Vorsicht mit Paracetamol

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Ritchie
Beiträge: 62
Registriert: 20.08.2005, 09:52
Wohnort: Zürich

Vorsicht mit Paracetamol

Beitrag von Ritchie » 19.04.2009, 15:54

Gewöhnlich werden Kindern mit Zahnschmerzen oder Fieber paracetamolhaltige fiebersenkende und schmerzlindernde Medikamente verabreicht (z.B. Dafalgan, Tylenol, Treupel, Panadol, Neo Citran etc). Gemäss Dr. Leichtman (Genetiker, Kinderarzt und Down-Syndrom-Spezialist, Virginia Beach, USA) und Prof. Dr. Jill James (Down-Syndrom-Forscherin, Univ. of Denver, Colorado, USA) sollten wir dies im Falle unserer Kinder mit Down-Syndrom unterlassen oder möglichst nur ausnahmsweise tun, jedenfalls nicht über mehrere Tage oder noch länger. Der Grund? Paracetamol bewirkt im Stoffwechsel aller Menschen eine vorübergehende Senkung des Glutathion-Gehalts sowohl im Blut als auch in der Leber, wo das Medikament abgebaut wird. Glutathion ist der Hauptbestandteil des Enzyms Glutathion-Peroxidase, das dem oxidativen Stress durch freie Radikale in unseren Zellen entgegenwirkt. Bei Menschen mit Down-Syndrom ist ein Mangel an diesem Enzym festzustellen, und dadurch besteht schon natürlicherweise ein Ungleichgewicht in ihrem Stoffwechsel, weil das Gleichgewicht zwischen dem verdreifachten Enzym SOD (Superoxid-Dismutase, das vermehrt oxidativen Stress verursacht) und dem normal zweifach vorhandenen GSHpx (Glutathion-Peroxidase) gestört ist. Durch die Einnahme von Paracetamol wird dieses Ungleichgewicht weiter verschärft und die Körperzellen (speziell die empfindlichen Hirnzellen) sind den aggressiven freien Radikalen in noch verstärkterem Masse ausgeliefert.

Gibt es eine Alternative? Ibuprofen (Handelsname: Nurofen) ist ein gleichwertiges, unbedenkliches Ersatzmittel, aber aufgepasst: nach OPs ist auch hier Vorsicht angezeigt, weil es leicht blutverdünnend wirkt. Bitte in diesem Fall mit den behandelnden Ärzten beratschlagen, was das beste ist.

Nachfolgend sind einige wissenschaftliche Studien angeführt, die diese Zusammenhänge
belegen. Wer sie nachlesen will, kann das unter http://www.ncbi.nlm.nih.gov/entrez/query.fcgi tun.
(Einfach den Titel der Studie eingeben).

Gruss,
Richard/Zürich


1. Gluthation-Spiegel bei Down-Syndrom signifikant reduziert:

Pastore A, Tozzi G, Gaeta LM, Giannotti A, Bertini E, Federici G,
Digilio MC, Piemonte F:
Glutathione metabolism and antioxidant enzymes in children with Down
syndrome
Laboratory of Biochemistry, Molecular Medicine Unit, Children's
Hospital and Research Institute Bambino Gesu, Rome, Italy
J Pediatr 142 (5): 583-5 (2003 May)

Oxidative stress has been proposed as a pathogenic mechanism of atherosclerosis, cell aging, and neurologic disorders in Down syndrome. This study demonstrates a systemic decrease of all glutathione forms, including glutathionyl-hemoglobin, in the blood of children with Down syndrome. Furthermore, we obtained a disequilibrium, in vivo, between the antioxidant enzyme activities.
________

Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James
SJ:Homocysteine metabolism in children with Down syndrome: in vitro
modulation
Division of Biochemical Toxicology, Food and Drug Administration
National Center for Toxicological Research, Jefferson, AR, 72079, USA
Am J Hum Genet 69 (1): 88-95 (2001 Jul)

