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Sven Schmiedl,
Jacek Szymanski,
Marietta Rottenkolber,
Bernd Drewelow,
Grit Haase,
Marion Hippius,
Ilselore R. Reimann,
Werner Siegmund,
Karen May,
Sara Haack,
Jörg Hasford, Petra A. Thürmann,
für die Deutsche Pharmakovigilanz-Studiengruppe
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ABSTRACT: Hintergrund:Obwohl der klinische Nutzen einer Digitalistherapie bei Herzinsuffizienz begrenzt ist, wurden in Deutschland im Jahre 2004
ca. 255 Mio. Tagesdosen Digitalisglykoside (DGs) verordnet.
Methodik:Für den Zeitraum 2000–2004 analysierten die Autoren zur stationären Aufnahme führende unerwünschte Arzneimittelwirkungen (UAWs)
der nationalen Pharmakovigilanzzentren, deren Zusammenhang mit einer DG-Therapie als mindestens „wahrscheinlich“ bewertet
wurde.
Ergebnisse:Von 3 092 Patienten mit aufnahmebedingender UAW lag bei 314 Patienten (10,2%, 244 Frauen) eine DG-assoziierte UAW vor. Patienten
mit DG-assoziierter UAW waren signifikant älter und leichter als Patienten mit anderen UAWs. Die Inzidenz [95%-CI] betrug
1,9 [1,0; 3,3] pro 1 000 DG-Exponierte je Quartal. Von 296 Patienten (228 Frauen) mit oraler Digitoxintherapie erhielten 70,6%
der Frauen, aber nur 29,3% der Männer eine zu hohe tägliche Dosis, d.h. > 1 μg/kg Körpergewicht. Bei Frauen fanden sich signifikant
höhere körpergewichtsbezogene Digitoxintagesdosen und Digitoxinserumspiegel. Bei Patienten mit nicht erhöhten Digitoxinspiegeln
waren häufig pharmakodynamische Medikamenteninteraktionen (z.B. β-Blocker) entscheidend für die UAW-Entstehung. 42,4% der
DG-UAWs wurden als vermeidbar eingeschätzt.
Schlussfolgerung:Die Verschreibung einer körpergewichtsadaptierten Digitoxindosis ist wesentlich für die Verhinderung vermeidbarer DG-UAWs,
insbesondere bei älteren, leichten Frauen. Regelmäßige Serumspiegelkontrollen sind auch aufgrund einer möglicherweise verlängerten
Halbwertszeit bei sehr alten Patienten wichtig, ebenso die Beachtung pharmakodynamischer und pharmakokinetischer Interaktionen.
Background:Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of
digitalis glycosides (DGs) were prescribed in Germany in 2004.
Method:The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance
Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least “probable” ADR were included.
Results:Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related
ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed
to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in
296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 μg/kg body weight per day). Women received
significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs
in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., β-blockers).
Overall, 42.4% of the ADRs were supposed to be preventable.
Conclusion:Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight.
Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma
concentrations are crucial accounting for the increased half-life of digitoxin in the very old.
04/2012; 102(8):603-611.
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ABSTRACT: Certain drugs are classified as potentially inappropriate medications (PIM) for the elderly because they carry an increased risk of adverse drug events in this patient group. PIM lists from other countries are of limited usefulness in Germany because different drugs are on the market in each country and prescribing practices vary as well. Thus, a list of potentially inappropriate medications for the elderly was developed specifically for use in Germany.
A preliminary PIM list suitable for the German market was created on the basis of a selective literature search and a qualitative analysis of published international PIM lists. The final German PIM list was developed by means of a comprehensive, structured expert survey in two rounds (a so-called Delphi process).
83 drugs in a total of 18 drug classes were rated as potentially inappropriate for elderly patients. For 46 drugs, the experts came to no clear decision after the second Delphi round. For cases in which the administration of a PIM is clinically necessary, the final PRISCUS list contains recommendations for clinical practice, e.g. monitoring of laboratory values and dose adaptation. Therapeutic alternatives are also listed.
Potentially inappropriate medications carry the risk of causing adverse drug events in the elderly. A drawback of using a Delphi process to generate a PIM list, as was done for the new German list, is that little scientific evidence is currently available for the evaluation of active substances, potential therapeutic alternatives, and indicated monitoring procedures. Thus, the validity and practicability of the PRISCUS list remain to be demonstrated (and the same holds for PIM lists already published in other countries). It should be used as a component of an overall concept for geriatric pharmacotherapy in which polypharmacy and interacting medications are avoided, and doses are regularly re-evaluated.
