- Email: [email protected]
Third World Smoking— The New Slave Trade
23
There is much scope for confusion in reports on NMR. Both classical and quantum mechanical explanations of the physics of NMR are used concurrently and much of the nomenclature for images has been transposed directly from spectroscopy. There is no general agreement on notation although the American College of Radiology has offered suggestions.52 Unlike X-ray CT images, which are dependent on a single image variable, NMR images are dependent on proton density, Tl, and T2 as well as flow effects. Small variations in the timing of pulse sequences can result in radical changes in the resultant image. There is considerable disagreement about the optimum field strength for imaging, and various magnets are used-permanent, resistive, and cryogenic-each with advantages and disadvantages. In X-ray CT all current machines are essentially similar but with NMR the range is likely to be diverse, some being designed for spectroscopy, some for imaging, and some for both. To date, spectroscopy has largely been a research technique with limited clinical application, whereas proton imaging has been developed with routine clinical applications in mind. Most of the existing NMR imaging machines are research prototypes, and, when the technology stabilises, the technique will need to be compared formally with other imaging methods. One of the notable features of NMR development in the UK has been the fruitful collaboration between commercial interests and the Medical Research Council, the Department of Health and Social Security, and the National Radiological Protection Board.
Third World Smoking— The New Slave Trade arrival of cholera and plague from the Orient
THE used to
great alarm in Britain until these epidemics were brought under control. Now the epidemic of tobacco smoking, which in the past 30 years has killed over one million people in the UK alone, is fast spreading to developing countries with the encouragement of tobacco companies based in the UK and the USA. In 1978 a World Health Organisation report declared that "In the absence of strong and resolute government action, we face the serious cause
will have affected the developing world within a decade and that a major avoidable public health problem will have been inflicted on countries least able to withstand it for the twin reasons of commercial enterprise and government inactivity". Five years later a new report’ catalogues the evidence that the smoking diseases have already arrived. High death rates for lung cancer are reported
probability
that the
52. American College of Radiology. of Radiology, 1983 1.
Smoking control strategies
in
smoking epidemic
Glossary ofNMR terms. Chicago: American College
developing countries.
WHO Tech
Rep Ser no 695,
1983.
from India, China, Hong Kong, and Cuba, and in the Bantu of Natal. Coronary heart disease associated with cigarette smoking is a major feature in India, Pakistan, and the Philippines. Perinatal mortality rates are doubled in Bangladeshi women who smoke. Even traditional forms such as bidi or hookah smoking are hazardous and oral cancer is frequent in Asian men and women who chew tobacco. Health for All by the Year 2000 is likely to be a vain hope for the millions in developing countries who succumb to the blandishments of the tobacco companies. WHO once more makes a strong appeal for effective change, but will governments and health ministries face up to this challenge any more than they did to the two previous WHO reports on smoking? Developing countries are now urged to give high priority to smoking control activities. Although malnutrition and infectious diseases may seem to be more pressing, only action now can prevent their exacerbation by smokingrelated diseases. A central agency with responsibility for smoking control action should be set up in each country. Special steps should be taken to safeguard the health of children through educational programmes. Sale of cigarettes to minors should be prohibited. Particular attention should be paid to traditional smoking materials as a cause of ill-health. All advertising and promotion of tobacco products should be banned. Where tobacco is already a commercial crop every effort should be made to reduce its role into the national economy and to investigate alternative uses of land and labour. Research into the economic role of tobacco is needed if only to provide evidence that the benefits from tobacco production and trade are outweighed by the losses associated with absence from work and care of those with smoking-related diseases. FAO and the World Bank should be approached for help to find crops to replace tobacco. Governments of developed countries are recommended to apply much more stringent controls to their own tobacco
companies. As the first country to produce a report on the hazards of smoking, as a country with high mortality from cigarette-related diseases, and as a country where three of the six largest world tobacco companies are based (British American Tobacco, Imperial, and Rothmans together made f743 million in pre-tax profits on tobacco alone in 1982) the UK bears considerable responsibility. Yet, far from discouraging exports to developing countries, the reverse is the case. Rothman’s International were given the 1983 Queen’s Award for Export Achievements. Some export brands and those manufactured under licence overseas still have much higher tar and nicotine content than those smoked at home. Britain provides no overseas aid for anti-smoking programmes-unlike Norway and Sweden who give substantial sums to the International Union Against Cancer and WHO for this purpose. Instead, between 1974 and 1979 the UK gave about 3/2 million to four Commonwealth countries for the development of their tobacco industries.
