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Titolo:
EXTENSION OF THE 4-WEEK SAFETY STUDY FOR DETECTING IMMUNE-SYSTEM IMPAIRMENT APPEARS NOT NECESSARY - EXAMPLE OF CYCLOSPORINE-A IN RATS
Autore:
DESCOTES G; PINARD D; GALLAS JF; PENACCHIO E; BLOT C; MOREAU C;
Indirizzi:
INST RECH INT SERVIER,6 PL PLEIADES F-92415 COURBEVOIE FRANCE SANOFI WINTHROP,DEPT DRUG SAFETY ASSESSMENT F-21600 LONGVIC LES DIJONFRANCE FAC MED,LAB IMMUNOL & IMMUNOTHERAPIE CANC F-21000 DIJON FRANCE FAC PHARM CHATENAY MALABRY,INSERM CJF9301 F-92296 CHATENAY MALABRY FRANCE SANOFI WINTHROP,DEPT PRECLIN BIOSTAT COLLEGEVILLE PA 19426
Titolo Testata:
Toxicology
fascicolo: 3, volume: 112, anno: 1996,
pagine: 245 - 256
SICI:
0300-483X(1996)112:3<245:EOT4SS>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
IMMUNOTOXICITY; TOXICITY; BATTERY; THYMUS; CELLS;
Keywords:
IMMUNOTOXICITY (IMMUNOMODULATION) EVALUATION; CONVENTIONAL 4-WEEK STUDY; RAT; OECD GUIDELINE 407; CYCLOSPORINE A;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
23
Recensione:
Indirizzi per estratti:
Citazione:
G. Descotes et al., "EXTENSION OF THE 4-WEEK SAFETY STUDY FOR DETECTING IMMUNE-SYSTEM IMPAIRMENT APPEARS NOT NECESSARY - EXAMPLE OF CYCLOSPORINE-A IN RATS", Toxicology, 112(3), 1996, pp. 245-256

Abstract

A 4-week study was conducted to shed light on the question of whethercompounds impairing immune homeostasis may escape the standard safetytesting, Wistar rats were orally treated with cyclosporin A at dosages of 0 (control: olive oil), 1, 5 or 25 mg/kg/day, Ten rats/sex/group (study segment 1) were not immunized while six other rats/sex/group (study segment 2) were immunized 4 days before killing to perform a plaque forming cell (PFC) assay; All rats were subjected to routine safetyevaluations (OECD guideline 407) and determination of IgM and IgG serum levels, Other immune parameters were evaluated using cells from spleen and mesenteric lymph nodes (segment 1). Effects on safety parameters were similar for immunized and non-immunized rats. A slight decrease of body weight gain (males, 25 mg/kg) accompanied slight clinical chemical and histomorphologic evidence of renal tubulotoxicity, Changes in safety parameters indicative of immune system alterations were: increased thymic corticomedullary ratio (greater than or equal to 5 mg/kg) and (25 mg/kg) minimal lymphopenia, low thymus weight, thymic cortical lymphocytolysis and low lymphoid cellularity of spleen and lymph nodes, They were associated with (males at greater than or equal to 1 mg/kg) dose-related decreases of T-cell receptor(+) and CD4(+) cells andincreases of CD8(+) cells, and decreased PFC (greater than or equal to 5 mg/kg) and lymphoproliferative responses to mitogens and alloantigens (25 mg/kg), There were no changes in natural killer activity. The conventional assay identified the drug as a potential immunomodulator. Specific immune assays (phenotyping, PFC) improved the threshold of detection. These results did not support the incorporation of specific immune tests in the standard 4-week study protocol.

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Documento generato il 09/08/20 alle ore 20:17:40