1597
Women Prisoners (1987). In addition, the Bharatiya Janata Party (BJP) has all along favoured the setting up of a human rights commission in India, a point that the Congress Party also included in its 1991 manifesto for the general elections. Yet the initial cross-party parliamentary response to the Amnesty International report was denouncement of the publication. However, two weeks later, on May 18, the Union Minister of State for Home announced a decision to set up a Human Rights Commission and added that discussions and consultations on the structure and functions of the commission had started. It is unrealistic to expect circumstances to change immediately. The recent Rodney King case in the USA illustrates the difficulties that justice departments face in proving beyond reasonable doubt that police know that they are violating a prisoner’s rights. However, the increase in awareness of human rights issues precipitated by the report makes its publication a milestone in the development of the human rights movement in India. on
R. Srinivasa
Germany: Bring
on
Murthy
the limited list
For decades German physicians have insisted on therapeutic freedom-in particular, the right to prescribe the newest and most expensive medicines. Their prescribing costs are as high as their incomes, and for general practitioners almost twice as high (in the USA, prescriptions account for only one-third of fees to patients). Now the Health Minister’s announcement of dramatic cost-cutting measures has generated second thoughts. The Sick Fund Physician’s Association, realising that doctors will be required to pay for overprescribing, has called for a positive (limited) list of drugs prescribable to sick fund members. There is no doubt that sick fund patients could be properly looked after with a list including fewer than a thousand drugs, but who is going to decide which drugs? The Regulatory Authority (BGA) bound by the lenient drug law cannot do it; nor can critics of the pharmaceutical industry. There is no competent Government advisory board screened for independence and integrity; and academia, starved of public support and struggling for industry grants, should not be asked either. Why not just copy the Austrian or Swiss lists which are already in the German language and have served well for many years.
Karl H. Kimbel
concentration of flecainide was 482 p.g/1, but the boy continued to have palpitations despite increase of the dose to 150 mg a day. A pre-dose plasma concentration of flecainide was 391 p.g/1 (the then accepted therapeutic range was 400-1000 ug/1), so the dose was increased to 100 mg twice a day; subsequently the plasma concentration was not measured. He remained symptom-free until Dec 6 when he had a "fainting attack" on arrival at school. He lost consciousness for less than a minute and was briefly disorientated. His general practitioner thought this was a vasovagal faint and reassured the parents . The GP clinical assistant at the local hospital thought likewise at the boy’s next routine outpatient visit on Jan 18. Three days later the boy had a second fainting attack, again in the morning at school. The family doctor, having just received a letter from the hospital that all was well, thought this attack similar to the previous event and again reassured the parents. On the morning of March 11 the boy collapsed at school for the third time, but did not recover despite prompt and long attempts at resuscitation. Necropsy revealed no cause of death, which was attributed to acute heart failure resulting from cardiac arrhythmia; no inquest seemed necessary. However, the post-mortem blood concentration of flecainide, taken 2 days after death, was very high. The boy’s parents asked for an inquest, which was delayed because five parties wished to be legally represented-the parents, the school, the family doctor, the health authority, and 3M Health Care, the manufacturers of flecainide. The clinical history and circumstances of the death suggested that it was due to an arrhythmia but offered no clue as to which type. SVT in children is generally regarded as benign if attacks last less than 2 h, and flecainide itself can cause arrhythmias.! Flecainide may have played a part in precipitating an arrhythmia even if the blood concentration in life was in the therapeutic range. (It was argued in court that the most likely explanation of the high post-mortem blood concentration of flecainide was redistribution of the drug after death.) Experts agreed that few antiarrhythmic drugs have been tested in children as much as flecainide, and it is generally judged to be safe and effective for controlling SVT in a child with a normal heart.2 After publication of the preliminary results of the CAST studythe safety of flecainide in the treatment of non-life-threatening
arrhythmias was questioned, but many physicians thought that the results of CAST should not be applied to patients with structurally normal hearts and recommended its continued use.4,5 An extensive review by the paediatric electrophysiology group6 and a publication search7 yielded report of flecainide-associated death in such a child. The assembled experts thought that the two fainting episodes before the boy’s final collapse were also most likely to have been due to an arrhythmia and that his death might have been prevented had he been reassessed on the basis of flecainide blood level and 24-h electrocardiography after the no
Medicine and the Law Death of child with supraventricular
tachycardia The inquest by the Milton Keynes coroner on June 8 into the death of a 5-year-old boy with paroxysmal supraventricular tachycardia (SVT) raised issues not only about safety of antiarrhythmic drugs in children but also about division of responsibility for care. After his initial presentation at age 4 months the boy remained well on digoxin and sotalol. However, at age 5 years his attacks became more frequent and a paediatric cardiologist recommended flecainide on Sept 27. The boy was started on 50 mg twice a day, and steady-state 2 h post-dose serum
first
or
second attack. The jury returned an open verdict.
