- Email: [email protected]
Adverse reactions to levodopa: drug toxicity or progression of disease?
COMMENTARY
lymphocytes6 has led to the suggestion that this enzyme may be an endogenous factor in the pathogenesis of Parkinson’s disease. However, several points need to be examined. First, investigations with dopaminergic neuroblastoma SH-SY5Y cells have shown that only N-methyl-(R)salsolinol, but not its oxidation product (as in the case of MPTP model), is transported by an uptake system that is inhibited competitively by dopamine.7 Even so, the use of cell-lines does not provide enough evidence of selective dopamine uptake of N-methyl-(R)-salsolinol. Further experiments with synaptosomal preparations, rich in dopaminergic nerve endings, are required to show conclusively uptake by this mechanism. Moreover, the toxicity of both substances should be shown to be preventable in vivo by prior administration of inhibitors of presynaptic dopamine uptake. Second, the suggested specific neurotoxic effect on dopaminergic neurons has not been shown. Histological examination of the striatum indicates that the MPP+-like oxidation product of N-methyl-(R)-salsolinol is much more cytotoxic than its precursor, but morphological and neurochemical investigations show that the toxic effects are not restricted to dopaminergic neurons.4 Third, the suggestions that the striatal neutral (R)salsolinol N-methyl-transferase activity is increased in Parkinson’s disease and that the gene coding for this enzyme is an endogenous factor in the pathogenesis of this disorder are based on high activities of the enzyme in parkinsonian lymphocytes6 and increased concentrations of N-methyl-(R)-salsolinol in the cerebrospinal fluid of parkinsonian patients. The enzyme has neither been isolated from the human brain nor pharmacologically characterised. Other endogenous substrates, such as nicotinamide, can also serve as substrates for this enzyme. Furthermore, the alterations in R-salsolinol and its metabolising enzymes have not been shown to be specific for Parkinson’s disease, since they have not been investigated in other neurodegenerative disorders. In particular, it would be important to measure the concentrations of N-methyl-(R)-salsolinol and the activity of its synthesising enzyme in alcoholics, in whom (R)salsolinol concentrations are raised.8 Fourth, Parkinson’s disease is characterised by a chronic progressive loss of dopaminergic neurons.9 Whether long-term systemic exposure to small but cumulative doses of N-methyl-(R)-salsolinol triggers a cascade of progressive neurotoxic processes in nonhuman primates has not been investigated. Thus, despite the impressive effort in investigating the neurotoxicity of N-methyl-(R)-salsolinol and in analysing its concentrations and metabolism in parkinsonian tissue, further data are required before acceptance of the suggestion that this compound plays a part in the pathogenesis of Parkinson’s disease. However, this suggestion may be a promising line of research.
Manfred Gerlach, Eleni Koutsilieri, *Peter Riederer Division of Clinical Neurochemistry, Department of Psychiatry, University of Würzburg, D-97080 Würzburg, Germany 1
2
Gerlach M, Riederer P. Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 1996; 103: 987–1041. Naoi M, Maruyama W, Matsubara K, Hashizume Y. A neutral N-methyltransferase activity in the striatum determines the level of an endogenous MPP+-like neurotoxin, 1,2-dimethyl-6,7dihydroxysoquinolinium ion, in the substantia nigra of human brains.
THE LANCET • Vol 351 • March 21, 1998
3
4
5
6
7
8
9
Neurosci Lett 1997; 235: 81–84. Naoi M, Maruyama W, Zhang JH, Takahashi T, Deng Y, Dostert P. Enzymatic oxidation of the dopaminergic neurotoxin, 1(R),2(N)dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, into 1,2,(N),dimethyl-6,7-dihydroxyisoquinolinium ion. Life Sci 1995; 57: 1061–66. Naoi M, Maruyama W, Dostert P, Hashizume Y. N-methyl-(R)salsolinol as a dopaminergic neurotoxin: from an animal model to an early marker of Parkinson’s disease. J Neural Transm 1997; 50 (suppl): 89–105. Maruyama W, Abe T, Tohgi H, Dostert P, Naoi M. A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian cerebrospinal fluid. Ann Neurol 1996; 40: 119–22. Naoi M, Maruyama W, Nakao N, Ibi T, Sahashi K, Benedetti MS. (R)Salsolinol N-methyltransferase activity increases in parkinsonian lymphocytes. Ann Neurol 1998; 43: 212-16. Takahashi T, Deng Y, Maruyama W, Dostert P, Kawai M, Naoi M. Uptake of a neurotoxin-candidate, (R)1,2-dimethyl-6,7-dihydroxy1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system. J Neural Transm (GenSect) 1994; 98: 107–18. Rommelspacher H, Sllstrom-Baum S, Dufeu P, Schmidt LG. Determination of (R)- and (S)-salsolinol sulfate and dopamine sulfate levels in plasma of nonalcoholics and alcoholics. Alcohol 1995; 12: 309–15. Jellinger K. Pathology of Parkinson’s syndrome. In: Calne DB, ed. Handbook of experimental pharmacology. Berlin: Springer, 1988; 88: 47–112.
