Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs. Tbventy-six healthy subjects from 19 to 85 yr old took single 15-rng doses ...
Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs Tbventy-six healthy subjects from 19 to 85 yr old took single 15-rng doses offlurazepam (FLZ). Concentrations of desalkylflurazepam (DAFLZ), its principal metabolite, were measured by gas-liquid chromatography in multiple samples drawn 7 or more days after the dose. For the jirsr 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ ti2asdetected,from 12 hr onward. Its elimination halflife (1%) (range, 37 to 289 hr) was longer in elderly than in young m m ( x 74 and 160 hr, p < 0.05), but 2% in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withrlrawal period, and morning self-ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 nglml, P < 0.05), bur values were essentially the same in elderly and young women (85 and 86 nglml). Single-dose 1% correlated with washout I% after termination of FLZ treatment (r = 0.87, P < 0.01). Clinical self-ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, "deeper" sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of "overshoot" sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported.
David J. Greenblatt, M.D., Marcia Divoll, B.S., Jerold S. Harmatz, B.A., Dean S. MacLaughlin, Ph.D., and Richard I. Shader, M.D. Boston, Mass. Division of Clinical Pharmacology, Departments cf Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center Hospital
Supported in part by Grant MH-34223 from the United States Public Health Service, by Grant 77-61 1 from the Foundations' Fund for Research in Psychiatry, and by a Grant-in-Aid from HoffmannLaRoche, Inc., Nutley, N.J. Received for publication Feb. 14, 1981. Accepted for publication June 2 , 1981. Reprint request to: David J. Greenblatt, M.D., Division of C h i cal Pharmacology, Box 1007, New England Medical Center Hospital, 171 Harrison Ave., Boston, MA 021 11.
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Flurazepam (FLZ, Dalmane) is an extensively prescribed hypnotic with efficacy during both short- and long-term use.g3 'O Available kinetic data suggest that its N-dealkylated metabolite, desalkylflurazepam (DAFLZ), is a major pharmacologically active substance detected
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FLURAZEPAM HYDROCHLORIDE
DESALKYLFLURAZEPAM
Fig. 1. Structure of FLZ and its major metabolite DAFLZ.
in humans receiving the drug.Ix. 2" (Fig. 1). DAFLZ has a very long elimination half-life (t%P), such that multiple-dose therapy with the parent compound leads to its cumulation. l 8 Clinical studies suggesting cumulative daytime sedation and performance-impairing effects of have led to concern regarding potential FLZ" .'" hazards of its long-term use.Z'. '7 Hypnotic drug use in the elderly is also a problem of medical and public health concern; there was a greater frequency of drowsiness and hangover reported after 30-mg doses of FLZ in hospitalized patients older than 60 yr than in patients of 50 yr or less.8 No age-related effects were observed at lower doses. The apparent sensitivity of the elderly to the sedative effect of FLZ after high doses might be partially explained by age-related changes in the disposition of DAFLZ, which lead to more extensive cumulation and therefore more profound clinical effects. We assessed the clinical effects of FLZ and the kinetics of its principal metabolite, DAFLZ, after single and repeated doses in healthy young and elderly noninsomniac subjects of both sexes. Methods
Single-dose study. Twenty-six healthy noninsomniac men and women participated. They were divided into four groups based on age: young men, young women, elderly men, and elderly women (Table I). All of the young sub-
