Übersicht wichtiger Publikationen
- Monographie: Trockenextrakt (35-67:1) aus Ginkgo-biloba-Blättern, extrahiert mit Aceton-Wasser
Auszug aus der im Bundesanzeiger Nr. 133 vom 19.7.1994 publizierten Monographie der Kommission E des Bundesgesundheitsamtes (heute: BfArM)
- Welche Inhaltsstoffe von Ginkgo-Extrakt üben neuroprotektive Effekte aus?
Tierexperimentelle und in vitro-Untersuchungen der Universität Marburg
(Quelle: Josef Krieglstein, Franz Ausmeier, Hanan El Abhar, Klaus Lippert, Matthias Welsch, Katrin Rupalla, Petra Henrich-Noack:
Neuroprotective effects of Ginkgo biloba constituents. European
Journal of Pharmaceutical Sciences 3 1995: 39-48)
- Demenztherapie: Ginkgo-Spezialextrakt EGb 761 verbessert die kognitiven Fähigkeiten und die Alltagskompetenz signifikant
Eine placebokontrollierte Doppelblindstudie mit 327 Demenzpatienten, die am New York Institute for Medical Research über einen Zeitraum von 52 Wochen durchgeführt wurde (Quelle: P. L. Le Bars et al: A Placebo-Controlled, Double-blind,
Randomized Trial of an Extract of Ginkgo Biloba for Dementia. JAMA, October 22/29, 1997 – Vol. 278, 1327-1332)
- Ginkgo-Extrakt hemmt die neuronale Apoptose
Eine Untersuchung an Nervenzellen, durchgeführt an der Universität
(Quelle: B. Ahlemeyer, A. Möwes, Josef Krieglstein: Inhibition of serum depriviation- and staurosporin-induced neuronal apoptosis by ginkgo biloba extract and some of its constituents. European Journal of Pharmacology 367 1999: 423-430)
- Pharmakologische Wirkungen von Ginkgo biloba
Eine Übersicht der bisher publizierten klinisch-pharmakologischen Untersuchungen
(aus: Ginkgo biloba: Müller, W.E., Juretzek, W. in Neuro- Psychopharmaka, Bd. 5, 2. Auflage. Riederer P., Laux G., Pöldinger W. (Hrsg.), Springer Verlag Wien 1999)
- Vergleich der klinischen Wirksamkeit von Ginkgo-Spezialextrakt EGb 761 mit Acetylcholinesterase-Hemmern
Eine vergleichende Analyse der wichtigsten placebokontrollierten Doppelblindstudien von Antidementiva (Quelle: A. Wettstein: Cholinesterasehemmer und Ginkgoextrakte – in der Demenztherapie vergleichbar?
Fortschritte der Medizin 117. Jhg., Originalien Nr. 1, 1999, 11-18)
- Ginkgo-Spezialextrakt EGb 761: Wirksamkeit bei Demenzerkrankungen placebokontrolliert belegt
Eine placebokontrollierte Doppelblindstudie der Abteilung für Gerontopsychiatrie der Freien Universität Berlin mit 216 Patienten
(Quelle: S. Kanowski, W. M. Herrmann, K. Stephan, W. Wierich, R. Hörr: Proof of Efficacy of the Ginkgo Biloba Special Extract EGb 761 in Outpatients Suffering from Mild to Moderate Primary Degenerative Dementia of the Alzheimer Type or Multi-infarct Dementia.
Pharmacopsychiat. 29, 1996: 47-56; Ginkgo biloba Extract EGb 761 in Dementia: Intent-to-treat Analyses of a 24-week, Multi-center, Double-blind, Placebo-controlled, Randomized Trail. Pharmacopsychiat. 2003; 36: 297-303)
Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial.
