- Email: [email protected]
PERCUTANEOUS ABSORPTION OF PHENOLS
412 or exhibit sex limitation, 10 but in human disease differences in prevalence-rates and in the pattern of the disease process exist in very many common disorders. Vessey 11 points out that much of this difference may be due to environmental factors. Hormonal differences probably also play a substantial part, but genetic differences in cellular reaction and
provide a selective effect on the virus population analogous to that provided by a partially immune population which leads to antigenic drift. An interesting feature of the work in Paris is that a point was reached at which further antigenic drift could not be induced. It was therefore suggested that the laboratory-produced variant represented the end of a series of antigenic changes which, had they taken place in man under natural conditions, would be followed by the appearance of a new subtype of virus. A further, and very important, aspect of the studies was the existence of a characteristic junior/senior relationship between the various antigenic variants produced in the laboratory, in that antibody to the " senior strain was capable of reacting with all the more junior " strains from which it was derived, whilst antibody to the " junior " virus (the 1968 isolate) reacted poorly with more " senior " viruses. An obvious practical application of these investigations is to use the most " senior " laboratory-produced variant for preparation of current inactivated influenza vaccine, on the basis that such a vaccine might be expected to be useful over an extended period of time, perhaps up to 1978, despite repeated antigenic changes in the viruses prevalent in man. The success of these extremely elegant experiments clearly depends on whether the pathway of antigenic variation in vitro parallels those which will occur in
to
genes sex
susceptibility
may well be
equally
if
not more
impor-
tant.12Z
"
ANTIGENIC VARIANTS OF INFLUENZA VIRUS
"
"
INFLUENZA virus is unique amongst viruses of man in its ability to undergo repeated antigenic changes, the appearance of variant viruses in the population being closely associated with the recurrence of epidemics. Antigenic changes in the influenza-A virus are of two types. The term antigenic drift describes the progressive minor modifications which take place in the surface antigens (hxmagglutinin and neuraminidase) of a given subtype of influenza virus at intervals during its period of prevalence. Such changes occur at intervals of two to five years. Each ten years or so a complete change in one or both of these antigens occurs, resulting in appearance of a virus of a new subtype. The appearance of new subtypes is followed by pandemics of disease, and current evidence strongly suggests that new subtypes of virus may emerge directly or indirectly, from the reservoirs of influenzaA viruses which exist in many non-human hosts (mammalian and avian). Antigenic drift is associated with the less widespread outbreaks which occur in inter-pandemic periods. This antigenic instability of the influenza virus leads to considerable practical problems in the long-term planning of influenza vaccination programmes, since conventional influenza vaccines become redundant after a few years and there are inevitably delays before vaccines containing the new
variant
are
generally available.
Increased
"
sur-
veillance of influenza on a world-wide scale and the use of recombination techniques to prepare strains suitable for the manufacture of vaccines have in recent years been used effectively to reduce this delay. The work lately announced by the Pasteur Institute in Paris is an attempt to overcome the problems posed by antigenic variation in influenza. Starting with the Hong Kong strain of influenza-A virus (A/Hong Kong/1/68 [H3Nr]) which was isolated in 1968, Hannoun and St. Groth succeeded in producing a series of antigenic variants by serial cultivation of the virus in laboratory cultures in the presence of antibody. This experiment resulted in the isolation of a virus which, it is predicted by the group in Paris, resembles’ antigenically the variants which will appear in the human population towards the end of the present decade. This finding led to their claim to have anticipated, by at least five years, future antigenic: changes in the influenza-A virus. The immunological pressure applied in the laboratory studies is expectedl ’
: -
10.
Carter, C. O. in Gender Differences: Their Ontogeny and Signi-ficance (edited by C. Ounsted and D. C. Taylor). Edinburgh,
11. 12.
Vessey, M. ibid. Taylor, C. D., Ounsted, C. ibid.