Adverse reactions to levodopa: drug toxicity or progression of disease? Introduced 30 years ago, levodopa remains the mainstay of treatment for Parkinson’s disease. This naturally occurring neutral aminoacid is converted to dopamine in the brain. Since dopamine depletion, especially in the striatum, is the major neurochemical abnormality in Parkinson’s disease, treatment with levodopa is a form of dopamine-replacement therapy. The drug is given together with a peripheral dopa-decarboxylase inhibitor, such as benserazide or carbidopa, which dampens peripheral production of dopamine and thus limits sideeffects of peripheral origin while increasing the availability of dopamine to the brain. At the start of treatment, levodopa is highly effective in relieving parkinsonian symptoms, but eventually two types of problems emerge. First, after several years of treatment, disabling motor effects such as dyskinesias and motor fluctuations (wearing-off and on-off phenomena) begin to appear and necessitate careful adjustment of the amount or timing of the dose of levodopa. To deal with these motor complications other drugs, especially directly acting dopamine agonists, monoamine-oxidase inhibitors, and catechol-O-methyl-transferase inhibitors, are commonly added to the therapeutic regimen. Some physicians have advocated that levodopa be limited to low doses, or that its prescription be delayed to postpone the development of dyskinesia and motor swings. Others, however, think that these complications are the result of the severity and progression of the neurodegenerative process (ie, due to progressive depletion of brain dopamine despite levodopa), so they do not hesitate to introduce levodopa early in the course of the disease. The second problem is that in patients with advanced disease, the response of some symptoms to levodopa usually declines. There is controversy over whether the diminished effectiveness of levodopa is due to acquired tolerance to the drugs, or to the appearance of new symptoms (postural instability, gait disorders, sphincter dysfunction, dysarthria, mental deterioration), which respond poorly, if at all, to levodopa.2 Another concern is whether levodopa, which is 851
COMMENTARY
prescribed for long periods, accelerates progression of the disease because it might be a source of free radicals and hence might hasten the degeneration of already fragile dopaminergic neurons.3 If so, is the toxic effect one of irreversible damage leading to cell loss? Or is it just cell dysfunction, which may temporarily or permanently contribute to the occurrence of the side-effects? To address these questions, a meeting of 25 experts was held in Paris (Jan 8–9, 1998) to discuss studies of levodopa toxicity done in tissue culture, animal models of parkinsonism, and human beings, and to try to arrive at some agreement on whether or how the findings should influence prescribing of the drug. The detailed discussion, together with published conflicting findings, will appear elsewhere. The main conclusions can be summarised as follows. ● Levodopa is still the most effective treatment for parkinsonian symptoms, and it decreases mortality rate from this disease.4 ● There is no evidence that long-term administration of levodopa contributes to or worsens the underlying neurodegenerative brain lesions in patients with Parkinson’s disease.5 ● Levodopa-induced motor complications result from both degeneration of brain dopaminergic systems (a process for which there is no means of prevention) and the repeated administration of levodopa6 (which can be modified according to the condition of the patient). ● There is no convincing evidence that therapeutic doses of levodopa result in nerve-cell death in animal models of parkinsonism.7 ● Levodopa can induce cell death in vitro but only when high concentrations are used in the absence of glial cells;8,9 however, the relevance of in-vitro work to patients with Parkinson’s disease is uncertain. In sum, there is no cause for concern that levodopa is dangerous for patients. How and when to prescribe levodopa should be influenced not by fear that the drug is toxic, but by how the patient reacts to the drug.