24
What can individual doctors in Britain do? They can provide an example by pressing for smoking control policies in all hospitals and health service premises. Many hospitals still sell cigarettes in their shops and do too little to control smoking on the wards. They can inform their MPs and voice their concern at the activities of the tobacco companies both at home and abroad. They can consider the propriety of holding tobacco shares either themselves or via the universities or institutions with which they are associated. They can,press for the kind of changes recommended by the Royal College of Physicians, to provide an example for developing countries. The WHO committee noted that "whenever the tobacco industry is threatened with action on smoking control it starts long drawn out negotiations with the health authorities with a view to creating confusion, delaying action and buying time, and preventing effective smoking control action". The situation has hardly changed since the late Senator Robert Kennedy stated in 1967 "The cigarette industry is peddling a deadly weapon. It is dealing with people’s lives for financial gain". These companies are causing a new form of Third World Slavery which is yearly killing tens of thousands who die unaware of the risks they have been taking. Wilberforce succeeded after 40 years. We shall have to take much stronger action if, with regard to smoking, we are to emulate his achievement.
THE QUINOLONES Lancet readers accustomed to a "market awash with cephalosporins" will soon have to evaluate an equally confusing group of highly active antibacterial agents-the nalidixic acid family, loosely called quinolones or quinolonecarboxylic acids. Sixty-two papers at the Intersciences Conference on Antimicrobial Agents and Chemotherapy at Las Vegas featured the group. Nalidixic acid has a relatively simple chemical structure. The carboxylic acid and neighbouring oxygen atoms are needed for antibacterial activity, but much of the remainder can be modified. Albrechtl listed over a thousand variants, in 1977, but few were more active than nalidixic acid and only cinoxacin is currently marketed in the UK. The antibacterial activity affects bacterial DNA topoisomerases (or gyrases), of which four subunits (two a, two 0) have been defined. The enzymes are required to supercoil strands of bacterial DNA (up to 140 m long) so they fit in the bacterial cell. Higher concentrations act on bacterial RNA. The only other antibiotic known to work on topoisomerases is novobiocin. Nalidixic acid is as active as ampicillin against aerobic gram-negative bacteria, but has little useful effect on grampositives or pseudomonas. It is only partly absorbed, then metabolised, so 4 g a day is needed to ensure adequate urinary levels in an adult. The high dose has been associated with side-effects including visual disturbances. Although nalidixic acid resistance is not transferable on plasmids, it develops 2 Health
or
smoking follow-up report of the Royal College of Physicians London:
Pitman, 1983. 1 Albrecht R
Development of
1977; 21: 9-104
antibacterial agents of the nalidixic type.
Progr Drug Res
easily. Nonetheless this agent was the "standard" member of the family for many years and has been used for bowel decontamination and treatment of bacillary dysentery2 as well as cystitis. Addition of a piperazinyl radical to the molecule produced pipemidic acid, which has some activity against pseudomonas and has been widely used in Europe. Addition of a fluorine atom at the 6-position produced norfloxacin, a fluoroquinolinecarboxylic acid that is a hundred times as active as nalidixic acid with a spectrum that includes enterococci and staphylococci as well as
pseudomonas.33 On view at Las Vegas were data on seven new agents with differing structures but all containing the fluorine atom and piperazinyl group. Four originated in Japan, two in Europe, and one in the USA. The first job for a prospective user is to grapple with names. The drugs start life as numbers which are replaced with generic then trade names. The situation is complicated by the fact that three Japanese compounds have been taken up by international companies and given extra 715 or MKO 366 is now called norfloxacin and will be marketed as ’Utinor’; AT 2266 or CI 919 is called enoxacin; DL8280 is HOE 280 or ofloxacin; Bay 0 9867 is ciprofloxacin; 1589 RB is pefloxacin (perfloxacin in the USA); while WIN 49375 and AM 833 remain unnamed. All the agents share the increased potency and spectrum of norfloxacin; some are more active. Ciprofloxacin, for example, is the most potent anti-pseudomonas agent yet4 with fifty to five hundred times the activity of carbenicillin. Few species of aerobic bacteria have been found resistant on initial tests; these include some pseudomonads, providence, and acinetobacter strains. Gram-positive bacteria are less susceptible but can be controlled by drug levels achievable in urine; pneumococci are relatively resistant, and so data on lung activity are awaited with interest. The anaerobic bacteria are more resistant-a factor that may be of value in terms of gut "colonisation resistance". The newer agents have some useful activity against nalidixic-acid-resistant enterobacteria, and although resistant mutants can be generated in the laboratory, they are still moderately
