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Re: Establishment of PK/PD model to help identify potential therapeutic failure in clopidogrel thera
Re: CYP3A5 non-expressor genotype a risk factor for clopidogrel cessation atherothrombotic events
CYP3A5 non-expressor genotype a risk factor for clopidogrel cessation atherothrombotic events?
Establishment of PK/PD model to help identify potential therapeutic failure in clopidogrel therapy
We need clinical tool in bedside evaluating drug efficacy.
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Hyo-Soo Kim Seoul National University Hospital
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hyosoo{at}snu.ac.kr Hyo-Soo Kim
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Authors : Jung-Won Suh (1, 2), Bon-Kwon Koo (1, 2) and Hyo-Soo Kim(1, 2) 1) Cardiovascular Center, Seoul National University Hospital; 2) Department of Internal Medicine, Seoul National University College of Medicine We thank Dr Guirguis for the valuable comment on our paper. As we mentioned as one of limitations in the 'interpretation' section, we did not assay the active metabolite of clopidogrel directly, and a platelet aggregation test with ADP was performed and used as an indirect marker of the active clopidogrel metabolite, as done by previous investigators. Therefore, we cannot rule out the involvement of other factors between the interaction of the active metabolite and the platelet ADP receptor. We totally agree with Dr Guirguis that pharmacokinetics (PK)/ pharmackdynamics (PD) data are important to confirm the individual variation of clopidogrel metabolism. However, PK/PD analysis has not been established at present due to the difficulty in assaying the metabolite of clopidogrel. Some researchers are actively investigating the clopidogrel metabolism using various methods(1-3) and we are looking forward to applying these to the clinical studies in near future. 1.Taubert D, Kastrati A, Harlfinger S, Gorchakova O, Lazar A, von Beckerath N, Schomig A, Schomig E. Pharmacokinetics of clopidogrel after administration of a high loading dose. Thromb Haemost 2004;92:311-6. 2.Ksycinska H, Rudzki P, Bukowska-Kiliszek M. Determination of clopidogrel metabolite (SR26334) in human plasma by LC-MS. J Pharm Biomed Anal. 2006;41:533-9. 3.Souri E, Jalalizadeh H, Kebriaee-Zadeh A, Shekarchi M, Dalvandi A. Validated HPLC method for determination of carboxylic acid metabolite of clopidogrel in human plasma and its application to a pharmacokinetic study. Biomed Chromatogr. 2006, in press. Conflict of Interest:None declared |
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Hyo-Soo Kim Seoul National University Hospital
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hyosoo{at}snu.ac.kr Hyo-Soo Kim
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Authors: Jung-Won Suh (1, 2), Bon-Kwon Koo (1, 2) and Hyo-Soo Kim(1, 2) 1) Cardiovascular Center, Seoul National University Hospital; 2) Department of Internal Medicine, Seoul National University College of Medicine We deeply appreciate the comment of McLachlan CS, et al. They suggested the possibility of rebound atherothrombotic events after cessation of clopidogrel in susceptible patients like CYP3A5 non-expressors. Our data showed that CYP3A5 non-expressors had more atherothrombotic events and events after one month occurred only in CYP3A5 non-expressors. However, all patients who had atherothrombotic events after 1 month had been taking both clopidogrel and aspirin at the time of events. Therefore, our data do not support the concept that CYP3A5 non-expressors would be more vulnerable to the risk of atherothrombotic events after cessation of clopidogrel. However, it is possible that these patients are more sensitive to rebound effects on platelet aggregation in the setting of CYP3A4 inhibition. The issue suggested by McLachlan CS, et al seems to be very important and further studies are needed. Conflict of Interest:None declared |
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Craig S McLachlan Department of Physiology, National University of Singapore
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reperfusion{at}hotmail.com Craig S McLachlan