08/2010; 107(31-32):543-51. · 2.92 Impact Factor
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ABSTRACT: Sex differences observed in the adverse effects associated with psychotropic drugs have not been reported consistently in the literature. In this review, we discuss the current published data on sex differences observed in the occurrence, symptomatology and reporting of the adverse effects associated with psychotropic drug effects, and discuss their clinical relevance. We reviewed the published data up to April 2009 on sex differences in the side effects of antipsychotics, antidepressant and mood stabilizers, by systematically searching PubMed using combinations of search terms and retrieving relevant references specifically reporting on these issues. The majority of the data was retrieved from clinical studies where the main outcome parameters did not relate specifically to sex differences. In most instances, sex was associated with other factors influencing side effects such as age, disease and body weight. Sex-related differences were reported in the side effects associated with antipsychotic drug-induced weight gain and metabolic syndrome, symptoms of sexual dysfunction caused by antidepressants and antipsychotic drugs and cardiac arrhythmic side effects associated with antipsychotic drugs. Women might differ from men not only in incidence but also in the presentation of clinical symptoms associated with adverse psychotropic drug effects. Clinicians should be made aware of the differences reported in the literature regarding the symptomatology, severity and recognition of the adverse psychotropic drug effects found in men and women.
Pharmacogenomics 09/2009; 10(9):1511-26. · 3.97 Impact Factor
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Petra A Thürmann
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ABSTRACT: Transferability of results originating from randomized, controlled clinical trials is characterized by their external validity. Clinical trials are experimental in their design and conducted under standardized terms, that is, rigorous inclusion and exclusion criteria as well as an artificial trial environment may hamper the transferability of results. Studies designed for approval of new medicines usually exclude elderly patients, multi-morbid patients, pregnant women and children. For example, the median age at diagnosis of colorectal cancer in Germany is 69 (men) and 75 (women) years, respectively. In clinical trials investigating chemotherapy, however, patients above the age of 70 years represent only 18% of the trial population. In cardiovascular trials, especially on acute coronary syndromes, women are usually under-represented. Guidelines derived from clinical trials should therefore explicitly mention a study's limitations. It should be communicated clearly for which patients and under which conditions the guideline is applicable.
Zeitschrift für Evidenz Fortbildung und Qualität im Gesundheitswesen 01/2009; 103(6):367-70.
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European Journal of Clinical Pharmacology 10/2008; 64(9):835-6. · 2.85 Impact Factor
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Sven Schmiedl,
Jacek Szymanski,
Marietta Rottenkolber,
Bernd Drewelow,
Grit Haase,
Marion Hippius,
Ilselore R Reimann,
Werner Siegmund,
Karen May,
Sara Haack,
Jörg Hasford, Petra A Thürmann
[show abstract]
[hide abstract]
ABSTRACT: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004.
The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included.
Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 mug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable.
Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.
Medizinische Klinik 08/2007; 102(8):603-11. · 0.34 Impact Factor
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Petra A Thürmann
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ABSTRACT: Following the disastrous experience with thalidomide women were largely excluded from clinical trials. A change in this paradigm can be observed most recently. For the pharmacokinetics and -dynamics of drugs a body of evidence does exist to prove the presence of significant sex-related differences. Especially fort he major drug metabolizing enzymes, the cytochrome P 450 family, but also for phase II reactions such as glucuronidation, sex-differences were observed. However, most of these differences are either clinically not relevant or were not just observed, because they result in slight increases in the frequency of adverse reactions. Major sex-specific differences were observed for the cardiac elektrophysiology, for opiate and benzodiazepine receptors. Women are significantly more likely to experience drug-induced QT-prolongation and torsade-de-pointes arrhythmia. It should also be considered that conditions such as depression, myocardial infarction and heart failure are characterized by gender-specific symptoms and therefore may deserve a gender-specific therapy. Different trials and epidemiological surveys have repeatedly shown that women experience more adverse drug effects than men.
Therapeutische Umschau 07/2007; 64(6):325-9.
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Drug Safety 02/2007; 30(12):1171-3; author reply 1173-4. · 3.63 Impact Factor
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Petra A Thürmann,
Sara Haack,
Ulrike Werner,
Jacek Szymanski,
Grit Haase,
Bernd Drewelow,
Ilselore R Reimann,
Marion Hippius,
Werner Siegmund,
Karen May,
Joerg Hasford
Clinical Pharmacology & Therapeutics 12/2006; 80(5):551-3. · 6.04 Impact Factor
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European Journal of Clinical Pharmacology 08/2006; 62(7):511-2. · 2.85 Impact Factor
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Clinical Pharmacology & Therapeutics 12/2005; 78(5):445-52. · 6.04 Impact Factor
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ABSTRACT: Adequate intake of lutein is postulated to reduce the risk of age-related macular degeneration, but kinetic information for developing a dosing regimen is sparse.
