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Br. J. clin. Pharmac. (1976), 3, 533-541

EFFECT OF AND FOSAZEPAM (A SOLUBLE DERIVATIVE OF DIAZEPAM) ON SLEEP IN MAN A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire

1 The effect of diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg), a soluble derivative of diazepam, on sleep was studied in six healthy adult males using electroencephalography for sleep measures, and analogue scales for subjective assessments of well-being and sleep quality. The effect of diazepam was limited to the night of ingestion, but the effect of fosazepam was carried over to the next night and so modified sleep for about 30 h after ingestion. 2 Effects on total sleep time were limited to the night of ingestion. There were increases with diazepam (10 mg) (P = 0.05), and with fosazepam (60 mg and 80 mg) (P = 0.001). For the night of ingestion sleep onset latencies were shortened, and awakenings were reduced by both drugs. The latency to stage 3 was shortened by fosazepam (60 mg and 80 mg) (P = 0.05). 3 The low and high dose of each drug reduced the duration (min) of stage 0 sleep (P = 0.01), but fosazepam also reduced the duration (min) of stage 1 sleep (P = 0.001), and there was an increase in stage 2 sleep (P = 0.01). With fosazepam there were carry over effects to the next night with reduction of stage 1 sleep (P = 0.05). There were no effects on the duration of stage 3, but there was evidence that stage 4 activity was reduced during the recovery night after ingestion of fosazepam (80 mg). No effects were observed on REM sleep. 4 Subjects reported an improved sense of well-being during the day after ingestion of diazepam and fosazepam, and with fosazepam they reported improved sleep. Correlations were calculated for sleep measures and subjective assessments.

Introduction

The suitability of an for persons involved Diazepam may be a particularly useful hyp- in skilled activity requires information which is notic, even though it has received little attention not usually included in the evaluation of drugs. from sleep researchers except for the brief report Individuals involved in skilled activity often work of Kales & Scharf (1973). In particular, its short irregular hours, and a suitable hypnotic must be elimination half time (De Silva, Koechlin & Bader, free from residual effects on performance, and 1966), and its limited effects on performance have effective when used at times which do not prompted the present study on the effect of 5 mg coincide with usually accepted sleep periods. Little and 10 mg on sleep in man. We have also studied work has been carried out on the effectiveness of the soluble derivative of diazepam, fosazepam, at unusual times, but several studies which, like diazepam, has a short elimination half have been concerned with residual effects on time. performance. Many hypnotics, including the , lead to impaired performance after overnight ingestion (Malpas, Rowan, Joyce & Methods Scott, 1970; Bond & Lader, 1972, 1973; Borland & Nicholson, 1974, 1975a; Borland, Nicholson & The subjects were six healthy male volunteers aged Wright, 1975), but it would appear that the between 19 and 43 years. They were familiar with persistence of impaired performance after the laboratory, and with the techniques used in diazepam is more limited than that after recording sleep activity. The assessment of each and hydrochloride (Bor- treatment (placebo or dose of a drug) involved 4 land & Nicholson, 1975a & b). days. For two nights the subjects slept at home 35 534 A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE

