846
LETTERS to the EDITOR
How much
drug
in the tablet?
SIR,-Several points made by Dr Herxheimer (Feb 9, p 346) have gained wide publicity and indeed support, including that from correspondents (March 16, p 670), but some sophistry has gone unchallenged. The digit preference for unit doses has been self-evident for years and hardly needed this exhaustive analysis. Spurious deductions then follow, and Herxheimer concludes with a call for a review of the evidence on which the dosage of existing medicines was based and, if necessary, dosage revision and even a change in tablet content. A dose-response study with a stepwise escalation can define the optimum single dose that achieves the desired pharmacological response. In an ideal situation that dose might be directly related to the blood concentration of the drug so that, with the pharmacokinetic profile, a multiple-dose regimen (ie, dose and timing interval) can be calculated and then confirmed in other clinical studies. In reality these elements are often unattainable; the clinical endpoint is not linearly measurable and/or is not related to the drug’s pharmacokinetic profile. Indeed, few drugs possess these prerequisites, including many of those new introductions listed in the article. Whether there is a measurable end-point or a global assessment (better or worse), the stepwise escalation of dose invariably begins with rounded figures (10, 20, 40, 80 mg... or 25, 50, 100 mg ... ). A second study may titrate downwards, revealing the inevitable terminal digit preference (10, 5,2-55 mg ... ) so eagerly denounced by Herxheimer. He deduces, solely from this finding, that these unit doses are selected not from such pharmacological studies but by some other means. Even if one began with doses based on animal studies and calculated according to body weight or surface area, there would be a similar rounding up; thus, an optimum therapeutic dose of 18-7 mg might become 20 mg, which would be indistinguisable clinically, and that adjustment can be justified if the adjacent higher dose (37 4 mg) was tolerated. So digit preference reflects a pragmatic, not irrational, approach that aims to simplify doses so that they are easily remembered, written, and read. Patients vary in their absorption, metabolism, and response to medicines, and these attributes are influenced in turn by other variables; some of these are fixed for the individual patient (hepatic or renal impairment) but most are not and may be capricious (food, drink, poor compliance, other drugs). The concept of the effective dose (ED) and its variation in the population, as portrayed by Herxheimer, implies that it is easy to identify the dose that is effective in 90% of the population (ED) or 25% (end2,). He recommends that these two unit doses should be available for some products. Unfortunately it is not easy to estimate these figures for many drugs-partly because of imprecise clinical end-points and partly because of population variables-and the confidence limits on these figures are wide and overlap. It is often necessary to make a pragmatic choice. I agree that in chronic diseases with a clear-cut pharmacodynamic response (eg, for antihypertensive agents) the dose should be titrated; but a rapid and consistent effect is required in many disorders, and the utility of an EDzs dose is questionable if 75% of patients are likely not to respond. Herxheimer asserts that some unit doses are excessive-up to 70% and on average 25% too high. This calculation is based on his assumption that doses reflect digit preference alone. These arithmetic percentages, even if true, would have a small pharmacodynamic impact at the upper end of a logarithmic plot of dose-response. However, they are not true and the consequences of rounding-up dose levels are negligible. Most side-effects have a pharmacological mechanism and their own dose-response curve. If the wanted and unwanted effects have different dose-response profiles-which they usually do, otherwise the medicine would not be developed-selection of effective dose is not too critical, and it could be the maximally effective dose. However, in most instances, the clinical response need not be 100% complete, and most