PURPOSE: Medical therapies for treatment of peripheral artery disease (PAD) are limited. Ginkgo biloba has been reported to increase maximal and pain-free walking distance among patients with PAD; however, the evidence is inconsistent. The objective of this study was to compare the effects of 300 mg/d of Ginkgo biloba (EGb 761) versus placebo on treadmill walking time and related cardiovascular measures among patients with PAD. METHODS: A double-blind, placebo-controlled, parallel design trial with a 4-month duration was used. Participants were 62 adults, aged 70 +/- 8 years (mean +/- SD), with claudication symptoms of PAD. The primary study outcomes were maximal and pain-free walking time on a treadmill. Secondary outcomes included flow-mediated vasodilation, a measure of antioxidant status as assessed by determining antibody levels to epitopes of oxidized low-density lipoprotein, and questionnaires addressing walking impairment and quality of life. RESULTS: Maximal treadmill walking time increased by 20 +/- 80 and 91 +/- 242 seconds in the placebo and the EGb 761 groups, respectively (P = .12). Pain-free walking time increased by 15 +/- 31 and 21 +/- 43 seconds, respectively (P = .28). No significant differences were detected between groups for any of the secondary outcomes. CONCLUSIONS: In older adults with PAD, Ginkgo biloba produced a modest but insignificant increase in maximal treadmill walking time and flow-mediated vasodilation. These data do not support the use of Ginkgo biloba as an effective therapy for PAD, although a longer duration of use should be considered in any future trials.
Stanford Prevention Research Center, Stanford University Medical School, Stanford, California 94305, USA. email@example.com
(Quelle: Gardner CD, Taylor-Piliae RE, Kiazand A, Nicholus J, Rigby AJ, Farquhar JW, J Cardiopulm Rehabil Prev., 2008 Jul-Aug; 28(4):258-65.)
External validity of clinical trials for treatment of dementia with ginkgo biloba extracts.
OBJECTIVES : Ginkgo bilobaextracts have been applied in the treatment of dementia of vascular origin and Alzheimer disease for a long time. However, in the most elaborated systematic review to date, Birks and colleagues drew quite a moderate conclusion in spite of the overall positive results. The reason for such a moderate interpretation often lies in the preference of internal validity such as randomisation and blinding, sometimes at the expense of external validity (conditions of everyday practice). Because of this, we analysed the clinical trials evaluated by Birks et al. in the light of the following questions: 1) To what extent are criteria of external validity considered? 2) Does the additional evaluation of external validity lead to differences in the estimation of efficacy? 3) What are the results of our analysis in regard to the efficacy of ginkgo biloba extract? MATERIAL AND METHODS : The selection of the clinical trials was based upon those included in the review carried out by Birks et al. (2002). The criteria for evaluating external validity were developed by consulting physicians specialised in geriatrics, experts in herbal pharmaceutics and affected/ related individuals (patients and relatives). RESULTS : We analysed 34 placebo-controlled clinical trials with a total of 37 comparisons. 21 trials showed significant results in favour of the ginkgo application in more than 50% of investigated outcome parameters, eight were significant for less than 50% of the parameters, four showed a trend in favour of ginkgo, and only two studies (with 4 comparisons) found no advantage for ginkgo. One of these negative studies used daily doses far below the usual dose range [corrected] We found no evidence for publication bias. None of the studies considered all criteria of external validity. Out of the seven studies with relatively high external validity and good overall quality, five showed a significant result in more than 50% of parameters, two in < or = 50%. Severe adverse effects were not mentioned in the studies. DISCUSSION AND CONCLUSIONS : 1) In the clinical studies analysed external validity was taken into account only moderately, especially with respect to additional non-pharmaceutical interventions and selection of participants. 2) The evaluation according to external validity led to a different selection of studies that were used for estimation of the ginkgo efficacy without effects on the overall result. 3) Sufficient evidence of the efficacy of ginkgo bilobaextracts in the treatment of dementia of vascular origin and Alzheimer disease is provided in spite of methodological limitations. Further studies should focus on effectiveness, ginkgo-sensitive subgroups, more individualised therapeutic goals and corresponding outcome measurements.
Lehrstuhl für Medizintheorie und Komplementärmedizin der Universität Witten/Herdecke, Gerhard-Kienle-Weg 4, 58313, Herdecke, Germany. firstname.lastname@example.org
(Quelle: Bornhöft G, Maxion-Bergemann S, Matthiessen PF, Z Gerontol Geriatr., 2008 Aug;41(4):298-312. Epub 2008 Mar 11. Erratum in: Z Gerontol Geriatr. 2008 Aug;41(4):313.)
Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects.
Objective: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (Pgp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.
Methods: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and Pgp activity, respectively.
Results: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC0–∞ and Cmax by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.
Conclusions: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir’s potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.
(Quelle: Robertson SM, Davey RT, Voell J, Formentini E, Alfaro RM, Penzak SR., Curr Med Res Opin., 2008 Feb;24(2):591-9.)
Modulation of cognitive performance following single doses of 120 mg Ginkgo biloba extract administered to healthy young volunteers.
Previous research from our laboratory demonstrated that administration of single doses (120, 240, 360 mg) of standardised Ginkgo biloba extract (GBE) had linear, dose-dependent, positive effects on the speed of performing attention tasks in comparison to placebo. However, whilst the lowest dose, which is typical of a recommended daily dose, had no effect on the speed of attention task performance it did engender mild improvements in secondary memory performance. The current study presents a reanalysis of data from three methodologically identical studies that each included a treatment of 120 mg GBE and matched placebo.All three studies were of a multiple dose, placebo-controlled, double-blind, balanced-crossover design, employing four or five treatment arms in total. Across the studies 78 healthy young participants received 120 mg GBE and placebo in randomly counterbalanced order, separated by a wash-out period of at least 7 days. On each study day participants’ performance on the Cognitive Drug Research (CDR) computerised cognitive assessment battery was measured immediately prior to dosing and at 1, 2.5, 4 and 6 hr following treatment, with scores collapsed into the six measures (speed of attention, accuracy of attention, secondary memory, working memory, speed of memory, quality of memory) which have previously been derived by factor analysis of the data from CDR subtests.The results showed that 120 mg of Ginkgo engendered a significant improvement on the ‘quality of memory’ factor that was most evident at 1 and 4 hr post-dose, but had a negative effect on performance on the ‘speed of attention’ factor that was most evident at 1 and 6 hr post-dose.The current study confirmed the previous observation of modestly improved memory performance following 120 mg of GBE, but suggests that acute administration of this typical daily dose may have a detrimental effect on the speed of attention task performance which is opposite to that seen previously following higher doses.
Human Cognitive Neuroscience Unit, Division of Psychology, Northumbria University, Newcastle upon Tyne, UK. email@example.com
(Quelle: Kennedy DO, Jackson PA, Haskell CF, Scholey AB., Hum Psychopharmacol., 2007 Dec;22(8):559-66.)
Ginkgo biloba for cognitive impairment and dementia.
BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals. OBJECTIVES: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline. SEARCH STRATEGY: Trials were identified on 10 October 2006 through a search of the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register which contains records from all main medical databases (MEDLINE, EMBASE, CINAHL, PsycINFO, SIGLE, LILACS), from ongoing trials databases such as Clinicaltrials.gov and Current Controlled Trials and many other sources. The search terms used were ginkgo*, tanakan, EGB-761, EGB761, “EGB 761” and gingko*. SELECTION CRITERIA: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity. DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated. MAIN RESULTS: Clinical global improvement as assessed by the physician, was dichotomized between participants who showed improvement or were unchanged and those who were worse. There are benefits associated with Ginkgo (dose greater than 200 mg/day) at 24 weeks (207/276 compared with 178/273, OR 1.66, 95% CI 1.12 to 2.46, P=.001) (2 studies), but not for the lower dose. Cognition shows benefit for Ginkgo (any dose) at 12 weeks (SMD -0.65, 95% CI -1.22 to -0.09 P=0.02, 5 studies) but not at 24 weeks.Five studies assessed activities of daily living (ADLs), using different scales. Some scales are more comprehensive than just ADLs. The results show benefit for Ginkgo (dose less than 200 mg/day) compared with placebo at 12 weeks (MD -5.0, 95% CI -7.88, -2.12, p=0.0007, one study), and at 24 weeks (SMD -0.16, 95% CI -0.31 to -0.01, p=0.03, 3 studies) but there are no differences at the higher dose. No study assessed mood and function separately, but one study used the ADAS-Noncog, which assesses function over several domains, but not cognitive function. There was no difference between Ginkgo and placebo.There are no significant differences between Ginkgo and placebo in the proportion of participants experiencing adverse events. There are no data available on Quality of Life, measures of depression or dependency. AUTHORS’ CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. The evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing.
