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Pharmaceutical prescriptions in four European countries
palliation of breathlessness, which currently depends on crude manipulation of cortical control by sedatives, morphine and its analogues, or psychological techniques, may have to consider, after all, arterial blood gas alterations as well. The practical benefits of astute application of these new physiological data could be great. clinical approach
to
Martin Muers Respiratory Unit, Killingbeck Hospital, Leeds, UK 1 Howell JBL. Breathlessness in respiratory medicine. In: Brewis RAL, Gibson GJ, Geddes DM, eds. Breathlessness. London: Baillière Tindall, 1990: 221-28. 2 Howell JBL. Breathing. In: Porter R, ed. Herring-Breuer centenary symposium. London: CIBA Foundation, Churchill, 1970: 287-301. 3 Merton PA. Human position sense and sense of effort. Soc Exp Biol Symp 1964; 18: 387-400. 4 Newsom Davis J. Contribution of somatic receptors in the chest wall to detection of added inspiratory airway resistance. Clin Sci 1967; 33: 249-60. 5 Campbell EJM, Godfrey S, Clarke TJH, Freedman S, Normal J. The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding during hypercapnia. Clin Sci 1969; 36: 323-28. 6 Gandevia SC, Killian K, McKenzie DK, et al. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during complete paralysis in humans. J Physiol 1993; 470: 85-107. 7 Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. "Air hunger" arising from increased PCO2 in mechanically ventilated quadriplegics. Resp Physiol 1989; 76: 53-68. 8 Banzett RB, Lansing RW, Brown R, et al. "Air hunger" from increased PCO2 persists after complete neuromuscular block in humans. Resp Physiol 1990; 81: 1-18. 9 McCloskey DI. Corollary discharges: motor commands and perception. In: Handbook of Physiology: the nervous system, vol II. Bethesda: American Physiological Society, 1981: 1415-47. 10 Fowler WS. Breaking point of breath holding. J Appl Physiol 1954; 6: 539-45. 11 Howell JBL. Behavioural breathlessness. Thorax 1990; 45: 287-92.
Pharmaceutical prescriptions in four European countries quality of therapy can be measured in various ways, including analysis of the most widely sold drugs. Such an analysis, extended to four European countries-Italy, France, Germany, and the UK-also tells us something about physicians’ prescribing habits, which are often influenced by commercial pressures. When we compared the first fifty pharmaceutical products most sold by value in 1992 in the four countries, we found, to our surprise, that only seven were common to all four lists, although not in the same order-ranitidine, nifedipine, omeprazole, enalapril, captopril, acyclovir, and simvastatin. Thus, in Italy two products containing ranitidine, an antiulcer drug, hold first and second position whereas in France they rank tenth and thirty-first and in Germany third and fourth; in the UK only one product ranks first. These differences reflect not only the volume but also the price of ranitidine, which is higher in Italy and Germany than in France or the UK. Acyclovir, an antiviral agent, scores seventh in Germany, fourteenth in the UK, sixteenth in France, and thirtyfourth in Italy. Another way to look at the sales of pharmaceuticals is to assess their impact in terms of therapeutic value. Accordingly, we classified products on three levels: A = drugs with efficacy shown by controlled clinical trials; B = drugs that represent a second choice after other similar drugs, drugs for which there is evidence of excess use in
The
relation to the registered indications, drugs that cost more than others showing similar efficacy, and combinations of active principles for which there is no evidence of superiority over the single principles; and C = drugs for which there is no evidence of efficacy. The table sets out the scores for the four countries, for the first twenty-five or the first fifty most widely sold products. Owing to the differences in price, the most-sold products are not necessarily the most-prescribed products. The pharmaceutical market in the UK certainly seems to be more rational in terms of using efficacious drugs than the other three countries. Germany has an intermediate score whereas in France and Italy the market is dominated by drugs with very little, if any, therapeutic value. If we focus on class C, in Italy we find that the first fifty products include gangliosides (two products) and drugs with alleged immunomodulatory effects such as thymostimuline, thymomoduline, and thymopentine (two products). The list for France likewise includes some agents such as flavonoids obtained from plant extracts or single flavonoids probably used for the treatment of phlebitis, extracts of Ginkgo biloba (two products) for various indications, and extracts of Pigeum africanum. In Germany Ginkgo biloba ranks first in sales; and thioctic acid (probably used for liver diseases) appears as well as flavonoids. Most of these drugs are not even mentioned in the standard pharmacology or therapeutics texts. The UK is an exception since there are no level C drugs among the first