The objective was to characterize lutein plasma kinetics in a multiple dosing design and to assess the effects of lutein intake on concentrations of other plasma carotenoids.
After a run-in period of 7 d, 19 healthy volunteers were assigned to receive daily oral doses of 4.1 mg lutein (n = 8; group 1) or 20.5 mg lutein (n = 8; group 2) for 42 d or no lutein (n = 3; control group). The supplement contained 8.3% zeaxanthin relative to lutein (100%). The time profiles of plasma xanthophyll concentrations were monitored over the dosing phase, and samples were collected frequently on day 42 and for 24 d after dosing.
Average plasma all-E-lutein concentrations increased from 0.14 to 0.52 +/- 0.13 and 1.45 +/- 0.69 micromol/L in groups 1 and 2, respectively. Dose-normalized lutein bioavailability in group 2 was approximately 60% of that in group 1. Kinetic disposition half-life did not differ significantly between groups. On average, dosing for 18 d was required to reach a >90% fraction of the steady state concentration, which is consistent with an effective half-life for accumulation of approximately 5.6 d. Plasma kinetics of all-E-lutein were paralleled by those of all-E-3-dehydro-lutein. Kinetic analysis indicated formation of all-E-3-dehydro-lutein from lutein. Lutein was well tolerated and did not affect the concentrations of other carotenoids.
Long-term supplementation with 4.1 and 20.5 mg lutein as beadlets increased plasma lutein concentrations approximately 3.5- and 10-fold, respectively.
American Journal of Clinical Nutrition 08/2005; 82(1):88-97. · 6.67 Impact Factor
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ABSTRACT: Adverse drug reactions (ADRs) contribute significantly to patient morbidity and mortality, as well as to costs for healthcare systems. Our aim was to evaluate the type and incidence of ADRs in a paediatric hospital population, comparatively ascertained by two different methodological approaches.
Our prospective study enrolled all patients admitted to two of the general children wards (46 beds) and the paediatric intensive care unit (6 beds) at the HELIOS Klinikum Wuppertal teaching hospital in Germany, over the study period of 3 months. We used two methods to detect ADRs. The intensified surveillance system relied on a trained physician conducting ward rounds and assessing patient charts. The computer-assisted screening of pathological laboratory parameters used values slightly below or above the age-specific normal range as a trigger signal for a potential ADR, which was subsequently assessed by trained personnel.
By applying both methods simultaneously we observed that 14.1% of children experienced an ADR while they were hospitalised and 2.7% of children were admitted to hospital because of the ADR. Intensified surveillance resulted in the detection of 101 ADRs in 11.9% of patients, predominantly presenting with gastrointestinal symptoms, skin and CNS disorders; computer-assisted screening identified 45 ADRs in 5.7% of patients, mainly with drug-induced blood dyscrasia and liver damage. Furthermore, the ADRs detected by the intensified method were more severe, affected younger children and showed a closer causal attributability to the reaction than the ADRs observed by the computerised method. The spectra of drugs involved were similar, with the anti-infectives being suspected most frequently. The sensitivities of the intensified surveillance system and the computerised surveillance screening came to 67.2% and 44.8%, respectively, with computer-assisted screening having a specificity of 72.8%. The mean positive predictive value of the pathological laboratory values under surveillance by computer-assisted screening was 18.6%. Approximately 25% of ADR-related drugs administered were used for off-label indications.
Using the published literature for comparison, we found that ADRs occur as frequently in paediatric patients as in adult patients. Intensified surveillance and computerised surveillance applied in the paediatric setting show substantial differences in their detection specificities. A higher number of and more severe ADRs can be detected by intensified surveillance than by computerised surveillance, but require higher personnel resources.
Drug Safety 02/2005; 28(5):453-64. · 3.63 Impact Factor
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Medizinische Klinik 04/2004; 99(3):137-46; quiz 147. · 0.34 Impact Factor
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ABSTRACT: Zeaxanthin is hypothesized to reduce the risk of age-related macular degeneration; however, kinetic information is limited.
The objective was to investigate the plasma kinetics of synthetic zeaxanthin after repeated oral doses and to assess the possible influence of other carotenoids on plasma zeaxanthin concentrations.
