262
Hogg and colleagues was invasive, necessitating two coronary angiograms within 24 hours. That coronary angiography has been used extensively in the management of acute myocardial infarction as a prelude to angioplasty or surgery does not automatically justify its use in this study because the procedure did not lead to any change in treatment of individual patients. Moreover, the most common clinical complication-bleeding from the catheter site-was directly attributable to coronary angiography. Ethical acceptability of this trial requires that additional serious risks are very slight and that its scientific value is commensurate with the extra discomfort and risks involved. We have previously expressed disquiet about experiments at the Hammersmith Hospital in which multiple for a physiological investigation was used angiography of the action of vasoactive peptides in the coronary tree.6 By contrast, the clinical value of the Glasgow trial seems undeniable, but would of course not justify exposing patients to a significant risk. Thus acceptability stands or falls by the definition of acceptable risk in this case. In a fully equipped cardiac unit with supporting facilities, the risks of serious complications are low6 and would seem justifiable in the Glasgow study. These results are a valuable step in the evaluation of the main therapeutic advances of recent years; open discussion of the issues involved is nevertheless essential to preserve standards of scientific clinical investigation. Italiano Per Lo Studio Della Streptochinasi Nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-401. 2. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 3. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebocontrolled clinical trial. Lancet 1988; i: 545-49. 4. Wilcox RG, Olsson CG, Skene AM, et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; ii: 525-30. 5. Editorial. Peptides into the coronary arteries. Lancet 1989; ii: 958-59. 6. Cumberland DC. Coronary angiography and angioplasty. Medicine Int 1989; 68: 2834-36.
1. Gruppo
Are you
taking the medicine?
Thomas Willisl observed in the 17th century that severe asthma could be life-threatening, the low case-fatality rate from the disorder among patients of an individual practitioner subsequently encouraged the view of Osler two hundred years later that asthma is seldom fatal. New Zealand has lately experienced a second "epidemic" of asthma deaths,33 equal in magnitude to that of the 1960s, while the death rate in the UK has probably been rising steadily over the past ten years, especially among males aged 15-34 years.4 The increase in asthma mortality has occurred against a backdrop of increased prescribing of anti-asthma therapy. There are many reasons why
Although
influenced case-fatality rates, most notably poor assessment of the severity of asthma by patients and doctors,6 and a reluctance to prescribe adequate therapy, especially steroids.7 Another important factor is that patients often do not adhere to the prescribed drug regimen. Studies of patient compliance are remarkably consistent in revealing full compliance rates of only 30-50% (in whatever condition is studied8), and patients with asthma are no different, despite the symptomatic nature of their disease.9-11 treatment
has
not
Compliance may be best defined as the extent to which a person’s behaviour (whether in terms of taking drugs, following diets, or executing changes in personal lifestyle) coincides with medical advice. Such definition assumes that the recommendations of the patients’ medical advisors are always correct and should therefore be followed. Full and complete compliance is the state in which the patient takes all the prescribed drug for the entire period intended by the prescribing physician. The term partial compliance implies that the patient has taken only some of the total intended number of doses, either taking the drug fewer times each day, though for the correct number of days, or possibly the full dose but for a shorter period than prescribed. The biological effects of taking all doses for only the first half of a course may, of course, be profoundly different from those of taking only half the prescribed number of tablets every day. Asthmatic patients unfortunately may require both long-term treatment taken 2-4 times a day and short courses of oral drugs such as steroids. Systematic study of the extent and determinants of patients’ compliance and non-compliance with antiasthma therapy has been hampered by the difficulties of assessment. Simply asking patients whether they are taking their drugs is easy and universally applicable but is notoriously unreliable, overestimating true compliance by roughly 30%.12 Assessment by weighing returned pressurised aerosol cannisters is confounded both by the widespread practice of conducting "test-firings" before actual inhalation of drug and by the concurrent use of multiple different inhalers of the same drug (especially of rescue beta agonists). Counting returned dry powder capsules may merely drive poorly compliant patients away from follow-up, increasing noncompliance further. Mechanical devices have been devised to monitor use of pressurised aerosols automatically (eg, the ’Nebuliser Chronolog’ manufactured by ATP, Denver, USA13), but until they are an integral part of the inhaler the influence of the device itself on compliance will remain uncertain. Reiser and Warner14 argued that the mere inclusion of patients in a prospective study may lead to a
