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PHENYLPROPANOLAMINE OVER THE COUNTER
839
from their operative strokes makes comparison with the natural history studies difficult since such investigations did not distinguish between strokes of different durations. Careful patient selection will reduce the risk of surgery. However, patients with stable or no neurological signs, no ischaemic heart disease, and only focal disease on angiographylmay have not only a low surgical risk, but also a low risk in the natural course of events. In general, nonrandomised comparisons lead to overestimates of treatment effects,14 and the efficacy of carotid endarterectomy for amaurosis fugax-or any other form of cerebrovascular disease, will not be established reliably by analysis of surgical series which bear mostly on the safety of the procedure itself. Unfortunately the single published randomised trial was inconclusive.15 Perhaps this matter will be resolved by further randomised trials, and at least one has been started in fifteen British centres. Meanwhile, physicians who favour carotid endarterectomy will investigate their amaurosis fugax patients with angiography and refer them for surgery, while those who have had unhappy surgical experiences will avoid both angiography and surgery. If there are enough physicians who are prepared to allocate their patients randomly (several hundred patients will be needed) to surgery or no-surgery, then we shall get a better notion of the place of carotid
endarterectomy.
PHENYLPROPANOLAMINE OVER THE COUNTER PHENYLPROPANOLAMINE is a sympathomimetic amine widely used as a decongestant for rhinitis, sinusitis, and cough. In many countries it is available either over the counter or on prescription, usually in combination with other drugs. While it may relieve some of the miseries associated with the common cold, proof of its efficacy in preventing complications of upper-respiratory-tract infections is lacking.’ A report2 of 3 cases of myocardial injury after ingestion of both therapeutic and excessive doses of phenylpropanolamine raises doubt about its safety. One woman had severe hypertension (204/148 mm Hg) and chest pain with abnormalities of the electrocardiogram and cardiac muscle enzymes after ingestion ofa single capsule containing phenylpropanolamine 50 mg, chlorpheniramine 4 mg, and belladonna alkaloids 0’ 2 mg. In that study all 3 of those patients recovered but other workers3,4 have described fatal cases of phenylpropanolamine overdose with arrhythmias, severe hypertension, and myocardial damage. In normal subjects,5,6 modest doses (up to 85 mg) have caused 13. Sundt
TM, Sandok BA, Whisnant JP. Carotid endarterectomy. Complications and preoperative assessment of risk. Mayo Clin Proc 1975; 50: 301-06. 14. Peto R. Clinical trial methodology. Biomedicine (special issue) 1978; 28: 24-36. 15. Fields WS, Maslenikov V, Meyer JS, Hass WK, Remington RD, MacDonald M. Joint Study of Extracranial Arterial Occlusion. V Progress report of prognosis following surgery or non-surgical treatment for transient cerebral ischaemic attacks and cervical carotid artery lesions. JAMA 1970; 211: 1993-2003. 1. Randall JE, Hendley JO.
A decongestant-antihistamine mixture in the prevention of otitis media in children with colds. Pediatrics 1979; 63: 483-85. 2. Pentell PR, Mikell FL, Zavorai JH. Myocardial injury after phenylpropanolamine ingestion. Br Heart J 1982; 47: 51-54. 3. Rumack BH, Anderson BH, Wolf R, et al. Ornade and anticholinergic toxicity: Hypertension, hallucinations and arrhythmias. Clin Toxicol 1974; 7: 573-81. 4. Chouinard G, Ghadirian AM, Jones BD. Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contac-C capsule. Can Med Assoc J 1978; 119: 729-31. 5. Frewin DB, Leonello PP, Frewin ME. Hypertension after ingestion of Trimolets. Med J Aust 1978; ii: 497-98. 6. Horowitz JD, Howes LG, Christophidis N, et al. Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1980; i: 60-61.