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Authors: Craig S McLachlan(1,3), Stacey KH Tay(2,3), Zakaria Almsherqi(1) and Shu-Hui Chia(1) 1)Department of Physiology, National University of Singapore; 2)Department of Paediatrics, National University of Singapore 3)Genetic Medicine Group, Center for Molecular Medicine, A*STAR, Singapore. We read with interest the recent study by Suh et al (1), where the investigators show an increased risk of atherothrombotic events 1-month to 6-months post coronary bare metal stenting in a sub-set of patients with the CYP3A5 non-expressor genotype. Importantly, we note that these atherothrombotic events only occurred after the cessation of clopidogrel. Extensive clinical trial data shows that combined thienopyridines and aspirin are beneficial in patients undergoing bare-metal stent implantation, and effective after drug-eluting stent implantation (2). However, with in a sub-population of patients taking clopidogrel there is increasing concern over “hyper” or rebound effects on platelet aggregation following acute cessation of thienopyridines (2). The mechanism for this rebound effect / observation has not yet been identified. A recent study by Angiolillo et al (3) showed that clopidogrel withdrawal is associated with an increase in platelet and inflammatory biomarkers in diabetic patients. In summary we interpret the study by Suh et al as confirming the increased risk of late atherothrombotic events when premature withdrawal of thienopyridines occurs, with the additional finding that cytochrome P450 3A5 polymorphism may be a risk factor or biomarker for the “rebound” clopidogrel withdrawal effect. Additionally, the continued administration of aspirin does not always prevent a rebound clopidogrel withdrawal effect (4). Finally, one needs to also consider aspects of aspirin resistance, and prior aspirin-clopidogrel interactions in atherothrombotic events following clopidogrel withdrawal (4, 5). 1. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ, Lee DS, Sohn DW, Lee MM, Kim HS. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ. 2006 Jun 6;174(12):1715-22. 2. Biondi-Zoccai GG, Agostoni P, Sangiorgi GM, Iakovou I, Antoniucci D, Grube E, Tamburino C, Di Mario C, Reimers B, Michev I, Goktekin O, Airoldi F, Chieffo A, Cosgrave J, Tassanawiwat W, Colombo A; TRUE (Taxus in Real-Life Usage Evaluation) Study Investigators. Comparison of ticlopidine vs. clopidogrel in addition to aspirin after paclitaxel-eluting stent implantation: insights from the TRUE (Taxusin Real-life Usage Evaluation) Study. Int J Cardiol. 2006 Apr 14;108(3):406-7. 3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006 Mar;55(3):780-4. 4. Jimenez-Quevedo P, Angiolillo DJ, Bernardo E, Sabate M. Late stent thrombosis (> 1 year) following clopidogrel withdrawal after brachytherapy treatment: need to assess aspirin resistance? Catheter Cardiovasc Interv. 2004 May;62(1):39-42. 5. Almsherqi ZA, McLachlan CS, Sharef SM. More on: enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized cross-over trial. J Thromb Haemost 2006; 4: 1–2. DOI: 10.1111/j.1538-7836.2006.01926.x. Conflict of Interest:None declared |
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Micheal Guirguis Covance Labs
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mguirgui{at}hotmail.com Micheal Guirguis
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In their article of June 6, 2006, Suh et. al. observed failures in clopidogrel therapy in patients with the CYP3A5 non-expressor genetopye (*3 allele). As clopidogrel is a prodrug, a reduction in drug effectiveness with reduced parent metabolism is a reasonable hypothesis. Unfortunately the lack of any concentration data (either parent or metabolite) precludes its confirmation. With no clopidogrel pharmacokinetics data, the failures in clopidogrel therapy observed by Suh et. al. can not be linked to a change in clopidogrel metabolism or in CY3A activity. In the future an examination of these significant observations should include concentration data to confirm a change in clopidogrel pharmacokinetics and establish a pharmacokinetic/pharmacodynamic (PK/PD) model. A PK/PD study in a pharmacogenomicly diverse population, would determine the impact of the CYP3A5 non-expressor genetopye (*3 allele) on clopidogrel PK/PD. Once a clopidogrel PK/PD model is established, clinicians may be able to quickly determine if additional anti-platelet therapy is needed with a single blood draw.
