- Email: [email protected]
Colitis associated with docetaxel-based chemotherapy
CORRESPONDENCE
advantage of being presented in 20 mg or 30 mg scored tablets so withdrawal programmes are easier to devise. Since patent expiry, fluoxetine is now available in at least 12 generic formats.2 Generic drugs, for licensing purposes, are allowed up to 20% difference in bioequivalence from the brand original.3 Therefore, even patients on continuous therapy, could, if dispensed products emanating from different manufacturers, receive back to back prescriptions where the medicine given varies up to 40% in dose. So, in some cases, we are likely to see discontinuation symptoms in patients still on medication. I recommend that patients receive continuity of supply from the dispenser, with no intermanufacturer switching. I would also recommend that tablets come in a scored formulation so that slow and consistent withdrawal can be followed. Gillian S Wade Celtic Dimensions, Morawelon, Gwynedd LL53 6EB, UK (e-mail: [email protected]) 1
2 3
Young A, Haddad P. Discontinuation symptoms and psychotic drugs. Lancet 2000; 355: 1184. Chem Drug Gener List April–Sept 2000: 25. Generic medicine—can quality be assured? Drug Ther Bull 1997; 35: 9–11.
Fetal surveillance must go on Sir—Few areas of medicine are causing as much concern as that of intrapartum fetal surveillance. Byrony Strachan and colleagues (Feb 5, p 456)1 presented the outcome of a randomised trial of cardiotocography versus cardiotocography plus fetal electrocardiography (ECG) PR-interval analysis. They could not find any difference in outcome between the two groups based on 957 patients. In his commentary Martin Whittle2 suggested that we have seen the end of fetal ECGbased developments because no study has shown improvements in outcome measures of the baby. After more than 25 years of dedicated work, I would agree that improved outcome measures are required and the ECG is the only currently available parameter to allow such a possibility. Some years ago a European Community multicentre study was done to collect fetal ECG data from cases of intrapartum hypoxia. The first report3 focused on changes in P-R and R-R intervals. The study on 618 fullterm fetuses with normal outcome showed that a positive association was
THE LANCET • Vol 355 • May 20, 2000
indicative of a reactive heart rate and accelerations, and that all decelerations were associated with a shortening of the PR interval. Thus, it is not surprising that fetal ECG time constant analysis failed to provide additional information regarding intrapartum hypoxia. The second report4 focuses on ST waveform changes. ST changes were identified automatically by the computer (ST log). All five fetuses with the most striking ST change (a rise in the T:QRS ratio of >0·10 units and lasting more than 10 min) had signs of ongoing intrapartum hypoxia and all six fetuses with evidence of intrapartum asphyxia, showed ST changes. These data are in accordance with those of the Plymouth randomised trial of cardiotocography versus cardiotocography plus ST-interval analysis where, apart from a 46% reduction in operative interventions (p<0·001, OR 1·96 [1·42–2·71]), there was also a trend to less neonatal metabolic acidosis (p=0·09, OR 2·63 [0·93–7·39]) and fewer low 5 min Apgar scores (p=0·12, OR 1·62 [0·92–2·85]).5 The aim of intrapartum fetal surveillance should be to identify fetuses that respond to the hypoxic stress of labour. A cord artery metabolic acidosis cut-off of 7·05 and a base-deficit extracellular fluid concentration of 12 mmol/L seems to be a stringent goal with an incidence of 1·3% in cases where a scalp electrode was applied.5 This means that the 2400 cases included in the Plymouth trial were not sufficient, because 3600 cases would have been required to show a 50% reduction in the number of cases with cord artery pH of less than 7·05 and BDecf of more than 12 mmol/L (=0·20 and ␣=0·05). The aim of a study underway in Sweden is to verify the ability of cardiotocography plus ST-interval analysis so that the incidence of metabolic acidosis can be reduced. Hopefully this trial will provide conclusive evidence of the clinical value of fetal cardiotocographic ECG (ST) analysis during labour. K G Rosén Neoventa Medical, Lilla Bommen 1, SE 411 04 Gothenburg, Sweden 1
2
3
Strachan BK, van Wijngaarden W, Sahota D, Chang A, James DK. Cardiotocography only versus cardiotocography plus PR-interval analysis in intrapartum surveillance: a randomised, multicentre trial. Lancet 2000; 355: 456–59. Whittle M. Is it time to abandon cardiotocographic ECG analysis? Lancet 2000; 355: 422. Luzietti R, Erkkola R, Hasbargen U, Mattson LA, Thoulon JM, Rosen KG. European community multicentre trial “fetal ECG analysis during labour”: the P-R interval. J Perinat Med 1997; 25: 27–34.