*Y Agid, T Chase, D Marsden *INSERM U 289 and Féderation de Neurologie-Hôpital de la Salpêtrière, 75013 Paris, France; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; and National Hospital for Neurology and Neurosurgery, London, UK 1
2
3 4
5
6
7
8
9
Marsden CD. On-off phenomena in Parkinson’s disease. In: Rinne UK, Klinger S, Stamm G, eds. Current progress, problems and management. Amsterdam: North Holland Biomedical Press, 1980: 241–54. Bonnet AM, Loria Y, Saint-Hilaire MH, Lhermitte F, Agid Y. Does long term aggravation of Parkinson’s disease result from nondopaminergic lesions? Neurology 1987; 37: 1539–42. Fahn S. Is levodopa toxic? Neurology 1996; 47 (suppl 3): S184–95. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. Multi-center study of Parkinson’s mortality with early versus late dopa treatment. Ann Neurol 1987; 22: 8–12. Yahr MD, Wolf A, Antunes JL, Miyoshi K, Duffy P. Autopsy findings in parkinsonism following treatment with levodopa. Neurology 1972; 22 (suppl): 56–71. Mouradian MM, Chase TN. Improved dopaminergic therapy of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders 3. Oxford: Butterworth-Heinemann Ltd, 1994: 181–99. Dziewczapolski G, Murer G, Agid Y, Gershanik O, Raisman-Vozari R. Absence of neurotoxicity of chronic L-DOPA treatment in 6hydroxydopamine lesioned rats. Neuroreport 1997; 8: 975–79. Mena MA, Casajeros LJ, Carazo A, Paino CL, de Yebenes JG. Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity. Neuroreport 1996; 7: 441–45. Han SK, Mytilineou C, Cohen F. L-DOPA up-regulates glutathione and protects mesencephalic culturs oxidative stress. J Neurochem 1996; 66: 501–10.
852
WHO’s tuberculosis research initiative Although essentially curable, tuberculosis kills up to 3 million adults every year, more than any other infectious disease. Compounding the situation is a vast disparity between the burden of human disease attributable to tuberculosis (3% worldwide) and the amount spent on tuberculosis research (an optimistic guess is 0·2% of the health research budget). To establish a rational approach to setting priorities for research, the WHO global tuberculosis programme (GTB) has started the global tuberculosis research initiative (GTRI). Under GTRI, tuberculosis researchers, policy-makers, and representatives of national programmes met in Geneva on March 3–5 to start priority setting. Their recommendations emphasise the need for research into optimising the delivery of directly observed therapy, short-course (DOTS), the strategy that lies at the heart of the WHO tuberculosis-control programme. The need to improve the delivery of DOTS is based on knowledge that the strategy works, but that only about 12% of tuberculosis patients worldwide are covered by DOTS and that most large key epidemic countries have low DOTS coverage. The GTRI recommendations stress the importance of developing operational-research capacity in the countries worst affected by tuberculosis and of coordinating research with the routine functions of national tuberculosis programmes. Another need is to make operational research more “glamorous”, to attract funding and the best scientists. For strategic research the priority areas are improvement in the accuracy of surveillance and epidemiological data, identification of drug-resistance trends, and development of new diagnostic tools, drugs, and vaccines. However, strategic research might take decades to bear fruit, hence the emphasis placed on operational research. GTB must disseminate widely the GTRI recommendations and take account of the views of tuberculosis scientists and fieldworkers, particularly those in developing countries. The essential next step is to establish the mechanisms to turn GTRI recommendations into actions once they have passed through a Byzantine series of WHO committees. It would be a shame if bureaucracy inhibits the good intentions of the GTRI.
John McConnell The Lancet, London WC1B 3SL, UK
The Lancet and the Internet, mark II The pace of change is nowhere quicker than on the Internet. Return to the worldwide web (the multimedia section of the Internet) after an absence of a few months and you will find a landscape transformed in richness and variety. As a medium for academic publishing the Internet now offers opportunities unimaginable in paper. The Lancet Interactive website (http://www.thelancet.com) launched this week is a step forward in our challenge, according to Tony Delamothe in the supplement that accompanies this issue, to the “paper mindset”. Rapidly updated readers’ comments form an integral part of the site, and we look forward to publishing research supported by video and sound.
