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Home , Butriptyline, Methaqualone

Br. J. clin. Pharmac. (1977), 4 LETTERS TO THE EDITORS 245

In conclusion, butriptyline produces mild HARTMANN, E. & CRAVENS, J. (1973). Long-term sedation and promotes sleep, but it is also possible effects on human sleep. In Sleep, ed. Koella, W.P. to detect a sleep-disturbing action of a type found & Levin, P., pp. 477-485. Basel: S. Karger. with other . Compared with other JARAMILLO, J. & GREENBERG, R. (1975). Com- parative pharmacological studies on butriptyline and related drugs butriptyline causes less unpleasant some related standard tricycic . Can. J. subjective effects. PhysioL Pharmac., 53, 104-112. MILLER, R.G. (1966). Simultaneous Statistical Inference. VLASTA BREZINOVA, SHARON BORROW, I. New York: McGraw-Hill. OSWALD & DOROTHY ROBINSON OSWALD, I. LEWIS, S.A., DUNLEAVY, D., BREZINOVA, V. & BRIGGS, M. (1971). Drugs of University Department of Psychiatry, Royal dependence though not of abuse: and Edinburgh Hospital, Morningside Park, Edinburgh . Br. med. J., 3, 70-73. EH10 SHF, Scotland OSWALD, I., BkEZINOVA, V. & DUNLEAVY, D. (1972). On the slowness of action of tricyclic Received October 4, 1976 drugs. Br. J. Psychiat., 120, 673-677. PUGSLEY, T.A. & LIPPMANN, W. (1974). Effect of butriptyline on the brain uptake mechanisms for noradrenaline and 5-hydroxytryptamine. J. Pharm. References Pharmac., 26, 778-782. RECHTSCHAFFEN, A. & KALES, A. (1968). A Manual DUNLEAVY, D., BkEZINOVA, V., OSWALD, I., of Standardized Terminology, Techniques and Scoring MACLEAN, A. & TINKER, M. (1972). Changes System for Sleep Stages of Human Subjects. Washing- during weeks in effects of tricyclic drugs on the ton, D.C.: U.S. Government Printing Office, N.I.H. human sleeping brain. Br. J. Psychiat., 120, 663-672. publication no. 204. GRIVOIS, H. (1971). Butriptyline, a new antidepressant SIEGEL, S. (1956). Nonparametric Statistics for the compound. J. Med. (Basel), 2, 276-289. Behavioural Sciences. New York: McGraw-Hill.

THE EFFECT OF ETHANOL ON RESIDUAL PLASMA METHAQUALONE CONCENTRATIONS AND BEHAVIOUR IN VOLUNTEERS WHO HAVE TAKEN MANDRAX

It has been demonstrated that with long Twelve healthy volunteers, six male and six half lives impair performance in both simple and female, aged 21-39 years took part in the trial. complex tasks several hours after their therapeutic They normally drank only in moderation effect has ceased (Malpas, Rowan, Joyce & Scott, and were receiving no other current medication. 1970; Borland & Nicholson, 1975; Bond & Lader, During the course of the study they were 1975). We have undertaken a preliminary study to requested to abstain from alcohol for 10 h prior to investigate the possibility that ethanol might taking the until the tests were complete interact with residual concentrations of Mandrax on the third evening each week. The subjects were present 24, 48 and 72 h after a single dose and so allocated at random under double blind conditions produce even greater impairment of performance to each of the following three treatments which on behavioural tests than either alcohol or drug were arranged in a fully balanced design over three alone. Since recent reports have shown that consecutive weeks. ethanol may modify drug concentrations in body fluids (Mould, Curry & Binns, 1972; Rubin, Gang, A Two Mandrax tablets (methaqualone 250 mg, Misra & Leiber, 1970) and earlier studies (Swaby, hydrochloride 25 mg) to be 1973; Williams, 1975) have indicated that it taken at 22 h 30 min on day 1 and a weight interacts with methaqualone residues to modify related dose of flavoured ethanol mixture (0.5 g performance, plasma levels of the drug were ethanol/kg) at 17 h 30 min on each of the measured on each evening of the study to establish following three evenings. any possible relationship between behavioural B Two Mandrax placebo tablets and ethanol as in changes and differences in drug concentrations. A. 246 LETTERS TO THE EDITORS Br. J. clin. Pharmac. (1977), 4

