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Abstract

A. Bouzamondo¹, T. Damy¹, G. Montalescot² and P. Lechat¹

¹Pharmacology Department, and ²Cardiology Department,
Pitié-Salpêtrière Hospital, Paris, France
Objective: Many treatments and procedures have been tested to reduce complications after myocardial infarction. Our objective was to assess in this clinical situation the best evidence-based medicine revascularization strategy including the most recently developed interventions such as thrombolysis, angioplasty, stent implantation and glycoprotein IIb/IIIa (GpIIb/IIIa) antagonists. Material and methods: We performed the meta-analyses of randomized controlled trials by testing the addition of a stent to primary angioplasty, the addition of GpIIb/IIIa antagonists to primary angioplasty, the addition of GpIIb/IIIa antagonists to primary angioplasty + stent and finally addition of GpIIb/IIIa antagonists to thrombolytics. The primary outcome was the combined endpoint of death or myocardial infarction or urgent revascularization at 1 month. Results: The combined endpoint was significantly reduced by 31% (95% CI: 11% – 47%) at 30 days when stent was added to primary angioplasty. GpIIb/IIIa blockers provided an additional benefit by reducing the combined criteria by 50% (95% CI: 27% – 66%) in patients who underwent primary angioplasty, and by 42% (95% CI: 16% – 60%) when associated with angioplasty and stent implantation. Administration of GpIIb/IIIa in addition to thrombolytics, aspirin and heparin was associated with a significant reduction in the combined criteria by 17% (95% CI: 10% – 23%) and a significant excess of major bleeding by 69% (95% CI: 38% – 109%). However, the risk/benefit ratio indicates that patients with this association should be treated with the corresponding doses used in these trials. Conclusion: In acute myocardial infarction, stent implantation provides therapeutic benefit when added to primary angioplasty. The addition of GpIIb/IIIa blockers appears to provide further benefit if bleeding complications are minimized.Correspondence to:
Dr. A. Bouzamondo
Pharmacology Department
Pitié-Salpêtrière Hospital
47, boulevard de l’hôpital
F-75013 Paris, France
Email: anissa.bouzamondo@psl.ap-hop-paris.fr

Abstract

M.M. Engler, M.B. Engler, M. Malloy, E. Chiu, D. Besio, S. Paul, M. Stuehlinger, J. Morrow, P. Ridker, N. Rifai and M. Mietus-Snyder

¹University of California at San Francisco, San Francisco, CA, USA,
²Division of Cardiology, University Clinic of Innsbruck, Innsbruck, Austria, ³Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA, and ⁴Brigham an
Objective: The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated. Methods: In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9 – 19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2’ deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography. Results: FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet. Conclusion: This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.Correspondence to:
Dr. M.M. Engler
Professor and Vice-Chair
University of California, San Francisco
2 Koret Way, Room N631
San Francisco, CA 94143-0610, USA
Email: marguerite.engler@nursing.ucsf.edu

Abstract

J. Bonelli, K. Felsenstein, E.H. Prat and M. Schwarz

Imabe-Institute for Medical Anthropology and Bioethics, Vienna, Austria
Todays evidence-based medicine has brought the practicing physician a vast amount of statistical evidence from which various stakeholders in the healthcare system obtain their arguments for and against the use of new therapies. Physicians assume an obligation to prescribe these new treatment options for their patients, firstly because of their eagerness to provide the best medicine, and secondly because of their fear of litigations. On looking at the published data, however, we have observed that the arguments for saving lives with a new treatment are not always supported by the underlying data. Sometimes the data show that the effect of treatment, in real terms, is only a relatively small gain in lifetime prolongation. It is concluded that EBM-based concepts such as NNT (number needed to treat), absolute risk and relative risk fall short in ensuring real benefit for the patient. We have, therefore, put forward a mathematic model which takes into account the benefit of a treatment for the individual patient in terms of expected gain in lifetime duration. This model is readily applicable to published results on the clinical effects of a medical therapy and gives the practicing physician a useful tool for deciding whether to administer a medical therapy or not. By looking at the duration of treatment and the individual gain in lifetime expected, we have derived an effectiveness coefficient which can be used to categorize medical treatments into highly effective (close to 100%) and not effective (< 5%), and at the same time arrive at a cost-benefit analysis of the treatment in question. These simple concepts will help physicians and individual patients to make informed decisions based only on those medical therapies which are proven and appropriate. The model we have developed provides a new perspective in therapy for the individual patient using medicines that constitute a rational therapy i.e. a therapy that makes “sense” (sense-orientated medicine = SOM).Correspondence to:
Prof. Dr. J. Bonelli
Imabe-Institute for Medical Anthropology and Bioethics
Landstrasser Hauptstrasse 4/13
1030 Vienna, Austria
Email: bonelli@imabe.org