Conflict of Interest:None declared |
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Sergio Stagnaro Biophysical Semeiotics Research Laboratory
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dottsergio{at}semeioticabiofisica.it Sergio Stagnaro
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Sirs, regarding the paper CMAJ • June 6, 2006; 174 (12). doi:10.1503/cmaj.060664.Research Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel Jung-Won Suh, Bon-Kwon Koo, Shu-Ying Zhang, Kyung-Woo Park, Joo-Youn Cho, In-Jin Jang, Dong-Soon Lee, Dae-Won Sohn, Myoung-Mook Lee and Hyo-Soo Kim, we need clearly usefull clinical tool, reliable in bedside assessing both vessel disorders, even silent, like CAD, and drug efficacy, wich can be applied on very large scale without great expense. The method suggested by the authors is really complicated, expensive and not suitable for large population. On the contrary,in following, I suggest an useful, reliable and easy clinical manoeuvre, that allows doctor to recognize, for instance, both CAD Real Risk and silent CAD, and allows the objective monitoring under treatment (1-3). This brief clinical procedure proved to be really useful in my 50-year- long clinical experience, also in order to bed-side recognizing heart ischaemic disease before cardiac pathology occurs. Moreover, it is well known that patients with coronary artery disease (CAD) may have no symptoms at all for many years or decades and that the electrocardiographic features of ischaemia may be induced by exercise without accompaning angina (1). (For further information: See web site http://www.semeioticabiofisica.it, Practical Applications; Bibliography). In other words, we have to utilize a clinical tool reliable in rapid detecting CAD, even clinically silent, initiating from CAD “real risk”, doctor can now utilize in his day-to-day practice (1). In addition, such as tool plays a pivotal role in therapeutic monitoring. Surely one among these methods is "Myocardial Ischaemic Biophysical- Semeiotic Preconditioning", described elsewhere(1-3). From the tehnical viewpoint, doctor has to know, at least, the auscultatory percussion of the stomach, described even in old acŕdemic books of two last centuries (Rasario IX edition). Briefly, in healthy individuals, digital pressure of mean intensity, applied upon heart cutaneous projection area, brings about the so-called gastric aspecific reflex (= in the stomach, fundus and body are dilated; on the contrary, antral-pyloric region contracts) after an age-dependent latency time of 8 sec., that lasts less than 4 sec. (= parameter value of paramount significance since it parallels the efficicacy of coronary microvessel Microcirculatory Funcional Reserve). A second, successive evaluation after an interval of 5 sec. exactly, provokes the identical reflex, but after lt. of 12 sec. or more: physiological myocardial preconditioning, typeI. On the contrary, in patients involved by CAD, even silent, i.e. subclinical,latency time persists identical in both evaluations, or results clearly lower in the second one, in relation with disease seriousness: type II and respectively type III precosnditioning. Of course, biophysical semeiotic preconditioning evaluation, really more complex than it appears in the above brief description, can be applied to all others biological systems, with favourable influences on primary prevention and diagnosis (1-5). As a consequence, usefull and efficacious CAD therapy shows ameliorating of heart preconditioning. 1) Stagnaro-Neri M., Stagnaro S. Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of Ischaeemic Heart Disease even silent. Acta Medica Mediterranea 13, 109-116, 1997. 2) Stagnaro S. A clinical efficacious maneouvre, reliable in bed-side diagnosing coronary artery disease, even initial or silent, as well as "heart coronary risk". 3rd Virtual International Congress of Cardiology, FAC,2003, http://www.fac.org.ar/tcvc/marcoesp/marcos.htm 3) Stagnaro Sergio.Biophysical Semeiotic Constitutions, Genomics, and Cardio-Vascular Diseases. BMC Cardiovascular Disorders, 2004, http://www.biomedcentral.com/1471-2261/4/20/comments#95454 4) Stagnaro Sergio Endothelial cell function can ameliorate under safer drugs, such as Melatonin-Adenosine. BMC Cardiovascular disorders. 2004 http://www.biomedcentral.com/1471-2261/4/4/comments 5) Stagnaro S. Pre-Metabolic Syndrome: Locus primary prevention. NYAS web site. 1999 http://www.memberconnections.com/olc/membersonly/NYAS/mboards.html Conflict of Interest:None declared |
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