jects were free of identifiable medical disease and were taking no regular medications (women were not taking oral contraceptives). All elderly subjects were active and in good general health. One elderly woman had atrial fibrillation controlled with digoxin and one elderly male had mild hypertension treated with a thiazide diuretic. After fasting for at least 4 hr, subjects took a single 15-mg capsule of FLZ (Dalmane) with 100 to 200 ml water. Venous blood samples were drawn from an indwelling butterfly cannula (kept patent by flushing with dilute heparin solution) or by venipuncture into heparinized tubes before the dose and at 15, 30, 45, and 60 minand 1 . 5 , 2 , 2 . 5 , 3 , 4 , 6 , 8, 1 2 , a n d 2 4 h r after the dose. Further samples were drawn every 24 to 48 hr for 7 to 9 days. Plasma was separated and frozen until the time of assay. Preliminary analysis of plasma samples from one of the elderly male subjects indicated an unusually long t % P for DAFLZ that could not be reliably estimated from 9 days of sampling. Estimation of DAFLZ kinetic variables in this subject was based on a second study, performed at a later date, in which he received a single 30-mg dose of FLZ. Blood sampling proceeded for 23 days as described above. Multiple-dose study. Eighteen of the 26 subjects participated in the multiple-dose study after a washout period of at least 2 wk. Each took single 15-mg doses of FLZ nightly for 15 consecutive nights. Venous blood samples were
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Table I. Subject characteristics and kinetics of desalky@urazepam (mean with range) Yo~rrlg 111~~11
Young women
Elderly men
Elderly women
Subject characteristics Age (yr) Weight (kg) Smoking (cigaretteslday) Single-dose kinetics No. of subjects Peak plasma concentration (nglml) Time of peak concentration (hr) Elimination t% (hr) Multiple-dose kinetics No. of subjects Accumulation t% (hr) Total Css (ngiml) Unbound fraction (%) Unbound Css (ngiml) Observed accumulation ratio Predicted accumulation ratio tV2w (hr) Difference between young and elderly males: *t =
tt = St =
2.48, P < 0.05. 2.87, P < 0.05. 2.72, P < 0.05.
drawn in the morning on day 2 (the first dose was taken the night before) and again in the morningondays 3 , 4 , 5 , 6 , 8 , 9 , 10, 11, 12, 13, and 15. Additional evening samples were drawn (before dose) in the evening on days 3 , 5 , 8, 10, 12, and 15. The final dose was taken on day 15. After this dose blood samples were drawn at 15, 30, 45, and 60 min and 1.5, 2, 2.5, 3, 4, 8, and 12 hr. A sample was drawn in the evening on day 16 (24 hr after the last dose), in the morning on day 17, and then every 24 to 48 hr for 10 days after the last dose. Clinical status, mood state, and sleep patterns
were evaluated by a series of thirty-nine 100mm visual analogue scales* described in detail elsewhere.". Subjects completed the rating scales in the morning on at least three occasions prior to the start of the multiple-dose study and again in the morning on days 2, 3, 4, 5 , 6, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, and 22. Subjects always completed the scales without access to their prior evaluations. Analysis of plasma samples. DAFLZ con-
"
*Copies of the rating scales are available on request from the authors.
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FEMALE. 20 years
MALE. 71 years
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Fig. 2. Plasma DAFLZ concentrations after 15-mg doses of FLZ in representative young and elderly subjects.
centrations in all plasma samples were determined by electron-capture gas-liquid chromatography using modifications of described techniques." After addition of a benzodiazepine analogue internal standard (Ro 5-3027 or Ro 7-9749)* to 0.5- to 1.O-ml aliquots of plasma, samples were extracted with benzene containing 1.5% isoamyl alcohol. The organic extracts were separated, evaporated to dryness, and reconstituted before chromatographic analysis. A series of calibration standards containing known concentrations of DAFLZ* were extracted and analyzed daily along with each set of unknowns. The analytic instrument was a Hew*Pure reference standards were kindly supplied by Dr. W. E. Scon, Hoffmann-LaRoche, Inc., Nutley, N.J.