badly- very well. In each case a favourable a b 0t < OH3 response tended toward the 100 extreme of the P scale. CH Three ingestions of placebo, each a separate 4 day assessment, were included to determine CH3 CH2 whether any trends in sleep measures occurred during the study. Each subject received three ingestions of placebo, diazepam (5 mg and 10 mg), and fosazepam (60 mg and 80 mg). The study was double blind. Fosazepam (7-chlor - 1 - (dimethyl - phosphinylmethyl) - 5 - phenyl - 1, 3 - dihydro - 2H - ci N 1, 4 - benzodiazepin - 2 - on) is a soluble derivative of diazepam (greater than 50% at 200C) with an elimination half time of 1.8 ± 0.3 h. The formula is C18H18CIN202P (Figure 1) with a molecular weight of 360.5. Details of recording techniques, scoring of the electroencephalographic (EEG) records into sleep Figure 1 The structural formulae of diazepam and stages, and statistical analysis of the EEG measures fosazepam. The metabolism of diazepam includes and analogue scales are given in a previous paper demethylation with the formation of N-desmethyl- (Nicholson, Stone, Clarke & Ferres, 1976). diazepam (nordiazepam). A similar process occurs with fosazepam. The dimethyl-phosphinymethyl group is lost and nordiazepam is formed. Results Consistent trends were not observed in the sleep and retired at a set time between 23.00 and measures with the three separate ingestions of 23.30 h, and for the next two nights the subjects placebo, and so the values were combined. slept in the sleep laboratory. They were required The effect of diazepam (5 mg and 10 mg) and to refrain from napping and undue exercise, and to fosazepam (60 mg and 80 mg) on total sleep time, abstain from caffeine and after mid-day on number of stage shifts in the first 6 h, latency to the days which involved recordings. The sleep stage 3 and the appearance of the first REM laboratory was sound attenuated, and the period, and the REM/NREM ratio are given in temperature (18 ± 1°C) and humidity (55 ± 2%) Table 1. The effects on total sleep time were were controlled. Nine to twelve days separated limited to the night of ingestion. There were no each assessment. effects of diazepam (5 mg). With diazepam The subjects reported to the sleep laboratory (10 mg) total sleep time increased to 457.8 min 1.5 h before their set time to retire. At 0.5 h (P = 0.05). and with fosazepam (60 mg and 80 mg) before lights out subjects completed an assessment the total sleep times were 484.4 min and of their well-being related to a 100 mm analogue 514.2 min (P= 0.001). A regression equation scale. The assessment (A) was: How did you feel (P = 0.05) was fitted to the fosazepam data-total during the day? The extremes of the scale were sleep time = 412.5 + 1.245 dose (mg), and the Tired (00) and Fresh (100). Drug or placebo was dose of fosazepam equivalent to the effect of ingested on the third night only i.e. first night in 10 mg diazepam on total sleep time was 36.4 mg. the laboratory. On each occasion the subjects There were no effects of the drugs on stage shifts, ingested two idientical capsules. They were taken but the latency to stage 3 was reduced with with water at the set time between 23.00 and fosazepam (P = 0.05). The latency to the first 23.30 h (lights out). No capsules were ingested on REM period, and the REM/NREM ratio were not the fourth night i.e. second night in the sleep altered by the drugs. laboratory, and this night (recovery night) was The means for sleep onset latency, and number used to observe any residual effects of the drugs. and duration (min) of awakenings are given in In the morning the subjects were allowed to wake Tables 1 and 2, but the data were analysed using naturally, and 0.5 h after awakening completed the hypothesis that the observations were four assessments. The assessments and the distributed equally around critical values. For extremes of the 100 mm analogue scales were, B: I sleep onset latency the critical values were 20, 25 slept, very poorly - very well, C: Now I feel, very and 30 min. With placebo the hypothesis was sleepy - wide awake, D: I fell asleep, never - supported for each of these values, but with immediately, and E: After I fell asleep I slept, very diazepam the hypothesis was rejected at the DIAZEPAM AND SLEEP IN MAN 535

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30 min (P = 0.01) latency for night of ingestion, 25 minutes. Diazepam had little effect on reducing and at the 30 and 25 min (P= 0.01) latencies for the number of awakenings to 0, 1 or 0 + 1, except the recovery night. With fosazepam the hypothesis that awakenings to I and 0 + 1 on the recovery was rejected at the 30 min (P= 0.02) latency for night were reduced compared with placebo. night of ingestion and recovery night. Fosazepam reduced the number of awakenings to The analysis for awakenings is given in Tables 3 0 and 0 + 1 on the night of ingestion, but did not and 4. For number of awakenings to stage 0 and reduce the number of awakenings during the 0 + 1 the critical values were 9, 12 and 1 5, and for recovery night. The effect of diazepam and the number of awakenings to stage 1 the values fosazepam on the duration (min) of awakenings were 6, 9 and 12. For duration (min) of was more marked. Diazepam and fosazepam awakenings to 0 and 1 the values were 6, 9 and reduced the duration of awakenings to 0 activity 12 min, and for 0 + 1 the values were 1 5, 20 and compared with placebo, and with fosazepam the

Table 3 Levels of significance for deviation from equal distribution around critical values for number of awakenings with placebo, diazepam and fosazepam

Awakening (sleep stage) Treatment Night of ingestion Recovery night <9 <12 <15 <9 < 12 < 15 0 Placebo NS NS * * NS Diazepam NS NS * * * NS Fosazepam NS * * * NS NS NS <6 <9 <12 <6 <9 <12 1 Placebo NS * * * NS NS NS Diazepam NS NS * NS NS Fosazepam NS * * * NS NS <9 <12 <15 <9 < 12 < 15 0 + 1 Placebo NS NS * NS NS * * * Diazepam NS * * * * * Fosazepam NS * * * NS * *