fifty products. What fraction of sales is accounted for by products with legitimate claim to be regarded as drugs? Only about 50% of the pharmaceutical expenditure in Italy and France goes on the purchase of agents showing efficacy; this figure rises to about 70% for Germany and 95% for the UK. Italy and France devote about 20% of their expenditure to agents of dubious value; the figure is lower-about 12%for Germany whereas in the UK the problem does not exist. Finally we should look at the peculiarities of the various markets. Italy is the only country where a benzodiazepine
no
an fluoxetine, (anxiolytic-tranquilliser) appears; antidepressant agent, appears only in the UK; and cimetidine (two products), an antiulcer agent, is present only in the UK whereas in the other three countries ranitidine is the preferred drug for this indication. For the treatment-of diabetes, glycazide, a synthetic hypoglycaemic agent, is preferred in France whereas in Germany recombinant human insulin holds pride of place and in the
other two countries no antidiabetic agents appear in the first fifty compounds sold. Calcitonin (four products) is a best-seller in Italy for the treatment of osteoporosis; in Germany calcium gluconate is preferred and in the other two countries there are no anti-osteoporosis agents. In Italy three products containing interferon are among the top fifty but this compound is not present in the lists of the other
1191
three countries. Four products containing beclomethasone are used widely in the UK but not elsewhere. We conclude that the European market shows considerable heterogeneity. The UK differs from the other three countries in not selling questionable products. Put another way, despite frequent complaints about excess expenditure for health at least 20% of the sales of the first fifty compounds in Italy and France and 12% in Germany are a waste of money. The other three countries might be interested in looking at the reasons for this difference in order to spend their own resources more wisely. Another factor is that the expenses of the UK National Health Service are among the lowest per caput and in relation to the gross national product. The differences in the most sold drugs in the four countries suggest market pressure rather than the patients’ interest. Any evaluation should ultimately rely on the relation between prescriptions and epidemiological data, but it is hard to believe, for example, that the large sales of immunomodulators or calcitonin in Italy reflect important underlying differences in the prevalence of the disease. The European Community should surely pay attention to these startling differences, especially in view of the establishment of the European Drug Agency. The need for harmonisation of prescriptions may offer the opportunity for research aimed at making doctors’ approaches to therapy more rational.
Silvio Garattini, Livio Garattini Centro di Economia Sanitaria "A Valenti", Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
Pestilence, war, and lice See page 1213
Large military forces are deployed for many reasons world wide, with various degrees of logistic support. With any lengthy campaign, especially in tropical areas, entomologists and field laundries are essential components of such support. By these means the armies are protected against pestilence, and ultimately civilian populations too. Collapse of the support infrastructure has serious consequences for civilians. There are few places where the threshold for epidemics is
lower than in Ethiopia. Tenuous public health facilities in a population with pockets of overcrowding where louseborne relapsing fever (LBRF) is endemic means that it takes little social upheaval for unbridled release of this pestilence on the local inhabitants. A lengthy civil war consequently created the ideal stimulus for spread of the spirochaete Borrelia recurrentis by the infected body louse Pediculus humanus humanus, which excretes the organism in its faeces. The irritation of the bite provokes scratching that inoculates the skin of the potential patient. The clinical manifestations of the ensuing recurrent attacks of vasculitis have been well described.1-4 Combatants in the civil war provided the nidus for the epidemic. Other than food and ordnance, there was no logistic support so that, unprotected medically, their .