1.2_ Ratings on the VAS showed an interaction between residual methaqualone and ethanol. Treatment A induced greater mental and physical -gE 1.0_X sedation on the third evening than ethanol alone. Similarly the Stroop test showed a significant c 0 reduction in cognitive skills on the third evening (P < 0.01). Differences in KVA were not signifi- cantly different on any occasion but this may have been due to the very large effect of ethanol alone Eco 0.6 - which could have swamped any small change due to the presence of methaqualone. E This preliminary study therefore showed that co 0.4 - residual levels of methaqualone present after a single dose of Mandrax will interact with ethanol 72 h later and result in greater subjective mental 0.2_ and physical sedation and impairment of cognitive tasks than either drug residual or ethanol alone. In addition, the regular moderate consumption of 01 ethanol resulted in higher methaqualone con- 24 48 72 centrations than those obtained after placebo Time(h) alcohol. A similar investigation has been carried out Figure 1 Mean plasma methaqualone concentrations with (Mogadon®) using the same obtained from twelve volunteers, after two Mandrax study design. However, preliminary analysis shows tablets, who were subsequently challenged with that no interaction between nitrazepam and placebo (e) and alcohol (a) mixtures. alcohol can be detected in any of the tests carried out during the three evenings after the drug was taken. Information on plasma nitrazepam levels is not at present available. C Two Mandrax tablets and a similar volume of The authors would like to thank Roussel Laboratories Ltd placebo alcohol mixture which contained a for a grant towards the cost of this study. little ethanol to impart the characteristic smell and taste. S. RODEN, P. HARVEY' & M. MITCHARD On each of the three evenings following the Department of Therapeutics & Clinical ingestion of the tablets, the volunteers were and 1 Department of Psychiatry, required to complete a visual analogue scale (VAS) Queen Elizabeth Hospital, Birmingham B15 2TH (Norris, 1971) in order to measure subjective feelings, including those of mental and physical Received August 11, 1976 sedation. They then received the dose of alcohol or placebo mixture which they sipped slowly over 10 min. Twenty minutes later a blood sample was withdrawn for assay of blood ethanol (Curry, Walker & Simpson, 1966) and plasma metha- References qualone (Mitchard & Williams, 1972) concentra- BOND, A.J. & LADER, M.H. (1975). Residual effects of tions by g.l.c. A second VAS was then completed . Br. J. clin. Pharmac., 2, 143-150. and measurements of kinetic visual acuity (KVA) BORLAND, R.G. & NICHOLSON, A.N. (1975). Com- (Clayton, 1972) and cognitive skills using the parison of the residual effects of two Stroop Colour Word test (Stroop. 1935; Jensen & (nitrazepam and hydrochloride) and Rohwer, 1966; Dyer, 1973) were made. pentobarbitone sodium on human performance. Br. J. The mean plasma methaqualone concentrations clin. Pharmac., 2, 9-17. detected after treatments A (Mandrax + ethanol) CLAYTON, A.B. (1972). The effects of certain tran- + quilUisers and alcohol upon kinetic visual acuity. and C (Mandrax placebo alcohol) are shown in Proceedings of the 16th conference of the American Figure 1. Although the levels obtained on the first Association for Automotive Medicine, Chapel Hill evenings were similar they were subsequently N.C. 199-215. higher after treatment A than C, the difference CURRY, A.S., WALKER, G.W. & SIMPSON, G.S. (1966). being highly significant on the third evening The determination of ethanol in blood by gas (P < 0.005). chromatography. Analyst, 91, 742-743. Br. J. clin. Pharmac. (1977), 4 LETTERS TO THE EDITORS 247