and sometimes chest had a cerebral haemorrhage.7 pain; patient The formulation of phenylpropanolamine may be important since hypertensive episodes8are more likely to follow ingestion of a simple-dosage form than ingestion of slow-release preparations. Often phenylpropanolamine is combined in a single tablet with other drugs which enhance its toxicity. Popular congeners include caffeine, which increases catecholamine and levels,9 plasma chlorpheniramine, which inhibits neuronal reuptake of catecholamines.lo Hypertensive crises may also occur when phenylpropanolamine is taken with monoamine oxidase and inhibitors, 11 methyldopa oxprenolol,12 or indomethacin.13 There have been several reports of psychotic reactions after small doses of phenylpropanolamine. Manic episodes14 and hallucinations 15 have been recorded. In Sweden these adverse reactions are commonly reported and in 1979 61 cases were notified.16 Paranoid episodes 17 and grand mal seizures 18 have also been seen after various doses of
substantial
changes in blood-pressure
one
phenylpropanolamine. few reports of deaths from overdose’" of phenylpropanolamine. In the United States the drug is promoted as an over-the-counter slimming aid, and poison control centres and hospital emergency rooms have been seeing many cases of overdosage with this and other syrnpathomimetics.11 Unfortunately, some of this overuse21 of phenylpropanolamine seems to have resulted from a tightening of regulations for the prescription of amphetamines which has led to an increase in the use of There
are
phenylpropanolamine as a "street drug". There has lately an attempt, by an agency outside the ethical pharmaceutical industry, to promote phenylpropanolamine in the United Kingdom as an appetite suppressant.22 Since been
of
serious adverse reactions to have arisen in previously healthy phenylpropanolamine after of modest doses, it may be that people ingestion alternative remedies are safer for relief of symptoms of some
the
most
congestion from colds and flu. The regulatory authorities will doubtless be scrutinising attempts to market the drug as an anorexiant in view of its potential as a drug of abuse. King J. Hypertension and cerebral haemorrhage after trimolets ingestion. Med J Aust 1979; ii: 258. 8. Cuthbert MR. Anorectic and decongestant preparations containing phenylpropanolamine. Lancet 1980; i: 367. 9. Robertson D, Johnson GA, Robertson RM, et al. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation
7.
1979; 59: 637-43. 10. Horn AS, Coyle JT, Snyder SH. Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurones. Mol Pharmacol 1970; 7: 66-80. 11. Cuthbert MF, Greenburg MP, Morley SW. Cold and cough remedies: a potential danger to patients on monoamine oxidase inhibitors. Br Med J 1969; i: 404-06. 12. McLaren EH. Severe hypertension produced by interaction of phenylpropanolamine with methyldopa and oxprenolol. Br Med J 1976; ii: 283-84. 13. Lee KY, Beilin LJ, Vandogen R. Severe hypertension after ingestion of an appetite suppressant (phenylpropanolamine) with indomethacin. Lancet 1979; i: 1110-11. 14. Achor MB, Extein I. Diet aids, mania and affective illness. Am J Psychiatry 1981; 138: 392. 15. Dietz AJ. Amphetamine-like reactions to phenylpropanolamine. JAMA 1981; 245: 601-02. 16. Norvenius G, Widerlov E, Lonnerholm G. Phenylpropanolamine and mental disturbances. Lancet 1979; ii: 1367-68. 17. Schaffer CB, Pauli MW. Psychotic reaction caused by proprietary oral diet agents. Am J Psychiatry 1980; 137: 1256-57. 18. Deocampo PD. Convulsive seizures due to phenylpropanolamine. J Med Soc New Jersey 1979; 76: 591-92. 19. Patterson FK. Delayed fatal outcome after possible Ru-Tuss overdose. J Forens Sci 1980; 25: 344-52. DA, Cohen BI, Flow MI. Phenylpropanolamine weight control products. National Clearing House Poisons Control Centers Bull 1981; 25: 16-18. 21. Phenylpropanolamine—an over the counter amphetamine. JAMA 1981; 245:
20. Bracanto
1346-47. 22.