University of Oxford, Nuffield Department of Clinical Medicine, CDCIG Room 5802, John Radcliffe Hospital, Oxford, UK, OX3 9DU. firstname.lastname@example.org
(Quelle: Birks J, Grimley Evans J., Cochrane Database Syst Rev., 2007 Apr 18;(2):CD003120.)
Statement to the preliminary report of the IQWiG A05-19B ginkgo-containing preparation at Alzheimers dementia.
Klinik für Geriatrie, Krankenhaus Lindenbrunn, Lindenbrunn 1, 31863, Coppenbrügge, Germany. email@example.com
(Quelle: Gogol M, Lüttje D, Sieber C, Werner H., Z Gerontol Geriatr., 2007 Aug;40(4):282-4.)
Influence of Ginkgo biloba on ocular blood flow.
PURPOSE: To investigate the effect of Ginkgo biloba extract (EGb761) on ocular blood flow. METHODS: This randomized, double-masked, placebo-controlled, two-way crossover study included 15 healthy male volunteers. Measurements were taken with laser Doppler flowmetry, laser Doppler velocimetry, a retinal vessel analyser, laser interferometry and applanation tonometry, before and up to 3 hours after oral intake of 240 mg EGb761. RESULTS: At baseline, no significant differences in ocular and systemic haemodynamic parameters were observed between the two study days. Ginkgo biloba significantly decreased retinal venous diameters (p < 0.05 versus baseline), but there was no significant difference between the two groups. Blood pressure, retinal arterial and venous diameters, choroidal blood flow, fundus pulsation amplitude, intraocular pressure and retinal blood flow remained unchanged in both groups and did not differ between groups. Optic nerve head blood flow significantly increased in response to Ginkgo biloba (p < 0.002 versus baseline), but this effect was not significant compared with that of placebo. CONCLUSIONS: The results of this study indicate that a single administration of Ginkgo biloba does not influence ocular blood flow to a relevant degree. Whether the drug may influence ocular blood flow in patients with ocular vascular disease after longterm treatment remains to be investigated in a randomized, placebo-controlled clinical trial.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Quelle: Wimpissinger B, Berisha F, Garhoefer G, Polak K, Schmetterer L., Acta Ophthalmol Scand., 2007 Jun;85(4):445-9. Epub 2007 Feb 27.)
Special ginkgo extract in cases of vertigo: a systematic review of randomised, double-blind, placebo controlled clinical examinations.
BACKGROUND: The concept for the medical treatment of vertigo has changed over the last 30 years due to recognition of the dependence of the vertiginous sensation on vestibular compensation and the dependence of vestibular compensation on the state of vigilance. METHODS: In this systematic review, experimental studies of the influence of the special ginkgo extract EGb 761 on vestibular compensation in animals and randomized, double-blind clinical studies of EGb 761 in vestibular and non-vestibular vertigo are described and critically evaluated. RESULTS: The beneficial effect of EGb 761 on vestibular compensation has been demonstrated in preclinical and clinical studies. CONCLUSION: Evidence of the efficacy of EGb 761 for the treatment of vertiginous syndromes is presented in the available studies.
HNO-Klinik, Klinikum rechts der Isar, München. firstname.lastname@example.org
(Quelle: Hamann KF, HNO, 2007 Apr;55(4):258-63.)
The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs.
BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined. PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society’s perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted. RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis. RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.
Institut für Empirische Gesundheitsokonomie, Burscheid.
(Quelle: Heinen-Kammerer T, Motzkat K, Daniel D, Gertz HJ, Koller M, Lorenz W, Pilartz H, Zimmer B, Habs M, von den Driesch V, Rychlik R., MMW Fortschr Med., 2005 Oct 6;147 Suppl 3:127-33)
Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers.