manufacturers choose an optimally effective dose that is high on the steep part of the S-shaped response curve. Even in large clinical trials it is not possible to differentiate the effects of all doses in the vicinity of this optimum. In most cases, the dose will be on the flat, lower end of the side-effect curve. An alternative and lower dose unit is often chosen which is half the standard one, as long as it still falls in the steep part of the response curve, and that is the sensible option for those needing a lower dose, because of renal impairment, for example. A few medicines do have a narrow therapeutic index and some products have had their dosage revised downwards. Here all variables must be identified and their impacts assessed so that the recommended regimen avoids untoward effects. That often means titration of the individual patient’s dose, so the unit doses available must allow the necessary flexibility. In general, manufacturers make the right decision in choosing the strength of the unit doses, but the regulatory authority and its advisers will examine the evidence and may question it and require more work, which may result in a change in the dose before the product is approved. They definitely require that the influence of age and renal or hepatic impairment be investigated and dosage adjustments be recommended. The few revisions needed later are timely reminders that occasionally our science and the assumptions on which it is based may be wrong when applied in routine clinical practice. They do not signal a widespread problem and the need for a wholesale review. Despite inter-patient variability most medicines are effective and safe at the recommended doses. Calls for such extensive action, based on weak evidence and wrong deductions, must be rejected, as must the statement that the regulatory review is lax. Clinical and Regulatory Directorate, Glaxo Group Research Ltd, Greenford UB6 0HE UK
ROBERT N. SMITH
Bone scintigraphy as clue to
previous
torture
S!R,—Torture is used by certain branches of government in countries, and Turkey, unfortunately, is one of them. Officially it is denied or seen as an isolated act of individuals. However, when we formed a medical investigation committee and announced it, the flood of applications left the strong impression that torture is a routine practice by Turkish police. A questionnaire distributed under the supervision of the prison authorities revealed various
that 73% of prisoners had been tortured while in police custody,’ and an international survey2 came up with a similar figure. The most frequent method isfalanga, beating the soles of the feet Most victims are too frightened to report this maltreatment and the occasional hero who is may find that his claim does not convince a court because he had been released from prison long after the physical signs of torture had disappeared. Any objective sign of torture that persists would be very valuable. We have investigated alleged torture cases using techniques such as ultrasound, computerised axial tomography (CAT), and bone scintigraphy; the latter has emerged as a promising test. A 35-year-old woman was arrested for suspicion of involvement in a kidnapping. She was heavily beaten for about 2 days and released a week later because she was found to be innocent. Subsequently, she required extended psychiatric inpatient care. 1 week after the incident clinical examination and the CAT scan revealed soft-tissue oedema of the feet, and there was increased activity in the first and second metatarsal bones of the left foot on bone scintigraphy with technetium-99m (figure). Conventional radiography was normal with no sign of bone fracture. This patient has been followed up for 12 months now and bone scintigraphy has been persistently positive in thirteen scans done every 2-4 weeks. She is still under psychiatric treatment.
847
and the project will continue as a joint effort by RCT and the Human Rights Foundation of Turkey in three large Turkish cities. We hope that the project will fall short of its aim of one hundred
patients. 1442 Sok 42/2 Alsancak, Izmir 35220,
VELI LOK
Turkey
MEHMET TUNCA
Izmir
Özel Izmir Ege Nukleer Tip Laboratuari, Izmir
KAMIL KUMANLIOĞLU
Izmir
EMRE KAPKIN
BILRAD Izmir
Bilgisayarli Tomografi Merkezi,
GÜRKAN DIRIK
Ürum T. Türkiye’de Ceza ve &Ibreve;slahevlerindeki Durum Arastirmasi. Izmir, 1990 (in Turkish). 2. Jensen SB, Schaumburg E, Lerory B, Larsen BØ, Thorup M. Psychiatric care in refugees exposed to organized violence. Acta Psychiatr Scand 1989; 80: 125-31. 3. Rasmussen OV. Medical aspects of torture. Dan Med Bull 1990; 37 (suppl 1): 1-88. 4. Goldstein HA. Bone scintigraphy. Orthop Clin North Am 1983; 14: 243-56. 5. Sfakianakis GN, Haase GM, Ortiz VN, Morse TS. The value of bone scanning in the early recognition of deliberate child abuse. JNucl Med 1979; 20: 675. 6. Deutsch SD, Gandsman EJ. The use of bone scanning for the diagnosis and management of musculoskeletal trauma. Surg Clin North Am 1983; 63: 567-85. 1.