permitted ready spread among themselves and to local civilians.1,2 Supervision of the return of hundreds of thousands of soldiers from the battlefields of northern Ethiopia to their areas of original recruitment was a formidable task entrusted to the International Committee
musters
1192
of the Red Cross, which organised camps on the southbound routes. That this exercise was completed successfully while treatment for LBRF was provided was praiseworthy in itself; that any numerical observations were recorded in such mayhem is truly exceptional. In this issue Sundnes and Haimanot provide unique data which confirm that control of an epidemic of LBRF can be achieved by elimination of the vector in combination with antibiotic treatment.
underscores the need for sound advice so that, when there is a large infested entomological effort is not wasted on superfluous activities. population, Although the body louse feeds on the skin, it lives and lays its eggs on the warm adjacent garments. The only action that is necessary is insufflation of pediculicidal powder such Their
account
10% dichlorodiphenyl-trichloroethane (DDT) or, better, 1% malathion or 0-5% permethrin at moderate pressure under the clothes.56 Shaving and washing the as
body and spraying belongings and tents are pointless, wasteful, and costly in terms of time, resources, and effort. Borrelia recurrentis is highly sensitive to single doses of many cheap antibiotics such as tetracycline, penicillin, and erythromycin. 1-3,7 The attendant discomfort of the JarischHerxheimer reaction, which occurs in a higher proportion (16-80%) of LBRF cases 1,5,8,9 than of other spirochaetal diseases (eg, syphilis, Lyme disease, and leptospirosis) is noteworthy and may be related to changes in cytokines8 and glucose homoeostasis.1O With treatment, LBRF is seldom fatal, but LBRF or the Jarisch-Heixheimer reaction does not guarantee immunity from reinfection, which depends on successful vector control The lesson learned by the British Army over fifty years agoll that the advice of entomologists is essential, economical, and effective must be made known to agencies such as the Red Cross. Vigilance in former Yugoslavia, with ready recourse to entomological advice, is essential if epidemic typhus, a more serious louse-borne disease, is to be prevented. M World Royal Army Medical College, London, UK
1
Borgnolo G, Denku B, Chiabrera F, Hailu B. Relapsing fever in Ethiopian children: a clinical study. Ann Trop Paediatr 1993; 13:
2
Borgnolo G, Hailu B, Ciancarelli A, et al. Louse-borne relapsing fever: a clinical and an epidemiological study of 389 patients in Asella Hospital, Ethiopia. Trop Geogr Med 1993; 45: 66-69. Daniel E, Bayene H, Tessema T. Relapsing fever in children: demographic, social and clinical features. Ethiopian Med J 1992; 30:
165-71.
3
207-14. Brown V, Larouze B, Desve G, et al. Clinical presentation of louseborne relapsing fever among Ethiopian refugees in northern Somalia. Ann Trop Med Parasitol 1988; 82: 499-502. 5 Alexander J O’D. Arthropods and human skin. Berlin: Springer Verlag, 1984: 32, 41, 45, 49. 6 Gordon RM, Lavipierre M M J. Entomology for students of medicine. Oxford: Blackwell, 1962: 230. 7 Gebrehinot T, Fiseha A. Tetracycline versus penicillin in the treatment of louse-borne relapsing fever. Ethiopian Med J 1992; 30: 175-81. 8 Negussie Y, Remick DG, Deforge LE, et al. Detection of plasma tumor necrosis factor, interleukins 6 and 8 during the JarischHerxheimer reaction of relapsing fever. J Exp Med 1992; 175: 1207-12. 9 Zein ZA. Louse-borne relapsing fever (LBRF): mortality and frequency of Jarisch-Herxheimer reaction. J R Soc Health 1987; 107: 146-47. 10 Teklu B, Habte-Michael A, White NJ, et al. Glucose and insulin homeostasis during the Jarisch-Herxheimer reaction. Trans R Soc Trop Med Hyg 1985; 79: 74-77. 11 Burgess NRH. Fifty years of military entomology. In: Prospectus of the Army Medical Services. Golspie, UK: Method Publishing
4
Company,
1992: 46-47.