lett-Packard gas chromatograph (model 5837A or 5840A) equipped with a 15 mCi 63-nickel electron-capture detector, an electronic integrator, and an automatic sampler. The column was coiled glass, 4 ft in length by 2 mm internal diameter, packed with 3% SP-2250 on 801100 Supelcoport (Packing 1- 1767, Supelco) operated at 240". Injection port and detector temperatures were 310". The carrier gas was argon:methane (95 :5) at a flow rate of 30 mllmin. The sensitivity limits for the technique are 1 ng of DAFLZ per milliliter of original sample. The coefficients of variation for identical samples did not exceed 6%. Recovery of DAFLZ and the internal standard is more than 95% complete. The extent of DAFLZ binding to plasma protein for each subject in the multiple-dose study
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was determined from a single plasma sample drawn in the nonfasting state at least 72 hr after the last exposure to the heparin solution used to flush the blood sampling cannula. Binding was determined by equilibrium dialysis". of duplicate 2-ml samples spiked to contain 200 ng DAFLZ per milliliter. Binding was independent of plasma DAFLZ concentration over a range of 50 to 2,000 nglml. Kinetic and statistical analysis. After single doses of FLZ the apparent t%P of DAFLZ was determined by least-squares regression analysis of the terminal log-linear portion of the plasma concentration curve. Rate and extent of DAFLZ cumulation during multiple FLZ dosing were determined by iterative nonlinear least-squares regression analysis. DAFLZ data points during the 15 days of treatment were fitted by computer to the following function: C
=
Css ( 1
-
ckt)
where C is the plasma DAFLZ concentration at time t (in days) after the start of repeated dosing,I3 Css is the steady-state plasma concentration at "infinite" time, and k is the apparent rate constant for DAFLZ cumulation, which was used to calculate an apparent t% of cumulation. After termination of repeated dosing, the half-life of DAFLZ elimination or "washout" (tlhw) was calculated by linear regression analysis of logarithm of concentration versus time after termination of FLZ dosage. The unbound steady-state plasma concentration for each subject was calculated as the product of Css and the free fraction of DAFLZ in plasma. The observed DAFLZ cumulation ratio was calculated as the area under the 24 hr plasma concentration curve (AUC) after the final dose of FLZ divided by the AUC for the first 24 hr after 15 mg of FLZ in the single-dose study. The predicted cumulation ratio was calculated as previously described6 with the washout rate constant (0.693Itsw) and the dosage interval (24 hr). Individual pretreatment clinical self-ratings were averaged and used as baseline values. Ratings obtained during and after repeated doses of FLZ were expressed as the change over the baseline value. The effects of age, sex, and time on clinical ratings were evaluated by analysis of variance.
Fig. 3. A , Chromatogram of a plasma extract from a subject before FLZ. B. Chromatogram of a plasma extract from the same subject 1 hr after a single dose of drug. Peak 1 corresponds to DAFLZ, the major metabolite, peaks 2 and 3 correspond to FLZ aldehyde and hydroxyethylflurazepam, two transiently appearing metabolites, and peak 4 is not definitively identified.
Results
Single-dose study. The rate of appearance of DAFLZ in plasma after single doses of FLZ was variable. The time of highest measured concentration ranged from 0.5 to 96 hr after dose and was not influenced by age (Table I, Fig. 2). Peak DAFLZ concentrations ranged from 5 to 20 nglml and tended to be higher in women than in men, possibly due to the lower body weights of women. In all subjects, at least three chromatographic peaks in addition to that corresponding to DAFLZ were seen in plasma samples drawn for up to 6 hr after dose (Fig. 3); none of these corresponded to intact FLZ. One peak corresponded to the hydroxyethyl derivative of FLZ and another has been tentatively
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Fig. 4. Relation of age to DAFLZ tl/zp in the single-dose study among men and women. Solid lines were determimed by least-squares regression analysis.
