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Immunopharmacology Aug 1997The azaspiranes are novel immunomodulators which are effective in a variety of animal models of autoimmune disease and transplantation. The compounds appear to target...
The azaspiranes are novel immunomodulators which are effective in a variety of animal models of autoimmune disease and transplantation. The compounds appear to target macrophages and alter their functional activity. One of these compounds, SK&F 106615 (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride), is now in phase II clinical trials for rheumatoid arthritis. As many drugs/compounds effective in autoimmune disease and transplantation are overtly immunosuppressive, we designed studies to show that SK&F 106615 has selective immunomodulatory effects and that it does not perform in a manner characteristic of classical immunosuppressive agents on immune function. SK&F 106615 inhibited mouse and rat spleen cell and rat peripheral blood mononuclear cell proliferation in vitro with an IC50 of 500 nM. In vivo, treatment of C57BL/6 mice (15 mg/kg/day, i.p.) or rats (20 mg/kg/day, p.o.) for 2 weeks had no effects on specific antibody synthesis to ovalbumin (OVA) compared to rapamycin (RAP) which completely suppressed the antibody response. Compared to cyclosporin A (CsA), FK 506 and RAP which suppressed the antibody (plaque forming) response to particulate (sheep red blood cells) antigen in a dose responsive manner, SK&F 106615 administered at a dose of 50 mg/kg was inactive. There was an inhibition of the proliferative response of lymph node cells from treated mice and rats to mitogen and antigen in ex vivo assays. SK&F 106615, but not RAP, induced cells in the spleens of mice that could inhibit normal spleen cell proliferation in a co-culture assay. Thus, a selective immunomodulatory effect can be shown for SK&F 106615 in the absence of generalized immunosuppression.
Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibody Formation; Antirheumatic Agents; Cells, Cultured; Female; Leukocytes, Mononuclear; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Ovalbumin; Rats; Rats, Inbred Lew; Spiro Compounds; Spleen
PubMed: 9285244
DOI: 10.1016/s0162-3109(97)00003-9 -
Arthritis and Rheumatism Mar 1996To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA).
Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease magnetic resonance imaging and bone mineral density measurements.
OBJECTIVE
To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA).
METHODS
AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0-16 or days 0-23) or therapeutically (days 10-23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound.
RESULTS
Prophylactic treatment (days 0-16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 545 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10-23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema.
CONCLUSION
Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.
Topics: Absorptiometry, Photon; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Bone Density; Interleukin-6; Joints; Magnetic Resonance Imaging; Male; Rats; Rats, Inbred Lew; Spiro Compounds
PubMed: 8607900
DOI: 10.1002/art.1780390319 -
International Journal of... 1989SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited...
SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited immune-mediated hindpaw inflammation with an ED50 of 20 mg/kg/day. Both prophylactic and therapeutic administration were effective in this model. 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). Spleens of normal rats treated with SK&F 105685 were found to contain a population(s) of suppressor cells (SC) which inhibited the response of normal cells to Concanavalin A (Con A) in co-culture assays. The association between SC induction and anti-arthritic activity was determined by evaluating a series of chemically related azaspiranes in the AA rat model and for SC induction in normal rats. A statistically significant correlation was demonstrated (r = 0.79, P less than 0.001), indicating that SC induction may be responsible for the therapeutic activity of these compounds.
Topics: Adjuvants, Immunologic; Animals; Arthritis, Experimental; Autoimmune Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Lymphoid Tissue; Male; Rats; Rats, Inbred Lew; Spiro Compounds; T-Lymphocytes, Regulatory
PubMed: 2532178
DOI: 10.1016/0192-0561(89)90138-0 -
American Journal of Clinical Oncology Aug 1985Spirogermanium, a heavy metal compound in which germanium has been substituted in an azaspirane ring structure, was studied in 39 patients with advanced malignant... (Clinical Trial)
Clinical Trial
Spirogermanium, a heavy metal compound in which germanium has been substituted in an azaspirane ring structure, was studied in 39 patients with advanced malignant neoplasms. Thirty-one patients were considered evaluable for toxic effects of spirogermanium. Transient neurological symptoms occurred in 12 patients (39%), including dizziness or lightheadedness, marked fatigue, visual blurring, ataxia, paresthesia, and nausea. These symptoms could be reduced by infusing the drug over 2 hours rather than over 1 hour. Persistent neurotoxicity in the form of partial loss of taste or extreme weakness was observed in three patients. No evidence of hematologic, renal, or hepatic toxicity was observed. Antitumor activity of spirogermanium was not identified in this group of heavily pretreated patients. Spirogermanium had limited and acceptable toxicity in utilizing a dose of 120 mg/m2 infused over 2 hours, three times weekly.
Topics: Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Germanium; Half-Life; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Neoplasms; Organometallic Compounds; Spiro Compounds
PubMed: 3909806
DOI: 10.1097/00000421-198508000-00014 -
Journal of Medicinal Chemistry Jan 1965
Topics: Antipsychotic Agents; Behavior, Animal; Chemistry, Pharmaceutical; Pharmacology; Rats; Research; Spiro Compounds; Toxicology; Tranquilizing Agents
PubMed: 14287269
DOI: 10.1021/jm00325a015