Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats

Abstract

Pre-treatment of male Sprague-Dawley rats with long-acting bromocryptine microcapsules (CBLA) significantly inhibited the arthritic response to Freund's complete adjuvant and reduced weight loss, thymolysis, splenomegaly and leukocytosis. In the prevention of adjuvant arthritis (AA), the combination of CBLA plus sub-optimal doses of cyclosporine A (CsA) was more efficient than either of the drugs alone. Sub-optimal doses of CsA were 0.1 and 1.0 mg/kg/day s.c. for 5 days. Furthermore, CBLA alone did not decrease the incidence of experimental allergic uveitis (EAU) in the male Lewis rats. Low-dose CsA reduced the incidence of uveitis by 50%, and with the addition of CBLA, 100% of rats were protected. Low-dose CsA was 2 mg/kg/day i.m. for 14 days. Long-term treatment of male Sprague-Dawley rats with CBLA alone reduced the incidence and severity of spontaneous autoimmune periarteritis nodosa (PN) in a dose-dependent manner; CsA was less potent than CBLA, and only additive effects were obtained. Finally, for the prevention of spontaneous autoimmune insulin-dependent diabetes (DM), the administration of CBLA did not improve the effect of a low-dose CsA in male BB rats. Nevertheless, a delay in onset of DM could be achieved. A sequential therapy using CsA plus CBLA clearly showed beneficial effects. The dose of CsA was 10 mg/kg p.o. 6 days/week for 21 weeks. Compared with Sprague-Dawley or Lewis male rats, BB male rats showed only weak prolactin suppression after the same doses of CBLA. It is suggested that the use of CBLA may be particularly beneficial in autoimmune disorders. The effectiveness of the combination therapy CBLA plus CsA, however, was dependent on the model considered. Various factors could play a role: (1) the different ways of administering CsA (s.c. in AA, i.m. in EAU and PN, oral in DM); (2) strain-dependency in the capacity of CBLA to suppress Prl secretion; and (3) at least in the BB rats, the transient increase of CsA bioavailibility which was possibly induced by CBLA.

Interaction of Cytochrome P450 3A Inhibitors with P-Glycoprotein

“…For example, a transient increase in CsA bioavailability and synergism in prevention of autoimmune disease in rats has been noted previously when long-acting bromocriptine microcapsules were administered concurrently (Niedhart, 1996); and erythromycin increases the plasma concentration of ␣-dihydroergocryptine in humans (de Mey et al, 2001). These drug interactions are thought to be mediated by CYP3A because ergotamine and dihydroergotamine were proposed as CYP3A substrates (Pichard et al, 1990), and ergots such as ergotamine, dihydroergotamine, and bromocriptine are potent inhibitors of CYP3A-mediated metabolism (Pichard et al, 1990).…”

Green tea catechins alleviate autoimmune symptoms and visual impairment in a murine model for human chronic intraocular inflammation by inhibiting Th17-associated pro-inflammatory gene expression

“…Splenomegaly is associated with severity of autoimmune disorders in both animal studies 12 and clinical investigations 13,14 . Both spleen weight and size were significantly elevated by EAU ( P < 0.05).…”

Bromocriptine treatment of systemic lupus erythematosus

“…30 If bromocriptine treatment was given before Lewis rats were injected with spinal cord homogenate, the occurrence of experimental allergic encephalomyelitis was reduced and the disease that did develop was relatively less severe. 30,32,33 Bromocriptine was effective in some instances when it was used after clinical signs of induced autoimmune disease appeared. 30,32,33 Bromocriptine was effective in some instances when it was used after clinical signs of induced autoimmune disease appeared.…”

“…28 Bromocriptine decreased the incidence of experimental autoimmune uveitis in female Lewis rats 29 but was effective in males only if it was given with low-dose cyclosporine A. 30 If bromocriptine treatment was given before Lewis rats were injected with spinal cord homogenate, the occurrence of experimental allergic encephalomyelitis was reduced and the disease that did develop was relatively less severe. 31 Injections of bromocriptine also inhibited development of adjuvant arthritis in rats.…”