The gene for cystathionine beta-synthase (CBS) is located on chromosome 21 and is overexpressed in children with Down syndrome (DS), or trisomy 21. The dual purpose of the present study was to evaluate the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. Plasma samples were obtained from 42 children with karyotypically confirmed full trisomy 21 and from 36 normal siblings (mean age 7.4 years). Metabolites involved in homocysteine metabolism were measured and compared to those of normal siblings used as controls. Lymphocyte DNA methylation status was determined as a functional endpoint. The results indicated that plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblings. Plasma levels of cystathionine and cysteine were significantly increased, consistent with an increase in CBS activity. Plasma glutathione levels were significantly reduced in the children with DS and may reflect an increase in oxidative stress due to the overexpression of the superoxide dismutase gene, also located on chromosome 21. The addition of methionine, folinic acid, methyl-B(12), thymidine, or dimethylglycine to the cultured trisomy 21 lymphoblastoid cells improved the metabolic profile in vitro. The increased activity of CBS in children with DS significantly alters homocysteine metabolism such that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established "folate trap," creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder.
________


2. Paracetamol senkt Gluthation-Spiegel:

Slattery JT, Wilson JM, Kalhorn TF, Nelson SD.: Dose-dependent
pharmacokinetics of acetaminophen: evidence of glutathione depletion
in humans.

Clin Pharmacol Ther. 1987 Apr;41(4):413-8.

The time course of excretion of acetaminophen and its metabolites in urine was determined in eight healthy adults (seven men and one woman) who ingested 1 gm of the drug and collected timed urine samples for 24 hours. The mean time of peak excretion rate was 1.3 to 3.7 hours for acetaminophen, its glucuronide, sulfate, cysteine, mercapturate, and methoxy metabolites but 13.5 hours for methylthioacetaminophen. The mean half-life of acetaminophen was 3.1 hours and the mean half-life of the metabolites other than methylthioacetaminophen ranged from 4.1 to 5.7 hours. The half-life of methylthiometabolite could not be determined because of its very late peak time. In a second study the effect of dose on the clearance of acetaminophen was determined in nine healthy adult subjects (eight men and one woman) who received doses of 0.5 and 3 gm acetaminophen on separate occasions, separated by 4 to 10 days. The renal clearance of acetaminophen and the formation clearances of the sulfate, glutathione, and catechol metabolites were lower (by 38%, 41%, 35%, and 46%, respectively) at the higher dose. The renal clearance of acetaminophen sulfate and glucuronide conjugates were not different between doses. In a third study (10 men), 10 gm N-acetylcysteine was found to increase the formation clearance of the sulfate conjugate by 27% and that of the glutathione conjugate by 10%. The data suggest that the hepatic supply of reduced glutathione and 3'-phosphoadenosine 5'-phosphosulfate begins to be depleted over the range of 0.5 to 3 gm acetaminophen and that the depletion is overcome by the administration of N-acetylcysteine.
________

Shaheen SO, Sterne JA, Songhurst CE, Burney PG: Frequent paracetamol
use and asthma in adults.

Department of Public Health Sciences, Guy's, King's and St Thomas'
School of Medicine, London SE1 3QD, UK. seif.shaheen@kcl.ac.uk

Thorax. 2000 Apr;55(4):266-70.

BACKGROUND: The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma. METHODS: Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16-49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined. RESULTS: Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (<monthly), 1.22 (0.87 to 1.72) in monthly users, 1. 79 (1.21 to 2.65) in weekly users, and 2.38 (1.22 to 4.64) in daily users (p (trend) = 0.0002). This association was present in users and non-users of aspirin and was stronger when cases with more severe disease were compared with controls; amongst cases increasing paracetamol use was associated with more severe disease. Frequency of aspirin use was not associated with asthma when cases as a whole were compared with controls, nor with severity of asthma amongst cases. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not. CONCLUSIONS: Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.
_______

Nuttall SL, Khan JN, Thorpe GH, Langford N, Kendall MJ.: The impact of
therapeutic doses of paracetamol on serum total antioxidant capacity.

Department of Clinical Pharmacology, Division of Medical Sciences and
Wolfson Applied Technology Laboratory, Queen Elizabeth Hospital,
Birmingham, UK.