identified as an aldehyde metabolite*; the other (unidentified) peak may correspond to another metabolic product. '" .Within 8 to 12 hr after single doses, only DAFLZ could be detected in blood. DAFLZ t % P ranged from 37 to 289 hr. One young male subject (a heavy cigarette smoker) had such a high value for t % P that it could not be reliably quantitated because the sampling time was not sufficient. This subject was not available for restudy. With this data deleted from parametric analyses, t%P was found to increase with age in both sexes and there was difference between young and elderly men (Table I, Fig. 4). Nonparametric testing with inclusion of this subject yielded similar results. The rank-order correlation of t % P with age among men just failed to attain statistical significance (Spearman rho = 0.49, P = 0.086), as did the difference between young andelderly men using the Wilcoxon two-sample test (P = 0.074). The relation of age to DAFLZ t%p was not confounded by cigarette smoking. Among all subjects, smoking was not related to t?hp
*Garland WA: Personal communication, 1981
(Spearman rho = -0.04, N.S.). Multiple regression analysis (using t%P as a ranked variable) indicated that age, sex, and cigarette smoking collectively explained 28% of overall variability in t?hP (multiple r2 = 0.28, P < 0.06). The largest standardized regression coefficient (SRC) was associated with age (SRC = 0.55, P < 0.01). SRC for sex and smoking were considerably smaller (0.30 and 0.23) and did not reach statistical significance. SRC for smoking was a positive value, indicating that, if anything, smoking was associated with longer rather than shorter values of t % p Multiple-dose study. Kinetics. DAFLZ cumulated slowly during the 15 days of FLZ treatment. Values of cumulation t% ranged from 45 to 243 hr and tended to be longer (although not significantly so) in the elderly than in the young of both sexes (Table I). Attainment of steady state was essentially complete among subjects with shorter values of accumulation t% (Fig. 5); in those with long t% values, the 15 days of treatment were not sufficient for complete attainment of the steady-state condition (Fig. 6). The extent of DAFLZ cumulation was considerable. Overall mean observed and predicted
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Fig. 5. DAFLZ plasma concentrations during and after the multiple-dose study. The two subjects are the same as in Fig. 2 and represent relatively rapid accumulators. The solid lines correspond to kinetic functions representing DAFLZ cumulation and postdosage washout. The horizontal dotted line represents the Css.
cumulation ratios (7.5 and 8.1) were not significantly different but the correlation between the two, although statistically significant, was weak (r = 0.49, P < 0.05). Observed and predicted ratios both tended to be larger in the elderly than in the young of both sexes (Table I). Css for total (free and bound) DAFLZ ranged from 34 to 151 nglml and generally were higher in women than in men, partly due to differences in body weight. Mean Css for young and elderly women were essentially identical (85 vs 86 nglml), but mean Css for elderly men (81 nglml) was greater than in young men (53 nglml, P < 0.05). DAFLZ was extensively bound to plasma protein. The unbound fraction ranged from
2.4% to 4.3% of the total plasma concentration. Unbound fraction increased with age regardless of sex (r = 0.56, P < 0.05), partly because of lower plasma albumin concentrations in the elderly. After correction of Css for individual values of free fraction, unbound Css was higher in the elderly than in the young of both sexes (Table I); the difference was especially large between young and elderly men (1.8 and 3.0 nglml, t = 2.72, P < 0.05). Consistent with the slow rate of DAFLZ cumulation, washout after termination of FLZ treatment was also slow. The t?hw ranged from 43 to 268 hr and tended to be longer in the elderly than in the young (particularly among men, Table I). Among individuals with long
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Fig. 6. DAFLZ plasma concentrations during and after the multiple-dose study. The two subjects
represent slow accumulators. Solid lines are as in Fig. 5. Dashed line represents the projected pattern of cumulation if FLZ dosage continued until steady-state was attained. The horizontal dotted line represents the projected Css. t%ws (Fig. 6), DAFLZ plasma concentrations remained high even 10 days after the last dose of FLZ. After termination of the repeated multiple doses of FLZ, tM w correlated strong1y (r = 0.87) with values of t % P from the singledose study. Clinical effects. Two-way analysis of variance indicated changes over time in self-rated sedation based on morning scores on visual analogue scales. Self-rated morning sedation scores increased progressively in subjects while on FLZ and returned to or near baseline values 2 to 3 days after the last dose (Fig. 7). There were also time-related changes of a similar pattern in self-ratings of "thinking speed, " "seclusive,
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and "contented" (the last two increased). Age-time interaction terms in "thinking " and "contented" were statistically significant, with quantitatively greater changes in the young than in the elderly groups. Changes over time in "fatigue, " "pleasant" (increased), and "nervous" (decreased) were significant only when interacting with age; changes in the young group were greater than in the elderly. Subjects' spontaneous informal reports were consistent with rating-scale changes. A progressive increase in daytime calmness or fatigue over the course of the study was described by some subjects and some reported taking afternoon naps contrary to their usual habits.