The consultant paediatric cardiologist, who visited the local hospital every three months, was experienced in the use of flecainide and recommended it. The consultant paediatrician, also conversant with flecainide, had directly supervised treatment initially. But neither the GP nor the GP clinical assistant in the outpatient clinic was familiar with the use of flecainide in children and neither recognised the importance of the faints. Flecainide may have contributed to the boy’s death, yet several experts testified they too would have used flecainide in his case but with closer and more direct supervision than in this case.
1598
Flecainide is not recommended or licensed for use in so the data sheet includes no information about such use. If drugs such as flecainide are to be used in children and not monitored in a specialist unit, everyone concerned at a local level must know what do to. The NHS Management Executive puts the responsiblity for providing the requisite information on hospital consultants who prescribe or recommend a drug that is to be continued or monitored by the GP.8 The case reported here shows that this responsibility must be taken seriously, ultimately by distributing brief user-friendly guidelines with any letter making such specialist therapeutic recommendations. These guidelines should cover dose, duration of treatment, special monitoring requirements, potential interaction, and possible adverse effects.99
children,
Jan Till
Andrew Herxheimer 1.
Perry JC, McQuinn RI, Smith RT, Gothing C, Fredell P, Garson A. Flecainide acetate for resistant arrhythmias in the young: efficacy and
pharmacokinetics. JACC 1989; 13: 185-91. 2. Till JA, Shinebourne EA, Rowland E, et al. Paediatric use of flecainide in supraventricular tachycardia: clinical efficacy and pharmacokinetics. Br Heart J 1989; 62: 133-39. 3. The cardiac arrhythmia suppression trial (CAST) investigators preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.
N Engl J Med 1989; 321: 406-12. C, Ward DE, Camm AJ. Lessons from the cardiac arrhythmia suppression trial. Br Med J 1989; 299: 805-06. 5. Perry JC, Garson A. Ecainide and flecainide in children: separating the wheat from the chaff. JACC 1991; 18: 366-67. 6. Fish FA, Gillette PC, Benson DW and the paediatric electrophysiology group. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. JACC 1991; 18: 356-65. 7. Perry JC, Garson A. Flecainide acetate for paediatric tachyarrhythmias. Am J Cardiol (in press). 8. NHS Management Executive: the responsibility for prescribing between hospitals and GPs. EL(91)217, 1991. 9. Jones R, Rawlins MD. Prescribing at the interface between hospital and GPs. Br Med J 1992; 30: 4-5.