1972.
the next few years. A useful indication of the soundness of the French predictions, however, is that during the studies an intermediate variant was obtained which was closely related to the strain A/England/42/72 which lately produced epidemics in several countries; and this may be regarded as evidence of parallel evolution of virus antigens in the It seems unlikely that this approach two systems. will solve all the problems of influenza-in particular, the method will probably not be of value in anticipating the antigenic composition of the completely new subtype of influenza-A virus which may well emerge before 1980. In addition, it would seem reasonable to study the protective efficacy of any new vaccine exhaustively in clinical trials before recommending it for general use in the population. nature over
PERCUTANEOUS ABSORPTION OF PHENOLS UNTIL the advent of corticosteroids, few investigations were done on absorption and metabolism of therapeutic agents applied to the skin. 2-naphthol was introduced as a local application by Ludwig and Kaposi in 1881 and was later found to have toxic effects when applied to children’s skin.1 Little was known of its rate of absorption or fate in man. In 1966, Harkness
Beveridge2 reported that approximately 10% of 2-naphthol applied as a paste to the back was recovered from the urine of a youth being treated for acne over about 20% of his body. Hemels3 has now investigated the absorption and metabolism of 2-naphthol in much greater detail, using gas-chromatographic methods to detect free 2-naphthol and conjugated 2-naphthol in and
1. Burger, L. Berl. klin. Wschr. 1918, 55, 1025. Harkness, R. A., Beveridge, G. W. Nature, 1966, 211, 413. Hemels, H. G. W. M. Br. J. Derm. 1972, 87, 614.
2. 3.
413
plasma and urine. His work shows that an average 5% of the cutaneous dose is excreted, mostly in the first 24 hours after application, and that more is excreted when the 2-naphthol is applied to the back than when it is applied to the face. Plasma-levels confirmed that absorption was rapid and, as in animals,most of the 2-naphthol was converted to the glucuronide. The mean value for free 2-naphthol excreted in the urine was 37% of the total, but this was very variable, perhaps because of differences in individual metabolism or in urinary pH. This investigation leads to the conclusion that peeling pastes with 2-naphthol should be applied only for short periods and to a limited area (150 sq. cm.). It may also be advantageous to ensure a high output of an alkaline urine. Other phenols used in the treatment of the skin may not be metabolised in exactly the same way, but they too are likely to be readily absorbed. It is perhaps fortunate that there is less need for these potent peeling agents today. The work of Hemels illustrates the need for pharmacological investigation of many traditional local applications about which there is very little information.
QUO VADIS, VIATOR? THE increase of international travel and the lure of exotic holidays at moderate cost have created new conditions for importation of various communicable diseases into temperate countries. Such exotic infections are potentially dangerous, and not less so in those advanced countries where tropical diseases are a rarity and the medical profession is unprepared for their timely diagnosis and treatment.5Malaria is one of the most common exotic diseases, and the incidence of cases
imported from abroad has risen considerably in 7
many countries. A report of the
World Health Organisation8 estimates that, by the end of 1971, out of 1827 million people living in the originally malarious parts of the globe some 1346 million (73 %) are now in areas where malaria has been eradicated or where anti-malaria programmes are in progress. But the report admits that, while malaria has retreated from most of the temperate and subtropical areas in the past two decades, the hard cores of endemic malaria in Africa, several countries of southern and south-east Asia, Australasia, and Central and South America changed little. Nearly 480 million people, two-thirds of them on the African continent, still live in areas where malaria is endemic. During the past five years the resurgence of malaria in Sri Lanka (Ceylon), northern and central parts of India, in Pakistan and Bangladesh, in Indonesia, and in some South American countries has been causing considerable concern. Despite the great achievements of the global programme of malaria eradication, large reservoirs of infection remain over most of the tropics. And in view of the impact of modern travel on the spread of new diseases the existing situation may well 4. Corner, E. D. S., Young, L. Biochem. J. 1954, 58, 647. 5. Maegraith, B. G. Lancet, 1963, i, 401. 6. Maegraith, B. G. Exotic Diseases in Practice. London, 1965. 7. Bruce-Chwatt, L. J., Draper, C. C., Peters, W. Br. med. J. 1971, ii, 91. 8. World Health Organisation. Report of the Director-General to the 25th World Health Assembly. Geneva, 1972.
represent only
the beginning of a rapidly ascending curve.9-11 It is not so much the speed of modern air transport as its sheer volume that impedes many established practices of international control of communicable disease. Statistics of the International Civil Aviation Organisation show that over the period 1962-66 the number of international passengers rose from 28 million to 51 million. In 1971 the number of persons carried by scheduled national and international airlines amounted to 403 million and the forecast for 1973 is 450 million. 12 Parliamentary discussion on the Maplin Development Bill indicated that by 1980 an average aircraft would carry 120 passengers instead of 80 at the present time. With the introduction of planes capable of carrying 500 or more travellers, this figure may increase to 155 in 1985 and to 200 in 1990. Within the next ten years London Airport will have to cope with 60 million passengers annuallymore than double the present figure.13 In 1971 about 6 million British people went abroad for their holidays, about a fifth of them outside Europe; 7 million foreign tourists visited Britain and the figure is expected to reach 8 million in 1973.12 An additional problem is worker migration in the European Economic Community. There are probably now over 7 million migrant workers in all the countries of Western Europe. A large proportion of them come from Greece, Italy, Portugal, Spain, Turkey, and Yugoslavia, but the number from North Africa is increasing.