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Fig. 7. Clinical self-ratings of morning sedation and depth of sleep during and after the multipledose study. Each point is the mean for all subjects at the corresponding time. All values are expressed as the change over the pretreatment baseline (dashed line). Values differing (P < 0.05) from zero change are indicated by an asterisk.
Self-rated depth of sleep, directed toward "deeper" sleep, changed over time (Fig. 7); ratings did not return to baseline until 7 days after the last dose. Changes over time in latency to sleep onset (reduced), sleep duration (prolonged), and number of awakenings (reduced) also were statistically significant (Fig. 8); after the last dose, values returned to or "overshot" the pretreatment baseline. Sleep latency on the fifth and seventh days after the last FLZ dose averaged 8 min longer than the pretreatment mean of 16.4 min. Age-sex interactions, with greater changes in young than in elderly subject
groups, were observed in sleep depth and sleep latency. Clinical self-ratings relating to muscular function and coordination (feeling "weak, " difficulty with personal hygiene, tremulousness, etc.) did not change with time. Subjects' informal reports also indicated no perceived decrement in ability to perform usual daily intellectual and motor tasks despite a feeling of fatigue. No consistent within- or between-subject associations were observed between kinetic variables and clinical ratings. Other than the clinical
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Fig. 8. Clinical self-ratings of sleep latency and sleep duration during and after the multiple-dose study. Each point is the mean for all subjects at the corresponding time. All values are expressed as the change over the pretreatment baseline (dashed line). Values different (P < 0.05) from zero change are indicated by an asterisk.
effects described above, no side effects or adverse reactions were encountered. Discussion
The kinetic profile of FLZ after single oral doses in man is complex. At least four chromatographic peaks can be identified in plasma extracts for up to 8 hr after a single dose. None of these peaks corresponds to intact FLZ, of which only trace amounts appear in human plasma after usual therapeutic doses.4 Chromatographic peaks probably represent metabolic products of FLZ formed by stepwise deg-
radation of the N-1 alkyl side chain during the process of absorption from the gastrointestinal tract or by hepatic biotransformati~n.'~~ 25 These relatively short-acting metabolites are pharmacologically activez4 and may contribute to the induction of sleep. The principal metabolite, DAFLZ, is formed by complete removal of the N-1 alkyl side chain. Unlike the other components, DAFLZ is eliminated very slowly and remains detectable in plasma for days or weeks after single doses of FLZ. As in the case of the closely related benzodiazepines diazepam" and desmethyldiazepam,' DAFLZ tMP is longer in
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elderly than in young subjects, particularly in elderly men. The slow elimination of DAFLZ by all is consistent with several clinical studies demonstrating measurable dynamic effects of FLZ the day after single bedtime doses.' The effect of age on DAFLZ cumulation was consistent with findings in the single-dose study. Css of total as well as unbound DAFLZ were higher in elderly than young men, whereas age-related differences among women were small. In all subjects, DAFLZ cumulation was extensive as well as slow, which is consistent with clinical study findings indicating greater sleep-inducing effects after several nights of dosing and carry-over of nocturnal hypnotic effects into the postdosage "withdrawal" period.'", 