LETTERS TO THE EDITORS

Br. J. cin. Pharmac. (1978),6

References ALTOUNYAN, R.E.C. (1964). Variation of drug action on airway obstruction in man. Thorax, 19,406-415. BENSON, M.K. (1978). Bronchial responsiveness to inhaled histamine and isoprenaline in patients with airway obstruction. Thorax, 33, 211-213. CHICK, T.W. & JENNE, J.W. (1977). Comparative bronchodilator responses to atropine and terbutaline in asthma and chronic bronchitis. Chest, 72, 719-723. CROMPTON, G.K. (1968). A comparison of responses to bronchodilator drugs in chronic bronchitis and chronic asthma. Thorax, 23,46-55. MATTHYS, H., MULLER, M., KONIETZO, N. & ADAM, W.E.

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without Sch 1000 using technetium sulphate (99m Tc) particles. Postgrad. med. J., Suppl. (7), 5 1, 108. MAY, C.S. & PALMER, K.N.V. (1977). Effect of aerosol ipratropium bromide (Sch 1000) on sputum viscosity and volume in chronic bronchitis. Br. J. clin. Pharmnac., 4, 491-492. PETRIE, G.R. & PALMER, K.N.V. (1975). Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma..Br. med. J., 1, 430-432. RUFFIN, R.E., WOLFF,R.K., DOLOVICH, M.B., ROSSMAN, C.M., FITZGERALD, J,D. & NEWHOUSE, M.T. (1978). Aerosol therapy with'Sch 1000. Short-term mucociiary clearance in normal and bronchitic subjects and toxicology in normal subjects. Chest, 73, 501-506.

(1975). Tracheo-bronchial clearance studies with and

MEASUREMENT OF SYSTOLIC TIME INTERVALS In recent years, the use of the measurement of systolic time intervals (STI) as a measure of cardiac contractility has become increasingly more popular (Dobbs, Kenyon & Dobbs, 1977; Lewis, Milne & Goldberg, 1976; Sykes, Wright, Malins & Pentecost, 1977). Briefly, the technique involves the simultaneous recording of electrocardiogram, phonocardiogram, and the carotid artery pressure pulse, from which the time of total electromechanical systole (QS2) and left ventricular ejection time (LVET) can be obtained. The pre-ejection period (PEP) and various derived quantities e.g. PEP/LVET, can be calculated. The most commonly used protocol involves the subject resting in a supine position for between 10-30 min followed by the recording of between ten and twenty consecutive heart beats. The mean values for LVET, QS2 and heart rate are then calculated, and the LVET and QS2 data are corrected using the regression equations obtained by Weissler, Harris & Schoenfeld

this laboratory, to investigate such effects, four healthy, male volunteer subjects, aged between 20 and 35 years were used. Each gave his informed consent, and the experiment was approved by the Hospital Research and Ethical Committee. The subjects were given a standardized, light breakfast at 07.00h on each morning of the experiment, but this did not include tea or coffee. A light lunch, including 500 ml fluid was given after the 6 h recordings had been made. Systolic time intervals were measured following the i.v. administration of digoxin (1 mg), f6-methyl digoxin (1 mg), ouabain (0.5 mg) and a placebo consisting of propylene glycol which was used as the vehicle for the other injections. The injections were carried out at 08.30 h and systolic time intervals were measured at 30 min intervals up to 6 h following injection, and then hourly up to 12 h. Recordings of twenty consecutive beats were made in the supine

(1968), viz

LVET=-1.7HR+413 males QS2 =-2.1 HR+ 546 }

The data leading to these regression equations were obtained from a large number of normal male subjects (similar data were obtained from female subjects) with the recordings being made between 08.00 and 10.00 h, although the latter time could be extended to 15.00 h. This technique has been applied to investigations into the pharmacodynamic effects of digoxin and beta methyl digoxin in man (Das, Talmers & Weissler, 1977; Hinderling & Garrett, 1977) where the shortening of QS2 or LVET has been used as a measure of the cardiac effects of these drugs. However, there have been few studies carried out in which changes in STI following placebo administration have been measured. In a balanced cross-over experiment undertaken in 36

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24 12 3 4 5 6 7 8 9 10 1112 Time from injection (h) Figure 1 Changes in LVET obtained from one subject after placebo (O), digoxin (0), P-methyl digoxin (V) and ouabain (0). The mean s.d. for each point is ± 5.0 ms.

