroff

1989

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“…After a single intravenous injection to mice, benzodiazepine receptor occupancy (based on ex vivo binding techniques) was maximal 1 min after a dose of diazepam (Sethy et al 1983). For alprazolam, however, maximal binding was observed 10 min postdose.…”

Section: Lipid Solubility and Brain Uptakementioning

confidence: 99%

Clinical Pharmacokinetics of Alprazolam

Greenblatt

Wright

1993

Clinical Pharmacokinetics

341

108

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Alprazolam is a triazolobenzodiazepine that is extensively prescribed in the Western world for the treatment of anxiety and panic disorders. Its benzodiazepine receptor binding characteristics are qualitatively similar to those of other benzodiazepines. The drug is metabolised primarily by hepatic microsomal oxidation, yielding alpha-hydroxy- and 4-hydroxy-alprazolam as principal initial metabolites. Both have lower intrinsic benzodiazepine receptor affinity than alprazolam and appear in human plasma at less than 10% of the concentrations of the parent drug. Plasma concentrations of the 4-hydroxy metabolite exceed those of the alpha-hydroxy derivative, but urinary recovery of alpha-hydroxy-alprazolam greatly exceeds that of 4-hydroxy-alprazolam. This may be explained by chemical instability of 4-hydroxy-alprazolam in vitro. After single 1 mg oral doses in humans, typical pharmacokinetic variables for alprazolam are: a peak plasma concentration 12 to 22 micrograms/L occurring 0.7 to 1.8h postdose, a volume of distribution of 0.8 to 1.3 L/kg, elimination half-life of 9 to 16h and clearance of 0.7 to 1.5 ml/min/kg. Absolute bioavailability of oral alprazolam averages 80 to 100%. Pharmacokinetics are dose-independent and are unchanged during multiple-dose treatment. On average, mean steady-state plasma alprazolam concentrations change by 10 to 12 micrograms/L for each daily dosage change of 1 mg/day. Most studies show that alprazolam pharmacokinetics are not significantly influenced by gender. Clearance of alprazolam is reduced in many elderly individuals, even those who are apparently healthy. Clearance is significantly reduced in patients with cirrhosis. Renal disease causes reduced plasma protein binding of alprazolam (increased free fraction) and some data suggest reduced free clearance of alprazolam in such patients. Pharmacokinetics of alprazolam are not significantly altered in abstinent alcoholics or patients with panic disorder, and are not influenced by the phase of the menstrual cycle in women. Coadministration of cimetidine, fluoxetine, fluvoxamine or propoxyphene significantly impairs alprazolam clearance. However, alprazolam clearance is not altered by coadministration of propranolol, metronidazole, disulfiram, oral contraceptives or ethanol. Imipramine clearance may be impaired if alprazolam is coadministered. Alprazolam does not alter the pharmacokinetics of digoxin. Although a therapeutic concentration range is not clearly established, some studies indicate that optimal reduction of anxiety associated with panic disorder occurs at steady-state plasma alprazolam concentrations of 20 to 40 micrograms/L. Concentrations higher than this may be needed for suppression of the actual panic attacks. Side effects associated with alprazolam (drowsiness, sedation, etc.) are consistent with its primary benzodiazepine agonist action and increase in frequency with higher steady-state plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Triazolam produces sedative, anticonvulsant, and anxiolytic effects, which are similar to effects produced by diazepam and chlordiazepoxide (Hester et al 1971 ;Eberts 1974;Sethy et al 1983). On a short term basis triazolam is a highly effective therapeutic treatment for insomnia and for some neuroses associated with excessive feelings of anxiety.…”

mentioning

confidence: 93%

“…Triazolam is a structural analog of diazepam which has a high affinity for benzodiazepine receptors (Sethy et al 1983). Triazolam produces sedative, anticonvulsant, and anxiolytic effects, which are similar to effects produced by diazepam and chlordiazepoxide (Hester et al 1971 ;Eberts 1974;Sethy et al 1983).…”

mentioning

confidence: 97%

Triazolam attenuates amphetamine but not morphine conditioned place preferences

1989

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In a series of four experiments the benzodiazepine triazolam was tested for reinforcing effects and for effects on reinforcement induced by amphetamine and morphine. Reinforcement was assessed in a conditioned place preference paradigm. Triazolam did not produce reinforcing or aversive effects when administered in doses ranging from 0.0625 to 0.5 mg/kg. Triazolam did attenuate reinforcing effects produced by 0.75 and 1.25 mg/kg amphetamine. No effect of triazolam was observed on morphine-induced reinforcement. These results indicate that the administration of triazolam can affect the brain mechanisms that mediate the reinforcing effects of amphetamine but not morphine.

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Interaction of triazolobenzodiazepines with benzodiazepine receptors

Cited by 19 publications

References 2 publications

Acute effects of alprazolam and adinazolam on the concentrations of corticotropin‐releasing factor in the rat brain

Acute effects of alprazolam and adinazolam on the concentrations of corticotropin‐releasing factor in the rat brain

Clinical Pharmacokinetics of Alprazolam

Triazolam attenuates amphetamine but not morphine conditioned place preferences

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