DYER, F.N. (1973). The Stroop phenomenon and its use NORRIS, H. (1971). The action of on brain in the study of perceptual, cognitive and response stem oculomotor systems in man. Neuropharmac., 10, processes. Memory and Cognition, 1, 106-120. 181-191. JENSEN, A. & ROHWER, W. (1966). The Stroop Colour RUBIN, E., GANG, H., MISRA, P.S. & LIEBER, C.S. Word Test. A review. Acta Psychologica, 25, 36-93. (1970). Inhibition of by acute MALPAS, A., ROWAN, A.J., JOYCE, C.R.B. & SCOTT, ethanol intoxication. A hepatic microsomal D.F. (1970). Persistent behavioural and electro- mechanism. Am. J. Med., 49, 801-806. encephalographic changes after single doses of STROOP, J.R. (1935). Studies of interference in serial nitrazepam and amylobarbitone sodium. Br. med. J., verbal reactions. J. exp. PsychoL, 18, 643.662. 2, 762-764. SWABY, M.C.A. (1973). The effects of Mandrax with MITCHARD, M. & WILLIAMS, M.E. (1972). An alcohol. Unpublished M.Sc. dissertation, University of improved quantitative gas liquid chromatographic Birmingham. assay for the estimation of methaqualone in biological WILLIAMS, M.E. (1975). Biopharmaceutical studies on fluids. J. Chromatog., 72, 29-34. methaqualone. Unpublished Ph.D. Thesis, University MOULD, G.P., CURRY, S.H. & BINNS, T.B. (1972). of Birmingham. Interaction of and phenobarbitone with ethanol in man. J. Pharm. Pharmac., 24, 894-899.

PLASMA URIC ACID AND SPIRONOLACTONE RESPONSE IN HEALTHY SUBJECTS

In healthy subjects treated with fludrocortisone sodium and potassium concentration by flame there was a negative relationship between plasma photometry using as the internal standard; uric acid concentration (PUA) and the urinary creatinine by an automated method and canrenone log 10 Na/K ratio following single doses of by a fluorimetric method (Gochman & Gantt, the aldosterone antagonist spironolactone 1962). Statistical methods used were the analysis (Aldactone®, Searle) (Ramsay, Hessian & Tidd, of variance and product moment correlations. Log 1975), a finding which has been confirmed in transformation of the urine Na/K ratio was used as subsequent unpublished studies. Interpretation of this provides a sensitive index of response to these observations has been hampered by the mineralocorticoid antagonists (Ramsay, Harrison, complexity of the studies, involving as they did Shelton & Tidd, 1975). treatment with both fludrocortisone and spirono- In the 24 h following spironolactone mean lactone. In the present study we have examined sodium excretion was increased by 35% the relationship between PUA and spironolactone (P< 0.001), urine log Na/K was increased by 15% response in a simplified protocol. (P< 0.01) and potassium concentration was Twelve healthy subjects were studied on two reduced by 23% (P < 0.05). Potassium excretion, occasions separated by an interval of one week. urine volume and creatinine clearance did not After an overnight fast they received at 09.00 h differ significantly from placebo values (P> 0.1) either spironolactone (100 mg) or identical (Table 1). PUA concentration after spironolactone placebos in a random balanced crossover design. In did not differ from placebo values at any sampling the 24 h following treatment the subjects con- time. Two values of PUA were calculated for each sumed a diet which was constant on each occasion subject: the pretreatment PUA (means of two and designed to provide mild sodium restriction estimates per subject) and the overall PUA (means (calculated sodium content 90 mmol). Urine was of all estimates before and after treatment, i.e. 10 collected during the 24 h period for measurement estimates per subject). True spironolactone of sodium, potassium and creatinine excretion. responses (A) were calculated as the difference Venous blood for measurement of PUA and between placebo and spironolactone results for creatinine was taken immediately before treat- each subject. PUA concentration correlated signifi- ment, and at 2, 4, 8 and 24 h after treatment. The cantly with A sodium excretion and A potassium subjects were ambulant. Alcohol and all forms of concentration using either the pretreatment or the medication were prohibited during the study. Uric overall PUA values (Table 2). Correlations between acid in plasma and urine was measured by an PUA and A log 10 Na/K were negative but not automated colorimetric method (Nishi, 1967); significant. The direction of these correlations was