John McConnell, Richard Horton The Lancet, London WC1B 3SL, UK
THE LANCET • Vol 351 • March 21, 1998
lymphocytes6 has led to the suggestion that this enzyme may be an endogenous factor in the pathogenesis of Parkinson’s disease. However, several points need to be examined. First, investigations with dopaminergic neuroblastoma SH-SY5Y cells have shown that only N-methyl-(R)salsolinol, but not its oxidation product (as in the case of MPTP model), is transported by an uptake system that is inhibited competitively by dopamine.7 Even so, the use of cell-lines does not provide enough evidence of selective dopamine uptake of N-methyl-(R)-salsolinol. Further experiments with synaptosomal preparations, rich in dopaminergic nerve endings, are required to show conclusively uptake by this mechanism. Moreover, the toxicity of both substances should be shown to be preventable in vivo by prior administration of inhibitors of presynaptic dopamine uptake. Second, the suggested specific neurotoxic effect on dopaminergic neurons has not been shown. Histological examination of the striatum indicates that the MPP+-like oxidation product of N-methyl-(R)-salsolinol is much more cytotoxic than its precursor, but morphological and neurochemical investigations show that the toxic effects are not restricted to dopaminergic neurons.4 Third, the suggestions that the striatal neutral (R)salsolinol N-methyl-transferase activity is increased in Parkinson’s disease and that the gene coding for this enzyme is an endogenous factor in the pathogenesis of this disorder are based on high activities of the enzyme in parkinsonian lymphocytes6 and increased concentrations of N-methyl-(R)-salsolinol in the cerebrospinal fluid of parkinsonian patients. The enzyme has neither been isolated from the human brain nor pharmacologically characterised. Other endogenous substrates, such as nicotinamide, can also serve as substrates for this enzyme. Furthermore, the alterations in R-salsolinol and its metabolising enzymes have not been shown to be specific for Parkinson’s disease, since they have not been investigated in other neurodegenerative disorders. In particular, it would be important to measure the concentrations of N-methyl-(R)-salsolinol and the activity of its synthesising enzyme in alcoholics, in whom (R)salsolinol concentrations are raised.8 Fourth, Parkinson’s disease is characterised by a chronic progressive loss of dopaminergic neurons.9 Whether long-term systemic exposure to small but cumulative doses of N-methyl-(R)-salsolinol triggers a cascade of progressive neurotoxic processes in nonhuman primates has not been investigated. Thus, despite the impressive effort in investigating the neurotoxicity of N-methyl-(R)-salsolinol and in analysing its concentrations and metabolism in parkinsonian tissue, further data are required before acceptance of the suggestion that this compound plays a part in the pathogenesis of Parkinson’s disease. However, this suggestion may be a promising line of research.
Manfred Gerlach, Eleni Koutsilieri, *Peter Riederer Division of Clinical Neurochemistry, Department of Psychiatry, University of Würzburg, D-97080 Würzburg, Germany 1
2
Gerlach M, Riederer P. Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 1996; 103: 987–1041. Naoi M, Maruyama W, Matsubara K, Hashizume Y. A neutral N-methyltransferase activity in the striatum determines the level of an endogenous MPP+-like neurotoxin, 1,2-dimethyl-6,7dihydroxysoquinolinium ion, in the substantia nigra of human brains.
THE LANCET • Vol 351 • March 21, 1998
3
4
5
6
7
8
9
Neurosci Lett 1997; 235: 81–84. Naoi M, Maruyama W, Zhang JH, Takahashi T, Deng Y, Dostert P. Enzymatic oxidation of the dopaminergic neurotoxin, 1(R),2(N)dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, into 1,2,(N),dimethyl-6,7-dihydroxyisoquinolinium ion. Life Sci 1995; 57: 1061–66. Naoi M, Maruyama W, Dostert P, Hashizume Y. N-methyl-(R)salsolinol as a dopaminergic neurotoxin: from an animal model to an early marker of Parkinson’s disease. J Neural Transm 1997; 50 (suppl): 89–105. Maruyama W, Abe T, Tohgi H, Dostert P, Naoi M. A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian cerebrospinal fluid. Ann Neurol 1996; 40: 119–22. Naoi M, Maruyama W, Nakao N, Ibi T, Sahashi K, Benedetti MS. (R)Salsolinol N-methyltransferase activity increases in parkinsonian lymphocytes. Ann Neurol 1998; 43: 212-16. Takahashi T, Deng Y, Maruyama W, Dostert P, Kawai M, Naoi M. Uptake of a neurotoxin-candidate, (R)1,2-dimethyl-6,7-dihydroxy1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system. J Neural Transm (GenSect) 1994; 98: 107–18. Rommelspacher H, Sllstrom-Baum S, Dufeu P, Schmidt LG. Determination of (R)- and (S)-salsolinol sulfate and dopamine sulfate levels in plasma of nonalcoholics and alcoholics. Alcohol 1995; 12: 309–15. Jellinger K. Pathology of Parkinson’s syndrome. In: Calne DB, ed. Handbook of experimental pharmacology. Berlin: Springer, 1988; 88: 47–112.