4
5
Luzietti R, Erkkola R, Hasbargen U, Mattson L, Thoulon J-M, Rosén KG. European community multi-centre trial “fetal ECG analysis during labour”: ST plus CTG analysis. J Perinat Med 1999; 27: 431–40. Westgate J, Harris M, Curnow JSH, Greene KR. Plymouth randomised trial of cardiotocogram only versus ST waveform plus cardiotocogram for intrapartum monitoring: 2400 cases. Am J Obstet Gynaecol 1993; 169: 1151–60.
Colitis associated with docetaxel-based chemotherapy Sir—Nuhad K Ibrahim and colleagues (Jan 22, p 281)1 report an association of colitis with docetaxel-based chemotherapy in patients with metastatic breast cancer. It is obvious that the chemotherapy regimen used in this phase I study was a dose-intensive one, since it was necessary to use granulocyte-colony-stimulating factor (G-CSF) in a prophylactic manner. The data of this report do not necessarily establish an association between colitis and docetaxel itself, but underline the well-known association between colitis and aggressive chemotherapy resulting in mucositis and neutropenia. Although it is possible that docetaxel may induce more bowel damage than other chemotherapeutic drugs, taxanecontaining polychemotherapy protocols are among the most intensive regimens used for the treatment of breast cancer and may therefore be associated with typhlitis more frequently than others. Unfortunately, the incidence of this complication in patients treated with docetaxel was not given in the paper. There are several reports of typhlitis in patients with breast cancer treated with intensive chemotherapy—eg, carboplatin, cyclophosphamide, and thiotepa given with stem-cell support2 or paclitaxel and doxorubicin given with GCSF support.3 In the latter study, all patients developed typhlitis at the doselevel above the maximum-tolerated dose. On the other hand, typhlitis was already reported in patients with solid tumours in the era before taxanes.4 For typhlitis, the following sequence of events has been proposed: mucosal damage of the bowel; bacterial invasion; increased proliferation of bacteria resulting from decreased immunocompetence (neutropenia); production of bacterial endotoxins; intramural haemorrhage; ulceration; ischaemia; and in some cases necrosis of the bowel wall and perforation.5 Although two of the patients Ibrahim and colleagues report on were not neutropenic when symptoms occurred, these patients clearly had signs of severe bowel damage. Furthermore, the
1823
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
investigators claim that their patients would not fit the classic picture of typhlitis since the onset of symptoms was early after chemotherapy (median, day 8). In previous studies the median timepoint of the onset of symptoms of colitis in patients with breast cancer treated with intensive chemotherapy was also day 8.2,3 We would like to emphasise the importance of neutropenia as a risk for mortality as a result of chemotherapy associated colitis in the series reported by Ibrahim and colleagues, since both patients without neutropenia recovered but two of four patients with neutropenia died. *Orhan Sezer, Jan Eucker, Kurt Possinger
Another study has been reported in which the following regimen was used: docetaxel 60 mg/m2 intravenously and vinorelbine 25 mg/m2 intravenously on days 1 and 15 with G-CSF added only if the patient developed National Cancer Institute grade 3–4 neutropenia. In this report, two toxic deaths were reported as a result of neutropenic enterocolitis.3 Therefore, this phenomenon did not appear to be dose related, and as emphasised, the patient does not necessarily need to be neutropenic to die. Early onset neutropenia and the potential association of death as a complication warrant special attention being paid to this symptom complex.
