Pharmacokinetic-Pharmacodynamic Modeling in Drug Development: Comments and Applications
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
To further separate the effects of these compounds, a study similar to that described above was performed in 24 healthy male subjects to assess the effects produced by intravenous administration of adinazolam and NDMAD.26 Doses of 0, 5, 10, 15, and 20 mg of adinazolam and 0, 10, 20, 30, and 40 mg NDMAD were administered as 30-min IV infusions. These doses were selected to cover the range of plasma concentrations of these compounds seen following oral administration; the doses differed because the absolute bioavailabilities of these compounds differ by a factor of ≈2 (0.39 vs. 0.74, respectively).27 As expected, N-demethyladinazolam administration resulted in dose-related decrements in performance. However, even at the highest dose, adinazolam failed to produce significant decrements in performance (Figure 8). This is despite the fact that the plasma concentrations of adinazolam achieved after IV administration exceeded those observed after a 60-mg single oral dose, a dose which produces substantial psychomotor performance decrements. The results may be explained by examining the plasma-time profiles for the parent compound and metabolite shown in Figure 9; IV adinazolam administration results in maximal plasma concentrations of the metabolite which are too low to produce substantial psychomotor performance decrements. These results show that adinazolam itself is devoid of benzodiazepine-like side effects in man; these effects are primarily mediated by the y N-demethyl metabolite.
Pharmacotherapy of Mixed Anxiety/Depression Disorders
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
The so-called high-potency benzodiazepines (i.e., alprazolam and adinazolam) appear to be quite promising in the treament of comorbid anxiety-depression conditions, since they have been shown to have both an anxiolytic and an antidepressant activity. The mechanisms underlying this complex clinical profile are not completely known. Alprazolam has been reported to have an effect on corticotropin-releasing hormone (CRH) [148] as well as noradrenergic properties [149], and both these parmacodynamic properties may well account for its antidepressant activity.
Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014–2017
Published in Clinical Toxicology, 2019
Joseph E. Carpenter, Brian Patrick Murray, Camille Dunkley, Ziad N. Kazzi, Melissa H. Gittinger
We retrieved coded, de-identified data for all intentional single-agent exposures to the following compounds: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Corresponding Poisindex codes are available in the supplementary material. Etizolam exposures have been tracked since 2007, however specific exposure codes for all other agents were not added until 2016. Though there are additional compounds within the designer benzodiazepine class, at the time of this study these agents did not have a specific coded designation within NPDS, and therefore could not be retrieved. All exposure routes were included. Accidental ingestions and any subjects with exposure to more than one substance were excluded.
Occurrence and time course of NPS benzodiazepines in Sweden – results from intoxication cases in the STRIDA project
Published in Clinical Toxicology, 2019
Matilda Bäckberg, Madeleine Pettersson Bergstrand, Olof Beck, Anders Helander
The NPS BZD covered in this study (Figure 2) were adinazolam, bentazepam, clonazolam, cloniprazepam, diclazepam, deschloroetizolam, flubromazolam, flunitrazolam, 3-hydroxyflubromazepam, ketazolam, meclonazepam, metizolam, nifoxipam, nitrazolam, pivoxazepam, and pyrazolam (1 mg/mL solutions from Chiron, Trondheim, Norway), bromazepam, clobazam, etizolam, estazolam, flurazepam, 3-hydroxyphenazepam, N-desmethylflunitrazepam, nimetazepam, phenazepam, and prazepam (1 mg/mL solutions from Cerilliant, Round Rock, TX), flubromazepam (1 mg/mL solution from LGC, Teddington, UK), and tetrazepam (0.1 mg/mL solution from LGC). All solutes were obtained in acetonitrile or methanol.
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