Br. J. clin. Pharmac. (1978), 6

LETTERS TO THE EDITORS

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position following a 10 min rest period. Mean values of LVET and QS2 were calculated and corrected for heart rate using the regression equations above. Figure 1 shows the time course of changes in LVET obtained from one subject following the administration of the four preparations, and the mean results for the four subjects are shown in Figure 2. Although the drugs showed an initial shortening with a peak occurring between 1.5-3 h after injection, a similar effect was noted following the placebo injection, and it is evident that each curve follows a similar time course. This was confirmed when the mean percentage changes in LVET were plotted (Figure 3), indicating that the effect on LVET of any of the drugs could not be distinguished from that of the placebo (P> 0.05 using Student' t-test). The placebo effect is almost certainly due to failure of the above regression equations to completely correct for changes in heart rate. Similar results have been noted following oral administration indicating that these effects are not simply due to the trauma of the injection. These results strongly suggest that the use of a resting protocol and the application of the above regression equations to correct STI for variations in heart rate is not a suitable technique to investigate the pharmacodynamic effects of cardio-active drugs unless the marked placebo effect is taken into account. A more satisfactory method would appear to involve the use of an exercise protocol similar to that described by Van der Hoeven, Clerens, Donders, Beneken & Vonk (1977) which allows individual STI v heart rate relationships to be obtained. These relationships will vary from subject to subject and also according to the type of protocol adopted. The results of a cross-over study carried out in this laboratory using such an exercise protocol will be presented in a future article.

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10 Figure 2 Mean changes in LVET obtained from the four subjects after placebo (@), digoxin (0), P-methyl digoxin (V) and ouabain (0). The mean standard deviation for each point is ± 8.2 ms.

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Figure 3 Mean percentage changes in LVET obtained from the four subjects after placebo (e), digoxin (0), P-methyl digoxin (V) and ouabain (0). The mean s.d. for each point is +2.2%.

A.W. KELMAN & D.J. SUMNER

Department of Clinical Physics and Bio-Engineering, 11 West Graham Street, Glasgow G4 9LF J.R. LAWRENCE & B. WHITING Department of Materia Medica, University of Glasgow, Stobhill General Hospital, Glasgow G21 3UW Received August 17, 1978 References DAS, G., TALMERS, F.M. & WEISSLER, A.M. (1977).

Comparative pharmacodynamics of betamethyl digoxin and digoxin in man. Clin. Pharmac. Ther., 22, 280-285. DOBBS, S.M., KENYON, W.I. & DOBBS, RJ. (1977). Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients. Br. med. J., 1, 749-752. HINDERLING, P.H. & GARRETIT, E.R. (1977). Pharmacokinetics of P-methyl digoxin in healthy humans. III: Pharmacodynamic correlations. J. pharm. Scd., 66, 326-329. LEWIS, B.S., MILNE, FJ. & GOLDBERG, B. (1976). Left ventricular function in chronic renal failure. Br. Heart J., 38, 1229-1239. SYKES, C.A., WRIGHT, A.D., MALINS, J.M. & PENTECOST, B.L. (1977). Changes in systolic time intervals during

treatnent of diabetes mellitus. Br. Heart J., 39,

255-259. VAN DER HOEVEN, G.M.A., CLERENS, PJ.A., DONDERS, JJ.H., BENEKEN, J.E.W. & VONK, J.T.C. (1977). A study

of systolic time intervals during uninterrupted exercise. Br. Heart J., 39, 242-254. WEISSLER, A.M., HARRIS, W.S. & SCHOENFELD, C.D. (1968). Systolic time intervals in heart faflure in man.

Circulation, 37, 149-159.

Measurement of systolic time intervals.

LETTERS TO THE EDITORS Br. J. cin. Pharmac. (1978),6 References ALTOUNYAN, R.E.C. (1964). Variation of drug action on airway obstruction in man. Tho...
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