unrepresentatively high compliance rates simply because these patients receive more attention. However, there are no objective prospective studies of the influence of such trials on compliance for good or bad. Only unannounced assay of drugs in biological
263
fluids is both reliable and unlikely to alter compliance rates artificially. Measurement of inhaled drugs is difficult, but the development of assays for inhaled beta agonists, especially salbutamol in urine, 15 has allowed an initial insight into the pattern of patient compliance in asthma. Horn et al,16 using such an assay, lately showed that compliance cannot be assumed, even with a drug that provides instant subjective benefit. In a retrospective assessment, only 60% of patients had urine salbutamol levels appropriate to the timing and dose of inhaled salbutamol declared. Some patients were taking less but a higher proportion were using more salbutamol than had been prescribed. The same workers, in a large prospective study in the community where asthmatics were managed with increasing doses of inhaled salbutamol and beclomethasone dipropionate, 17 have now confirmed the clinical importance of compliance with inhaled therapy. Thirty patients whose asthma was brought under good control in terms of symptoms and severity of airflow obstruction (assessed by home peak expiratory flow rate monitoring and forced expiratory volume) had materially higher concentrations of salbutamol in the urine at all stages of the study than did a similar group of thirty patients whose asthma remained poorly controlled despite an identical prescribed drug regimen. Urine salbutamol levels in the latter group indicated that patients were probably relying on rescue bronchodilation alone. There were only a few patients who had not responded to their prescribed regimen and whose urine drug levels suggested compliance (at least on the days of visit to the surgery). Lack of improvement appeared more related to compliance with therapy than to irreversible airflow obstruction. Athma is still underdiagnosed and undertreated, both in the under-use of prophylactic drugs and in the failure to exploit available drugs to the maximum safe therapeutic doses. However, in patients who are correctly diagnosed and subsequently managed rationally, lack of response to therapy may reflect poor compliance. The factors leading to poor compliance need to be determined so that the patients’ use of drugs can be improved, with a consequent reduction in morbidity.
1. Willis T. Practice of physick. London: Thomas Dring, 1678. 2. Osler W. The principles and practice of medicine. New York: Appleton, 1892. 3. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. Br Med J 1982; 285: 771-74. 4. Burney PJ. Asthma mortality in England and Wales: evidence for a further increase. Lancet 1986; ii: 323-26. 5. Keating G, Mitchell EA, Jackson R, Beaglehole R, Rea H. Trends in sales of drugs for asthma in New Zealand, Australia and the United Kingdom 1975-81. Br Med J 1984; 289: 348-51. 6. British Thoracic Society. Death from asthma in two regions of England. Br Med J 1982; 285: 1251-55. 7. Macdonald JB, Macdonald ET, Seaton A, Williams DA. Asthma deaths in Cardiff 1963-74: 53 deaths in hospital. Br Med J 1976; ii: 721-23.
8. Sackett DL, Snow JC. Magnitude of compliance and non-compliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979: 11-22. 9. Kleiger JH, Dirks JF. Medication compliance in chronic asthmatic patients. J Asthma Res 1979; 16: 93-96. 10. Chryssidis E, Frewin DB, Frith PA, Dawes ER. Compliance in aerosol therapy in chronic obstructive lung disease. J Asthma 1981; 94: 375-77. 11. James PNE, Anderson JB, Prior JG, White JP, Henry JA, Cochrane GM. Patterns of drug taking in patients with chronic airflow obstruction. Postgrad Med J 1985; 61: 7-10. 12. Gordis L. Conceptual and methodological problems in measuring patient compliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979: 23-45. 13. Spector SL, Kinsman R, Mawhinny H, et al. Compliance of patients with asthma with an experimental aerolised medication. Implications for controlled clinical trials. J Allergy Clin Immunol 1986; 77: 65-70. 14. Reiser J, Warner JO. The value of participating in an asthma trial. Lancet 1985; i: 206-07. 15. Colthup PV, Dallas FAA, Baynor DA, Carey PF, Skidmore LF, Martin LE. Determination of salbutamol in human plasma and urine by high-peformance thin-layer chromatography. J Chromatogr 1985; 345: 111-18. 16. Horn CR, Essex E, Hill P, Cochrane GM. Does urinary salbutamol reflect compliance with inhaled drug regimens by asthmatics. Respir Med 1989; 83: 15-18. 17. Horn CR, Clark TJH, Cochrane GM. Compliance with inhaled therapy and morbidity from asthma. Respir Med 1990; 84: 67—70.