Abstract

S. Malhotra, A. Kondal, N. Shafiq, S. Sidhu, D.K. Bhasin and P. Pandhi

¹Department of Pharmacology and ²Department of Gastroenterology,

Postgraduate Institute of Medical Education & Research, Chandigarh, India
Objectives: To compare the efficacy of heparin in ulcerative colitis (UC) as demonstrated in observational studies and controlled clinical trials. Introduction: Ulcerative colitis (UC) is a chronic condition with a relapsing and remitting course. Several studies have been conducted (observational and controlled clinical trials) to test the usefulness of heparin in this condition but the results of these studies are variable. Some studies demonstrate efficacy while others do not. Methods: We pooled the results of observational studies and clinical trials separately in order to compare the results of observational studies and clinical trials using meta-analysis. With the aid of Medline and a manual search in Index Medicus and cross-references of articles published up to July 2003, we identified studies designed to evaluate the effects of heparin on UC. The pooled cure rate in observational studies was calculated. Results: The results of controlled clinical trials evaluated using meta-analysis showed that the pooled cure rate for observational studies was 87.7% (range 80 – 100). The odds ratio for the controlled trial was 0.34 (95% CI 0.08 – 1.49) using a random effects model and 0.21 (95% CI 0.06 – 1.38) using a fixed effects model. The results of meta-analysis demonstrate a non-significant effect of heparin in controlled clinical trials. Conclusion: The findings of the clinical trials differ markedly from observational studies and indicate a lack of efficacy of heparin in patients with ulcerative colitis.Correspondence to:
Dr. (Prof.) P. Pandhi
Head of the Department
Department of Pharmacology
Postgraduate Institute of Medical Education & Research
Chandigarh – 160012, India
Email: ppandhi17@hotmail.com

Abstract

A.O. Mück, H. Seeger and D. Wallwiener

Section of Endocrinology and Menopause, University Women’s Hospital, Tübingen, Germany
Objective: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature. Methods: In the present study, the effect of two statins on the proliferation of breast cancer cells in the presence and absence of estradiol was investigated. Results: Atorvastatin and fluvastatin were able to inhibit the proliferation of MCF-7 cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect which may be mediated by the down-regulation of the anti-apoptotic protein Bcl-2 rather than up-regulation of Fas-L or p53. However, in the presence of estradiol the inhibitory effect of the statins was less pronounced. Conclusions: The present data indicate that statins may possess anticancerogenic properties concerning the development of breast cancer in postmenopausal women. Clinical trials are necessary to prove a beneficial statin effect on breast cancer risk when combined with long-term hormone therapy.Correspondence to:
Dr. A.O. Mück
Section of Endocrinology and Menopause
University Women’s Hospital
Calwerstraße 7
72076 Tübingen, Germany
Email: endo.meno@med.uni-tuebingen.de