Universitätsklinikum Charité, HumboldtUniversität, Department of Oncology and Haematology, 10098 Berlin, Germany (e-mail: [email protected])
Nuhad K Ibrahim
1
1
2
3
4
5
Ibrahim NK, Sahin AA, Dubrow RA, et al. Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer. Lancet 2000; 355: 281–83. Boggio L, Pooley R, Roth SI, Winter JN. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transplant 2000; 25: 321–26. Fisherman JS, Cowan KH, Noone M, et al. Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 774–82. Dosik GM, Luna M, Valdivieso M, et al. Necrotizing colitis in patients with cancer. Am J Med 1979; 67: 646–56. Keidan RD, Fanning J, Gatenby RA, Weese JL. Recurrent typhlitis: a disease resulting from aggressive chemotherapy. Dis Colon Rectum 1989; 32: 206–09.
Author’s reply Sir—We agree with the remarks made by Orhan Sezer and Kurt Possinger about the different reports of typhlitis associated with intensive chemotherapy given in doses above the maximum tolerated dose. The median time to onset of symptoms of colitis in intensive chemotherapy was reported on day 8 by Boggio and colleagues1 but none of the chemotherapies were taxane-based. However, in our docetaxel-vinorelbine study, we did not administer doses higher than those recommended for phase II studies, as established by Fumoleau and colleagues.2 In their study, the dose-limiting toxicity was neutropenia and stomatitis. We added G-CSF to lower the risk of neutropenic fever and stomatitis, not to intensify the schedule. Also, the additional three patients on whom we reported used taxanes at or well below the Food and Drug Administration (FDA)-approved doses for those drugs and without cytokine support. None of the patients in our report received chemotherapy at doses higher than those recommended and FDA-approved.
1824
Department of Breast Medical Oncology-56, University of Texas, MD Anderson Cancer Center, Houston, TX 77030-4095, USA
2
3
Boggio L, Pooley R, Roth SI, et al. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transpl 2000; 25: 321–26. Fumoleau P, Fety R, Delecroix V, et al. Docetaxel combined with vinorelbine: phase I results and new study designs. Oncology 1997; 11: 29–31. Gomez-Bernal A, Cruz JJ, Garcia Palomo A, et al. Docetaxel and vinorelbine in patients with metastatic breast cancer after using anthracycline [abstr]. San Antonio Breast Cancer Symposium 1999: 341.
The heart of psychotropic drug therapy Sir—In two consecutive issues, The Lancet has published articles that clearly link CYP2D6 (debrisoquine hydroxylase) and the human heart. First, Thomas Thum and Jürgen Borlak (March 18, p 979)1 reported the expression of several cytochrome P450 (CYP) genes, including CYP2D6, in the right ventricle, and J G Reilly and colleagues (March 25, p 1048)2 noted certain risk factors in psychiatric patients undergoing psychotropic drug therapy. Sadly, the Newcastle group2 seem to have missed this association when they claim that four variables (age over 65 years, the use of tricyclic antidepressants, droperidol, or thioridazine) are significant predictors of rate-corrected QT (QTc)-interval abnormalities, which occurred in 40 (8%) of 495 of their patient group and 23 (8%) of 286, five (11%) of 44, and eight (15%) of 53 of those taking antipsychotic drugs, tricyclic antidepressants (TCAs) alone, and in combination with antipsychotics and TCAs, respectively. I propose that it is compromised metabolism by CYP2D6 that leads to cardiotoxicity in patients taking antipsychotic and antidepressant
