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PSEUDOEPHEDRINE LINCTUS
1180 ASPIRIN: ADDITIONAL MECHANISMS OF ACTION
AMIODARONE AND PLASMA DIGOXIN LEVELS
SIR,-Professor Willson (April 7, p 804) raises several interesting points relevant, not least, to the mechanism of action of aspirin. It is now widely accepted that many of the therapeutic effects of aspirin can be attributed to inhibition of cyclo-oxygenase,u2 resulting in diminished formation of prostaglandins and thromboxanes. This action involves acetylation of the enzyme.4Willson’s letter, however, highlights the possibility that alternative or additional mechanisms of action for aspirin, free radical or otherwise, cannot be ruled out. We have been especially intrigued by the widely differing doses of aspirin required in man to exert platelet antiaggregatory, analgesic, and anti-inflammatory or antirheumatic activity, the ratio of these doses being about 1:30:300 in man. Our own studies5,6 and those of Siegal et al7 have led us to speculateb that an additional effect of aspirin-inhibition of the hydroperoxy fatty acid peroxidase in the lipoxygenase pathway of arachidonic acid metabolism-may also be important with respect to the antiinflammatory and antirheumatic effects of aspirin which require the highest doses of aspirin (up to 6 g daily) in man. The mechanism of aspirin inhibition of this peroxidase has not been fully elucidated. Might it involve a free radical process of the type suggested by
SIR,-Dr Douste-Blazy and colleagues (April 21, p 905) have shown that concomitant therapy with amiodarone not only increases plasma digoxin levels but also increases urinary excretion of the drug. To explain their findings they suggest that amiodarone might displace digoxin from its tissue binding sites. The major specific binding site for digoxin is Na , K -ATPase. In the study of cardiac glycoside binding to this enzyme in human tissues erythrocytes are commonly used because of their accessibility. We have looked at the effect of a range of concentrations of amiodarone on 3H-ouabain binding to erythrocytes in vitro. 3H-ouabain (Amersham International; specific activity 33 Ci/mmol), final concentration 13 nmol/1, was incubated for 1 h at 370C with washed erythrocytes (final haematocrit 12%) in a potassium-free buffer (NaCI 145; MgS04 2, CaCl2 2, Na2HP044, NaH2P04 1, glucose 10 mmol/1) in the absence of amiodarone and in the presence of the drug. Each concentration was studied in duplicate. After incubation, the cells were washed four times in cold (4°C) MgCl2 and then lysed in 0-5mol/1 perchloric acid. The supernatant was counted. The results, expressed as percentage of binding in the absence of amiodarone, were, for ten-fold dilutions from 0 - 00to 10 mol/1, 98-5%, 10 1 . 5%, 98 - 5%, 101-2%, and 103 . 5°70, respectively. The concentrations of amiodarone used embrace the therapeutic range of the drug.’ Non-specific binding was less than 2%. The results suggest that amiodarone does not displace digoxin from tissues by direct competition for its binding to
Willson? Miles Laboratories Ltd, Stoke Poges,
Slough SL2 4LY
W. J. McDONALD-GIBSON
Department of Biochemistry, Brunel University, Uxbridge, Middlesex
R. G. McDONALD-GIBSON
Na+, K+ -ATPase.
HALLUCINATIONS IN A CHILD AFTER DRINKING TRIPROLIDINE/PSEUDOEPHEDRINE LINCTUS
SIR,-I would like who took
an
to
describe
of hallucinations in a child commonly used decongestant
overdose of ’Actifed’,
a
East
Birmingham Hospital, Bordesley Green East, Birmingham B9 5ST
F. M. ACKLAND
Inhibition ofprostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232-35. Smith JB, Willis AL Aspirin selectively inhibits prostaglandin production in human platelets. Nature 1971; 231: 235-37. Higgs GA, Moncada S, Vane JR. The mode of action of anti-inflammatory drugs which prevent the peroxidation ofarachidonic acid In: Huskisson EC, ed. Anti-rheumatic drugs. New York: Praeger, 1983: 11-36. Rome LH, Lands WEM, Roth GR, Majerus PW. Aspirin as a quantitative acetylating reagent for the fatty acid oxygenase that forms prostaglandins. Prostaglandins 1976,
1. Vane JR.
4.
