Psychomotor and Memory Effects of Two Adinazolam Formulations Assessed by a Computerized Neuropsychological Test Battery

Fleishaker, Joseph C.; Sisson, Theresa A.; Sramek, John J.; Conrad, Julie G.; Verof, Amy E.; Cutler, Neal R.

doi:10.1002/j.1552-4604.1993.tb04689.x

Cited by 8 publications

(3 citation statements)

References 20 publications

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“…administration of doses ranging from 5 to 20 mg (30-33), p.o. administration of immediate release (IR) formulations of doses ranging from 15 to 60 mg (31,32,(34)(35)(36)(37)(38)(39), and p.o. administration of sustained release (SR) formulations of doses ranging from 15 to 60 mg (32,(38)(39)(40).…”

Section: Adinazolammentioning

confidence: 99%

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Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Lukáčová

Woltosz

Bolger

2009

AAPS J

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Abstract. The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlus TM (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration-time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/ PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs' bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

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Section: Adinazolammentioning

confidence: 99%

“…The in vivo PD data (sedation scores) were reported for p.o. IR formulations of doses ranging from 20 to 60 mg (34,36,38,39), and a 60-mg p.o. SR formulation.…”

Section: Adinazolammentioning

confidence: 99%

Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Lukáčová

Woltosz

Bolger

2009

AAPS J

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“…Previous studies investigating the pharmacodynamic effects of adinazolam and its active metabolite mainly utilized subjective measures of CNS activity, as well as semi‐objective measures of CNS activity, psychomotor performance, and memory 8,11,12 . Computerized analysis of the electroencephalogram (EEG) is recognized as an objective approach to quantitating the CNS effects of benzodiazepine agonists.…”

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confidence: 99%

Kinetics and Dynamics of Intravenous Adinazolam, N‐Desmethyl Adinazolam, and Alprazolam in Healthy Volunteers

Venkatakrishnan

Culm

Ehrenberg

et al. 2005

The Journal of Clinical Pharma

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The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.

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Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

et al. 1995

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Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P = 0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P = 0.031), and the difference in maximum category recall decrement was marginally significant (P = 0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.

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Psychomotor and Memory Effects of Two Adinazolam Formulations Assessed by a Computerized Neuropsychological Test Battery

Cited by 8 publications

References 20 publications

Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Kinetics and Dynamics of Intravenous Adinazolam, N‐Desmethyl Adinazolam, and Alprazolam in Healthy Volunteers

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects

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