16, 23 Some (but not all) studies also suggest cumulative daytime sedation ("hangover") and some impairment of psychomotor performance during use of 30-mg doses of FLZ." 22 We emphasize, however, that central nervous system adaptation or tolerance may partly or completely offset the potential central depressant effects of DAFLZ cumulation7 and that results of laboratory tests of psychomotor function do not necessarily apply to performance of "real-life " tasks. Interpretation of clinical data from our study is complicated by the fact that our subject population consisted of noninsomniacs and that the blood sampling requirements for the kinetic study precluded the use of a placebo. However, subjects always completed clinical ratings without access to prior ratings and were not aware, in general, of the possible clinical consequences of FLZ cumulation. Despite the limitations, the findings provide information on the clinical effects of repeated dosing with FLZ. Self-rated morning sedation increased progressively over the 15-day duration of drug use and then gradually reverted to baseline in the several days after termination of drug. Similar changes were also observed in other self-ratings; these reports are consistent with the daytime sedative and calming effects associated with DAFLZ cumulation. Sleep patterns also changed. Selfrated depth of sleep increased with time, as did total sleep duration. Sleep latency and number of awakenings decreased. There were carryover effects after termination of dosing which
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was consistent with the plasma level profile and with many previous studies. Five to seven days after the last dose values of sleep latency, duration, and number of awakenings "crossed over" the pretreatment baseline. Although not supported statistically, this pattern suggests a transient period of posthypnotic disturbance of sleep that requires further evaluation. In other reports this highly controversial "rebound" phenomenon has been associated mainly with short-acting hypnotics and occurs immediately 1 7 3 21 Our data after drug discontinuation.'*, suggest that rebound effects may not be unique to short-acting drugs, but may also occur after termination of treatment with FLZ, although the onset is delayed due to the slow washout of DAFLZ . Our study provides no evidence of increased sensitivity to FLZ among elderly subjects at the plasma DAFLZ concentrations that were achieved by 15-mg doses since changes in several clinical ratings were greater in young than in elderly subjects. This could partly reflect age-related differences in interpretation of rating scale questions or a tendency to deny or minimize subjective effects in the elderly group. Nonetheless, the results are consistent with studies demonstrating the safety of 15-mg FLZ doses among elderly subject^.^ These results cannot be extrapolated to 30-mg doses without further clinical and kinetic study. It may well be that the increased cumulation of total and unbound DAFLZ in elderly as opposed to young males could lead to more profound clinical effects in the elderly at higher doses.
'"
We are grateful for the assistance of Ann Locniskar, Lomna L. Jason, Ann Werner, and Lawrence J. Moschitto.
References 1. Allen MD, Greenblatt DJ, Harmatz JS, Shader RI: Desmethyldiazepam kinetics in the elderly THER after oral prazepam. CLIN PHARMACOL 28: 196-202, 1980. 2. Borland RG, Nicholson AN: Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance. Br J Clin Pharmacol 2:9-17, 1975. 3. Church MW, Johnson LC: Mood and performance of poor sleepers during repeated use of