4. Garratt
Conference Lyme disease Lyme disease comes second to AIDS as the most funded infection for research in the United States. It was therefore no surprise that the number of registrants (over 800) for the Fifth International Conference on Lyme Disease in Washington was more than three times greater than that at the fourth conference two years ago. The proceedings were enlivened when many delegates expressed their rage over how patient-support groups got papers reinstated in the meeting programme that had been rejected as unscientific. The topic that attracted the greatest interest was the new genomic classification of Borrelia burgdorferi based on DNA/DNA hybridisation studies and other genetic and phenotypic characteristics.1-5 The single species Borrelia burgdorferi was subdivided into Borrelia burgdorferi sensu stricto, which tended to correlate with arthritis, especially in North American patients; Borrelia garinii (after Garin’s 70 year-old paper6 describing meningoradiculitis preceded by tick bite), which in Europe tends to be associated with neuroborreliosis; and an un-named group VS461, linked with acrodermatitis chronica atrophicans. Occasionally there have been strains of Borrelia burgdorferi that do not fit this classification and may eventually form a fourth group. In Europe both B burgdorferi sensu stricto and B garinii are
common whereas common
whereas in the United States over 90% of isolates
are B burgdorferi sensu stricto. The lack of heterogeneity in American strains may imply that Lyme disease originated in Europe-how long ago is uncertain, although American tick and rodent specimens dating from the turn of the century contain B burgdorferi DNA. Whether believing the various species will differ in antibiotic sensitivities remains to be determined. For diagnosis, serological tests based on enzyme linked immunosorbent assay and western blot remain the standard techniques. Recombinant antigens are being evaluated by these methods and show greater specificity but lower sensitivity than do natural antigens. The use of cocktails of recombinant antigens may overcome these disadvantages. The polymerase chain reaction has been used to detect borrelial DNA in clinical specimens such as skin, urine, cerebrospinal fluid, and whole blood but with disappointingly fewer positives than might have been ’
expected. The discovery that the animal reservoir in California is maintained in the dusky footed wood rat by a species specific tick, Ixodes neotomae, offers a new perspective to borrelia ecology. Ixodes pacificus, the tick responsible for transmitting the disease to man, only rarely bites the woodrat, which explains why Lyme disease is less common on
the West Coast of America than in other parts of the
country.
Immunity to Lyme disease is another vexed topic. Re-infection, as diagnosed clinically, has been described in high occupational risk groups, such as forestry workers, which perhaps indicates that the normal immune response is not protective. This observation has not prevented the hunt for appropriate antigens as candidates for vaccine. Vaccination with major outer membrane proteins such as Osp A and Osp C (pC) are protective in animal models. The Osp A protein varies between strains and even forms the basis of a serotyping system, so it is not surprising that experiments have shown only limited cross-protection between isolatef,The detection of escape mutant strains expressing altered or absent Osp A suggests that B burgdorferi may undergo antigenic variation of its surface proteins, thereby evading the host’s immune response. These mutants were selected by exposure to monoclonal and polyclonal antisera. There is also the possibility that, even if a specific immune response is generated, the development of anti-idiotype-specific IgG may downregulate the immune response, as may happen in neuroborreliosis, thereby accounting for the tendency of the disorder to resolve. Lastly, an Osp A containing vaccine may trigger a deleterious immune response resulting in chronic arthritis in patients with haplotype HLA-DR4 and 2. Department of Medical Microbiology, Westminster and Charing Cross Medical Schools, London
K. J. Cann
D. J. M. Wright
G, et al. Taxonomy of Borrelia spp. Scand J Infect Dis 1991; S7: 108-29. 2. Adam T, Gassman GS, Rasiah C, Gobel UB. Phenotypic and genotypic analysis of Borrelia burgdorferi isolates from various sources. Infect 1. Wilske B, Anderson JF, Baranton
Immun 1991; 59: 2579-85. 3. Boerlin P, Peter O, Bretz AG, Postic D, Baranton G, Piffaretti JC. Population genetic analysis of Borrelia burgdorferi isolates by multilocus enzyme electrophoresis. Infect Immun 1992; 60: 1677-83. 4. Picken RN, Polymerase chain reaction primers and probes derived from flagellin gene sequences for specific detection of the agents of Lyme disease and North American Relapsing fever. J Clin Microbiol 1992; 30: 99-114. 5. Marconi RT, Garon CF. Phylogenetic analysis of the genus Borrelia: a comparison of North American and European isolates of Borrelia burgdorferi. J Bacteriol 1992; 174: 241-44. 6. Garin C, Bujadoux A. Paralysie les tiques. J Med Lyon 1922; 7: 765-67.
