Disease relevance of Skf 105685

• SK&F 105685 is a novel azaspirane with immunosuppressive activity in animal models of autoimmune disease [1].
• Beneficial effects of long-term treatment with SK&F 105685 in murine lupus nephritis [2].
• Compared to AA control rats, SK&F 105685 suppressed hindpaw edema 64% or 41-54% in AA rats receiving 30 or 20 mg/kg/day, respectively [3].
• In addition, SK&F 105685 inhibited skin wheal responses to purified protein derivative (PPD) of tuberculin in AA rats and the development of hindleg paralysis associated with experimental allergic encephalomyelitis (EAE) [4].
• In a therapeutic protocol, where dosing was initiated on day 10 after disease induction, SK&F 105685 (20 mg/kg/day) effectively halted disease progression, and the inflammatory lesion was suppressed by 70% following treatment for 20 days [5].

Psychiatry related information on Skf 105685

• AM from SK&F 105685-treated rats had an enhanced ability to kill the opportunistic pathogen Candida albicans in vitro indicating that there was no impairment of macrophage-dependent host defense mechanisms [6].

High impact information on Skf 105685

• The azaspirane SKF 105685 (N,N-dimethyl-8, 8-dipropyl-2-azaspiro (4.5) decane-2-propanamine dihydrochloride) has been shown to attenuate or reverse the course of immunologic disease in several animal models, possibly through the induction of nonspecific suppressor activity [7].
• Induction of nonspecific x-irradiation-resistant suppressor cell activity in vivo and prolongation of vascularized allograft survival by SK&F 105685, a novel immunomodulatory azaspirane [1].
• SK&F 105685 therapy diminished the immunohistological features of acute rejection, with the cellular infiltrate suppressed and the induction of IL-2/transferrin receptors, and elaboration of IL-2/IFN-gamma essentially abolished, as compared with the grafts in untreated hosts [1].
• Studies performed to determine the mechanism of the decrease in serum cholesterol caused by SK&F 105685 indicated that it was not due to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase or acyl-CoA:cholesterol acyltransferase activities, or to a potentiation of cholesterol-7 alpha-hydroxylase activity [8].
• We demonstrate here that administration of SK&F 105685 increases the number of granulocyte-macrophage colony-forming units (CFU-GM) within the bone marrow 24 h after injection in a dose-dependent manner [9].

Biological context of Skf 105685

• These results demonstrate that SK&F 105685 and rIL-1 stimulate myelopoiesis in vivo and suggest a mechanism by which prophylactic treatment with these agents protects mice from otherwise lethal irradiation [9].
• Because we hypothesized that the induction of SC was associated with enhanced hematopoiesis, we sought to determine the hematopoietic potential of SK&F 105685 [9].
• Administration of the immunosuppressive agent, SK&F 105685, has demonstrated immunosuppressive activity in several animal models of autoimmunity such as adjuvant arthritis and experimental autoimmune encephalomyelitis [10].
• SK&F 105685 however, was able to inhibit the generation of a specific in vitro antibody response to sheep red blood cells (SRBC) by splenocytes from treated animals [11].
• AA control rats and AA rats treated prophylactically or therapeutically with SK&F 105685 had significant and similar increases in their total white blood cell (WBC), neutrophil, monocyte and platelet counts [5].

Anatomical context of Skf 105685

• Oral administration of SK&F 105685 starting at 12 weeks of age prevented the increased urinary protein loss, inhibited the histologic changes in the glomeruli, reduced the increase in spleen and lymph node weight and modified the phenotypic profile of the lymphoid cells [2].
• Histologically SK&F 105685 markedly attenuated the extent and severity of the inflammatory lesion and preserved the basic integrity of bone and cartilaginous tissues, including the content and distribution of proteoglycans of the articular cartilages [3].
• Oral administration of SK&F 105685 and SK&F 106615 caused PL accumulation in bronchoalveolar lavage macrophages (AM) but to a far lesser extent (three- to fivefold) than chlorphentermine [6].
• Treatment with SK&F 105685 also resulted in significantly enhanced myelopoiesis as measured by a 128% increase in the frequency of bone marrow myeloid progenitors (CFU-GM) [10].
• The activity of SK&F 105685 in these models is associated with the induction of non-specific suppressor cell (SC) activity as defined by the ability of cells from drug-treated animals to inhibit the proliferative response of lymphocytes from control animals to concanavalin A [11].

Associations of Skf 105685 with other chemical compounds

• MTX did not induce splenic SC activity and, despite the structural similarities between CHL and SK&F 105685, only the latter induced suppressor cells [12].

Gene context of Skf 105685

• On the basis of this evidence, we conclude that SK&F 105685 can attenuate the progression of renal damage in MRL/lpr mice by exerting a unique effect on cells which may be involved in the autoimmune process [2].
• Our studies show that SK&F 105685 has remarkable protective effects on the joints of AA rats and suggests that it may attenuate the overall inflammatory process and retard the degenerative loss of skeletal tissue in rheumatoid arthritis in humans [3].
• Relatively early event(s) in cell proliferation were affected by SK&F 105685 since delaying addition of the drug by 24 to 48 hours after Con A stimulation of rat spleen cells resulted in reduced levels of suppression [13].

Analytical, diagnostic and therapeutic context of Skf 105685

• The azaspirane SKF 105685 ameliorates renal allograft rejection in rats [7].
• Six days after transplantation, GFR (inulin clearance, 1.46 +/- 0.27 versus 0.41 +/- 0.15 mL/min per kg; P < 0.005) and RPF (p-aminohippurate clearance, 5.48 +/- 0.98 versus 1.99 +/- 0.72 mL/min per kg; P < 0.01) were significantly higher in SKF 105685-treated rats compared with vehicle-treated control rats [7].
• Spleen cells from SK&F 105685 treated rats had a reduced capacity to respond to concanavalin A and contained suppressor cell activity as measured in a coculture assay [3].
• Beneficial effects of SK&F 105685 in rat adjuvant arthritis: prophylactic and therapeutic effects on disease parameter progression [5].
• Taken together, these results suggest that, in a therapeutic setting, SK&F 105685 is unlikely to compromise the immune status of the host as it can down-regulate a specific immune response without causing generalized immunosuppression [11].

References