Experimental and Clinical Aspects of Drug Toxicity

Zbinden, G.

doi:10.1016/s1054-3589(08)60085-x

Cited by 59 publications

(22 citation statements)

References 273 publications

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“It would be very desirable if the harmful effects of newly developed compounds could be recognized in animals before any damage is done to human subjects. For that reason it has become a standard practice to subject every drug to extensive trials in laboratory animals prior to their release for human use.” [26]

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Section: Principles Of Animal Toxicity Testsmentioning

confidence: 99%

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The mechanisms of sudden-onset type adverse reactions to oseltamivir

Hama¹,

Bennett

2016

Acta Neurol Scand

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Oseltamivir is contraindicated for people aged 10 to 19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First the importance of animal models and the concept of human equivalent dose (HED) is summarised. Second, the specific condition for oseltamivir use: influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular-level of evidence (channels, receptors, and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA, GABAB, and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic) respectively.

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Section: Principles Of Animal Toxicity Testsmentioning

confidence: 99%

“…Thus, the toxicity experiment tries to imitate the clinical use of the drug and although bold exaggerations with respect to dose and duration of treatment are common and permissible, it is important that the future therapeutic applications in man guide the planning of a toxicity study. ” [26]. …”

Section: Principles Of Animal Toxicity Testsmentioning

confidence: 99%

The mechanisms of sudden-onset type adverse reactions to oseltamivir

Hama¹,

Bennett

2016

Acta Neurol Scand

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“…Although the term toxicity is used instead of ADR, one interesting model is that of Zbinden [1963]. Within this classification, biochemical toxicity is defined as drug-induced organ changes routinely detected by chemical methods and not accompanied by anatomical changes (e.g., agranulocytosis).…”

Section: Side Effects As Observable Signs and Symptomsmentioning

confidence: 99%

Measuring side effects of psychopharmacologic medication in individuals with mental retardation and developmental disabilities

Kalachnik

1999

Ment. Retard. Dev. Disabil. Res. Rev.

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“…On days 15, 30, 45, 75 and 90 of administration of Arafia mandshurica, blood samples were obtained, under light ether anaesthesia, by means of retroorbital puncture with a microcapillary tube. On day 90, the rats were killed by decapitation (Zbinden, 1963;Boyd, 1968;Poole and Leslie, 1989;Jurado , 1989).…”

Section: R Burgos Et a Lmentioning

confidence: 99%

Toxicological assessment of Aralia mandshurica (Araliaceae) root extract after subchronic administration in rats. A biochemical and histological study

Burgos

Hancke

Wikman

et al. 1994

Phytotherapy Research

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The toxic subchronic effect of an extract of Aralia mandshurica on rats of both sexes was studied over a period of 90 days (0.2,1.7,3.4 g/kg p.0.). The toxic effects of Amlia mandshurica on the following enzymes were evaluated: danine amino transferase (ALT), aspartate amino transferase (AST), serum alkaline phosphatase (SAP), total proteins and serum urea. Blood samples were obtained by means of retroorbital puncture with a microcapillary tube on days 15, 30,45,75 and 90 of the administration of Araliu mandshurica. The body weight was registered every week, and at the end of the study a necropsy was performed and the liver, lungs, kidneys, heart, spleen, gonads and adrenal glands were weighed. Liver, gonads and kidneys were examined histologically.There was an increase in the levels of AST and SAP enzymes with a dose of 3.4 g/kg in both sexes on day 90 of administration, but no changes were observed in urea and serum protein. A significant decrease of the body weight was recorded in both sexes with a dose of 3.4 glkg. Moreover, the animals treated with doses of 1.7 and 3.4 g/kg showed a diminution of faecal consistence. An increase of the liver weight was produced with all the doses of A r a b mandshurica, but neither macroscopic nor histological alterations were observed, as in the rest of the organs. Possible liver damage associated with this enzyme is discussed.

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Experimental and Clinical Aspects of Drug Toxicity

Cited by 59 publications

References 273 publications

The mechanisms of sudden-onset type adverse reactions to oseltamivir

The mechanisms of sudden-onset type adverse reactions to oseltamivir

Measuring side effects of psychopharmacologic medication in individuals with mental retardation and developmental disabilities

Toxicological assessment of Aralia mandshurica (Araliaceae) root extract after subchronic administration in rats. A biochemical and histological study

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