Three serious aspects of imported malaria have been pointed out. 7 , 14 The first is the severity of some Plasmodium falciparum infections in non-immune persons returning from abroad. The second is the complication by relapsing latent malaria of any acute disease, delivery, or surgical intervention in individuals who previously inhabited an endemic area. The third is the possibility of transfusion malaria if the donor of whole blood is a symptomless carrier of plasmodia. 15 Much information on malaria and other communicable diseases contracted abroad can be found in booklets for the traveller or the medical practitioner.11, 17 The traveller ought to be well informed on how to protect himself from the risk of infection and what to do if he falls ill on return home from abroad. The doctor needs concise guidance on chemotherapy of malaria and also up-to-date information on the likelihood of exposure to infection in a large number of countries-notably in those open to mass tourism. Both types of information have now been provided in a special issue of the Weekly
Epidemiological Record published by the World Health Organisation. 1This issue will be of value to authorities dealing with fellowships abroad, to leaders of scientific expeditions, to travel agencies, to tourist information 9. Dorolle, P. Br. med. J. 1968, iv, 789. 10. Dorolle, P. Lancet, 1972, ii, 525. 11. Bruce-Chwatt, L. J. Trans. R. Soc. trop. Med. Hyg. 1970, 64, 776. 12. International Tourism and Tourism Policy. Organisation for Economic Co-operation and Development. Paris, 1972. 13. Times, Feb. 9, 1973. 14. Bruce-Chwatt, L. J. Lancet, 1970, ii, 143. 15. ibid. 1972, i, 32. 16. Preservation of Personal Health in Warm Climates. Ross Institute of Tropical Hygiene. London, 1971. 17. Communicable Diseases Contracted Outside Great Britain. Department of Health and Social Security. London, 1972. 18. Wkly epidem. Rec. 1973, 48, no. 3. Reprints of this article can be obtained from World Health Organisation Headquarters, 1211 Geneva 27, Switzerland.
provide a selective effect on the virus population analogous to that provided by a partially immune population which leads to antigenic drift. An interesting feature of the work in Paris is that a point was reached at which further antigenic drift could not be induced. It was therefore suggested that the laboratory-produced variant represented the end of a series of antigenic changes which, had they taken place in man under natural conditions, would be followed by the appearance of a new subtype of virus. A further, and very important, aspect of the studies was the existence of a characteristic junior/senior relationship between the various antigenic variants produced in the laboratory, in that antibody to the " senior strain was capable of reacting with all the more junior " strains from which it was derived, whilst antibody to the " junior " virus (the 1968 isolate) reacted poorly with more " senior " viruses. An obvious practical application of these investigations is to use the most " senior " laboratory-produced variant for preparation of current inactivated influenza vaccine, on the basis that such a vaccine might be expected to be useful over an extended period of time, perhaps up to 1978, despite repeated antigenic changes in the viruses prevalent in man. The success of these extremely elegant experiments clearly depends on whether the pathway of antigenic variation in vitro parallels those which will occur in
to
genes sex
susceptibility
may well be
equally
if
not more
impor-
tant.12Z
"
ANTIGENIC VARIANTS OF INFLUENZA VIRUS
"
"
INFLUENZA virus is unique amongst viruses of man in its ability to undergo repeated antigenic changes, the appearance of variant viruses in the population being closely associated with the recurrence of epidemics. Antigenic changes in the influenza-A virus are of two types. The term antigenic drift describes the progressive minor modifications which take place in the surface antigens (hxmagglutinin and neuraminidase) of a given subtype of influenza virus at intervals during its period of prevalence. Such changes occur at intervals of two to five years. Each ten years or so a complete change in one or both of these antigens occurs, resulting in appearance of a virus of a new subtype. The appearance of new subtypes is followed by pandemics of disease, and current evidence strongly suggests that new subtypes of virus may emerge directly or indirectly, from the reservoirs of influenzaA viruses which exist in many non-human hosts (mammalian and avian). Antigenic drift is associated with the less widespread outbreaks which occur in inter-pandemic periods. This antigenic instability of the influenza virus leads to considerable practical problems in the long-term planning of influenza vaccination programmes, since conventional influenza vaccines become redundant after a few years and there are inevitably delays before vaccines containing the new
variant
are
generally available.