GENES AND COLOUR BLINDNESS Colour vision in man is trichromatic-ie, it is based on three spectrally distinct classes of photoreceptor. In most mammals, however, colour vision is limited because only two classes of cone are present, one maximally sensitive in the yellow-green region (around 550 nm) and the other maximally sensitive at shorter wavelengths in the blue
region (around 450 nm). Such animals can distinguish blue from yellow, but are red-green colour blind. Trichromacy appeared in mammals with the evolution of the primates and was brought about by the introduction of another class of cone in the yellow-green spectral region. In man the three cone types contain visual pigments with peak sensitivities at about 563, 535, and 420 nm, respectively, that enable us to distinguish blues from yellow and also reds from greens. Most defects of colour vision arise within the red-green system; about 8% of men but only 0-5% of women have some form of red-green colour deficiency. Why should this be? Nathans and colleagues in 19861 identified the genes that encode the opsins, the proteins that combine with retinol to form visual pigments. In man, the gene for the opsin of the blue-sensitive pigment is located on chromosome 3, whereas the genes for pigments sensitive to red and green are found in tandem on the long arm of the X chromosome. Since the X chromosome genes show 96 % homology at the nucleotide level, they probably represent a fairly recent duplication of the longer-wavelength pigment of our mammalian ancestors that occurred during primate evolution. The two loci subsequently diverged to produce the medium-wavelength and long-wavelength pigments. The close similarity between these two genes is probably the main reason for the high frequency of colour anomalies in man. Extensive homology between adjacent genes promotes misalignment of gene sequences, and the resulting unequal crossing-over will lead to gene duplication and deletion and to the production of hybrid loci-precisely what is
The green gene has an extensive numerical polymorphism; gene deletion and the presence of hybrid genes give rise to red-green colour blindness and to anomalous trichromacy. In red-green colour blindness only seen.
Hogg and colleagues was invasive, necessitating two coronary angiograms within 24 hours. That coronary angiography has been used extensively in the management of acute myocardial infarction as a prelude to angioplasty or surgery does not automatically justify its use in this study because the procedure did not lead to any change in treatment of individual patients. Moreover, the most common clinical complication-bleeding from the catheter site-was directly attributable to coronary angiography. Ethical acceptability of this trial requires that additional serious risks are very slight and that its scientific value is commensurate with the extra discomfort and risks involved. We have previously expressed disquiet about experiments at the Hammersmith Hospital in which multiple for a physiological investigation was used angiography of the action of vasoactive peptides in the coronary tree.6 By contrast, the clinical value of the Glasgow trial seems undeniable, but would of course not justify exposing patients to a significant risk. Thus acceptability stands or falls by the definition of acceptable risk in this case. In a fully equipped cardiac unit with supporting facilities, the risks of serious complications are low6 and would seem justifiable in the Glasgow study. These results are a valuable step in the evaluation of the main therapeutic advances of recent years; open discussion of the issues involved is nevertheless essential to preserve standards of scientific clinical investigation. Italiano Per Lo Studio Della Streptochinasi Nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397-401. 2. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 3. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebocontrolled clinical trial. Lancet 1988; i: 545-49. 4. Wilcox RG, Olsson CG, Skene AM, et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988; ii: 525-30. 5. Editorial. Peptides into the coronary arteries. Lancet 1989; ii: 958-59. 6. Cumberland DC. Coronary angiography and angioplasty. Medicine Int 1989; 68: 2834-36.
1. Gruppo
Are you
taking the medicine?