to
Martin Muers Respiratory Unit, Killingbeck Hospital, Leeds, UK 1 Howell JBL. Breathlessness in respiratory medicine. In: Brewis RAL, Gibson GJ, Geddes DM, eds. Breathlessness. London: Baillière Tindall, 1990: 221-28. 2 Howell JBL. Breathing. In: Porter R, ed. Herring-Breuer centenary symposium. London: CIBA Foundation, Churchill, 1970: 287-301. 3 Merton PA. Human position sense and sense of effort. Soc Exp Biol Symp 1964; 18: 387-400. 4 Newsom Davis J. Contribution of somatic receptors in the chest wall to detection of added inspiratory airway resistance. Clin Sci 1967; 33: 249-60. 5 Campbell EJM, Godfrey S, Clarke TJH, Freedman S, Normal J. The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath-holding during hypercapnia. Clin Sci 1969; 36: 323-28. 6 Gandevia SC, Killian K, McKenzie DK, et al. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during complete paralysis in humans. J Physiol 1993; 470: 85-107. 7 Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. "Air hunger" arising from increased PCO2 in mechanically ventilated quadriplegics. Resp Physiol 1989; 76: 53-68. 8 Banzett RB, Lansing RW, Brown R, et al. "Air hunger" from increased PCO2 persists after complete neuromuscular block in humans. Resp Physiol 1990; 81: 1-18. 9 McCloskey DI. Corollary discharges: motor commands and perception. In: Handbook of Physiology: the nervous system, vol II. Bethesda: American Physiological Society, 1981: 1415-47. 10 Fowler WS. Breaking point of breath holding. J Appl Physiol 1954; 6: 539-45. 11 Howell JBL. Behavioural breathlessness. Thorax 1990; 45: 287-92.
Pharmaceutical prescriptions in four European countries quality of therapy can be measured in various ways, including analysis of the most widely sold drugs. Such an analysis, extended to four European countries-Italy, France, Germany, and the UK-also tells us something about physicians’ prescribing habits, which are often influenced by commercial pressures. When we compared the first fifty pharmaceutical products most sold by value in 1992 in the four countries, we found, to our surprise, that only seven were common to all four lists, although not in the same order-ranitidine, nifedipine, omeprazole, enalapril, captopril, acyclovir, and simvastatin. Thus, in Italy two products containing ranitidine, an antiulcer drug, hold first and second position whereas in France they rank tenth and thirty-first and in Germany third and fourth; in the UK only one product ranks first. These differences reflect not only the volume but also the price of ranitidine, which is higher in Italy and Germany than in France or the UK. Acyclovir, an antiviral agent, scores seventh in Germany, fourteenth in the UK, sixteenth in France, and thirtyfourth in Italy. Another way to look at the sales of pharmaceuticals is to assess their impact in terms of therapeutic value. Accordingly, we classified products on three levels: A = drugs with efficacy shown by controlled clinical trials; B = drugs that represent a second choice after other similar drugs, drugs for which there is evidence of excess use in
The
relation to the registered indications, drugs that cost more than others showing similar efficacy, and combinations of active principles for which there is no evidence of superiority over the single principles; and C = drugs for which there is no evidence of efficacy. The table sets out the scores for the four countries, for the first twenty-five or the first fifty most widely sold products. Owing to the differences in price, the most-sold products are not necessarily the most-prescribed products. The pharmaceutical market in the UK certainly seems to be more rational in terms of using efficacious drugs than the other three countries. Germany has an intermediate score whereas in France and Italy the market is dominated by drugs with very little, if any, therapeutic value. If we focus on class C, in Italy we find that the first fifty products include gangliosides (two products) and drugs with alleged immunomodulatory effects such as thymostimuline, thymomoduline, and thymopentine (two products). The list for France likewise includes some agents such as flavonoids obtained from plant extracts or single flavonoids probably used for the treatment of phlebitis, extracts of Ginkgo biloba (two products) for various indications, and extracts of Pigeum africanum. In Germany Ginkgo biloba ranks first in sales; and thioctic acid (probably used for liver diseases) appears as well as flavonoids. Most of these drugs are not even mentioned in the standard pharmacology or therapeutics texts. The UK is an exception since there are no level C drugs among the first