J Clin Pharm Ther. 2003 Aug;28(4):289-94.

INTRODUCTION: A link between regular paracetamol intake and asthma in adults has recently been postulated. Detoxification of paracetamol may deplete stores of glutathione, which is one of the major antioxidants present in the lung. A reduced source of glutathione in the lung may lead to increased oxidative damage to the epithelium and hence increased frequency and severity of asthma attacks in susceptible individuals. AIM OF STUDY: This study aimed to determine whether regular intake of maximum therapeutic doses of paracetamol reduced serum antioxidant capacity in healthy volunteers. METHODS: Fifteen young healthy volunteers (nine men, six women, mean age 21.3 years, range 19-32) took maximum therapeutic doses of paracetamol (1 g four times a day) for 14 days. On days 0 and 14 blood samples were taken at baseline and hourly for a period of 4 h following ingestion of 1 g paracetamol. Single venous blood samples were collected 1 h after ingestion of 1 g paracetamol on days 4, 7 and 10. Blood samples were analysed for serum paracetamol concentration and total antioxidant capacity. RESULTS: Mean total antioxidant capacity was significantly reduced over the 3-h post-dosing on both days 0 and 14 (P < 0.01). The results from days 4, 7 and 10 showed a trend towards reduced antioxidant activity over time. On day 14 values were consistently lower compared with the corresponding times on day 0 (P < 0.01 at 0, 1, 3 and 4 h, P < 0.05 at 2 h). CONCLUSIONS: Chronic ingestion of maximum therapeutic doses of paracetamol depletes serum antioxidant capacity in healthy volunteers in as few as 14 days, possibly by a reduction in glutathione. This may have implications for analgesic use in asthmatic individuals. Further studies are now required to assess the impact of paracetamol on antioxidant defences in the lung.
_______

Dimova S, Hoet PH, Dinsdale D, Nemery B.: Acetaminophen decreases
intracellular glutathione levels and modulates cytokine production in
human alveolar macrophages and type II pneumocytes in vitro.

Laboratory of Pneumology, Unit of Toxicology, K.U. Leuven, Herestraat
49, B-3000 Leuven, Belgium.

Int J Biochem Cell Biol. 2005 Aug; 37 (8) 1727-37. Epub 2005 Apr 26.

Recent epidemiological observations suggest that acetaminophen (paracetamol) may contribute to asthma morbidity. Impaired endogenous antioxidant defences may have a role in the pathogenesis of a number of inflammatory pulmonary diseases, including asthma. We studied the effect of acetaminophen on the intracellular level of reduced glutathione (GSH) with and without inhibitors of cytochrome P450 or prostaglandin H synthetase, and TNF-alpha, IL-6 and IL-8 protein production in human alveolar macrophages and type II pneumocytes in vitro. Following a 20 h incubation with acetaminophen, cytotoxicity was apparent from > or = 5 and > or = 10 mM in macrophages and type II pneumocytes, respectively. A time- and concentration-dependent decrease of intracellular GSH occurred after acetaminophen (0.05-1 mM) exposure (1-4 h) in pulmonary macrophages (up to 53%) and type II pneumocytes (up to 34%). Diethyldithiocarbamic acid, potassium ethyl xanthate, and indomethacin decreased significantly acetaminophen-induced GSH depletion in the two cell types tested, suggesting the involvement of cytochrome P450 (mainly CYP2E1) and/or prostaglandin H synthetase. In macrophages, acetaminophen decreased the secretion of TNF-alpha (at 4 and 24 h, concentration-related) and IL-6 (at 24 h, at 0.1 mM), and did not affect significantly IL-8 production. These in vitro observations demonstrate that clinically relevant concentrations of acetaminophen decreased: (i) intracellular GSH in human pulmonary macrophages and type II pneumocytes and (ii) the secretion of TNF-alpha and possibly IL-6 by human pulmonary macrophages. These findings provide experimental plausibility to the challenging observations that frequent use of APAP may be a risk factor for asthma morbidity.


Saskia & Richard
mit Jamie *4.12.2004/DS/ASDII/GERD/Schilddrüsenunterfunktion

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