Eagle R. The Fabrini
file. World Med Sept
19, 1981, p 25-28.
from their operative strokes makes comparison with the natural history studies difficult since such investigations did not distinguish between strokes of different durations. Careful patient selection will reduce the risk of surgery. However, patients with stable or no neurological signs, no ischaemic heart disease, and only focal disease on angiographylmay have not only a low surgical risk, but also a low risk in the natural course of events. In general, nonrandomised comparisons lead to overestimates of treatment effects,14 and the efficacy of carotid endarterectomy for amaurosis fugax-or any other form of cerebrovascular disease, will not be established reliably by analysis of surgical series which bear mostly on the safety of the procedure itself. Unfortunately the single published randomised trial was inconclusive.15 Perhaps this matter will be resolved by further randomised trials, and at least one has been started in fifteen British centres. Meanwhile, physicians who favour carotid endarterectomy will investigate their amaurosis fugax patients with angiography and refer them for surgery, while those who have had unhappy surgical experiences will avoid both angiography and surgery. If there are enough physicians who are prepared to allocate their patients randomly (several hundred patients will be needed) to surgery or no-surgery, then we shall get a better notion of the place of carotid
endarterectomy.
PHENYLPROPANOLAMINE OVER THE COUNTER PHENYLPROPANOLAMINE is a sympathomimetic amine widely used as a decongestant for rhinitis, sinusitis, and cough. In many countries it is available either over the counter or on prescription, usually in combination with other drugs. While it may relieve some of the miseries associated with the common cold, proof of its efficacy in preventing complications of upper-respiratory-tract infections is lacking.’ A report2 of 3 cases of myocardial injury after ingestion of both therapeutic and excessive doses of phenylpropanolamine raises doubt about its safety. One woman had severe hypertension (204/148 mm Hg) and chest pain with abnormalities of the electrocardiogram and cardiac muscle enzymes after ingestion ofa single capsule containing phenylpropanolamine 50 mg, chlorpheniramine 4 mg, and belladonna alkaloids 0’ 2 mg. In that study all 3 of those patients recovered but other workers3,4 have described fatal cases of phenylpropanolamine overdose with arrhythmias, severe hypertension, and myocardial damage. In normal subjects,5,6 modest doses (up to 85 mg) have caused 13. Sundt
TM, Sandok BA, Whisnant JP. Carotid endarterectomy. Complications and preoperative assessment of risk. Mayo Clin Proc 1975; 50: 301-06. 14. Peto R. Clinical trial methodology. Biomedicine (special issue) 1978; 28: 24-36. 15. Fields WS, Maslenikov V, Meyer JS, Hass WK, Remington RD, MacDonald M. Joint Study of Extracranial Arterial Occlusion. V Progress report of prognosis following surgery or non-surgical treatment for transient cerebral ischaemic attacks and cervical carotid artery lesions. JAMA 1970; 211: 1993-2003. 1. Randall JE, Hendley JO.
A decongestant-antihistamine mixture in the prevention of otitis media in children with colds. Pediatrics 1979; 63: 483-85. 2. Pentell PR, Mikell FL, Zavorai JH. Myocardial injury after phenylpropanolamine ingestion. Br Heart J 1982; 47: 51-54. 3. Rumack BH, Anderson BH, Wolf R, et al. Ornade and anticholinergic toxicity: Hypertension, hallucinations and arrhythmias. Clin Toxicol 1974; 7: 573-81. 4. Chouinard G, Ghadirian AM, Jones BD. Death attributed to ventricular arrhythmia induced by thioridazine in combination with a single Contac-C capsule. Can Med Assoc J 1978; 119: 729-31. 5. Frewin DB, Leonello PP, Frewin ME. Hypertension after ingestion of Trimolets. Med J Aust 1978; ii: 497-98. 6. Horowitz JD, Howes LG, Christophidis N, et al. Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1980; i: 60-61.