fifty products. What fraction of sales is accounted for by products with legitimate claim to be regarded as drugs? Only about 50% of the pharmaceutical expenditure in Italy and France goes on the purchase of agents showing efficacy; this figure rises to about 70% for Germany and 95% for the UK. Italy and France devote about 20% of their expenditure to agents of dubious value; the figure is lower-about 12%for Germany whereas in the UK the problem does not exist. Finally we should look at the peculiarities of the various markets. Italy is the only country where a benzodiazepine
no
an fluoxetine, (anxiolytic-tranquilliser) appears; antidepressant agent, appears only in the UK; and cimetidine (two products), an antiulcer agent, is present only in the UK whereas in the other three countries ranitidine is the preferred drug for this indication. For the treatment-of diabetes, glycazide, a synthetic hypoglycaemic agent, is preferred in France whereas in Germany recombinant human insulin holds pride of place and in the
other two countries no antidiabetic agents appear in the first fifty compounds sold. Calcitonin (four products) is a best-seller in Italy for the treatment of osteoporosis; in Germany calcium gluconate is preferred and in the other two countries there are no anti-osteoporosis agents. In Italy three products containing interferon are among the top fifty but this compound is not present in the lists of the other
1191
three countries. Four products containing beclomethasone are used widely in the UK but not elsewhere. We conclude that the European market shows considerable heterogeneity. The UK differs from the other three countries in not selling questionable products. Put another way, despite frequent complaints about excess expenditure for health at least 20% of the sales of the first fifty compounds in Italy and France and 12% in Germany are a waste of money. The other three countries might be interested in looking at the reasons for this difference in order to spend their own resources more wisely. Another factor is that the expenses of the UK National Health Service are among the lowest per caput and in relation to the gross national product. The differences in the most sold drugs in the four countries suggest market pressure rather than the patients’ interest. Any evaluation should ultimately rely on the relation between prescriptions and epidemiological data, but it is hard to believe, for example, that the large sales of immunomodulators or calcitonin in Italy reflect important underlying differences in the prevalence of the disease. The European Community should surely pay attention to these startling differences, especially in view of the establishment of the European Drug Agency. The need for harmonisation of prescriptions may offer the opportunity for research aimed at making doctors’ approaches to therapy more rational.
Silvio Garattini, Livio Garattini Centro di Economia Sanitaria "A Valenti", Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
Pestilence, war, and lice See page 1213
Large military forces are deployed for many reasons world wide, with various degrees of logistic support. With any lengthy campaign, especially in tropical areas, entomologists and field laundries are essential components of such support. By these means the armies are protected against pestilence, and ultimately civilian populations too. Collapse of the support infrastructure has serious consequences for civilians. There are few places where the threshold for epidemics is
lower than in Ethiopia. Tenuous public health facilities in a population with pockets of overcrowding where louseborne relapsing fever (LBRF) is endemic means that it takes little social upheaval for unbridled release of this pestilence on the local inhabitants. A lengthy civil war consequently created the ideal stimulus for spread of the spirochaete Borrelia recurrentis by the infected body louse Pediculus humanus humanus, which excretes the organism in its faeces. The irritation of the bite provokes scratching that inoculates the skin of the potential patient. The clinical manifestations of the ensuing recurrent attacks of vasculitis have been well described.1-4 Combatants in the civil war provided the nidus for the epidemic. Other than food and ordnance, there was no logistic support so that, unprotected medically, their .