Thomas Willisl observed in the 17th century that severe asthma could be life-threatening, the low case-fatality rate from the disorder among patients of an individual practitioner subsequently encouraged the view of Osler two hundred years later that asthma is seldom fatal. New Zealand has lately experienced a second "epidemic" of asthma deaths,33 equal in magnitude to that of the 1960s, while the death rate in the UK has probably been rising steadily over the past ten years, especially among males aged 15-34 years.4 The increase in asthma mortality has occurred against a backdrop of increased prescribing of anti-asthma therapy. There are many reasons why
Although
influenced case-fatality rates, most notably poor assessment of the severity of asthma by patients and doctors,6 and a reluctance to prescribe adequate therapy, especially steroids.7 Another important factor is that patients often do not adhere to the prescribed drug regimen. Studies of patient compliance are remarkably consistent in revealing full compliance rates of only 30-50% (in whatever condition is studied8), and patients with asthma are no different, despite the symptomatic nature of their disease.9-11 treatment
has
not
Compliance may be best defined as the extent to which a person’s behaviour (whether in terms of taking drugs, following diets, or executing changes in personal lifestyle) coincides with medical advice. Such definition assumes that the recommendations of the patients’ medical advisors are always correct and should therefore be followed. Full and complete compliance is the state in which the patient takes all the prescribed drug for the entire period intended by the prescribing physician. The term partial compliance implies that the patient has taken only some of the total intended number of doses, either taking the drug fewer times each day, though for the correct number of days, or possibly the full dose but for a shorter period than prescribed. The biological effects of taking all doses for only the first half of a course may, of course, be profoundly different from those of taking only half the prescribed number of tablets every day. Asthmatic patients unfortunately may require both long-term treatment taken 2-4 times a day and short courses of oral drugs such as steroids. Systematic study of the extent and determinants of patients’ compliance and non-compliance with antiasthma therapy has been hampered by the difficulties of assessment. Simply asking patients whether they are taking their drugs is easy and universally applicable but is notoriously unreliable, overestimating true compliance by roughly 30%.12 Assessment by weighing returned pressurised aerosol cannisters is confounded both by the widespread practice of conducting "test-firings" before actual inhalation of drug and by the concurrent use of multiple different inhalers of the same drug (especially of rescue beta agonists). Counting returned dry powder capsules may merely drive poorly compliant patients away from follow-up, increasing noncompliance further. Mechanical devices have been devised to monitor use of pressurised aerosols automatically (eg, the ’Nebuliser Chronolog’ manufactured by ATP, Denver, USA13), but until they are an integral part of the inhaler the influence of the device itself on compliance will remain uncertain. Reiser and Warner14 argued that the mere inclusion of patients in a prospective study may lead to a
unrepresentatively high compliance rates simply because these patients receive more attention. However, there are no objective prospective studies of the influence of such trials on compliance for good or bad. Only unannounced assay of drugs in biological
263
fluids is both reliable and unlikely to alter compliance rates artificially. Measurement of inhaled drugs is difficult, but the development of assays for inhaled beta agonists, especially salbutamol in urine, 15 has allowed an initial insight into the pattern of patient compliance in asthma. Horn et al,16 using such an assay, lately showed that compliance cannot be assumed, even with a drug that provides instant subjective benefit. In a retrospective assessment, only 60% of patients had urine salbutamol levels appropriate to the timing and dose of inhaled salbutamol declared. Some patients were taking less but a higher proportion were using more salbutamol than had been prescribed. The same workers, in a large prospective study in the community where asthmatics were managed with increasing doses of inhaled salbutamol and beclomethasone dipropionate, 17 have now confirmed the clinical importance of compliance with inhaled therapy. Thirty patients whose asthma was brought under good control in terms of symptoms and severity of airflow obstruction (assessed by home peak expiratory flow rate monitoring and forced expiratory volume) had materially higher concentrations of salbutamol in the urine at all stages of the study than did a similar group of thirty patients whose asthma remained poorly controlled despite an identical prescribed drug regimen. Urine salbutamol levels in the latter group indicated that patients were probably relying on rescue bronchodilation alone. There were only a few patients who had not responded to their prescribed regimen and whose urine drug levels suggested compliance (at least on the days of visit to the surgery). Lack of improvement appeared more related to compliance with therapy than to irreversible airflow obstruction. Athma is still underdiagnosed and undertreated, both in the under-use of prophylactic drugs and in the failure to exploit available drugs to the maximum safe therapeutic doses. However, in patients who are correctly diagnosed and subsequently managed rationally, lack of response to therapy may reflect poor compliance. The factors leading to poor compliance need to be determined so that the patients’ use of drugs can be improved, with a consequent reduction in morbidity.