Abstract

N.L. Dirks, B. Huth, C.R. Yates and B. Meibohm

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, USA
Despite recent advancements in solid organ transplantation, African-American renal allograft recipients continue to exhibit poorer prognosis in long-term clinical outcome and graft survival compared to Caucasian patients. The role of immunosuppressants in post-transplant outcome is crucial, and associations between exposure-related pharmacokinetic parameters and clinical outcome have been made for several drugs in this class. Thus, ethnic differences in the pharmacokinetics of immunosuppressants are potentially a key factor in the observed differences in post-transplant outcome between African-Americans and Caucasians. Ethnic differences in pharmacokinetics of mycophenolate mofetil and azathioprine based on the current literature are either absent or only of minor relevance. Cyclosporine, tacrolimus, sirolimus and everolimus, however, have all been described to exhibit ethnicity-specific differences in bioavailability and/or dose-adjusted systemic exposure, although currently available reports are controversial for some of these drugs. Oral bioavailability of these drugs in African-Americans was between 20 and 50% lower than in Caucasians or Non-African-Americans, leading to higher dose requirements in African-Americans to maintain similar average concentrations of the respective immunosuppressant. Since all four drugs undergo extensive metabolism and are substrates for CYP3A isoenzymes as well as the drug transporter P-glycoprotein, interethnic variability in activity of these enzymes/transporter may provide a common mechanism for the observed ethnic differences. These ethnic differences are most likely mediated via several non-genetic as well as genetic factors, including known genetic variations that impair transporter/enzyme activity in genes such as CYP3A4, CYP3A5 and ABCB1 (MDR1). Appreciation of differences in immunosuppressant pharmacokinetics and dose requirements between African-Americans and Caucasians in clinical practice is expected to improve post-transplant immunosuppressive pharmacotherapy and may thus contribute to equalize prognostic outcome for all transplant patients.Correspondence to:
Dr. B. Meibohm
Department of Pharmaceutical Sciences
College of Pharmacy
The University of Tennessee Health Science Center
874 Union Avenue, Suite 5p
Memphis, TN 38163, USA
Email: bmeibohm@utmem.edu

Abstract

H.M. James, J.K. Coller, D. Gillis, J. Bahnisch, B.C. Sallustio and A.A. Somogyi

¹Division of Human Immunology, Institute of Medical and Veterinary Science, Adelaide, ²Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, ³Department of Cardiology and Clinical Pharmacology, The Queen Elizabeth Hospita
Aim: To establish a method suitable for diagnostic genotyping of CYP2D6 alleles by DNA sequencing. Methods: Initial PCR reactions were performed to specifically amplify exons 3, 4, 5 and 6 of the CYP2D6 gene using primers previously published. New primers were used to identify *2, *3, *4, *6, *7, *8, *9 and *41 in 2 sequencing reactions. Additional primers were designed for reverse sequencing in samples with 1 or 3 b.p. deletions. Previously published assays were used to detect *5, *10 and *16 alleles to complete genotype assignment. Results: We reliably detected the nonfunctional alleles, *3, *4, *6, *7 and *8, which are associated with the poor metabolizer phenotype, and 2 important alleles associated with decreased enzyme activity, *9 and *41. Observed allele frequencies were comparable to those found previously in Caucasian populations. Conclusion: CYP2D6 genotype has been shown in previous clinical studies to be a good predictor of CYP2D6 phenotype and, therefore, related to therapeutic response and the risk of drug toxicity. This genotyping method is simple and reliable, and, therefore, can be routinely performed on an isolated patient sample, providing a relatively quick turnaround time needed for clinical practice. In addition, the simultaneous drawing of blood with the commencement of drug therapy will allow dosage adjustment on the basis of the CYP2D6 genotype to reduce the risk of adverse drug reactions.Correspondence to:
Ms H.M. James Division of Human Immunology Institute of Medical and Veterinary Science PO Box 14 Rundle Mall Adelaide SA 5000, Australia
Email: heather.james@imvs.sa.gov.au

Abstract

R. Waschgler¹, W. Moll¹, P. König² and A. Conca²

¹Medical Central Laboratory, Feldkirch, and ²Department of Psychiatry I, Regional Hospital Rankweil, Rankweil, Austria
We describe an isocratic reversed-phase liquid chromatographic method for the determination of venlafaxine (VLX) and its main active metabolite O-desmethylvenlafaxine (ODV) in serum, using haloperidol as internal standard and liquid/liquid extraction for sample preparation. VLX and ODV were separated on a C18 column with a mobile phase of acetonitrile/buffer (30/70, v:v) at 60 °C and a flow rate of 1.5 ml/min. The measurement of the native fluorescence signals of the eluted compounds were carried out at 227/300 nm (excitation/emission) without interference from endogenous components in serum. High linearities for VLX and ODV for concentrations between 20 and 500 mg/l were obtained (r = 0.9997). A large spectrum of routinely prescribed drugs did not interfere in the assay. The coefficients of variation for repeatability varied between 5.40% and 5.99% and for reproducibility between 9.43% and 21.63%. Absolute recoveries were more than 52% for both substances.Correspondence to:
R. Waschgler

Medical Central

Laboratory, Toxicology

Carinagasse 41

A-6800 Feldkirch, Austria
Email: rwaschgler@mzl.at

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Volume 42, No. 12/2004(December)