After a run-in of 3 d, 20 healthy volunteers assigned to 2 parallel dose groups received once daily oral doses of either 1 mg (1.76 micro mol) or 10 mg (17.6 micro mol) zeaxanthin for 42 d. Plasma concentration-time profiles on days 1 and 42, concentrations immediately before zeaxanthin intake during the dosing period, and concentrations after the last dose until day 76 were monitored.
all-E-Zeaxanthin concentrations increased from 0.048 +/- 0.026 micro mol/L at baseline to 0.20 +/- 0.07 and 0.92 +/- 0.28 micro mol/L with 1 and 10 mg zeaxanthin, respectively. The dose-normalized bioavailability of all-E-zeaxanthin after the10-mg dose was 40% lower (P < 0.001) than after the 1-mg dose. Other kinetic parameters did not differ significantly between groups. After 17 d of dosing, >90% of steady state concentrations were reached, which was compatible with an effective half-life for accumulation of 5 d. The terminal elimination half-life was 12 +/- 7 d (n = 20). The time course of plasma all-E-3-'dehydro-lutein concentrations resembled that of all-E-zeaxanthin. The data provided evidence that all-E-3-'dehydro-lutein was derived from all-E-zeaxanthin. Concentrations of other carotenoids were not affected. Zeaxanthin was well tolerated.
Long-term oral intake of 1 and 10 mg zeaxanthin as beadlets increases plasma zeaxanthin concentrations approximately 4- and 20-fold, respectively. Evidence that all-E-3-dehydro-lutein is formed from zeaxanthin was strong.
American Journal of Clinical Nutrition 03/2004; 79(3):410-7. · 6.67 Impact Factor
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ABSTRACT: Bioavailability of beta-carotene is highly variable and depends on the source, the formulation and other nutritional factors.
It was the aim of the study to compare beta-carotene plasma response to b-carotene dosing with two commercially available drinks, containing beta-carotene from carrot juice or as water dispersible beta-carotene powder. Design In a randomized, parallel group study design, 4 volunteers per group received daily beta-carotene doses of 6-7 or 18-22 mg of either drink over 6 weeks. Blood samples for determination of carotenoid and vitamin A plasma concentrations were collected before supplementation and over the dosing period.
Apparent steady-state beta-carotene concentrations were attained after 40 days of supplementation. Consumption of the beverage containing beta-carotene as a water dispersible powder resulted in a higher response of beta-carotene plasma concentrations with increments of 3.84 +/- 0.60 micromol/L (p < 0.05, dose: 7.2 mg/d) and 5.04 +/- 0.72 micromol/L (p < 0.05, dose: 21.6 mg/d), respectively, in comparison to the carrot juice-based drink with increments of 0.42 +/- 0.33 micromol/L (dose: 6 mg/d) and 1.71 +/- 0.55 micromol/L (dose: 18 mg/d), respectively. beta-carotene was cleared from the plasma with an apparent half-life of 6-11 days. Plasma concentrations of alpha-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene remained almost unchanged, whereas retinol plasma concentrations increased slightly. By contrast, with the exception of elevated 13-cis-retinoic acid in one group (21.6 mg/d, water dispersible powder), the concentrations of all-trans-retinoic acid, and the oxo-derivatives or retinoic acid were not significantly affected by b-carotene supplementation.
The results confirm that the relative bioavailability of beta-carotene depends largely on the source of b-carotene and demonstrate the superior bioavailability of beta-carotene powder in comparison to that in carrot juice.
European Journal of Nutrition 10/2002; 41(5):228-35. · 2.75 Impact Factor
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ABSTRACT: Angiotensin II Type 1 receptor antagonists share most but not all of their pharmacological actions with angiotensin-converting enzyme inhibitors. The latter belong to standard heart failure therapy, with proven benefit in terms of morbidity and mortality. Promising data have been provided for angiotensin II Type 1 receptor antagonists in experimental models of heart failure. In patients with hypertension and those with diabetic nephropathy, favourable results have been observed with regards to blood pressure control, reversibility of structural changes or prevention of progression of disease. The currently available clinical trials in heart failure patients with angiotensin II Type 1 receptor antagonists suggest that they may be equivalent to angiotensin-converting enzyme inhibitors, but superiority has not been proven. There is no doubt about their effectiveness with regards to symptoms; however, their effect on hospitalisation and mortality is not unequivocally demonstrated. Further trials are warranted, particularly to define their role in comparison with and in addition to angiotensin-converting enzyme inhibitors and to further characterise heart failure patient populations who derive benefit from angiotensin II Type 1 receptor blockers above and beyond angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone.
Expert Opinion on Investigational Drugs 06/2002; 11(5):705-16. · 5.27 Impact Factor
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