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flurazepam. Psychopharmacology 61:309-316, 1979. 4. Glover W, Earley J, Delaney M, Dixon R: Radioimmunoassay of flurazepam in human plasma. J Pharm Sci 69:601-602, 1980. 5. Greenblatt DJ: Simultaneous gas chromatographic analysis for diazepam and its major metabolite, desmethyldiazepam, with use of double internal standardization. Clin Chem 24:18381841, 1978. 6. Greenblatt DJ, Koch-Weser J: Clinical pharmacokinetics. N Engl J Med 293:702-705, 964970, 1975. 7. Greenblatt DJ, Shader RI: Dependence, tolerance, and addiction to benzodiazepines: Clinical and pharmacokinetic considerations. Drug Metab Rev 8:13-28, 1978. 8. Greenblatt DJ, Allen MD, Shader RI: Toxicity of high-dose flurazepam in the elderly. CLIN PHARMACOL THER21:355-361, 1977. 9. Greenblatt DJ, Shader RI, Koch-Weser J: Flurazepam hydrochloride. CLINPHARMACOL THER 17:l-14, 1975. 10. Greenblatt DJ, Shader RI, Koch-Weser J: Flurazepam hydrochloride, a benzodiazepine hypnotic. Ann Intern Med 83:237-241, 1975. 11. Greenblatt DJ, Allen MD, Harmatz JS, Shader RI: Diazepam disposition determinants. CLIN PHARMACOL THER27:301-3 12, 1980. 12. Greenblatt DJ, Shader RI, Harmatz JS, Franke K, Koch-Weser J: Absorption rate, blood concentrations, and early response to oral chlordiazepoxide. Am J Psychiatry 134:559-562, 1977. 13. Greenblatt DJ, Allen MD, MacLaughlin DS, Huffman DH, Harmatz JS, Shader R1: Singleand multiple-dose kinetics of oral lorazepam in humans: the predictability of accumulation. J Pharmacokinet Biopharm 7: 159-179, 1979. 14. Hartse KM, Roth T, Piccione PM, Zorick FJ: Rebound insomnia. Science 208:423-424, 1980. 15. Kales A, Bixler EO, Kales JD, Scharf MB: Comparative effectiveness of nine hypnotic drugs: sleep laboratory studies. J Clin Pharmacol 17:207-213, 1977. 16. Kales A, Bixler EO, Scharf MB, Kales JD: Sleep laboratory studies of flurazepam: A model for evaluating hypnotic drugs. CLlN PHARMAc o THER ~ 19:576-583, 1976.
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17. Kales A, Scharf MB, Kales JD, Soldatos CR: Rebound insomnia: A potential hazard following withdrawal of certain benzodiazepines. JAMA 241:1692-1695, 1979. 18. Kaplan SA, deSilva JAF, Jack ML, Alexander K , Strojny N, Weinfeld RE, Puglisi CV, Weissman L: Blood level profile in man following chronic oral administration of flurazepam hydrochloride. J Pharm Sci 62:1932-1935, 1973. 19. Mahon WA, Inaba T, Stone RM: Metabolism of flurazepam by the small intestine. CLINPHARMACOL THER22:228-233, 1977. 20. Mendelson WB, Goodwin DW, Hill SY, Reichman JD: The morning after: Residual EEG effects of triazolam and flurazepam, alone and in combination with alcohol. Curr Ther Res 19: 155-163, 1976. 21. Nicholson AN: Hypnotics: Rebound insomnia and residual sequelae. Br J Clin Pharmacol 9~223-225,1980. 22. Oswald 1: The why and how of hypnotic drugs. Br Med J 1:1167-1168, 1979. 23. Oswald I, Adam K, Borrow S , Idzikowski C: The effects of two hypnotics on sleep, subjective feelings and skilled performance, in Passouant P, Oswald I, editors: Pharmacology of the states of alertness. Oxford and London, 1979, Pergamon Press, Inc. 24. Randall LO, Kappell B: Pharmacological activity of some benzodiazepines and their metabolites, in Garattini S, Mussini E, Randall LO, editors: The benzodiazepines. New York, 1973, Raven Press, pp. 27-5 1. 25. Schwartz MA, Postma E: Metabolism of flurazepam, a benzodiazepine, in man and dog. J Pharm Sci 59: 1800-1806, 1970. 26. Shader RI, Georgotas A, Greenblatt DJ, Harmatz JS, Allen MD: Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide. CLINPHARMACOL THER24:308-315, 1978. 27. Solomon F, White CC, Parron DL, Mendelson WB: Sleeping pills, insomnia, and medical practice. N Engl J Med 300:803-808, 1979. 28. Woo E, Greenblatt DJ: Pharmacokinetic and clinical implications of quinidine protein binding. J Pharm Sci 68:466-470, 1979.