Increased
"
sur-
veillance of influenza on a world-wide scale and the use of recombination techniques to prepare strains suitable for the manufacture of vaccines have in recent years been used effectively to reduce this delay. The work lately announced by the Pasteur Institute in Paris is an attempt to overcome the problems posed by antigenic variation in influenza. Starting with the Hong Kong strain of influenza-A virus (A/Hong Kong/1/68 [H3Nr]) which was isolated in 1968, Hannoun and St. Groth succeeded in producing a series of antigenic variants by serial cultivation of the virus in laboratory cultures in the presence of antibody. This experiment resulted in the isolation of a virus which, it is predicted by the group in Paris, resembles’ antigenically the variants which will appear in the human population towards the end of the present decade. This finding led to their claim to have anticipated, by at least five years, future antigenic: changes in the influenza-A virus. The immunological pressure applied in the laboratory studies is expectedl ’
: -
10.
Carter, C. O. in Gender Differences: Their Ontogeny and Signi-ficance (edited by C. Ounsted and D. C. Taylor). Edinburgh,
11. 12.
Vessey, M. ibid. Taylor, C. D., Ounsted, C. ibid.
1972.
the next few years. A useful indication of the soundness of the French predictions, however, is that during the studies an intermediate variant was obtained which was closely related to the strain A/England/42/72 which lately produced epidemics in several countries; and this may be regarded as evidence of parallel evolution of virus antigens in the It seems unlikely that this approach two systems. will solve all the problems of influenza-in particular, the method will probably not be of value in anticipating the antigenic composition of the completely new subtype of influenza-A virus which may well emerge before 1980. In addition, it would seem reasonable to study the protective efficacy of any new vaccine exhaustively in clinical trials before recommending it for general use in the population. nature over
PERCUTANEOUS ABSORPTION OF PHENOLS UNTIL the advent of corticosteroids, few investigations were done on absorption and metabolism of therapeutic agents applied to the skin. 2-naphthol was introduced as a local application by Ludwig and Kaposi in 1881 and was later found to have toxic effects when applied to children’s skin.1 Little was known of its rate of absorption or fate in man. In 1966, Harkness
Beveridge2 reported that approximately 10% of 2-naphthol applied as a paste to the back was recovered from the urine of a youth being treated for acne over about 20% of his body. Hemels3 has now investigated the absorption and metabolism of 2-naphthol in much greater detail, using gas-chromatographic methods to detect free 2-naphthol and conjugated 2-naphthol in and
1. Burger, L. Berl. klin. Wschr. 1918, 55, 1025. Harkness, R. A., Beveridge, G. W. Nature, 1966, 211, 413. Hemels, H. G. W. M. Br. J. Derm. 1972, 87, 614.
2. 3.
413
plasma and urine. His work shows that an average 5% of the cutaneous dose is excreted, mostly in the first 24 hours after application, and that more is excreted when the 2-naphthol is applied to the back than when it is applied to the face. Plasma-levels confirmed that absorption was rapid and, as in animals,most of the 2-naphthol was converted to the glucuronide. The mean value for free 2-naphthol excreted in the urine was 37% of the total, but this was very variable, perhaps because of differences in individual metabolism or in urinary pH. This investigation leads to the conclusion that peeling pastes with 2-naphthol should be applied only for short periods and to a limited area (150 sq. cm.). It may also be advantageous to ensure a high output of an alkaline urine. Other phenols used in the treatment of the skin may not be metabolised in exactly the same way, but they too are likely to be readily absorbed. It is perhaps fortunate that there is less need for these potent peeling agents today. The work of Hemels illustrates the need for pharmacological investigation of many traditional local applications about which there is very little information.