Women Prisoners (1987). In addition, the Bharatiya Janata Party (BJP) has all along favoured the setting up of a human rights commission in India, a point that the Congress Party also included in its 1991 manifesto for the general elections. Yet the initial cross-party parliamentary response to the Amnesty International report was denouncement of the publication. However, two weeks later, on May 18, the Union Minister of State for Home announced a decision to set up a Human Rights Commission and added that discussions and consultations on the structure and functions of the commission had started. It is unrealistic to expect circumstances to change immediately. The recent Rodney King case in the USA illustrates the difficulties that justice departments face in proving beyond reasonable doubt that police know that they are violating a prisoner’s rights. However, the increase in awareness of human rights issues precipitated by the report makes its publication a milestone in the development of the human rights movement in India. on
R. Srinivasa
Germany: Bring
on
Murthy
the limited list
For decades German physicians have insisted on therapeutic freedom-in particular, the right to prescribe the newest and most expensive medicines. Their prescribing costs are as high as their incomes, and for general practitioners almost twice as high (in the USA, prescriptions account for only one-third of fees to patients). Now the Health Minister’s announcement of dramatic cost-cutting measures has generated second thoughts. The Sick Fund Physician’s Association, realising that doctors will be required to pay for overprescribing, has called for a positive (limited) list of drugs prescribable to sick fund members. There is no doubt that sick fund patients could be properly looked after with a list including fewer than a thousand drugs, but who is going to decide which drugs? The Regulatory Authority (BGA) bound by the lenient drug law cannot do it; nor can critics of the pharmaceutical industry. There is no competent Government advisory board screened for independence and integrity; and academia, starved of public support and struggling for industry grants, should not be asked either. Why not just copy the Austrian or Swiss lists which are already in the German language and have served well for many years.
Karl H. Kimbel
concentration of flecainide was 482 p.g/1, but the boy continued to have palpitations despite increase of the dose to 150 mg a day. A pre-dose plasma concentration of flecainide was 391 p.g/1 (the then accepted therapeutic range was 400-1000 ug/1), so the dose was increased to 100 mg twice a day; subsequently the plasma concentration was not measured. He remained symptom-free until Dec 6 when he had a "fainting attack" on arrival at school. He lost consciousness for less than a minute and was briefly disorientated. His general practitioner thought this was a vasovagal faint and reassured the parents . The GP clinical assistant at the local hospital thought likewise at the boy’s next routine outpatient visit on Jan 18. Three days later the boy had a second fainting attack, again in the morning at school. The family doctor, having just received a letter from the hospital that all was well, thought this attack similar to the previous event and again reassured the parents. On the morning of March 11 the boy collapsed at school for the third time, but did not recover despite prompt and long attempts at resuscitation. Necropsy revealed no cause of death, which was attributed to acute heart failure resulting from cardiac arrhythmia; no inquest seemed necessary. However, the post-mortem blood concentration of flecainide, taken 2 days after death, was very high. The boy’s parents asked for an inquest, which was delayed because five parties wished to be legally represented-the parents, the school, the family doctor, the health authority, and 3M Health Care, the manufacturers of flecainide. The clinical history and circumstances of the death suggested that it was due to an arrhythmia but offered no clue as to which type. SVT in children is generally regarded as benign if attacks last less than 2 h, and flecainide itself can cause arrhythmias.! Flecainide may have played a part in precipitating an arrhythmia even if the blood concentration in life was in the therapeutic range. (It was argued in court that the most likely explanation of the high post-mortem blood concentration of flecainide was redistribution of the drug after death.) Experts agreed that few antiarrhythmic drugs have been tested in children as much as flecainide, and it is generally judged to be safe and effective for controlling SVT in a child with a normal heart.2 After publication of the preliminary results of the CAST studythe safety of flecainide in the treatment of non-life-threatening
arrhythmias was questioned, but many physicians thought that the results of CAST should not be applied to patients with structurally normal hearts and recommended its continued use.4,5 An extensive review by the paediatric electrophysiology group6 and a publication search7 yielded report of flecainide-associated death in such a child. The assembled experts thought that the two fainting episodes before the boy’s final collapse were also most likely to have been due to an arrhythmia and that his death might have been prevented had he been reassessed on the basis of flecainide blood level and 24-h electrocardiography after the no
Medicine and the Law Death of child with supraventricular
tachycardia The inquest by the Milton Keynes coroner on June 8 into the death of a 5-year-old boy with paroxysmal supraventricular tachycardia (SVT) raised issues not only about safety of antiarrhythmic drugs in children but also about division of responsibility for care. After his initial presentation at age 4 months the boy remained well on digoxin and sotalol. However, at age 5 years his attacks became more frequent and a paediatric cardiologist recommended flecainide on Sept 27. The boy was started on 50 mg twice a day, and steady-state 2 h post-dose serum
first
or
second attack. The jury returned an open verdict.
