title: Effects of sodium fusidate in animal models of insulin-dependent diabetes mellitus and septic shock.
abstract: We have evaluated the effects of the novel immunosuppressant sodium fusidate (fusidin) in the non-obese diabetic (NOD) mouse and in D-galactosamine (D-Gal)-presensitized BALB/c mice challenged with the bacterial superantigen, Staphylococcus aureus enterotoxin B (SEB) or with the endotoxin, Escherichia coli lipopolysaccharide (LPS). The NOD mouse model has clinical and histoimmunological features similar to those of human insulin-dependent diabetes mellitus (IDDM). The SEB- and LPS-treated BALB/c mouse models exhibit pathogenic similarities with human septic shock conditions. In the NOD mouse, fusidin suppressed the spontaneous development of insulitis (mean inhibition 73%) and hyperglycaemia (IDDM incidence 25% versus 0%) when administered at 40 mg/kg five times weekly for 8 consecutive weeks from the fourth week of age; concurrently treated animals exhibited reduced percentages of splenic T lymphocytes. This anti-diabetogenic effect was confirmed in the accelerated model of diabetes induced in the NOD mouse with cyclophosphamide (CY) (IDDM incidence 55% versus 21-6% using dosages of fusidin from 40 to 80 mg/kg five times weekly); protection from IDDM development was achieved even when the drug (80 mg/kg/day) was first administered 7 days after CY challenge. In contrast, fusidin did not reverse hyperglycaemia when administered to CY-treated animals within 3 days of IDDM development. In the two models of septic shock, prophylactic treatment with fusidin, 80 mg/kg given three times for 2 days prior to D-Gal/SEB or D-Gal/LPS challenge, drastically reduced the lethality compared with D-Gal/buffer-treated mice. This effect may depend on the inhibitory action of fusidin on the secretion of cytokines such as interferon-gamma and tumour necrosis factor-alpha, the serum levels of which were greatly diminished in the fusidin-treated mice (mean inhibition 50-90%). These results demonstrate that fusidin may have a role in the treatment of cell-mediated autoimmune diseases and cytokine-mediated infectious diseases in humans.
authors.affiliation: Institute of Internal Medicine, Infectious Diseases and Immunopathology, University of Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.forename: P
authors.initials: P
authors.lastname: Zaccone
authors.forename: R
authors.initials: R
authors.lastname: Di Marco
authors.forename: G
authors.initials: G
authors.lastname: Magro
authors.forename: S
authors.initials: S
authors.lastname: Grasso
authors.forename: S
authors.initials: S
authors.lastname: Morrone
authors.forename: A
authors.initials: A
authors.lastname: Santoni
authors.forename: G
authors.initials: G
authors.lastname: Tempera
authors.forename: P L
authors.initials: PL
authors.lastname: Meroni
authors.forename: K
authors.initials: K
authors.lastname: Bendtzen
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004195:Disease Models, Animal; D004768:Enterotoxins; D005260:Female; D005672:Fusidic Acid / Q000627:therapeutic use* / Q000633:toxicity; D006943:Hyperglycemia / Q000517:prevention & control; D007371:Interferon-gamma / Q000097:blood; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D012772:Shock, Septic / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004768:Enterotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal; D005672:Fusidic Acid; D007371:Interferon-gamma