Adverse reactions to levodopa: drug toxicity or progression of disease? Introduced 30 years ago, levodopa remains the mainstay of treatment for Parkinson’s disease. This naturally occurring neutral aminoacid is converted to dopamine in the brain. Since dopamine depletion, especially in the striatum, is the major neurochemical abnormality in Parkinson’s disease, treatment with levodopa is a form of dopamine-replacement therapy. The drug is given together with a peripheral dopa-decarboxylase inhibitor, such as benserazide or carbidopa, which dampens peripheral production of dopamine and thus limits sideeffects of peripheral origin while increasing the availability of dopamine to the brain. At the start of treatment, levodopa is highly effective in relieving parkinsonian symptoms, but eventually two types of problems emerge. First, after several years of treatment, disabling motor effects such as dyskinesias and motor fluctuations (wearing-off and on-off phenomena) begin to appear and necessitate careful adjustment of the amount or timing of the dose of levodopa. To deal with these motor complications other drugs, especially directly acting dopamine agonists, monoamine-oxidase inhibitors, and catechol-O-methyl-transferase inhibitors, are commonly added to the therapeutic regimen. Some physicians have advocated that levodopa be limited to low doses, or that its prescription be delayed to postpone the development of dyskinesia and motor swings. Others, however, think that these complications are the result of the severity and progression of the neurodegenerative process (ie, due to progressive depletion of brain dopamine despite levodopa), so they do not hesitate to introduce levodopa early in the course of the disease. The second problem is that in patients with advanced disease, the response of some symptoms to levodopa usually declines. There is controversy over whether the diminished effectiveness of levodopa is due to acquired tolerance to the drugs, or to the appearance of new symptoms (postural instability, gait disorders, sphincter dysfunction, dysarthria, mental deterioration), which respond poorly, if at all, to levodopa.2 Another concern is whether levodopa, which is 851
COMMENTARY
prescribed for long periods, accelerates progression of the disease because it might be a source of free radicals and hence might hasten the degeneration of already fragile dopaminergic neurons.3 If so, is the toxic effect one of irreversible damage leading to cell loss? Or is it just cell dysfunction, which may temporarily or permanently contribute to the occurrence of the side-effects? To address these questions, a meeting of 25 experts was held in Paris (Jan 8–9, 1998) to discuss studies of levodopa toxicity done in tissue culture, animal models of parkinsonism, and human beings, and to try to arrive at some agreement on whether or how the findings should influence prescribing of the drug. The detailed discussion, together with published conflicting findings, will appear elsewhere. The main conclusions can be summarised as follows. ● Levodopa is still the most effective treatment for parkinsonian symptoms, and it decreases mortality rate from this disease.4 ● There is no evidence that long-term administration of levodopa contributes to or worsens the underlying neurodegenerative brain lesions in patients with Parkinson’s disease.5 ● Levodopa-induced motor complications result from both degeneration of brain dopaminergic systems (a process for which there is no means of prevention) and the repeated administration of levodopa6 (which can be modified according to the condition of the patient). ● There is no convincing evidence that therapeutic doses of levodopa result in nerve-cell death in animal models of parkinsonism.7 ● Levodopa can induce cell death in vitro but only when high concentrations are used in the absence of glial cells;8,9 however, the relevance of in-vitro work to patients with Parkinson’s disease is uncertain. In sum, there is no cause for concern that levodopa is dangerous for patients. How and when to prescribe levodopa should be influenced not by fear that the drug is toxic, but by how the patient reacts to the drug.