drugs. No fewer than eight TCAs and 11 antipsychotic drugs, including thioridazine, are listed as substrates of CYP2D6 by the Human P450 Metabolism Database (http://www. gentest.com/human p450 database/ index.html, accessed April 28, 2000). Droperidol has not, to my knowledge been tested, but a-priori structural chemical considerations3 strongly suggest that it will be a CYP2D6 substrate. 5–10% European populations inherit the CYP2D6 poor metaboliser (PM) phenotype3 putting them at risk of the adverse reactions that arise from the alternative pharmacology of a drug which fails to be metabolised and builds up to abnormally high concentrations in the blood and tissues. It is axiomatic that PMs will not only be missing the hepatic component of CYP2D6-mediated metabolism, but will also lack the right ventricular CYP2D6 expression reported by Thum and Borlak. Thus, both presystemic and target tissue metabolism of most TCAs and antipsychotic drugs will be absent in 5–10% of the population. Reilly and colleagues state that electrocardiographic monitoring is needed in patients taking the aforementioned drugs, “particularly if other risk factors are present”. Although there is no mention in their paper of a pharmacogenetic risk factor, it is quite clear that one does exist. To attenuate the risk of arrhythmia and sudden death in patients taking psychotropic drugs, especially, but not exclusively, those identified by Reilly and colleagues, I urge the long-overdue introduction of pharmacogenotyping4,5 for such patient groups. This procedure was, ironically, in part pioneered in the very same Newcastle department. Perhaps this should be accounted for in any government-led restructuring of the UK National Health Service (NHS), not only for the obvious benefit to patients, but also because of ramifications for health budgets and efficiency. If the NHS does not offer such testing to patients, in time the private sector will surely do so. Jeffrey R Idle Zlatá ul. 34,360 05 Karlovy Vary, Czech Republic (e-mail: [email protected]) 1
2
3
Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet 2000; 355: 979–83. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52. Hadidi H, Güzey C, Idle JR. Pharmacogenetics and toxicological consequences of human drug oxidation and reduction. In: Ballantyne B, Marrs T,
THE LANCET • Vol 355 • May 20, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
advantage of being presented in 20 mg or 30 mg scored tablets so withdrawal programmes are easier to devise. Since patent expiry, fluoxetine is now available in at least 12 generic formats.2 Generic drugs, for licensing purposes, are allowed up to 20% difference in bioequivalence from the brand original.3 Therefore, even patients on continuous therapy, could, if dispensed products emanating from different manufacturers, receive back to back prescriptions where the medicine given varies up to 40% in dose. So, in some cases, we are likely to see discontinuation symptoms in patients still on medication. I recommend that patients receive continuity of supply from the dispenser, with no intermanufacturer switching. I would also recommend that tablets come in a scored formulation so that slow and consistent withdrawal can be followed. Gillian S Wade Celtic Dimensions, Morawelon, Gwynedd LL53 6EB, UK (e-mail: [email protected]) 1
2 3
Young A, Haddad P. Discontinuation symptoms and psychotic drugs. Lancet 2000; 355: 1184. Chem Drug Gener List April–Sept 2000: 25. Generic medicine—can quality be assured? Drug Ther Bull 1997; 35: 9–11.