Significance levels: * P= 0.05; ** P= 0.01; *** P= 0.001

Table 4 Levels of significance for deviation from equal distribution around critical values for duration (min) of awakenings with placebo, diazepam and fosazepam

Awakening (sleep stage) Treatment Night of ingestion Recovery night <6 <9 < 12 <6 <9 < 12 0 Placebo NS NS NS NS NS Diazepam NS NS NS Fosazepam NS NS NS NS <6 <9 <12 <6 <9 < 12 1 Placebo NS NS NS NS NS Diazepam NS NS NS NS NS Fosazepam NS NS NS < 15 <20 <25 < 15 <20 <25

0 + 1 Placebo NS NS NS NS NS NS Diazepam NS NS NS NS NS NS Fosazepam NS NS NS NS

Significance levels: * P = 0.05; ** P = 0.01; *** P = 0.001 DIAZEPAM AND SLEEP IN MAN 537

41 duration of awakenings to 1 activity was reduced.

(AC._ There were little, if any, effects of the drugs on duration of awakenings on the recovery night. x The percentage of total sleep time occupied by 0 each sleep stage is given in Table 5. Analysis of en (U variance was used for these measures. No effects EC. . . o. . o. could be demonstrated with diazepam (5 mg and E '-- co 0) t qt N C(D N 10 mg) on the night of ingestion or on the 0) co recovery night. There was a reduction in percent- (U age stage 1 after fosazepam, both 60 mg and 80 mg, coa) co0) CD C (P = 0.01 ) with carry over effects (P = 0.05). There o r- L Lt o L. CD CN4 were compensatory increases in stage 2 after fosazepam (60 mg) (P = 0.01) on the night of 40 CN r- 0 LOI ingestion with carry over effects to the next night li oi C cc; c3 = (U C- (P 0.05). There were no effects on stage 3, but 0. analysis of the stage 3 + 4 showed that there was a C) reduction during the recovery night with CII 00 Lf 0 0 fosazepam (P= 0.01). No effects were observed v- N with REM sleep. The effects of the drugs on duration (min) of 0.Q sleep stages in the first 6 h of sleep are given in -ccom C.) c Table 6. The high variability of the data of stage 0 e indicated that an analysis of variance was not 0U (U appropriate, and non-parametric analysis was used. E The Friedmann two-way analysis of variance VN X) 0sCD O- showed a significant effect, and the Wilcoxon Q (U ,c 0 c6 - (ootD N Matched-Pairs Signed-Ranks test showed that diazepam and fosazepam reduced the duration of E0 stage 0 (P= 0.05), but without carry over effects to the next night. No other effects of diazepam E 4-oIA.o CD were established. The reduction in the duration of 0 64 c4 ,: r stage 1 during the night of ingestion after fosazepam (60 mg and 80 mg) (P= 0.001) was cm 14 L oC C! carried over to the next night (P = 0.05). With o-(0 (U stage 2 there were increases after fosazepam i CD0I- 0.Nc (60mg, P=0.01: 80mg, P=0.001, and this 0 w-_ - 4 change was seen also during the next night U@nu ooLC) (U (P = 0.05). No effects were observed with stage 3, 0, but there was a reduction during the recovery (U._ night in the duration (min) of stage 3 + 4 with

CD ,- o-O- m 0)T- fosazepam (80 mg). No changes were observed X O E6 r- o X with Co C14 0' REM sleep. ECN E The two hourly distributions of sleep stages 1, Ul 0 2 and REM are given in Table 7. No effects were N x observed with diazepam. With stage 1 the effects co aB 20 -d of fosazepam were spread throughout the night.

%6- An analysis of variance on the combined data for the first two hourly interval of sleep showed an CN 1t %- .1 overall drug effect, and as the effects on stage 1 during the second (P= 0.01) and third (P= 0.01) 0) _ CN C") + LU *_ intervals were limited to fosazepam, it was possible 0 to identify that the effect during the first interval was due to this drug. There was evidence of carry over effects of fosazepam to the third interval of the next night.