*Y Agid, T Chase, D Marsden *INSERM U 289 and Féderation de Neurologie-Hôpital de la Salpêtrière, 75013 Paris, France; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; and National Hospital for Neurology and Neurosurgery, London, UK 1
2
3 4
5
6
7
8
9
Marsden CD. On-off phenomena in Parkinson’s disease. In: Rinne UK, Klinger S, Stamm G, eds. Current progress, problems and management. Amsterdam: North Holland Biomedical Press, 1980: 241–54. Bonnet AM, Loria Y, Saint-Hilaire MH, Lhermitte F, Agid Y. Does long term aggravation of Parkinson’s disease result from nondopaminergic lesions? Neurology 1987; 37: 1539–42. Fahn S. Is levodopa toxic? Neurology 1996; 47 (suppl 3): S184–95. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. Multi-center study of Parkinson’s mortality with early versus late dopa treatment. Ann Neurol 1987; 22: 8–12. Yahr MD, Wolf A, Antunes JL, Miyoshi K, Duffy P. Autopsy findings in parkinsonism following treatment with levodopa. Neurology 1972; 22 (suppl): 56–71. Mouradian MM, Chase TN. Improved dopaminergic therapy of Parkinson’s disease. In: Marsden CD, Fahn S, eds. Movement disorders 3. Oxford: Butterworth-Heinemann Ltd, 1994: 181–99. Dziewczapolski G, Murer G, Agid Y, Gershanik O, Raisman-Vozari R. Absence of neurotoxicity of chronic L-DOPA treatment in 6hydroxydopamine lesioned rats. Neuroreport 1997; 8: 975–79. Mena MA, Casajeros LJ, Carazo A, Paino CL, de Yebenes JG. Glia conditioned medium protects fetal rat midbrain neurones in culture from L-DOPA toxicity. Neuroreport 1996; 7: 441–45. Han SK, Mytilineou C, Cohen F. L-DOPA up-regulates glutathione and protects mesencephalic culturs oxidative stress. J Neurochem 1996; 66: 501–10.
852
WHO’s tuberculosis research initiative Although essentially curable, tuberculosis kills up to 3 million adults every year, more than any other infectious disease. Compounding the situation is a vast disparity between the burden of human disease attributable to tuberculosis (3% worldwide) and the amount spent on tuberculosis research (an optimistic guess is 0·2% of the health research budget). To establish a rational approach to setting priorities for research, the WHO global tuberculosis programme (GTB) has started the global tuberculosis research initiative (GTRI). Under GTRI, tuberculosis researchers, policy-makers, and representatives of national programmes met in Geneva on March 3–5 to start priority setting. Their recommendations emphasise the need for research into optimising the delivery of directly observed therapy, short-course (DOTS), the strategy that lies at the heart of the WHO tuberculosis-control programme. The need to improve the delivery of DOTS is based on knowledge that the strategy works, but that only about 12% of tuberculosis patients worldwide are covered by DOTS and that most large key epidemic countries have low DOTS coverage. The GTRI recommendations stress the importance of developing operational-research capacity in the countries worst affected by tuberculosis and of coordinating research with the routine functions of national tuberculosis programmes. Another need is to make operational research more “glamorous”, to attract funding and the best scientists. For strategic research the priority areas are improvement in the accuracy of surveillance and epidemiological data, identification of drug-resistance trends, and development of new diagnostic tools, drugs, and vaccines. However, strategic research might take decades to bear fruit, hence the emphasis placed on operational research. GTB must disseminate widely the GTRI recommendations and take account of the views of tuberculosis scientists and fieldworkers, particularly those in developing countries. The essential next step is to establish the mechanisms to turn GTRI recommendations into actions once they have passed through a Byzantine series of WHO committees. It would be a shame if bureaucracy inhibits the good intentions of the GTRI.
John McConnell The Lancet, London WC1B 3SL, UK
The Lancet and the Internet, mark II The pace of change is nowhere quicker than on the Internet. Return to the worldwide web (the multimedia section of the Internet) after an absence of a few months and you will find a landscape transformed in richness and variety. As a medium for academic publishing the Internet now offers opportunities unimaginable in paper. The Lancet Interactive website (http://www.thelancet.com) launched this week is a step forward in our challenge, according to Tony Delamothe in the supplement that accompanies this issue, to the “paper mindset”. Rapidly updated readers’ comments form an integral part of the site, and we look forward to publishing research supported by video and sound.
John McConnell, Richard Horton The Lancet, London WC1B 3SL, UK
THE LANCET • Vol 351 • March 21, 1998