Mortality related to thrombosis in congenital antithrombin III deficiency
99’Tc bone scintigraphs. Upper, patient 1, feet. at 1 month (left) and 12 months (right). Lower, patient 2, ribs on admission (left) and 5 months later
by the
A 41-year-old woman was interrogated police for about 24 hours about some missing jewels. When examined a week later, she said that she had been beaten (falanga), kicked, and hit. She had multiple bruising and the soles of the feet were tender. Whole-body bone scintigraphy 10 days after the incident revealed increased activity at the 9th thoracic vertebra, 9th left rib, 10th left costovertebral junction, and first metatarsal of the right foot (figure). Radiography and a CAT scan disclosed only LS-Sl spondylolisthesis and soft tissue oedema of the feet. 1 month later scintigraphy still indicated increased activity in the left 9th and right 10th ribs, and these findings were still present at 5 months. A 35-year-old man beaten by the police 2 days earlier with falanga and on the hands had CT evidence of soft tissue oedema of the feet but scintigraphy revealed increased activity in the second and the third metacarpals of the right hand only. A 27-year-old man beaten in the same incident had oedema of the feet, bruising, and cigarette burns. A CT scan of the feet disclosed soft-tissue oedema with no bone injury, scintigraphy showed hyperactivity at the first metatarsal bone of the left foot. These two patients did not attend for
follow-up. Bone scintigraphy is a sensitive indicator of trauma.’5 It may reveal small fractures missed by conventional radiographs. A positive scintigraph may remain positive for over 5 months .6 Since our patients did not have fractures corresponding to the active scintigraphic site the scans may be revealing periosteal damage caused by the beatings. These observations have been forwarded to the International Rehabilitation and Research Centre for Torture Victims (RCT),
SIR,-Dr Rosendaal and colleagues (Feb 2, p 260) studied 10 complete pedigrees of families with antithrombin III (AT III) hereditary deficiency, with 171 family members in total, finding no excess of mortality over that expected from the general population. They concluded that life-long treatment with anticoagulants cannot be recommended, at least in symptomless patients, to improve survival. No information was given about the causes of death or about the clinical penetrance of the defect in the families studied, so we cannot judge if these findings are related to the inclusion of kindreds with mild clinical expression of the defect. In our experience the AT III defect does seem relevant to mortality in affected kindreds: we are aware of a family with 9 deaths from thrombosis out of 35 family members over two generations.1 To evaluate the risk of death from thrombosis in hereditary AT III deficiency we reviewed published families and our own cases, including kindreds only if there were details on the clinical history of those who had died. Families with AT III qualitative deficiency type 2c (isolated impairment of heparin affinity) were not considered, since the low thrombotic risk related to this mutation is well established.2 We analysed thirty-seven families from 31 reports and three families from our series: AT III deficiency was type 1 (quantitative) in twenty-eight and type 2a or 2b (impaired serine protease inactivation)3 in twelve. We adopted the criteria of Rosendaal et al: subjects with normal AT III levels (n 403) were excluded and we considered only those with AT III at low functional levels (n 300), obligate carriers of the AT III trait (n=44), and those with a probability of deficiency of 0-5 (n = 208). 239 out of 552 subjects (43-2%) have had thrombosis; the prevalence in the 344 certainly affected was 54 3%, in agreement with other evaluations.4 In twenty-six families at least 1 death from thrombosis was recorded. Of 120 recorded deaths 44 (36-7%) were attributed to venous thromboembolism, 7 to cerebral or coronary artery thrombosis, and 6 to stroke of unspecified origin. Fatal pulmonary embolism occurred in 33 cases, mesenteric vein thrombosis in 10, "massive" thrombosis in 1, stroke in 7, and myocardial infarction in 6; 24 of these patients who died certainly had the AT III defect. Necropsy confirmed the diagnosis in 18 cases (8 pulmonary embolism, 8 mesenteric vein thrombosis,1 ischaemic stroke, 1 myocardial infarction). Age at death was reported in 52 cases: 35 were below the age of 45 and the mean age at death of those who died from thrombosis was 39. Fatal venous thromboembolism was recorded as recurrence of thrombosis in 22 cases. On the most restrictive criteria, including a post-mortem diagnosis, pulmonary embolism and mesenteric vein thrombosis were underlying causes of 16 (133%) out of 120 in these =
=
LETTERS to the EDITOR
How much
drug
in the tablet?