.20 With stage 2 the increases with fosazepam 0 became more pronounced as the night proceeded. No effect could be demonstrated during the first 538 A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE

two hourly interval, and the value in the second interval missed the least significant difference for 5% level of significance by the second place of decimals. The reduction in the duration of stage 2 in the third interval was very highly significant (P = 0.001). There were no changes in REM sleep. to g?o6 a u The variability of the data for stage 0, stage 3 and 0 CN stage 3 + 4 was such that it was not reasonable to include means of these measures as they had very N CV o 04 au ) ED little, if any, value. N C C-4O0 The means of assessments by the subjects are (A given in Table 8. For the night of ingestion changes in subjective assessments were limited to CY r- (A - 0) a) Pro sleep quality, and were seen only with fosazepam. ._ The subjects reported improved sleep. They fell asleep quicker and slept better. There were no 0 co Lo (6 6c - changes in the assessments of sleep quality related .SL CD(DOCO )O N to the recovery night. A sense of freshness during E N CN C) (D (N the day after ingestion of diazepam and fosazepam CU0 was reported, but there were no changes in the a _r LO - N4 CY assessments of wakefulness. Correlations showed 70 that subjectively improved sleep was related to 'IO _- CD '- EC)D (N increased total sleep time (P= 0.001), reduced CN 0)0 sleep onset latency (P= 0.01), less stage 0 E (P= 0.001) and stage 1 (P 0.001) with increased co CN CD NCU0) stage 3 + 4 (P= 0.01). A correlation of the C') C') assessment related to staying asleep (assessment E) ~0 Eg (D LuO_ oo emphasized increased stage 3 + 4 (P = 0.001) and included reduction of stage REM (P= 0.05). A CD CD 'i A ' sense of freshness during the day (assessment A) 0 E (N was associated with reduced sleep onset latency co(U a, (P = 0.05), increased latency to the first REM N period (P = 0.01) and reduced duration of stage E '4C)C lq REM (P = 0.001) and a feeling of wakefulness in C the morning (assessment C) was associated with

C reduced sleep onset latency (P= 0.001), less stage C C ('NNt 1 (P= 0.05) and stage REM (P= 0.01). co E (N 0 E 0 x 0 Discussion 0) v- L E .X0 (-3 E (N The present studies show that diazepam within the 4- CDV -5 range 5-10 mg has restricted effects on sleep in X man. LO . a-.' Total sleep time is increased with the 10 mg dose only, and reduction of sleep onset latencies is N- CD N 0) limited. Awakenings to 0 are reduced and there is C.) CD 4t CV v 0 0. .a less stage 0 activity, but there are no other effects (A 4E-- on sleep. On the other hand the effects of fosazepam within the range 60-80 mg are more pronounced. Though the effect on sleep onset 0'- (8N C._0 I~ - C ._i latencies and stage 0 activity is similar to that of co ',cE 4- diazepam, there is a marked increase in total sleep time, reduced latency to stage 3, and, in particular, reduced stage 1 (drowsy) activity. Stage 1 activity is reduced throughout the night of ingestion and during part of the recovery night. There is also reduced stage 3 + 4 activity during the recovery night, but these effects are not accompanied by DIAZEPAM AND SLEEP IN MAN 539 changes in latency to the first REM period or the with diazepam, latency to stage 3 is reduced duration and two hourly distribution of REM during the night of ingestion, and this effect was sleep. also observed with fosazepam. It is, therefore, The effects of fosazepam on sleep raise the likely that the effects of fosazepam, both during question whether they are related to the parent the night of ingestion and the recovery night, are drug or to the activity of one of its metabolites, related to nordiazepam. Substitution of the nordiazepam. Fosazepam has an elimination half methyl group weakens the activity of the time of around 2 h, and so effects specific to diazepam molecule (Figure 1), and the higher dose fosazepam would be seen during the night of necessary to preserve an hypnotic effect leads to ingestion, whereas effects related to nordiazepam, increased formation of the metabolite. which has a half life of around two days (Tansella, The subjective assessments were of particular Siciliani, Burti, Schiavon, Zimmermann Tansella, value. With both diazepam and fosazepam there Gerna, Tognoni & Morselli, 1975; Tognoni, was an improved sense of freshness during the day Gomeni, Maio, Alberti, Franciosi & Scieghi, 1975), after ingestion. There were no other changes would be seen more clearly during the recovery related to the ingestion of diazepam, but with night. In previous studies, Nicholson et al. (1976) fosazepam the subjects reported changes in described the carry over effects of nordiazepam to assessments related to the quality of sleep. On the the night after ingestion. The effects were reduced morning after ingestion they felt they had fallen stage 1 in the third 2-hourly interval, increased asleep quicker, and had slept better during the stage 2 and reduced stage 3 + 4 activity. These night. The subjects did not report increased changes were also observed with fosazepam. It is sleepiness the morning after ingestion of the drugs, also of interest that with nordiazepam, but not but such assessments related to residual effects