permitted ready spread among themselves and to local civilians.1,2 Supervision of the return of hundreds of thousands of soldiers from the battlefields of northern Ethiopia to their areas of original recruitment was a formidable task entrusted to the International Committee
musters
1192
of the Red Cross, which organised camps on the southbound routes. That this exercise was completed successfully while treatment for LBRF was provided was praiseworthy in itself; that any numerical observations were recorded in such mayhem is truly exceptional. In this issue Sundnes and Haimanot provide unique data which confirm that control of an epidemic of LBRF can be achieved by elimination of the vector in combination with antibiotic treatment.
underscores the need for sound advice so that, when there is a large infested entomological effort is not wasted on superfluous activities. population, Although the body louse feeds on the skin, it lives and lays its eggs on the warm adjacent garments. The only action that is necessary is insufflation of pediculicidal powder such Their
account
10% dichlorodiphenyl-trichloroethane (DDT) or, better, 1% malathion or 0-5% permethrin at moderate pressure under the clothes.56 Shaving and washing the as
body and spraying belongings and tents are pointless, wasteful, and costly in terms of time, resources, and effort. Borrelia recurrentis is highly sensitive to single doses of many cheap antibiotics such as tetracycline, penicillin, and erythromycin. 1-3,7 The attendant discomfort of the JarischHerxheimer reaction, which occurs in a higher proportion (16-80%) of LBRF cases 1,5,8,9 than of other spirochaetal diseases (eg, syphilis, Lyme disease, and leptospirosis) is noteworthy and may be related to changes in cytokines8 and glucose homoeostasis.1O With treatment, LBRF is seldom fatal, but LBRF or the Jarisch-Heixheimer reaction does not guarantee immunity from reinfection, which depends on successful vector control The lesson learned by the British Army over fifty years agoll that the advice of entomologists is essential, economical, and effective must be made known to agencies such as the Red Cross. Vigilance in former Yugoslavia, with ready recourse to entomological advice, is essential if epidemic typhus, a more serious louse-borne disease, is to be prevented. M World Royal Army Medical College, London, UK
1
Borgnolo G, Denku B, Chiabrera F, Hailu B. Relapsing fever in Ethiopian children: a clinical study. Ann Trop Paediatr 1993; 13:
2
Borgnolo G, Hailu B, Ciancarelli A, et al. Louse-borne relapsing fever: a clinical and an epidemiological study of 389 patients in Asella Hospital, Ethiopia. Trop Geogr Med 1993; 45: 66-69. Daniel E, Bayene H, Tessema T. Relapsing fever in children: demographic, social and clinical features. Ethiopian Med J 1992; 30:
165-71.
3
207-14. Brown V, Larouze B, Desve G, et al. Clinical presentation of louseborne relapsing fever among Ethiopian refugees in northern Somalia. Ann Trop Med Parasitol 1988; 82: 499-502. 5 Alexander J O’D. Arthropods and human skin. Berlin: Springer Verlag, 1984: 32, 41, 45, 49. 6 Gordon RM, Lavipierre M M J. Entomology for students of medicine. Oxford: Blackwell, 1962: 230. 7 Gebrehinot T, Fiseha A. Tetracycline versus penicillin in the treatment of louse-borne relapsing fever. Ethiopian Med J 1992; 30: 175-81. 8 Negussie Y, Remick DG, Deforge LE, et al. Detection of plasma tumor necrosis factor, interleukins 6 and 8 during the JarischHerxheimer reaction of relapsing fever. J Exp Med 1992; 175: 1207-12. 9 Zein ZA. Louse-borne relapsing fever (LBRF): mortality and frequency of Jarisch-Herxheimer reaction. J R Soc Health 1987; 107: 146-47. 10 Teklu B, Habte-Michael A, White NJ, et al. Glucose and insulin homeostasis during the Jarisch-Herxheimer reaction. Trans R Soc Trop Med Hyg 1985; 79: 74-77. 11 Burgess NRH. Fifty years of military entomology. In: Prospectus of the Army Medical Services. Golspie, UK: Method Publishing
4
Company,
1992: 46-47.