M. J. WEST P. L. WEISSBERG
11: 23-30. 5. Collier HOJ, McDonald-Gibson RG, McDonald-Gibson WJ, Power GM. The effect of acetylsalicylate on aggregation and arachidonate metabolism by human platelets suspended in plasma or buffer. J Physiol (Lond) 1984; 349: 44P. 6. McDonald-Gibson WJ, McDonald-Gibson RG, Power GM, Collier HOJ. The effect of acetylsalicylate on aggregation and arachidonate metabolism by human platelets suspended in plasma or buffer. Prostaglandins Leukotrienes Med 1984; 15: 1-14. 7. Siegal MI, McConnell RT, Cuatrecasas P. Aspirin-like drugs interfere with arachidonate metabolism inhibition of the by 12-hydroperoxy5,8,10,14—eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proc Natl Acad Sci USA 1979; 76: 3744-77. 8. Sankey RJ, Nunn AJ, Sills JA. Visual hallucinations in children receiving
decongestants. Br Med J 1984; 288: 1369.
RAPID DETECTION OF CHLAMYDIA TRACHOMATIS WITH MONOCLONAL ANTIBODIES
SIR,-Dr Ruijs and colleagues (April 28, p 960) suggested, from
experience in 53 male patients, that immunofluorescence microscopy with monoclonal antibodies may be a good alternative to the cumbersome culture method for diagnosing Chlamydia trachomatis infection. We have undertaken a preliminary evaluation of the direct slide test (C trachomatis direct specimen test [‘Microtrak’; Syva]) on patients attending two sexually-transmitteddisease (STD) clinics situated 15 and 18 miles from the laboratory. We studied only female patients, collecting from each two their
endocervical swabs for culture, the first of which was rolled on a slide for direct immunofluorescent staining. Of the first 50 patients, 34 were negative and 7 were positive by both the direct slide test and by culture using idoxuridine-treated McCoy cells and Giemsa staining. In 3 cases the slide test was negative but culture positive, although in each of these less than four inclusions were seen in only 1 of the duplicate cultures inoculated. In 6 cases culture was in 4 of negative but the slide test was recorded as positive, these fluorescing bodies were seen only in small clusters widely scattered across the slide. Of the 37 slide tests that were negative, 9 were difficult to interpret because of the presence of particles which were discounted because they were not of the right size or showed insufficiently bright fluorescence. Ruijs et al did not comment on any difficulties in interpretation of the slide test, possibly because urethral smears from their male patients were "cleaner" than those from the female cervix in our study. We believe, however, that priority should be given to the identification and treatment of C trachomatis infections, often asymptomatic, in women attending STD clinics or identified as contacts of men with non-specific urethritis. This policy is also relevant to the control of pelvic inflammatory disease and chlamydial infection in infants. Our experience suggests that in females the direct slide test may sometimes be difficult to interpret (13 of 50 slides in our study) in the laboratory and that it is not likely to be a reliable method for instant diagnosis in STD clinics by workers not highly skilled in
although
other medication.
3
M. R. WILKINS
a case
consisting of pseudoephedrine and triprolidine. Sankey et al8 have reported three similar cases, with hallucinations about insects and spiders, in young children. A previously well 5-year-old boy drank 60 ml actifed syrup which had been prescribed for an upper respiratory tract infection. No immediate action was taken by his parents. 5 h later, he woke screaming and complaining of flowers on his pillowcase. The general practitioner was called and gave 10 mg promethazine orally and later 5 mg diazepam intramuscularly. The child continued to hallucinate and was admitted to hospital 8 h after ingestion. He was flushed with dry skin and widely dilated pupils. He was agitated and constantly plucked at his skin, complaining that bees were stinging him. He refused to pass urine for 15 h after the actifed ingestion, complaining first that his penis was a snake and later that there were spiders on the bathroom floor. The hallucinations ceased after 18 h, having been intermittent for the last 4 h. By the next day he was quite well and was discharged. His parents denied the possibility that the boy could have taken any
2.
University of Birmingham, Department of Therapeutics and Clinical Pharmacology, Queen Elizabeth Hospital, Birmingham B15 2TH
microbiological techniques. 1. McKenna
WJ, Rowland E, Krickler DM. Amiodarone. the experience of the past decade. Br MedJ 1983; 287: 1654-56.