SIR,-Several points made by Dr Herxheimer (Feb 9, p 346) have gained wide publicity and indeed support, including that from correspondents (March 16, p 670), but some sophistry has gone unchallenged. The digit preference for unit doses has been self-evident for years and hardly needed this exhaustive analysis. Spurious deductions then follow, and Herxheimer concludes with a call for a review of the evidence on which the dosage of existing medicines was based and, if necessary, dosage revision and even a change in tablet content. A dose-response study with a stepwise escalation can define the optimum single dose that achieves the desired pharmacological response. In an ideal situation that dose might be directly related to the blood concentration of the drug so that, with the pharmacokinetic profile, a multiple-dose regimen (ie, dose and timing interval) can be calculated and then confirmed in other clinical studies. In reality these elements are often unattainable; the clinical endpoint is not linearly measurable and/or is not related to the drug’s pharmacokinetic profile. Indeed, few drugs possess these prerequisites, including many of those new introductions listed in the article. Whether there is a measurable end-point or a global assessment (better or worse), the stepwise escalation of dose invariably begins with rounded figures (10, 20, 40, 80 mg... or 25, 50, 100 mg ... ). A second study may titrate downwards, revealing the inevitable terminal digit preference (10, 5,2-55 mg ... ) so eagerly denounced by Herxheimer. He deduces, solely from this finding, that these unit doses are selected not from such pharmacological studies but by some other means. Even if one began with doses based on animal studies and calculated according to body weight or surface area, there would be a similar rounding up; thus, an optimum therapeutic dose of 18-7 mg might become 20 mg, which would be indistinguisable clinically, and that adjustment can be justified if the adjacent higher dose (37 4 mg) was tolerated. So digit preference reflects a pragmatic, not irrational, approach that aims to simplify doses so that they are easily remembered, written, and read. Patients vary in their absorption, metabolism, and response to medicines, and these attributes are influenced in turn by other variables; some of these are fixed for the individual patient (hepatic or renal impairment) but most are not and may be capricious (food, drink, poor compliance, other drugs). The concept of the effective dose (ED) and its variation in the population, as portrayed by Herxheimer, implies that it is easy to identify the dose that is effective in 90% of the population (ED) or 25% (end2,). He recommends that these two unit doses should be available for some products. Unfortunately it is not easy to estimate these figures for many drugs-partly because of imprecise clinical end-points and partly because of population variables-and the confidence limits on these figures are wide and overlap. It is often necessary to make a pragmatic choice. I agree that in chronic diseases with a clear-cut pharmacodynamic response (eg, for antihypertensive agents) the dose should be titrated; but a rapid and consistent effect is required in many disorders, and the utility of an EDzs dose is questionable if 75% of patients are likely not to respond. Herxheimer asserts that some unit doses are excessive-up to 70% and on average 25% too high. This calculation is based on his assumption that doses reflect digit preference alone. These arithmetic percentages, even if true, would have a small pharmacodynamic impact at the upper end of a logarithmic plot of dose-response. However, they are not true and the consequences of rounding-up dose levels are negligible. Most side-effects have a pharmacological mechanism and their own dose-response curve. If the wanted and unwanted effects have different dose-response profiles-which they usually do, otherwise the medicine would not be developed-selection of effective dose is not too critical, and it could be the maximally effective dose. However, in most instances, the clinical response need not be 100% complete, and most