During recent years, several case reports have been published in which the authors have voiced their suspicion of a causal relationship between hemorrhagic complications and the intake of Ginkgo biloba preparations. Therefore, a trial was conducted to investigate the influence of Ginkgo biloba special extract EGb 761 on hemostasiological parameters. Fifty healthy, male volunteers underwent 7 days of crossover treatment with 2 x 120 mg/day EGb 761 and placebo in randomized sequence. Between the two treatment phases, a washout-period of at least 3 weeks was inserted. The study’s main outcome measures were bleeding time, coagulation parameters, platelet activity in response to various agonists and platelet morphology. The equivalence of the two treatments was analyzed by computing the 90% Fieller confidence intervals for the ratio between the means of the pre-post treatment differences for EGb 761 and placebo, respectively. Treatment safety was investigated by clinical laboratory and vital signs assessment and by adverse events monitoring. Among the 29 coagulation and bleeding parameters assessed, none showed any evidence of an inhibition of blood coagulation and platelet aggregation through EGb 761. Furthermore, the study did not reveal any evidence to substantiate a causal relationship between the administration of EGb 761 and hemorrhagic complications. As regards treatment tolerability, there were no interpretable differences between EGb 761 and placebo except for a slight increase of gastrointestinal complaints during administration of the herbal extract.
Clinical Research Department, Dr Willmar Schwabe Pharmaceuticals, 76227 Karlsruhe, Germany. email@example.com
(Quelle: Kohler S, Funk P, Kieser M., Blood Coagul Fibrinolysis, 2004 Jun;15(4):303-9)
Effects of Ginkgo biloba on mental functioning in healthy volunteers.
BACKGROUND: There has been a lack of investigations examining the effects of Ginkgo biloba extract EGb 761 on mental functions and quality of life in healthy subjects with no cognitive impairment. Thus, the objective of the present study was to evaluate the relatively short-term (i.e., 4 weeks) effects of EGb 761 on mental functioning and quality of life in healthy volunteers. METHODS: The trial was conducted as a 4-week, randomized, double-blind, placebo-controlled, parallel-group, monocentric study. Sixty six healthy volunteers aged between 50 and 65 years without age-associated cognitive impairment were randomized, 32 into the placebo and 34 into the EGb 761-treatment group (240 mg, t.i.d.). Safety and compliance were monitored after 1, 2, 3 and 4 weeks. Primary outcome measures in this study are the subjects’ judgment of their own mental health (MH), their general health (GH) and their quality of life (QoL) operationalized on the basis of three different visual analog scales (VAS). Secondary outcome measures are 15 tests and experimental procedures based on a neurobiologically based classification or taxonomy of functions. RESULTS: Intergroup differences in self-estimated mental health as well as self-estimated quality of life were significant in favor of EGb 761. No intergroup differences were found in self-estimated general health. Secondary outcomes supporting the notion of superiority of the active drug were found for both motor performance and emotional evaluation. This study did not reveal evidence of unknown drug-induced side effects or intolerance. No serious adverse events were observed during the study. CONCLUSIONS: Both questions treated in this study, efficacy and safety, are important from a medical perspective because many persons take the agent studied in an effort to enhance their mental functioning and general well-being. The findings of this study support the adequacy of intake of EGb 761 to improve the functions indicated previously.
Institute for Medical Psychology, University of Munich, Germany. Alarcos.Cieza@phys.med.uni-muenchen.de
(Quelle: Cieza A, Maier P, Poppel E., Arch Med Res, 2003 Sep-Oct;34(5):373-81)
No alteration in platelet function or coagulation induced by EGb761 in a controlled study
Some cases of spontaneous bleeding have been reported in patients treated with Ginkgo biloba. A prospective, double-blind, randomized, placebo-controlled study was carried out in 32 young male healthy volunteers to evaluate the effect of three doses of Ginkgo biloba extract (120, 240 and 480 mg/day for 14 days) on hemostasis, coagulation and fibrinolysis. This study did not reveal any alteration of platelet function or coagulation. This suggests that the reported clinical bleeding events in patients receiving Ginkgo biloba extract are not related to pharmacological properties of EGb761.
Experimental Thrombosis and Atherosclerosis Laboratory, IVS, Lariboisiere Hospital, Paris, France.
(Quelle : Bal Dit Sollier C, Caplain H, Drouet L., Clin Lab Haematol., 2003 Aug;25(4):251-3.)