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OtherBEHAVIORAL PHARMACOLOGY

Alprazolam in Young and Elderly Men: Sensitivity and Tolerance to Psychomotor, Sedative and Memory Effects

Richard J. Bertz, Patricia D. Kroboth, Frank J. Kroboth, Ian J. Reynolds, Firoozeh Salek, C. Eugene Wright and Randall B. Smith
Journal of Pharmacology and Experimental Therapeutics June 1997, 281 (3) 1317-1329;
Richard J. Bertz
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Patricia D. Kroboth
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Frank J. Kroboth
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Ian J. Reynolds
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Firoozeh Salek
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C. Eugene Wright
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Randall B. Smith
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Abstract

This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22- 35) and 13 elderly (ages 65–75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and eliminationt [1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC50values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Mediant [1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.

Footnotes

  • Send reprint requests to: Patricia D. Kroboth, Ph.D., University of Pittsburgh/Pharmacodynamic Research Center, 904 Salk Hall, Pittsburgh, PA 15261

  • ↵1 This research was sponsored by The Upjohn Company and by NIH/NCRR/GCRC Grant 5-M01-RR00056 and was presented in two parts at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meetings in March 1994 and March 1995.

  • ↵2 Fellow of the American Foundation for Pharmaceutical Education. Present address: Abbott Laboratories, Research Pharmacokineticist, Department of Pharmacokinetics and Biopharmaceutics.

  • Abbreviations:
    AUC
    area under the plasma concentration curve
    AUEC
    area under the effect curve
    CS
    card sorting task
    CPT
    continuous performance test
    DSST
    digit symbol substitution test
    EC50
    concentration that elicits half-maximal response
    Eo
    baseline
    kt
    tolerance rate constant or effect offset rate constant
    MaxOE
    maximum observed effect
    Mn1–9hr
    mean alprazolam concentration from 1 to 9 hr
    MnE1–9hr
    mean effect from 1 to 9 hr
    NRSS
    nurse-rated sedation score
    RMT
    Randt Memory Test
    tMaxOE
    time to maximum effect
    t[1/2]β
    half-life for elimination of drug
    t[1/2]t
    half-life for offset of effect
    • Received July 11, 1996.
    • Accepted February 5, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 3
1 Jun 1997
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OtherBEHAVIORAL PHARMACOLOGY

Alprazolam in Young and Elderly Men: Sensitivity and Tolerance to Psychomotor, Sedative and Memory Effects

Richard J. Bertz, Patricia D. Kroboth, Frank J. Kroboth, Ian J. Reynolds, Firoozeh Salek, C. Eugene Wright and Randall B. Smith
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1317-1329;

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OtherBEHAVIORAL PHARMACOLOGY

Alprazolam in Young and Elderly Men: Sensitivity and Tolerance to Psychomotor, Sedative and Memory Effects

Richard J. Bertz, Patricia D. Kroboth, Frank J. Kroboth, Ian J. Reynolds, Firoozeh Salek, C. Eugene Wright and Randall B. Smith
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1317-1329;
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