The consultant paediatric cardiologist, who visited the local hospital every three months, was experienced in the use of flecainide and recommended it. The consultant paediatrician, also conversant with flecainide, had directly supervised treatment initially. But neither the GP nor the GP clinical assistant in the outpatient clinic was familiar with the use of flecainide in children and neither recognised the importance of the faints. Flecainide may have contributed to the boy’s death, yet several experts testified they too would have used flecainide in his case but with closer and more direct supervision than in this case.
1598
Flecainide is not recommended or licensed for use in so the data sheet includes no information about such use. If drugs such as flecainide are to be used in children and not monitored in a specialist unit, everyone concerned at a local level must know what do to. The NHS Management Executive puts the responsiblity for providing the requisite information on hospital consultants who prescribe or recommend a drug that is to be continued or monitored by the GP.8 The case reported here shows that this responsibility must be taken seriously, ultimately by distributing brief user-friendly guidelines with any letter making such specialist therapeutic recommendations. These guidelines should cover dose, duration of treatment, special monitoring requirements, potential interaction, and possible adverse effects.99
children,
Jan Till
Andrew Herxheimer 1.
Perry JC, McQuinn RI, Smith RT, Gothing C, Fredell P, Garson A. Flecainide acetate for resistant arrhythmias in the young: efficacy and
pharmacokinetics. JACC 1989; 13: 185-91. 2. Till JA, Shinebourne EA, Rowland E, et al. Paediatric use of flecainide in supraventricular tachycardia: clinical efficacy and pharmacokinetics. Br Heart J 1989; 62: 133-39. 3. The cardiac arrhythmia suppression trial (CAST) investigators preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.
N Engl J Med 1989; 321: 406-12. C, Ward DE, Camm AJ. Lessons from the cardiac arrhythmia suppression trial. Br Med J 1989; 299: 805-06. 5. Perry JC, Garson A. Ecainide and flecainide in children: separating the wheat from the chaff. JACC 1991; 18: 366-67. 6. Fish FA, Gillette PC, Benson DW and the paediatric electrophysiology group. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. JACC 1991; 18: 356-65. 7. Perry JC, Garson A. Flecainide acetate for paediatric tachyarrhythmias. Am J Cardiol (in press). 8. NHS Management Executive: the responsibility for prescribing between hospitals and GPs. EL(91)217, 1991. 9. Jones R, Rawlins MD. Prescribing at the interface between hospital and GPs. Br Med J 1992; 30: 4-5.
