Bacterial infections in cynomolgus monkeys given small molecule immunomodulatory antagonists.
J Immunotoxicol
; 7(2): 128-37, 2010.
Article
em En
| MEDLINE
| ID: mdl-20136396
ABSTRACT
Opportunistic infections (OIs) during the course of non-clinical toxicity studies can serve as a clinical indicator of immunosuppression. In monkeys, severity may be magnified since the possibility for fecal-oral and cage-to-cage transmission of bacteria exists, reserve capacity is low, and clinical signs of infection are not easily detected until the infectious process is well underway. This review summarizes a case study presented at the HESI-ILSI ITC-Sponsored workshop on Naturally Occurring Infections in Non-human Primates and Immunotoxicity Implications. It gives an overview on the impact of bacterial infections in monkeys on the development and regulatory assessment of three closely-related representative small molecule immunomodulatory (anti-inflammatory) drug candidates all inhibiting the same drug target. The infections, which sometimes progressed to bacteremia and death, originally manifested in the skin, upper respiratory tract, gastrointestinal tract, and less frequently as soft tissue abscesses. Infections were sporadic and not observed in all studies despite coverage of equivalent or higher systemic exposures or longer durations of treatment. To address concerns regarding inconsistency in the presentation and type of findings and their potential relationship to infection, steps were taken to identify causative agents (via culture, microscopy), implement various intervention and treatment regimens (supportive care, antibiotics, drug holiday), demonstrate reversibility of clinical and immune effects, and study major immune components/mechanisms affected (cytokine/stress protein profiling, immune cell phenotyping, and humoral/innate immune cell function tests). Appropriate diagnosis and characterization of the infection was critical to discrimination of these findings as a secondary pharmacologic effect rather than a direct drug-related target organ effect, and also guided clinical protocol design and regulatory acceptance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Infecções Bacterianas
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Infecções Oportunistas
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Anti-Inflamatórios não Esteroides
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Imunossupressores
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Macaca fascicularis
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Doenças dos Macacos
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article