Fetal surveillance must go on Sir—Few areas of medicine are causing as much concern as that of intrapartum fetal surveillance. Byrony Strachan and colleagues (Feb 5, p 456)1 presented the outcome of a randomised trial of cardiotocography versus cardiotocography plus fetal electrocardiography (ECG) PR-interval analysis. They could not find any difference in outcome between the two groups based on 957 patients. In his commentary Martin Whittle2 suggested that we have seen the end of fetal ECGbased developments because no study has shown improvements in outcome measures of the baby. After more than 25 years of dedicated work, I would agree that improved outcome measures are required and the ECG is the only currently available parameter to allow such a possibility. Some years ago a European Community multicentre study was done to collect fetal ECG data from cases of intrapartum hypoxia. The first report3 focused on changes in P-R and R-R intervals. The study on 618 fullterm fetuses with normal outcome showed that a positive association was
THE LANCET • Vol 355 • May 20, 2000
indicative of a reactive heart rate and accelerations, and that all decelerations were associated with a shortening of the PR interval. Thus, it is not surprising that fetal ECG time constant analysis failed to provide additional information regarding intrapartum hypoxia. The second report4 focuses on ST waveform changes. ST changes were identified automatically by the computer (ST log). All five fetuses with the most striking ST change (a rise in the T:QRS ratio of >0·10 units and lasting more than 10 min) had signs of ongoing intrapartum hypoxia and all six fetuses with evidence of intrapartum asphyxia, showed ST changes. These data are in accordance with those of the Plymouth randomised trial of cardiotocography versus cardiotocography plus ST-interval analysis where, apart from a 46% reduction in operative interventions (p<0·001, OR 1·96 [1·42–2·71]), there was also a trend to less neonatal metabolic acidosis (p=0·09, OR 2·63 [0·93–7·39]) and fewer low 5 min Apgar scores (p=0·12, OR 1·62 [0·92–2·85]).5 The aim of intrapartum fetal surveillance should be to identify fetuses that respond to the hypoxic stress of labour. A cord artery metabolic acidosis cut-off of 7·05 and a base-deficit extracellular fluid concentration of 12 mmol/L seems to be a stringent goal with an incidence of 1·3% in cases where a scalp electrode was applied.5 This means that the 2400 cases included in the Plymouth trial were not sufficient, because 3600 cases would have been required to show a 50% reduction in the number of cases with cord artery pH of less than 7·05 and BDecf of more than 12 mmol/L (=0·20 and ␣=0·05). The aim of a study underway in Sweden is to verify the ability of cardiotocography plus ST-interval analysis so that the incidence of metabolic acidosis can be reduced. Hopefully this trial will provide conclusive evidence of the clinical value of fetal cardiotocographic ECG (ST) analysis during labour. K G Rosén Neoventa Medical, Lilla Bommen 1, SE 411 04 Gothenburg, Sweden 1
2
3
Strachan BK, van Wijngaarden W, Sahota D, Chang A, James DK. Cardiotocography only versus cardiotocography plus PR-interval analysis in intrapartum surveillance: a randomised, multicentre trial. Lancet 2000; 355: 456–59. Whittle M. Is it time to abandon cardiotocographic ECG analysis? Lancet 2000; 355: 422. Luzietti R, Erkkola R, Hasbargen U, Mattson LA, Thoulon JM, Rosen KG. European community multicentre trial “fetal ECG analysis during labour”: the P-R interval. J Perinat Med 1997; 25: 27–34.
4
5
Luzietti R, Erkkola R, Hasbargen U, Mattson L, Thoulon J-M, Rosén KG. European community multi-centre trial “fetal ECG analysis during labour”: ST plus CTG analysis. J Perinat Med 1999; 27: 431–40. Westgate J, Harris M, Curnow JSH, Greene KR. Plymouth randomised trial of cardiotocogram only versus ST waveform plus cardiotocogram for intrapartum monitoring: 2400 cases. Am J Obstet Gynaecol 1993; 169: 1151–60.
