title: Circadian-time dependent tolerance and haematological toxicity to isoniazid in murine.
abstract: BACKGROUND
  Isoniazid (INH) is a widely used drug in the prophylaxis and treatment of tuberculosis. In the present study, isoniazid (INH)-induced toxicity was investigated according to the dosing-time in the 24-h scale in mice.
  
  
  METHODS
  Two studies were carried out on a total of 180 male Swiss mice synchronized for 3 weeks to 12-hour light (rest) and 12-hour dark (activity) cycle (L/D: 12/12). In the first study a potentially lethal dose of INH (180 mg/kg) was administered by intraperitoneal (i.p.) route at six different circadian-times: 1, 5, 9, 13, 17 and 21 hours after light onset (HALO). In the second one, a sublethal dose (120 mg/kg) was administered at three circadian-times (1, 9 and 17 HALO) in order to evaluate the variation of haematological toxicity. Rectal temperature, body weight loss, survival (study 1) and complete cell count (study 2) were determined as toxicity endpoints. The Cosinor and ANOVA methods were used for the data statistical analysis.
  
  
  RESULTS
  The Cosinor analysis of rectal temperature time series prior to treatment validated a circadian rhythm, which demonstrates that mice were well synchronized. Following INH injection, rectal temperature increased in all the six circadian stages at days 2 and 3. Body weight loss varied from -12% at 1 HALO to -7% at 13 HALO (P<0.001). The 24-h mean of mortality induced by INH was 38%. Such lethal toxicity varied according to the circadian dosing-time. Maximum (60%) and minimum (20%) survival rates were observed when INH was administered at 9 and 1 HALO respectively. The highest survival time (25 days) occurred when INH was injected at 9 HALO while the lowest survival time (7 days) occurred when INH was given at 1 HALO. The decrease of haematological variables (cytopenia) was dependent on the circadian dosing-time (P<0.001). The least haematological toxicity illustrated by leukopenia index, anaemia and thrombocytopenia was observed in the middle of the second half of the light-rest phase (9 HALO).
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5000 Monatir, Tunisia. Electronic address: nouha_souayed@yahoo.fr.
authors.forename: Nouha
authors.initials: N
authors.lastname: Souayed
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5000 Monatir, Tunisia. Electronic address: malek_chennoufi@yahoo.fr.
authors.forename: Malek
authors.initials: M
authors.lastname: Chennoufi
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5000 Monatir, Tunisia. Electronic address: boughattas_fida@yahoo.fr.
authors.forename: Fida
authors.initials: F
authors.lastname: Boughattas
authors.affiliation: Laboratory of Haematology, CHU Fattouma Bourguiba, University of Monastir, 5000 Monastir, Tunisia. Electronic address: mohsenhassine@yahoo.fr.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Hassine
authors.affiliation: Laboratory of Biomonitoring of the Environment (LR01/ES14), Faculty of Science of Bizerta, University of Carthage, 7021 Bizerta, Tunisia. Electronic address: mobenattia@yahoo.fr.
authors.forename: Mosaddok
authors.initials: M
authors.lastname: Ben Attia
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5000 Monatir, Tunisia. Electronic address: aouam_k@yahoo.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Aouam
authors.affiliation: Unit of Chronobiology, Foundation A.-de-Rothschild, 75940 Paris, France. Electronic address: bergarien@yahoo.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Reinberg
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, 5000 Monatir, Tunisia. Electronic address: naboughattas@yahoo.fr.
authors.forename: Naceur A
authors.initials: NA
authors.lastname: Boughattas
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects*; D004361:Drug Tolerance; D041905:Erythroid Cells / Q000187:drug effects; D007538:Isoniazid / Q000633:toxicity*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D007538:Isoniazid
keywords: Antituberculosis agent; Circadian rhythm; Cosinor method; Haematological toxicity; Isoniazid; Mice; Tolerance