numbers-thus, AM
susceptible. The early work on metabolism and pharmacokinetics has produced intriguing results. For example, while enoxacin is roughly half as active in minimum-inhibitory-concentration terms as norfloxacin, it is better absorbed so redressing the balance.3,5 Shah et al6 noted that norfloxacin (unlike nalidixic acid) loses some activity when tested against bacteria in pooled human urine-possibly owing to the pH. The agents are excreted slowly and give sustained blood levels after oral administration. Injectable preparations of WIN 49375, ciprofloxacin, and pefloxacin are in prospect and intravenous injection of the latter gives good levels in cerebrospinal fluid.’ The papers presented at Las Vegas provided data on treatment of acute urinary tract infection and gonorrhoea and 2 Moorhead PJ, Parry HE. Treatment of Sonne dysentery. Br Med J 1965; ii: 913. 3 Ito A, Hirai K, Inoue I, Koga H, Suzue S, Irikura T, Mitsuhashi S. In vitro activity of AM 715 a new nalidixic acid analog. Antimicrob Ag Chemother 1980; 17: 103-08. 4. Wise R, Andrews JM, Edwards LJV In vitro activity of BAY 0 9867. Antimicrob Ag
Chemother 1983; 23: 559-64 J-I, Miyamoto T, Minimaida A, Nishimura Y, Egawa H, Nishimura H. Structure-activity relationships of 4-oxo 1,8 naphthyridine 3 carboxylic acids including AT 2266 a new oral anti-pseudomonal agents. In: Nelson JD, Grassi C, eds. Current chemotherapy and infectious disease. Washington, DC. American Society for Microbiology, 1980: 454. 6 Shah PM, Ottrad M, Stille W. In vitro activity of norfloxacin in urine compared to that of cinoxacin, nalidixic acid and pipemidic acid. Europ J Clin Microbiol 1983, 2: 272-74. 7 Wolff M, Regnier B, Nkam M, Rohan JE, Daldoss C, Vachon F. Defloxacin penetrates into cerebrospinal fluid in patients with bacterial meningitis. Proceedings of 23rd Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1983: abstr 853 5. Matsumoto
There is much scope for confusion in reports on NMR. Both classical and quantum mechanical explanations of the physics of NMR are used concurrently and much of the nomenclature for images has been transposed directly from spectroscopy. There is no general agreement on notation although the American College of Radiology has offered suggestions.52 Unlike X-ray CT images, which are dependent on a single image variable, NMR images are dependent on proton density, Tl, and T2 as well as flow effects. Small variations in the timing of pulse sequences can result in radical changes in the resultant image. There is considerable disagreement about the optimum field strength for imaging, and various magnets are used-permanent, resistive, and cryogenic-each with advantages and disadvantages. In X-ray CT all current machines are essentially similar but with NMR the range is likely to be diverse, some being designed for spectroscopy, some for imaging, and some for both. To date, spectroscopy has largely been a research technique with limited clinical application, whereas proton imaging has been developed with routine clinical applications in mind. Most of the existing NMR imaging machines are research prototypes, and, when the technology stabilises, the technique will need to be compared formally with other imaging methods. One of the notable features of NMR development in the UK has been the fruitful collaboration between commercial interests and the Medical Research Council, the Department of Health and Social Security, and the National Radiological Protection Board.
Third World Smoking— The New Slave Trade arrival of cholera and plague from the Orient
THE used to
great alarm in Britain until these epidemics were brought under control. Now the epidemic of tobacco smoking, which in the past 30 years has killed over one million people in the UK alone, is fast spreading to developing countries with the encouragement of tobacco companies based in the UK and the USA. In 1978 a World Health Organisation report declared that "In the absence of strong and resolute government action, we face the serious cause
will have affected the developing world within a decade and that a major avoidable public health problem will have been inflicted on countries least able to withstand it for the twin reasons of commercial enterprise and government inactivity". Five years later a new report’ catalogues the evidence that the smoking diseases have already arrived. High death rates for lung cancer are reported
probability
that the
52. American College of Radiology. of Radiology, 1983 1.
Smoking control strategies
in
smoking epidemic
Glossary ofNMR terms. Chicago: American College
developing countries.