1. Willis T. Practice of physick. London: Thomas Dring, 1678. 2. Osler W. The principles and practice of medicine. New York: Appleton, 1892. 3. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. Br Med J 1982; 285: 771-74. 4. Burney PJ. Asthma mortality in England and Wales: evidence for a further increase. Lancet 1986; ii: 323-26. 5. Keating G, Mitchell EA, Jackson R, Beaglehole R, Rea H. Trends in sales of drugs for asthma in New Zealand, Australia and the United Kingdom 1975-81. Br Med J 1984; 289: 348-51. 6. British Thoracic Society. Death from asthma in two regions of England. Br Med J 1982; 285: 1251-55. 7. Macdonald JB, Macdonald ET, Seaton A, Williams DA. Asthma deaths in Cardiff 1963-74: 53 deaths in hospital. Br Med J 1976; ii: 721-23.
8. Sackett DL, Snow JC. Magnitude of compliance and non-compliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979: 11-22. 9. Kleiger JH, Dirks JF. Medication compliance in chronic asthmatic patients. J Asthma Res 1979; 16: 93-96. 10. Chryssidis E, Frewin DB, Frith PA, Dawes ER. Compliance in aerosol therapy in chronic obstructive lung disease. J Asthma 1981; 94: 375-77. 11. James PNE, Anderson JB, Prior JG, White JP, Henry JA, Cochrane GM. Patterns of drug taking in patients with chronic airflow obstruction. Postgrad Med J 1985; 61: 7-10. 12. Gordis L. Conceptual and methodological problems in measuring patient compliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in health care. Baltimore: Johns Hopkins University Press, 1979: 23-45. 13. Spector SL, Kinsman R, Mawhinny H, et al. Compliance of patients with asthma with an experimental aerolised medication. Implications for controlled clinical trials. J Allergy Clin Immunol 1986; 77: 65-70. 14. Reiser J, Warner JO. The value of participating in an asthma trial. Lancet 1985; i: 206-07. 15. Colthup PV, Dallas FAA, Baynor DA, Carey PF, Skidmore LF, Martin LE. Determination of salbutamol in human plasma and urine by high-peformance thin-layer chromatography. J Chromatogr 1985; 345: 111-18. 16. Horn CR, Essex E, Hill P, Cochrane GM. Does urinary salbutamol reflect compliance with inhaled drug regimens by asthmatics. Respir Med 1989; 83: 15-18. 17. Horn CR, Clark TJH, Cochrane GM. Compliance with inhaled therapy and morbidity from asthma. Respir Med 1990; 84: 67—70.
GENES AND COLOUR BLINDNESS Colour vision in man is trichromatic-ie, it is based on three spectrally distinct classes of photoreceptor. In most mammals, however, colour vision is limited because only two classes of cone are present, one maximally sensitive in the yellow-green region (around 550 nm) and the other maximally sensitive at shorter wavelengths in the blue
region (around 450 nm). Such animals can distinguish blue from yellow, but are red-green colour blind. Trichromacy appeared in mammals with the evolution of the primates and was brought about by the introduction of another class of cone in the yellow-green spectral region. In man the three cone types contain visual pigments with peak sensitivities at about 563, 535, and 420 nm, respectively, that enable us to distinguish blues from yellow and also reds from greens. Most defects of colour vision arise within the red-green system; about 8% of men but only 0-5% of women have some form of red-green colour deficiency. Why should this be? Nathans and colleagues in 19861 identified the genes that encode the opsins, the proteins that combine with retinol to form visual pigments. In man, the gene for the opsin of the blue-sensitive pigment is located on chromosome 3, whereas the genes for pigments sensitive to red and green are found in tandem on the long arm of the X chromosome. Since the X chromosome genes show 96 % homology at the nucleotide level, they probably represent a fairly recent duplication of the longer-wavelength pigment of our mammalian ancestors that occurred during primate evolution. The two loci subsequently diverged to produce the medium-wavelength and long-wavelength pigments. The close similarity between these two genes is probably the main reason for the high frequency of colour anomalies in man. Extensive homology between adjacent genes promotes misalignment of gene sequences, and the resulting unequal crossing-over will lead to gene duplication and deletion and to the production of hybrid loci-precisely what is
The green gene has an extensive numerical polymorphism; gene deletion and the presence of hybrid genes give rise to red-green colour blindness and to anomalous trichromacy. In red-green colour blindness only seen.