AMIODARONE AND PLASMA DIGOXIN LEVELS
SIR,-Professor Willson (April 7, p 804) raises several interesting points relevant, not least, to the mechanism of action of aspirin. It is now widely accepted that many of the therapeutic effects of aspirin can be attributed to inhibition of cyclo-oxygenase,u2 resulting in diminished formation of prostaglandins and thromboxanes. This action involves acetylation of the enzyme.4Willson’s letter, however, highlights the possibility that alternative or additional mechanisms of action for aspirin, free radical or otherwise, cannot be ruled out. We have been especially intrigued by the widely differing doses of aspirin required in man to exert platelet antiaggregatory, analgesic, and anti-inflammatory or antirheumatic activity, the ratio of these doses being about 1:30:300 in man. Our own studies5,6 and those of Siegal et al7 have led us to speculateb that an additional effect of aspirin-inhibition of the hydroperoxy fatty acid peroxidase in the lipoxygenase pathway of arachidonic acid metabolism-may also be important with respect to the antiinflammatory and antirheumatic effects of aspirin which require the highest doses of aspirin (up to 6 g daily) in man. The mechanism of aspirin inhibition of this peroxidase has not been fully elucidated. Might it involve a free radical process of the type suggested by
SIR,-Dr Douste-Blazy and colleagues (April 21, p 905) have shown that concomitant therapy with amiodarone not only increases plasma digoxin levels but also increases urinary excretion of the drug. To explain their findings they suggest that amiodarone might displace digoxin from its tissue binding sites. The major specific binding site for digoxin is Na , K -ATPase. In the study of cardiac glycoside binding to this enzyme in human tissues erythrocytes are commonly used because of their accessibility. We have looked at the effect of a range of concentrations of amiodarone on 3H-ouabain binding to erythrocytes in vitro. 3H-ouabain (Amersham International; specific activity 33 Ci/mmol), final concentration 13 nmol/1, was incubated for 1 h at 370C with washed erythrocytes (final haematocrit 12%) in a potassium-free buffer (NaCI 145; MgS04 2, CaCl2 2, Na2HP044, NaH2P04 1, glucose 10 mmol/1) in the absence of amiodarone and in the presence of the drug. Each concentration was studied in duplicate. After incubation, the cells were washed four times in cold (4°C) MgCl2 and then lysed in 0-5mol/1 perchloric acid. The supernatant was counted. The results, expressed as percentage of binding in the absence of amiodarone, were, for ten-fold dilutions from 0 - 00to 10 mol/1, 98-5%, 10 1 . 5%, 98 - 5%, 101-2%, and 103 . 5°70, respectively. The concentrations of amiodarone used embrace the therapeutic range of the drug.’ Non-specific binding was less than 2%. The results suggest that amiodarone does not displace digoxin from tissues by direct competition for its binding to
Willson? Miles Laboratories Ltd, Stoke Poges,
Slough SL2 4LY
W. J. McDONALD-GIBSON
Department of Biochemistry, Brunel University, Uxbridge, Middlesex
R. G. McDONALD-GIBSON
Na+, K+ -ATPase.
HALLUCINATIONS IN A CHILD AFTER DRINKING TRIPROLIDINE/PSEUDOEPHEDRINE LINCTUS
SIR,-I would like who took
an
to
describe
of hallucinations in a child commonly used decongestant
overdose of ’Actifed’,
a
East
Birmingham Hospital, Bordesley Green East, Birmingham B9 5ST
F. M. ACKLAND
Inhibition ofprostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971; 231: 232-35. Smith JB, Willis AL Aspirin selectively inhibits prostaglandin production in human platelets. Nature 1971; 231: 235-37. Higgs GA, Moncada S, Vane JR. The mode of action of anti-inflammatory drugs which prevent the peroxidation ofarachidonic acid In: Huskisson EC, ed. Anti-rheumatic drugs. New York: Praeger, 1983: 11-36. Rome LH, Lands WEM, Roth GR, Majerus PW. Aspirin as a quantitative acetylating reagent for the fatty acid oxygenase that forms prostaglandins. Prostaglandins 1976,
1. Vane JR.
4.