WHO Tech
Rep Ser no 695,
1983.
from India, China, Hong Kong, and Cuba, and in the Bantu of Natal. Coronary heart disease associated with cigarette smoking is a major feature in India, Pakistan, and the Philippines. Perinatal mortality rates are doubled in Bangladeshi women who smoke. Even traditional forms such as bidi or hookah smoking are hazardous and oral cancer is frequent in Asian men and women who chew tobacco. Health for All by the Year 2000 is likely to be a vain hope for the millions in developing countries who succumb to the blandishments of the tobacco companies. WHO once more makes a strong appeal for effective change, but will governments and health ministries face up to this challenge any more than they did to the two previous WHO reports on smoking? Developing countries are now urged to give high priority to smoking control activities. Although malnutrition and infectious diseases may seem to be more pressing, only action now can prevent their exacerbation by smokingrelated diseases. A central agency with responsibility for smoking control action should be set up in each country. Special steps should be taken to safeguard the health of children through educational programmes. Sale of cigarettes to minors should be prohibited. Particular attention should be paid to traditional smoking materials as a cause of ill-health. All advertising and promotion of tobacco products should be banned. Where tobacco is already a commercial crop every effort should be made to reduce its role into the national economy and to investigate alternative uses of land and labour. Research into the economic role of tobacco is needed if only to provide evidence that the benefits from tobacco production and trade are outweighed by the losses associated with absence from work and care of those with smoking-related diseases. FAO and the World Bank should be approached for help to find crops to replace tobacco. Governments of developed countries are recommended to apply much more stringent controls to their own tobacco
companies. As the first country to produce a report on the hazards of smoking, as a country with high mortality from cigarette-related diseases, and as a country where three of the six largest world tobacco companies are based (British American Tobacco, Imperial, and Rothmans together made f743 million in pre-tax profits on tobacco alone in 1982) the UK bears considerable responsibility. Yet, far from discouraging exports to developing countries, the reverse is the case. Rothman’s International were given the 1983 Queen’s Award for Export Achievements. Some export brands and those manufactured under licence overseas still have much higher tar and nicotine content than those smoked at home. Britain provides no overseas aid for anti-smoking programmes-unlike Norway and Sweden who give substantial sums to the International Union Against Cancer and WHO for this purpose. Instead, between 1974 and 1979 the UK gave about 3/2 million to four Commonwealth countries for the development of their tobacco industries.
24
What can individual doctors in Britain do? They can provide an example by pressing for smoking control policies in all hospitals and health service premises. Many hospitals still sell cigarettes in their shops and do too little to control smoking on the wards. They can inform their MPs and voice their concern at the activities of the tobacco companies both at home and abroad. They can consider the propriety of holding tobacco shares either themselves or via the universities or institutions with which they are associated. They can,press for the kind of changes recommended by the Royal College of Physicians, to provide an example for developing countries. The WHO committee noted that "whenever the tobacco industry is threatened with action on smoking control it starts long drawn out negotiations with the health authorities with a view to creating confusion, delaying action and buying time, and preventing effective smoking control action". The situation has hardly changed since the late Senator Robert Kennedy stated in 1967 "The cigarette industry is peddling a deadly weapon. It is dealing with people’s lives for financial gain". These companies are causing a new form of Third World Slavery which is yearly killing tens of thousands who die unaware of the risks they have been taking. Wilberforce succeeded after 40 years. We shall have to take much stronger action if, with regard to smoking, we are to emulate his achievement.
THE QUINOLONES Lancet readers accustomed to a "market awash with cephalosporins" will soon have to evaluate an equally confusing group of highly active antibacterial agents-the nalidixic acid family, loosely called quinolones or quinolonecarboxylic acids. Sixty-two papers at the Intersciences Conference on Antimicrobial Agents and Chemotherapy at Las Vegas featured the group. Nalidixic acid has a relatively simple chemical structure. The carboxylic acid and neighbouring oxygen atoms are needed for antibacterial activity, but much of the remainder can be modified. Albrechtl listed over a thousand variants, in 1977, but few were more active than nalidixic acid and only cinoxacin is currently marketed in the UK. The antibacterial activity affects bacterial DNA topoisomerases (or gyrases), of which four subunits (two a, two 0) have been defined. The enzymes are required to supercoil strands of bacterial DNA (up to 140 m long) so they fit in the bacterial cell. Higher concentrations act on bacterial RNA. The only other antibiotic known to work on topoisomerases is novobiocin. Nalidixic acid is as active as ampicillin against aerobic gram-negative bacteria, but has little useful effect on grampositives or pseudomonas. It is only partly absorbed, then metabolised, so 4 g a day is needed to ensure adequate urinary levels in an adult. The high dose has been associated with side-effects including visual disturbances. Although nalidixic acid resistance is not transferable on plasmids, it develops 2 Health
or
smoking follow-up report of the Royal College of Physicians London:
Pitman, 1983. 1 Albrecht R
Development of
1977; 21: 9-104
antibacterial agents of the nalidixic type.