and sometimes chest had a cerebral haemorrhage.7 pain; patient The formulation of phenylpropanolamine may be important since hypertensive episodes8are more likely to follow ingestion of a simple-dosage form than ingestion of slow-release preparations. Often phenylpropanolamine is combined in a single tablet with other drugs which enhance its toxicity. Popular congeners include caffeine, which increases catecholamine and levels,9 plasma chlorpheniramine, which inhibits neuronal reuptake of catecholamines.lo Hypertensive crises may also occur when phenylpropanolamine is taken with monoamine oxidase and inhibitors, 11 methyldopa oxprenolol,12 or indomethacin.13 There have been several reports of psychotic reactions after small doses of phenylpropanolamine. Manic episodes14 and hallucinations 15 have been recorded. In Sweden these adverse reactions are commonly reported and in 1979 61 cases were notified.16 Paranoid episodes 17 and grand mal seizures 18 have also been seen after various doses of
substantial
changes in blood-pressure
one
phenylpropanolamine. few reports of deaths from overdose’" of phenylpropanolamine. In the United States the drug is promoted as an over-the-counter slimming aid, and poison control centres and hospital emergency rooms have been seeing many cases of overdosage with this and other syrnpathomimetics.11 Unfortunately, some of this overuse21 of phenylpropanolamine seems to have resulted from a tightening of regulations for the prescription of amphetamines which has led to an increase in the use of There
are
phenylpropanolamine as a "street drug". There has lately an attempt, by an agency outside the ethical pharmaceutical industry, to promote phenylpropanolamine in the United Kingdom as an appetite suppressant.22 Since been
of
serious adverse reactions to have arisen in previously healthy phenylpropanolamine after of modest doses, it may be that people ingestion alternative remedies are safer for relief of symptoms of some
the
most
congestion from colds and flu. The regulatory authorities will doubtless be scrutinising attempts to market the drug as an anorexiant in view of its potential as a drug of abuse. King J. Hypertension and cerebral haemorrhage after trimolets ingestion. Med J Aust 1979; ii: 258. 8. Cuthbert MR. Anorectic and decongestant preparations containing phenylpropanolamine. Lancet 1980; i: 367. 9. Robertson D, Johnson GA, Robertson RM, et al. Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation
7.
1979; 59: 637-43. 10. Horn AS, Coyle JT, Snyder SH. Catecholamine uptake by synaptosomes from rat brain. Structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurones. Mol Pharmacol 1970; 7: 66-80. 11. Cuthbert MF, Greenburg MP, Morley SW. Cold and cough remedies: a potential danger to patients on monoamine oxidase inhibitors. Br Med J 1969; i: 404-06. 12. McLaren EH. Severe hypertension produced by interaction of phenylpropanolamine with methyldopa and oxprenolol. Br Med J 1976; ii: 283-84. 13. Lee KY, Beilin LJ, Vandogen R. Severe hypertension after ingestion of an appetite suppressant (phenylpropanolamine) with indomethacin. Lancet 1979; i: 1110-11. 14. Achor MB, Extein I. Diet aids, mania and affective illness. Am J Psychiatry 1981; 138: 392. 15. Dietz AJ. Amphetamine-like reactions to phenylpropanolamine. JAMA 1981; 245: 601-02. 16. Norvenius G, Widerlov E, Lonnerholm G. Phenylpropanolamine and mental disturbances. Lancet 1979; ii: 1367-68. 17. Schaffer CB, Pauli MW. Psychotic reaction caused by proprietary oral diet agents. Am J Psychiatry 1980; 137: 1256-57. 18. Deocampo PD. Convulsive seizures due to phenylpropanolamine. J Med Soc New Jersey 1979; 76: 591-92. 19. Patterson FK. Delayed fatal outcome after possible Ru-Tuss overdose. J Forens Sci 1980; 25: 344-52. DA, Cohen BI, Flow MI. Phenylpropanolamine weight control products. National Clearing House Poisons Control Centers Bull 1981; 25: 16-18. 21. Phenylpropanolamine—an over the counter amphetamine. JAMA 1981; 245:
20. Bracanto
1346-47. 22.
Eagle R. The Fabrini
file. World Med Sept
19, 1981, p 25-28.