Colitis associated with docetaxel-based chemotherapy Sir—Nuhad K Ibrahim and colleagues (Jan 22, p 281)1 report an association of colitis with docetaxel-based chemotherapy in patients with metastatic breast cancer. It is obvious that the chemotherapy regimen used in this phase I study was a dose-intensive one, since it was necessary to use granulocyte-colony-stimulating factor (G-CSF) in a prophylactic manner. The data of this report do not necessarily establish an association between colitis and docetaxel itself, but underline the well-known association between colitis and aggressive chemotherapy resulting in mucositis and neutropenia. Although it is possible that docetaxel may induce more bowel damage than other chemotherapeutic drugs, taxanecontaining polychemotherapy protocols are among the most intensive regimens used for the treatment of breast cancer and may therefore be associated with typhlitis more frequently than others. Unfortunately, the incidence of this complication in patients treated with docetaxel was not given in the paper. There are several reports of typhlitis in patients with breast cancer treated with intensive chemotherapy—eg, carboplatin, cyclophosphamide, and thiotepa given with stem-cell support2 or paclitaxel and doxorubicin given with GCSF support.3 In the latter study, all patients developed typhlitis at the doselevel above the maximum-tolerated dose. On the other hand, typhlitis was already reported in patients with solid tumours in the era before taxanes.4 For typhlitis, the following sequence of events has been proposed: mucosal damage of the bowel; bacterial invasion; increased proliferation of bacteria resulting from decreased immunocompetence (neutropenia); production of bacterial endotoxins; intramural haemorrhage; ulceration; ischaemia; and in some cases necrosis of the bowel wall and perforation.5 Although two of the patients Ibrahim and colleagues report on were not neutropenic when symptoms occurred, these patients clearly had signs of severe bowel damage. Furthermore, the
1823
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
investigators claim that their patients would not fit the classic picture of typhlitis since the onset of symptoms was early after chemotherapy (median, day 8). In previous studies the median timepoint of the onset of symptoms of colitis in patients with breast cancer treated with intensive chemotherapy was also day 8.2,3 We would like to emphasise the importance of neutropenia as a risk for mortality as a result of chemotherapy associated colitis in the series reported by Ibrahim and colleagues, since both patients without neutropenia recovered but two of four patients with neutropenia died. *Orhan Sezer, Jan Eucker, Kurt Possinger
Another study has been reported in which the following regimen was used: docetaxel 60 mg/m2 intravenously and vinorelbine 25 mg/m2 intravenously on days 1 and 15 with G-CSF added only if the patient developed National Cancer Institute grade 3–4 neutropenia. In this report, two toxic deaths were reported as a result of neutropenic enterocolitis.3 Therefore, this phenomenon did not appear to be dose related, and as emphasised, the patient does not necessarily need to be neutropenic to die. Early onset neutropenia and the potential association of death as a complication warrant special attention being paid to this symptom complex.
Universitätsklinikum Charité, HumboldtUniversität, Department of Oncology and Haematology, 10098 Berlin, Germany (e-mail: [email protected])
Nuhad K Ibrahim
1
1
2
3
4
5
Ibrahim NK, Sahin AA, Dubrow RA, et al. Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer. Lancet 2000; 355: 281–83. Boggio L, Pooley R, Roth SI, Winter JN. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transplant 2000; 25: 321–26. Fisherman JS, Cowan KH, Noone M, et al. Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 774–82. Dosik GM, Luna M, Valdivieso M, et al. Necrotizing colitis in patients with cancer. Am J Med 1979; 67: 646–56. Keidan RD, Fanning J, Gatenby RA, Weese JL. Recurrent typhlitis: a disease resulting from aggressive chemotherapy. Dis Colon Rectum 1989; 32: 206–09.
Author’s reply Sir—We agree with the remarks made by Orhan Sezer and Kurt Possinger about the different reports of typhlitis associated with intensive chemotherapy given in doses above the maximum tolerated dose. The median time to onset of symptoms of colitis in intensive chemotherapy was reported on day 8 by Boggio and colleagues1 but none of the chemotherapies were taxane-based. However, in our docetaxel-vinorelbine study, we did not administer doses higher than those recommended for phase II studies, as established by Fumoleau and colleagues.2 In their study, the dose-limiting toxicity was neutropenia and stomatitis. We added G-CSF to lower the risk of neutropenic fever and stomatitis, not to intensify the schedule. Also, the additional three patients on whom we reported used taxanes at or well below the Food and Drug Administration (FDA)-approved doses for those drugs and without cytokine support. None of the patients in our report received chemotherapy at doses higher than those recommended and FDA-approved.