QUO VADIS, VIATOR? THE increase of international travel and the lure of exotic holidays at moderate cost have created new conditions for importation of various communicable diseases into temperate countries. Such exotic infections are potentially dangerous, and not less so in those advanced countries where tropical diseases are a rarity and the medical profession is unprepared for their timely diagnosis and treatment.5Malaria is one of the most common exotic diseases, and the incidence of cases
imported from abroad has risen considerably in 7
many countries. A report of the
World Health Organisation8 estimates that, by the end of 1971, out of 1827 million people living in the originally malarious parts of the globe some 1346 million (73 %) are now in areas where malaria has been eradicated or where anti-malaria programmes are in progress. But the report admits that, while malaria has retreated from most of the temperate and subtropical areas in the past two decades, the hard cores of endemic malaria in Africa, several countries of southern and south-east Asia, Australasia, and Central and South America changed little. Nearly 480 million people, two-thirds of them on the African continent, still live in areas where malaria is endemic. During the past five years the resurgence of malaria in Sri Lanka (Ceylon), northern and central parts of India, in Pakistan and Bangladesh, in Indonesia, and in some South American countries has been causing considerable concern. Despite the great achievements of the global programme of malaria eradication, large reservoirs of infection remain over most of the tropics. And in view of the impact of modern travel on the spread of new diseases the existing situation may well 4. Corner, E. D. S., Young, L. Biochem. J. 1954, 58, 647. 5. Maegraith, B. G. Lancet, 1963, i, 401. 6. Maegraith, B. G. Exotic Diseases in Practice. London, 1965. 7. Bruce-Chwatt, L. J., Draper, C. C., Peters, W. Br. med. J. 1971, ii, 91. 8. World Health Organisation. Report of the Director-General to the 25th World Health Assembly. Geneva, 1972.
represent only
the beginning of a rapidly ascending curve.9-11 It is not so much the speed of modern air transport as its sheer volume that impedes many established practices of international control of communicable disease. Statistics of the International Civil Aviation Organisation show that over the period 1962-66 the number of international passengers rose from 28 million to 51 million. In 1971 the number of persons carried by scheduled national and international airlines amounted to 403 million and the forecast for 1973 is 450 million. 12 Parliamentary discussion on the Maplin Development Bill indicated that by 1980 an average aircraft would carry 120 passengers instead of 80 at the present time. With the introduction of planes capable of carrying 500 or more travellers, this figure may increase to 155 in 1985 and to 200 in 1990. Within the next ten years London Airport will have to cope with 60 million passengers annuallymore than double the present figure.13 In 1971 about 6 million British people went abroad for their holidays, about a fifth of them outside Europe; 7 million foreign tourists visited Britain and the figure is expected to reach 8 million in 1973.12 An additional problem is worker migration in the European Economic Community. There are probably now over 7 million migrant workers in all the countries of Western Europe. A large proportion of them come from Greece, Italy, Portugal, Spain, Turkey, and Yugoslavia, but the number from North Africa is increasing.
Three serious aspects of imported malaria have been pointed out. 7 , 14 The first is the severity of some Plasmodium falciparum infections in non-immune persons returning from abroad. The second is the complication by relapsing latent malaria of any acute disease, delivery, or surgical intervention in individuals who previously inhabited an endemic area. The third is the possibility of transfusion malaria if the donor of whole blood is a symptomless carrier of plasmodia. 15 Much information on malaria and other communicable diseases contracted abroad can be found in booklets for the traveller or the medical practitioner.11, 17 The traveller ought to be well informed on how to protect himself from the risk of infection and what to do if he falls ill on return home from abroad. The doctor needs concise guidance on chemotherapy of malaria and also up-to-date information on the likelihood of exposure to infection in a large number of countries-notably in those open to mass tourism. Both types of information have now been provided in a special issue of the Weekly
Epidemiological Record published by the World Health Organisation. 1This issue will be of value to authorities dealing with fellowships abroad, to leaders of scientific expeditions, to travel agencies, to tourist information 9. Dorolle, P. Br. med. J. 1968, iv, 789. 10. Dorolle, P. Lancet, 1972, ii, 525. 11. Bruce-Chwatt, L. J. Trans. R. Soc. trop. Med. Hyg. 1970, 64, 776. 12. International Tourism and Tourism Policy. Organisation for Economic Co-operation and Development. Paris, 1972. 13. Times, Feb. 9, 1973. 14. Bruce-Chwatt, L. J. Lancet, 1970, ii, 143. 15. ibid. 1972, i, 32. 16. Preservation of Personal Health in Warm Climates. Ross Institute of Tropical Hygiene. London, 1971. 17. Communicable Diseases Contracted Outside Great Britain. Department of Health and Social Security. London, 1972. 18. Wkly epidem. Rec. 1973, 48, no. 3. Reprints of this article can be obtained from World Health Organisation Headquarters, 1211 Geneva 27, Switzerland.