Public Health Service Study on Reye’s Syndrome and Medications

Hurwitz, Eugene S.; Barrett, Michael J.; Bregman, Dennis J.; Gunn, Walter J.; Schonberger, Lawrence B.; Fairweather, William R.; Drage, Joseph S.; LaMontagne, John R.; Kaslow, Richard A.; Quinnan, Gerald V.; Phillips, Kem F.; Pinsky, Paul F.; Dayton, Delbert H.; Dowdle, Walter R.

doi:10.1056/nejm198510033131403

Cited by 155 publications

(37 citation statements)

References 7 publications

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“…Several studies have indicated that the development of RS is linked to ASA therapy (24)(25)(26). Because of the possible inductive action of ASA on the whydroxylation system and the observation that DCAs in the serum of RS patients are mitochondrial inhibitors, ASA was administered to rats to determine its effect on the fatty acid whydroxylation system and in the formation of the DCAs using the 12-carbon atom fatty acid, LA, as substrate.…”

mentioning

confidence: 99%

Effect of Acetylsalicylic Acid on Fatty Acid ω-Hydroxylation in Rat Liver

Okita

1986

Pediatr Res

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ABSTRACT. The effect of acetylsalicylic acid on the cytochrome P-450-mediated fatty acid w-hydroxylation system was assessed in male Sprague-Dawley rats after they were fed a diet containing 1% (w/w) acetylsalicylic acid. A 3-fold increase in the specific activity of laurate w-hydroxylation was observed in the acetylsalicylic acid fed rats in comparison to control rats. This effect of acetylsalicylic acid was unique as the specific activities of other cytochrome P-450-mediated reactions were not increased. The induction of the laurate w-hydroxylation system was also manifested in a rapid formation of its dicarboxylic acid derivative, dodecanedioic acid, as the w-hydroxy derivative was further oxidized by alcohol and aldehyde dehydrogenases. These results suggest the acetylsalicylic acid is similar to other peroxisomal proliferating agents in that it also induces the microsomal fatty acid w-hydroxylation system and may account for the appearance of unique dicarboxylic acids in Reye's syndrome patients. that are ketotic (4) or in individuals that have an impaired fatty acid P-oxidation system such as in glutaric aciduria type I1 (5, 6), ethylmalonic-adipic aciduria (7), systemic carnitine deficiency (8), hypoglycin toxicity (9), acyl-CoA dehydrogenase deficiency (10, 1 l), and in RS (1, 2). The biochemical basis of RS has not been delineated and multiple etiological factors may be responsible for this syndrome (1 1). Fatty acids have been implicated as a factor in RS (1 I). The formation of DCAs is caused by the oxidation of the methyl carbon atom of fatty acids to a carboxyl group and is catalyzed by a series of enzymes that are referred to as the fatty acid w-oxidation system. The initial and rate-limiting step in this sequence of reactions is catalyzed by a microsomal cytochrome P-450-mediated hydroxylase which produces an whydroxy-fatty acid (1 2-14). This derivative is further oxidized by cytosolic alcohol and aldehyde dehydrogenases to form the DCA (15, 16).The cytochrome P-450 that catalyzes the w-hydroxylation reaction has considered to be a constitutive, noninducible member of the cytochrome P-450 family of isozymes (17), but recent studies have demonstrated that clofibrate (18, 19) and DEHP (20, 2 l), potent peroxisomal proliferating agents, are also inducers of the hepatic fatty acid w-hydroxylation system.ASA has been reported to be another peroxisomal proliferator and inducer of its fatty acid P-oxidation system (22, 23), but it has not been established if it is an inducer of the microsomal fatty acid w-hydroxylation system. Several studies have indicated that the development of RS is linked to ASA therapy (24-26). Because of the possible inductive action of ASA on the whydroxylation system and the observation that DCAs in the serum of RS patients are mitochondrial inhibitors, ASA was administered to rats to determine its effect on the fatty acid whydroxylation system and in the formation of the DCAs using the 12-carbon atom fatty acid, LA, as substrate.A recent study by Tonsgard and Getz (1) reported...

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confidence: 99%

Effect of Acetylsalicylic Acid on Fatty Acid ω-Hydroxylation in Rat Liver

Okita

1986

Pediatr Res

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“…27 Efforts to raise awareness of the link between aspirin and RS included journal publications; warning statements in 1982 by CDC consultants, the American Academy of Pediatrics, and the United States' Surgeon General; and a "Black Box" warning in 1986 advising against administering aspirin to children and teenagers with chicken pox or flu symptoms without consulting a physician. 6,24,25,[27][28][29][30][31][32][33] The British Risk Factor Study found excess aspirin exposure in RS children and a 1986 advisory by the Committee on Safety of Medicines warned against administering aspirin to children under twelve. 34 Warning labeling on aspirin containing preparations was introduced, and modified in 2003 to warn against giving aspirin to children under sixteen without consulting a physician.…”

Section: Reye's Syndromementioning

confidence: 99%

Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

et al. 2012

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Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common

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“…Especially in the latter field, the case-control method has proven its potential. Examples include studies on aspirin use and Reye's syndrome [14], and, recently, betaagonists and fatal asthma 1151.…”

Section: Essentials Of the Case-control Studymentioning

confidence: 99%

“…A more controversial issue is the inclusion of several control groups in a case-control comparison. In a study on aspirin and Reye's syndrome, for example, 4 control groups were chosen [14]. In general, a clear understanding of the essentials of the study base will lead to sampling of one control group only.…”

Section: The Choice Of a Control Groupmentioning

confidence: 99%

Case-control studies

Hoes

1995

The Netherlands Journal of Medicine

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Public Health Service Study on Reye’s Syndrome and Medications

Cited by 155 publications

References 7 publications

Effect of Acetylsalicylic Acid on Fatty Acid ω-Hydroxylation in Rat Liver

Effect of Acetylsalicylic Acid on Fatty Acid ω-Hydroxylation in Rat Liver

Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

Case-control studies

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