1824
Department of Breast Medical Oncology-56, University of Texas, MD Anderson Cancer Center, Houston, TX 77030-4095, USA
2
3
Boggio L, Pooley R, Roth SI, et al. Typhlitis complicating autologous blood stem cell transplantation for breast cancer. Bone Marrow Transpl 2000; 25: 321–26. Fumoleau P, Fety R, Delecroix V, et al. Docetaxel combined with vinorelbine: phase I results and new study designs. Oncology 1997; 11: 29–31. Gomez-Bernal A, Cruz JJ, Garcia Palomo A, et al. Docetaxel and vinorelbine in patients with metastatic breast cancer after using anthracycline [abstr]. San Antonio Breast Cancer Symposium 1999: 341.
The heart of psychotropic drug therapy Sir—In two consecutive issues, The Lancet has published articles that clearly link CYP2D6 (debrisoquine hydroxylase) and the human heart. First, Thomas Thum and Jürgen Borlak (March 18, p 979)1 reported the expression of several cytochrome P450 (CYP) genes, including CYP2D6, in the right ventricle, and J G Reilly and colleagues (March 25, p 1048)2 noted certain risk factors in psychiatric patients undergoing psychotropic drug therapy. Sadly, the Newcastle group2 seem to have missed this association when they claim that four variables (age over 65 years, the use of tricyclic antidepressants, droperidol, or thioridazine) are significant predictors of rate-corrected QT (QTc)-interval abnormalities, which occurred in 40 (8%) of 495 of their patient group and 23 (8%) of 286, five (11%) of 44, and eight (15%) of 53 of those taking antipsychotic drugs, tricyclic antidepressants (TCAs) alone, and in combination with antipsychotics and TCAs, respectively. I propose that it is compromised metabolism by CYP2D6 that leads to cardiotoxicity in patients taking antipsychotic and antidepressant
drugs. No fewer than eight TCAs and 11 antipsychotic drugs, including thioridazine, are listed as substrates of CYP2D6 by the Human P450 Metabolism Database (http://www. gentest.com/human p450 database/ index.html, accessed April 28, 2000). Droperidol has not, to my knowledge been tested, but a-priori structural chemical considerations3 strongly suggest that it will be a CYP2D6 substrate. 5–10% European populations inherit the CYP2D6 poor metaboliser (PM) phenotype3 putting them at risk of the adverse reactions that arise from the alternative pharmacology of a drug which fails to be metabolised and builds up to abnormally high concentrations in the blood and tissues. It is axiomatic that PMs will not only be missing the hepatic component of CYP2D6-mediated metabolism, but will also lack the right ventricular CYP2D6 expression reported by Thum and Borlak. Thus, both presystemic and target tissue metabolism of most TCAs and antipsychotic drugs will be absent in 5–10% of the population. Reilly and colleagues state that electrocardiographic monitoring is needed in patients taking the aforementioned drugs, “particularly if other risk factors are present”. Although there is no mention in their paper of a pharmacogenetic risk factor, it is quite clear that one does exist. To attenuate the risk of arrhythmia and sudden death in patients taking psychotropic drugs, especially, but not exclusively, those identified by Reilly and colleagues, I urge the long-overdue introduction of pharmacogenotyping4,5 for such patient groups. This procedure was, ironically, in part pioneered in the very same Newcastle department. Perhaps this should be accounted for in any government-led restructuring of the UK National Health Service (NHS), not only for the obvious benefit to patients, but also because of ramifications for health budgets and efficiency. If the NHS does not offer such testing to patients, in time the private sector will surely do so. Jeffrey R Idle Zlatá ul. 34,360 05 Karlovy Vary, Czech Republic (e-mail: [email protected]) 1
2
3
Thum T, Borlak J. Gene expression in distinct regions of the heart. Lancet 2000; 355: 979–83. Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52. Hadidi H, Güzey C, Idle JR. Pharmacogenetics and toxicological consequences of human drug oxidation and reduction. In: Ballantyne B, Marrs T,
THE LANCET • Vol 355 • May 20, 2000
For personal use only. Not to be reproduced without permission of The Lancet.