manufacturers choose an optimally effective dose that is high on the steep part of the S-shaped response curve. Even in large clinical trials it is not possible to differentiate the effects of all doses in the vicinity of this optimum. In most cases, the dose will be on the flat, lower end of the side-effect curve. An alternative and lower dose unit is often chosen which is half the standard one, as long as it still falls in the steep part of the response curve, and that is the sensible option for those needing a lower dose, because of renal impairment, for example. A few medicines do have a narrow therapeutic index and some products have had their dosage revised downwards. Here all variables must be identified and their impacts assessed so that the recommended regimen avoids untoward effects. That often means titration of the individual patient’s dose, so the unit doses available must allow the necessary flexibility. In general, manufacturers make the right decision in choosing the strength of the unit doses, but the regulatory authority and its advisers will examine the evidence and may question it and require more work, which may result in a change in the dose before the product is approved. They definitely require that the influence of age and renal or hepatic impairment be investigated and dosage adjustments be recommended. The few revisions needed later are timely reminders that occasionally our science and the assumptions on which it is based may be wrong when applied in routine clinical practice. They do not signal a widespread problem and the need for a wholesale review. Despite inter-patient variability most medicines are effective and safe at the recommended doses. Calls for such extensive action, based on weak evidence and wrong deductions, must be rejected, as must the statement that the regulatory review is lax. Clinical and Regulatory Directorate, Glaxo Group Research Ltd, Greenford UB6 0HE UK
ROBERT N. SMITH
Bone scintigraphy as clue to
previous
torture
S!R,—Torture is used by certain branches of government in countries, and Turkey, unfortunately, is one of them. Officially it is denied or seen as an isolated act of individuals. However, when we formed a medical investigation committee and announced it, the flood of applications left the strong impression that torture is a routine practice by Turkish police. A questionnaire distributed under the supervision of the prison authorities revealed various
that 73% of prisoners had been tortured while in police custody,’ and an international survey2 came up with a similar figure. The most frequent method isfalanga, beating the soles of the feet Most victims are too frightened to report this maltreatment and the occasional hero who is may find that his claim does not convince a court because he had been released from prison long after the physical signs of torture had disappeared. Any objective sign of torture that persists would be very valuable. We have investigated alleged torture cases using techniques such as ultrasound, computerised axial tomography (CAT), and bone scintigraphy; the latter has emerged as a promising test. A 35-year-old woman was arrested for suspicion of involvement in a kidnapping. She was heavily beaten for about 2 days and released a week later because she was found to be innocent. Subsequently, she required extended psychiatric inpatient care. 1 week after the incident clinical examination and the CAT scan revealed soft-tissue oedema of the feet, and there was increased activity in the first and second metatarsal bones of the left foot on bone scintigraphy with technetium-99m (figure). Conventional radiography was normal with no sign of bone fracture. This patient has been followed up for 12 months now and bone scintigraphy has been persistently positive in thirteen scans done every 2-4 weeks. She is still under psychiatric treatment.
847
and the project will continue as a joint effort by RCT and the Human Rights Foundation of Turkey in three large Turkish cities. We hope that the project will fall short of its aim of one hundred
patients. 1442 Sok 42/2 Alsancak, Izmir 35220,
VELI LOK
Turkey
MEHMET TUNCA
Izmir
Özel Izmir Ege Nukleer Tip Laboratuari, Izmir
KAMIL KUMANLIOĞLU
Izmir
EMRE KAPKIN
BILRAD Izmir
Bilgisayarli Tomografi Merkezi,
GÜRKAN DIRIK
Ürum T. Türkiye’de Ceza ve &Ibreve;slahevlerindeki Durum Arastirmasi. Izmir, 1990 (in Turkish). 2. Jensen SB, Schaumburg E, Lerory B, Larsen BØ, Thorup M. Psychiatric care in refugees exposed to organized violence. Acta Psychiatr Scand 1989; 80: 125-31. 3. Rasmussen OV. Medical aspects of torture. Dan Med Bull 1990; 37 (suppl 1): 1-88. 4. Goldstein HA. Bone scintigraphy. Orthop Clin North Am 1983; 14: 243-56. 5. Sfakianakis GN, Haase GM, Ortiz VN, Morse TS. The value of bone scanning in the early recognition of deliberate child abuse. JNucl Med 1979; 20: 675. 6. Deutsch SD, Gandsman EJ. The use of bone scanning for the diagnosis and management of musculoskeletal trauma. Surg Clin North Am 1983; 63: 567-85. 1.