Table 7 Effect of diazepam and fosazepam on the 2 hourly distributions (min) of sleep stages 1, 2 and REM from sleep onset latency (means for six subjects)

Night of ingestion Recovery night Stage Interval C/V Placebo Diazepam Fosazepam Placebo Diazepam Fosazepam 1 0-2 64 6.5 4.4 3.0 5.0 6.8 4.7 2-4 42 10.0 8.5 3.7 10.4 9.7 8.2 4-6 38 17.6 16.6 8.4 18.2 16.8 10.0 2 0-2 14 78.7 79.1 82.3 81.8 81.5 91.6 2-4 15 77.4 81.1 89.2 71.2 73.1 75.0 4-6 16 58.3 69.5 79.6 61.0 67.0 70.4 REM 0-2 62 6.7 3.3 6.0 8.4 7.5 5.4 2-4 40 20.5 18.5 17.2 23.4 25.5 28.5 4-6 37 31.3 29.0 29.4 29.6 27.9 32.8 Coefficient of variability (C/V) = s.d. x 100/mean

Table 8 Effect of diazepam and fosazepam on assessments of well-being and sleep quality (means for six subjects) (The data refer to mm on a 100 mm scale)

Assessment C/V Placebo Diazepam Fosazepam Placebo Diazepam Fosazepam Night of ingestion Recovery night A 18 56.8 61.6 59.7 50.6 64.4 62.8 Morning after ingestion Morning after recovery night B 27 53.8 69.2 78.1 68.3 61.1 66.1 C 20 54.7 63.9 59.4 68.3 60.1 65.3 D 13 66.6 75.2 84.5 66.6 73.3 74.1 E 20 58.0 72.5 80.3 71.1 66.2 71.8

Coefficient of variability (C/V) = s.d. x 100/mean 540 A.N. NICHOLSON, BARBARA M. STONE & CORAL H. CLARKE of drugs may not be reliable (Borland & It is evident that the pharmacological basis of Nicholson, 1975a). The residual effects of 5-10 mg the effect of diazepam and fosazepam on sleep diazepam would be limited (Borland & Nicholson, differ. The hypnotic effect of diazepam in the 1975b), but, as the activity of fosazepam may be dose range 5-10 mg depends on the activity of the related to that of nordiazepam, it is likely that parent compound, while that of fosazepam in the with fosazepam residual effects on performance dose range 60-80 mg is likely to depend more on would be present (Tansella, Zimmermann Tansella the activity of nordiazepam. Using the regression & Lader, 1974). It is of interest that subjectively equation for the effect of fosazepam on total sleep improved sleep was related only to fosazepam, time the dose of fosazepam equivalent to the even though with diazepam (10 mg) there was an effect of diazepam (10 mg) would be 36.4 mg. increase in total sleep time, reduced sleep onset However, the effect of diazepam (10 mg) on sleep latency and stage 0 activity. This may suggest that is limited, and it is suggested that the therapeutic a subjective assessment of improved sleep is range for fosazepam as an hypnotic for healthy associated with marked changes in sleep patterns, persons may be 40-60 mg. and that a useful improvement in sleep may not be The present study suggests separate clinical easily appreciated. Similar conclusions were drawn indications for the use of diazepam and its soluble in the previous study on the effects of derivative, fosazepam. Diazepam in the dose range nordiazepam on sleep (Nicholson et al., 1976). 5-10 mg has a limited duration of action and may Correlation of sleep measures and subjective prove to be particularly useful as an hypnotic for assessments proved to be a more sensitive persons involved in skilled activity, whereas approach to the use of assessments, and supported fosazepam with its longer duration of action may the findings of the previous study. Increased prove to be useful for persons with disorders of freshness during the day (assessment A) was sleep secondary to psychopathology. The single associated with reduced sleep onset latency, overnight administration of fosazepam could have increased latency to the first REM period and beneficial effects during the next day in patients reduced duration of REM sleep. A feeling of with . However, the effectiveness of wakefulness in the morning (assessment C) was diazepam on sleep is limited. Though the duration related to reduced sleep onset latency, reduced of stage 0 (awake) activity is reduced, it has little stage 1 and REM sleep. In the previous study the or no effect on stage 1 (drowsy) activity. and it correlates of improved sleep related to falling may be necessary for an effective dose to exceed asleep quicker and staying asleep could not be 10 mg. In this event impaired performance may separated, but with the present data it was found arise, as though diazepam has a short half life of that staying asleep was related, particularly, with 2-3 h the increasing formation of nordiazepam, increased stage 3 + 4 and reduced REM sleep. It with its half life of around 2 days, is likely to lead would appear that well-being and improved sleep to residual effects. are associated with less desynchronized (reduced The authors are indebted to Miss Helen M. Ferres for sleep onset latencies, increased latency to first statistical advice, and to Mr A.S. Day and Mrs S.M. REM period, decreased stage 0, 1 and REM Robertson for reduction of data. The assistance of Miss activity) and more synchronized (increased total P.A. Clarke and Miss C.M. Wright in recording the sleep sleep time and increased stage 3 + 4) electro- electroencephalograms is gratefully acknowledged. The encephalographic activity. drugs were kindly supplied by Hoechst Pharmaceuticals.