Progr Drug Res
easily. Nonetheless this agent was the "standard" member of the family for many years and has been used for bowel decontamination and treatment of bacillary dysentery2 as well as cystitis. Addition of a piperazinyl radical to the molecule produced pipemidic acid, which has some activity against pseudomonas and has been widely used in Europe. Addition of a fluorine atom at the 6-position produced norfloxacin, a fluoroquinolinecarboxylic acid that is a hundred times as active as nalidixic acid with a spectrum that includes enterococci and staphylococci as well as
pseudomonas.33 On view at Las Vegas were data on seven new agents with differing structures but all containing the fluorine atom and piperazinyl group. Four originated in Japan, two in Europe, and one in the USA. The first job for a prospective user is to grapple with names. The drugs start life as numbers which are replaced with generic then trade names. The situation is complicated by the fact that three Japanese compounds have been taken up by international companies and given extra 715 or MKO 366 is now called norfloxacin and will be marketed as ’Utinor’; AT 2266 or CI 919 is called enoxacin; DL8280 is HOE 280 or ofloxacin; Bay 0 9867 is ciprofloxacin; 1589 RB is pefloxacin (perfloxacin in the USA); while WIN 49375 and AM 833 remain unnamed. All the agents share the increased potency and spectrum of norfloxacin; some are more active. Ciprofloxacin, for example, is the most potent anti-pseudomonas agent yet4 with fifty to five hundred times the activity of carbenicillin. Few species of aerobic bacteria have been found resistant on initial tests; these include some pseudomonads, providence, and acinetobacter strains. Gram-positive bacteria are less susceptible but can be controlled by drug levels achievable in urine; pneumococci are relatively resistant, and so data on lung activity are awaited with interest. The anaerobic bacteria are more resistant-a factor that may be of value in terms of gut "colonisation resistance". The newer agents have some useful activity against nalidixic-acid-resistant enterobacteria, and although resistant mutants can be generated in the laboratory, they are still moderately
numbers-thus, AM
susceptible. The early work on metabolism and pharmacokinetics has produced intriguing results. For example, while enoxacin is roughly half as active in minimum-inhibitory-concentration terms as norfloxacin, it is better absorbed so redressing the balance.3,5 Shah et al6 noted that norfloxacin (unlike nalidixic acid) loses some activity when tested against bacteria in pooled human urine-possibly owing to the pH. The agents are excreted slowly and give sustained blood levels after oral administration. Injectable preparations of WIN 49375, ciprofloxacin, and pefloxacin are in prospect and intravenous injection of the latter gives good levels in cerebrospinal fluid.’ The papers presented at Las Vegas provided data on treatment of acute urinary tract infection and gonorrhoea and 2 Moorhead PJ, Parry HE. Treatment of Sonne dysentery. Br Med J 1965; ii: 913. 3 Ito A, Hirai K, Inoue I, Koga H, Suzue S, Irikura T, Mitsuhashi S. In vitro activity of AM 715 a new nalidixic acid analog. Antimicrob Ag Chemother 1980; 17: 103-08. 4. Wise R, Andrews JM, Edwards LJV In vitro activity of BAY 0 9867. Antimicrob Ag
Chemother 1983; 23: 559-64 J-I, Miyamoto T, Minimaida A, Nishimura Y, Egawa H, Nishimura H. Structure-activity relationships of 4-oxo 1,8 naphthyridine 3 carboxylic acids including AT 2266 a new oral anti-pseudomonal agents. In: Nelson JD, Grassi C, eds. Current chemotherapy and infectious disease. Washington, DC. American Society for Microbiology, 1980: 454. 6 Shah PM, Ottrad M, Stille W. In vitro activity of norfloxacin in urine compared to that of cinoxacin, nalidixic acid and pipemidic acid. Europ J Clin Microbiol 1983, 2: 272-74. 7 Wolff M, Regnier B, Nkam M, Rohan JE, Daldoss C, Vachon F. Defloxacin penetrates into cerebrospinal fluid in patients with bacterial meningitis. Proceedings of 23rd Intersciences Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1983: abstr 853 5. Matsumoto