M. J. WEST P. L. WEISSBERG
11: 23-30. 5. Collier HOJ, McDonald-Gibson RG, McDonald-Gibson WJ, Power GM. The effect of acetylsalicylate on aggregation and arachidonate metabolism by human platelets suspended in plasma or buffer. J Physiol (Lond) 1984; 349: 44P. 6. McDonald-Gibson WJ, McDonald-Gibson RG, Power GM, Collier HOJ. The effect of acetylsalicylate on aggregation and arachidonate metabolism by human platelets suspended in plasma or buffer. Prostaglandins Leukotrienes Med 1984; 15: 1-14. 7. Siegal MI, McConnell RT, Cuatrecasas P. Aspirin-like drugs interfere with arachidonate metabolism inhibition of the by 12-hydroperoxy5,8,10,14—eicosatetraenoic acid peroxidase activity of the lipoxygenase pathway. Proc Natl Acad Sci USA 1979; 76: 3744-77. 8. Sankey RJ, Nunn AJ, Sills JA. Visual hallucinations in children receiving
decongestants. Br Med J 1984; 288: 1369.
RAPID DETECTION OF CHLAMYDIA TRACHOMATIS WITH MONOCLONAL ANTIBODIES
SIR,-Dr Ruijs and colleagues (April 28, p 960) suggested, from
experience in 53 male patients, that immunofluorescence microscopy with monoclonal antibodies may be a good alternative to the cumbersome culture method for diagnosing Chlamydia trachomatis infection. We have undertaken a preliminary evaluation of the direct slide test (C trachomatis direct specimen test [‘Microtrak’; Syva]) on patients attending two sexually-transmitteddisease (STD) clinics situated 15 and 18 miles from the laboratory. We studied only female patients, collecting from each two their
endocervical swabs for culture, the first of which was rolled on a slide for direct immunofluorescent staining. Of the first 50 patients, 34 were negative and 7 were positive by both the direct slide test and by culture using idoxuridine-treated McCoy cells and Giemsa staining. In 3 cases the slide test was negative but culture positive, although in each of these less than four inclusions were seen in only 1 of the duplicate cultures inoculated. In 6 cases culture was in 4 of negative but the slide test was recorded as positive, these fluorescing bodies were seen only in small clusters widely scattered across the slide. Of the 37 slide tests that were negative, 9 were difficult to interpret because of the presence of particles which were discounted because they were not of the right size or showed insufficiently bright fluorescence. Ruijs et al did not comment on any difficulties in interpretation of the slide test, possibly because urethral smears from their male patients were "cleaner" than those from the female cervix in our study. We believe, however, that priority should be given to the identification and treatment of C trachomatis infections, often asymptomatic, in women attending STD clinics or identified as contacts of men with non-specific urethritis. This policy is also relevant to the control of pelvic inflammatory disease and chlamydial infection in infants. Our experience suggests that in females the direct slide test may sometimes be difficult to interpret (13 of 50 slides in our study) in the laboratory and that it is not likely to be a reliable method for instant diagnosis in STD clinics by workers not highly skilled in
although
other medication.
3
M. R. WILKINS
a case
consisting of pseudoephedrine and triprolidine. Sankey et al8 have reported three similar cases, with hallucinations about insects and spiders, in young children. A previously well 5-year-old boy drank 60 ml actifed syrup which had been prescribed for an upper respiratory tract infection. No immediate action was taken by his parents. 5 h later, he woke screaming and complaining of flowers on his pillowcase. The general practitioner was called and gave 10 mg promethazine orally and later 5 mg diazepam intramuscularly. The child continued to hallucinate and was admitted to hospital 8 h after ingestion. He was flushed with dry skin and widely dilated pupils. He was agitated and constantly plucked at his skin, complaining that bees were stinging him. He refused to pass urine for 15 h after the actifed ingestion, complaining first that his penis was a snake and later that there were spiders on the bathroom floor. The hallucinations ceased after 18 h, having been intermittent for the last 4 h. By the next day he was quite well and was discharged. His parents denied the possibility that the boy could have taken any
2.
University of Birmingham, Department of Therapeutics and Clinical Pharmacology, Queen Elizabeth Hospital, Birmingham B15 2TH
microbiological techniques. 1. McKenna
WJ, Rowland E, Krickler DM. Amiodarone. the experience of the past decade. Br MedJ 1983; 287: 1654-56.