References BOND, A.J. & LADER, M.H. (1972). Residual effects of BORLAND, R.G. & NICHOLSON, A.N. (1975b). hypnotics. Psychopharmacologia (Berl.), 25, 117-132. Immediate effects on human performance of a BOND, A.J. & LADER, M.H. (1973). The residual effects 1,5- () compared with the of flurazepam. Psychopharmacologia (Berl.), 32, 1,4-benzodiazepines, hydrochloride 233-235. and diazepam. Br. J. clin. Pharmac., 2, 215-221. BORLAND, R.G. & NICHOLSON, A.N. (1974). Human BORLAND, R.G., NICHOLSON, A.N. & WRIGHT, performance after a (heptabarbitone). Br. CATHERINE M. (1975). Behavioural sequelae of J. clin Pharmac., 1, 209-215. in man and in the monkey (Macaca BORLAND, R.G. & NICHOLSON, A.N. (1975a). mulatta). Br. J. clin. Pharmac., 2, 131-141. Comparison of the residual effects of two benzo- DE SILVA, J.A.F., KOECHLIN, B.A. & BADER, G. diazepines (nitrazepam and flurazepam hydrochloride) (1966). Blood level distribution patterns of diazepam and pentobarbitone sodium on human performance. and its major metabolite in man. J. pharm. Sci., 55, Br. J. clin. Pharmac., 2, 9-17. 692-702. DIAZEPAM AND SLEEP IN MAN 541

KALES, A. & SCHARF, M.B. (1973). Sleep laboratory LADER, M. (1974). The residual effects of N- and clinical studies of the effects of benzodiazepines desmethyldiazepam in patients. Psychopharmacologia on sleep. In The Benzodiazepines, eds Garattini, S., (Berl.), 38, 81-90. Mussini, E. & Randall, L.O. pp. 577-598. New York: TANSELLA, M., SICILIANI, O., BURTI, L., Raven Press. SCHIAVON, M., ZIMMERMANN TANSELLA, Ch. MALPAS, A., ROWAN, A.J., JOYCE, C.R.B. & SCOTT, GERNA, M., TOGNONI, G. & MORSELLI, P.L. D.F. (1970). Persistent behavioural and electro- (1975). N-desmethyldiazepam and amylobarbitone encephalographic changes after single doses of sodium as hypnotics in anxious patients. Plasma levels, nitrazepam and amylobarbitone sodium. Br. med. J., clinical efficacy and residual effects. Psycho- 2, 762-764. pharmacologia (Berl.), 41, 81-85. NICHOLSON, A.N., STONE, BARBARA M., CLARKE, TOGNONI, G., GOMENI, R., MAIO, D.DE, ALBERTI, CORAL H. & FERRES, HELEN M. (1976). Effect of G.G., FRANCIOSI, P. & SCIEGHI, G. (1975). N-desmethyldiazepam and a precursor, potassium Pharmacokinetics of N-desmethyldiazepam in patients , on sleep in man. Br. J. clin. Pharmac., 3, suffering from insomnia and treated with nor- 429-438. triptyline. Br. J. clin. Pharmac., 2, 227-232. TANSELLA, M., ZIMMERMANN TANSELLA, Ch. & (Received October 22, 1975)