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Comparative pathophysiology, toxicology, and human cancer risk assessment of pharmaceutical-induced hibernoma.
Radi, Zaher; Bartholomew, Phillip; Elwell, Michael; Vogel, W Mark.
Afiliação
  • Radi Z; Pfizer Worldwide Research and Development, Drug Safety R&D, 1 Burtt Rd., Andover, MA 01810, USA. Electronic address: zaher.radi@pfizer.com.
Toxicol Appl Pharmacol ; 273(3): 456-63, 2013 Dec 15.
Article em En | MEDLINE | ID: mdl-24141031
ABSTRACT
In humans, hibernoma is a very rare, benign neoplasm of brown adipose tissue (BAT) that typically occurs at subcutaneous locations and is successfully treated by surgical excision. No single cause has been accepted to explain these very rare human tumors. In contrast, spontaneous hibernoma in rats is rare, often malignant, usually occurs in the thoracic or abdominal cavity, and metastases are common. In recent years, there has been an increased incidence of spontaneous hibernomas in rat carcinogenicity studies, but overall the occurrence remains relatively low and highly variable across studies. There have only been four reported examples of pharmaceutical-induced hibernoma in rat carcinogenicity studies. These include phentolamine, an alpha-adrenergic antagonist; varenicline, a nicotine partial agonist; tofacitinib, a Janus kinase (JAK) inhibitor; and hydromorphone, an opiod analgesic. Potential non-genotoxic mechanisms that may contribute to the pathogenesis of BAT activation/proliferation and/or subsequent hibernoma development in rats include (1) physiological stimuli, (2) sympathetic stimulation, (3) peroxisome proliferator-activated receptor (PPAR) agonism, and/or (4) interference or inhibition of JAK/Signal Transducer and Activator of Transcription (JAK/STAT) signaling. The evaluation of an apparent increase of hibernoma in rats from 2-year carcinogenicity studies of novel pharmaceutical therapeutics and its relevance to human safety risk assessment is complex. One should consider the genotoxicity of the test article, dose/exposure and safety margins, and pathophysiologic and morphologic differences and similarities of hibernoma between rats and humans. Hibernomas observed to date in carcinogenicity studies of pharmaceutical agents do not appear to be relevant for human risk at therapeutic dosages.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lipoma / Neoplasias Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Toxicol Appl Pharmacol Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Lipoma / Neoplasias Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Toxicol Appl Pharmacol Ano de publicação: 2013 Tipo de documento: Article