Mortality related to thrombosis in congenital antithrombin III deficiency
99’Tc bone scintigraphs. Upper, patient 1, feet. at 1 month (left) and 12 months (right). Lower, patient 2, ribs on admission (left) and 5 months later
by the
A 41-year-old woman was interrogated police for about 24 hours about some missing jewels. When examined a week later, she said that she had been beaten (falanga), kicked, and hit. She had multiple bruising and the soles of the feet were tender. Whole-body bone scintigraphy 10 days after the incident revealed increased activity at the 9th thoracic vertebra, 9th left rib, 10th left costovertebral junction, and first metatarsal of the right foot (figure). Radiography and a CAT scan disclosed only LS-Sl spondylolisthesis and soft tissue oedema of the feet. 1 month later scintigraphy still indicated increased activity in the left 9th and right 10th ribs, and these findings were still present at 5 months. A 35-year-old man beaten by the police 2 days earlier with falanga and on the hands had CT evidence of soft tissue oedema of the feet but scintigraphy revealed increased activity in the second and the third metacarpals of the right hand only. A 27-year-old man beaten in the same incident had oedema of the feet, bruising, and cigarette burns. A CT scan of the feet disclosed soft-tissue oedema with no bone injury, scintigraphy showed hyperactivity at the first metatarsal bone of the left foot. These two patients did not attend for
follow-up. Bone scintigraphy is a sensitive indicator of trauma.’5 It may reveal small fractures missed by conventional radiographs. A positive scintigraph may remain positive for over 5 months .6 Since our patients did not have fractures corresponding to the active scintigraphic site the scans may be revealing periosteal damage caused by the beatings. These observations have been forwarded to the International Rehabilitation and Research Centre for Torture Victims (RCT),
SIR,-Dr Rosendaal and colleagues (Feb 2, p 260) studied 10 complete pedigrees of families with antithrombin III (AT III) hereditary deficiency, with 171 family members in total, finding no excess of mortality over that expected from the general population. They concluded that life-long treatment with anticoagulants cannot be recommended, at least in symptomless patients, to improve survival. No information was given about the causes of death or about the clinical penetrance of the defect in the families studied, so we cannot judge if these findings are related to the inclusion of kindreds with mild clinical expression of the defect. In our experience the AT III defect does seem relevant to mortality in affected kindreds: we are aware of a family with 9 deaths from thrombosis out of 35 family members over two generations.1 To evaluate the risk of death from thrombosis in hereditary AT III deficiency we reviewed published families and our own cases, including kindreds only if there were details on the clinical history of those who had died. Families with AT III qualitative deficiency type 2c (isolated impairment of heparin affinity) were not considered, since the low thrombotic risk related to this mutation is well established.2 We analysed thirty-seven families from 31 reports and three families from our series: AT III deficiency was type 1 (quantitative) in twenty-eight and type 2a or 2b (impaired serine protease inactivation)3 in twelve. We adopted the criteria of Rosendaal et al: subjects with normal AT III levels (n 403) were excluded and we considered only those with AT III at low functional levels (n 300), obligate carriers of the AT III trait (n=44), and those with a probability of deficiency of 0-5 (n = 208). 239 out of 552 subjects (43-2%) have had thrombosis; the prevalence in the 344 certainly affected was 54 3%, in agreement with other evaluations.4 In twenty-six families at least 1 death from thrombosis was recorded. Of 120 recorded deaths 44 (36-7%) were attributed to venous thromboembolism, 7 to cerebral or coronary artery thrombosis, and 6 to stroke of unspecified origin. Fatal pulmonary embolism occurred in 33 cases, mesenteric vein thrombosis in 10, "massive" thrombosis in 1, stroke in 7, and myocardial infarction in 6; 24 of these patients who died certainly had the AT III defect. Necropsy confirmed the diagnosis in 18 cases (8 pulmonary embolism, 8 mesenteric vein thrombosis,1 ischaemic stroke, 1 myocardial infarction). Age at death was reported in 52 cases: 35 were below the age of 45 and the mean age at death of those who died from thrombosis was 39. Fatal venous thromboembolism was recorded as recurrence of thrombosis in 22 cases. On the most restrictive criteria, including a post-mortem diagnosis, pulmonary embolism and mesenteric vein thrombosis were underlying causes of 16 (133%) out of 120 in these =
=