4. Garratt
Conference Lyme disease Lyme disease comes second to AIDS as the most funded infection for research in the United States. It was therefore no surprise that the number of registrants (over 800) for the Fifth International Conference on Lyme Disease in Washington was more than three times greater than that at the fourth conference two years ago. The proceedings were enlivened when many delegates expressed their rage over how patient-support groups got papers reinstated in the meeting programme that had been rejected as unscientific. The topic that attracted the greatest interest was the new genomic classification of Borrelia burgdorferi based on DNA/DNA hybridisation studies and other genetic and phenotypic characteristics.1-5 The single species Borrelia burgdorferi was subdivided into Borrelia burgdorferi sensu stricto, which tended to correlate with arthritis, especially in North American patients; Borrelia garinii (after Garin’s 70 year-old paper6 describing meningoradiculitis preceded by tick bite), which in Europe tends to be associated with neuroborreliosis; and an un-named group VS461, linked with acrodermatitis chronica atrophicans. Occasionally there have been strains of Borrelia burgdorferi that do not fit this classification and may eventually form a fourth group. In Europe both B burgdorferi sensu stricto and B garinii are
common whereas common
whereas in the United States over 90% of isolates
are B burgdorferi sensu stricto. The lack of heterogeneity in American strains may imply that Lyme disease originated in Europe-how long ago is uncertain, although American tick and rodent specimens dating from the turn of the century contain B burgdorferi DNA. Whether believing the various species will differ in antibiotic sensitivities remains to be determined. For diagnosis, serological tests based on enzyme linked immunosorbent assay and western blot remain the standard techniques. Recombinant antigens are being evaluated by these methods and show greater specificity but lower sensitivity than do natural antigens. The use of cocktails of recombinant antigens may overcome these disadvantages. The polymerase chain reaction has been used to detect borrelial DNA in clinical specimens such as skin, urine, cerebrospinal fluid, and whole blood but with disappointingly fewer positives than might have been ’
expected. The discovery that the animal reservoir in California is maintained in the dusky footed wood rat by a species specific tick, Ixodes neotomae, offers a new perspective to borrelia ecology. Ixodes pacificus, the tick responsible for transmitting the disease to man, only rarely bites the woodrat, which explains why Lyme disease is less common on
the West Coast of America than in other parts of the
country.
Immunity to Lyme disease is another vexed topic. Re-infection, as diagnosed clinically, has been described in high occupational risk groups, such as forestry workers, which perhaps indicates that the normal immune response is not protective. This observation has not prevented the hunt for appropriate antigens as candidates for vaccine. Vaccination with major outer membrane proteins such as Osp A and Osp C (pC) are protective in animal models. The Osp A protein varies between strains and even forms the basis of a serotyping system, so it is not surprising that experiments have shown only limited cross-protection between isolatef,The detection of escape mutant strains expressing altered or absent Osp A suggests that B burgdorferi may undergo antigenic variation of its surface proteins, thereby evading the host’s immune response. These mutants were selected by exposure to monoclonal and polyclonal antisera. There is also the possibility that, even if a specific immune response is generated, the development of anti-idiotype-specific IgG may downregulate the immune response, as may happen in neuroborreliosis, thereby accounting for the tendency of the disorder to resolve. Lastly, an Osp A containing vaccine may trigger a deleterious immune response resulting in chronic arthritis in patients with haplotype HLA-DR4 and 2. Department of Medical Microbiology, Westminster and Charing Cross Medical Schools, London
K. J. Cann
D. J. M. Wright
G, et al. Taxonomy of Borrelia spp. Scand J Infect Dis 1991; S7: 108-29. 2. Adam T, Gassman GS, Rasiah C, Gobel UB. Phenotypic and genotypic analysis of Borrelia burgdorferi isolates from various sources. Infect 1. Wilske B, Anderson JF, Baranton
Immun 1991; 59: 2579-85. 3. Boerlin P, Peter O, Bretz AG, Postic D, Baranton G, Piffaretti JC. Population genetic analysis of Borrelia burgdorferi isolates by multilocus enzyme electrophoresis. Infect Immun 1992; 60: 1677-83. 4. Picken RN, Polymerase chain reaction primers and probes derived from flagellin gene sequences for specific detection of the agents of Lyme disease and North American Relapsing fever. J Clin Microbiol 1992; 30: 99-114. 5. Marconi RT, Garon CF. Phylogenetic analysis of the genus Borrelia: a comparison of North American and European isolates of Borrelia burgdorferi. J Bacteriol 1992; 174: 241-44. 6. Garin C, Bujadoux A. Paralysie les tiques. J Med Lyon 1922; 7: 765-67.
