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International Journal of... 1991Administration of the immunosuppressive agent, SK&F 105685, has demonstrated immunosuppressive activity in several animal models of autoimmunity such as adjuvant...
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. The mechanism of action of SK&F 105685 in these autoimmune disease models appears to be the induction of non-specific suppressor cells (SC) detected in the spleen and bone marrow of treated animals. In this study we have examined the kinetics of SC appearance in the spleen and bone marrow following treatment with 30 mg/kg/day, p.o., for 1-6 days. SC activity was apparent following a single dose and increased with successive treatments. 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). Mechanistic studies indicated that in vitro treatment of bone marrow stromal cell cultures with SK&F 105685 upregulated the production of colony stimulating activity (CSA) detectable in a rat CFU-GM assay. Further, in vitro studies revealed that the SC in the bone marrow or spleens of SK&F 105685-treated rats admixed with normal marrow cells inhibited CFU-GM formation at a six-fold less cell concentration than cells obtained from control rats. These in vitro results suggest that the SK&F 105685-induced myelopoiesis is regulated by the subsequent generation of SC.
Topics: Adjuvants, Immunologic; Animals; Bone Marrow; Bone Marrow Cells; Colony-Forming Units Assay; Colony-Stimulating Factors; Hematopoiesis; Male; Rats; Rats, Inbred Lew; Spiro Compounds; T-Lymphocytes, Regulatory
PubMed: 1827431
DOI: 10.1016/0192-0561(91)90029-7 -
The Journal of Pharmacology and... Jan 1986Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium...
Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium also exhibits antiarthritic and immunoregulatory activities after p.o. administration to rats. Spirogermanium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered p.o. before or after the development of the arthritic lesions. After termination of spirogermanium administration, the adjuvant-injected hindleg lesions remained significantly suppressed for at least 2 weeks postdrug treatment; whereas, the uninjected, immune-mediated hindleg inflammation tended to increase postdrug treatment. In multiparameter ex vivo studies, untreated arthritic rats exhibited enhanced cyanine dye fluorescence in peripheral blood monocytes, enhanced interleukin (IL)-1 production by adherent spleen cells and depressed IL-2 and IL-3 production by splenic lymphocytes. Spirogermanium normalized these changes to various degrees, with the exception of the depressed IL-2 and IL-3 production. Spirogermanium administered to normal nonarthritic rats decreased mitogenic responses of spleen cells to Concanavalin A which was found to be caused, at least in part, by enhanced suppressor cell activity. The antiarthritic and immunoregulatory profile of spirogermanium appeared to be different from the profiles of the antiarthritic agents, auranofin and indomethacin.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis; Arthritis, Experimental; Auranofin; Aurothioglucose; Concanavalin A; Fluorescence; Germanium; Immunosuppressive Agents; Indomethacin; Interleukin-1; Interleukin-2; Macrophages; Male; Monocytes; Organometallic Compounds; Rats; Rats, Inbred Lew; Spiro Compounds; T-Lymphocytes, Regulatory
PubMed: 2934544
DOI: No ID Found -
The Journal of Rheumatology Mar 1994To determine the effects of SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the arthritic lesions in the tibiotarsal...
Effects of a novel azaspirane (SK&F 105685) on arthritic lesions in the adjuvant Lewis rat: attenuation of the inflammatory process and preservation of skeletal integrity.
OBJECTIVE
To determine the effects of SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the arthritic lesions in the tibiotarsal joint of adjuvant arthritic (AA) rats.
METHODS
Inhibition of hindpaw inflammation was measured by water displacement. The protective effects on joint integrity were determined by measuring radiographic and histological changes and by scanning electron microscopy.
RESULTS
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. Radiographic evaluation showed marked decreases in soft tissue swelling and in the severity of skeletal tissue loss at the tibiotarsal joint in both dose groups. 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. Cellular changes included decreases in the inflammatory infiltrate and in the number of osteoclasts and chondroclasts. Whereas AA control rats exhibited marked to severe loss (41-70%) of skeletal tissue mass, the loss in rats given 30 mg/kg SK&F 105685 was mild (< 20%). Scanning electron microscopy of the talus revealed only slight erosion of the articular cartilage and general preservation of the underlying bone. In contrast, in AA controls, there was marked erosion of the talar articular cartilage and severe loss of subchondral bone. 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.
CONCLUSION
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.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Bone and Bones; Cells, Cultured; Drug Evaluation, Preclinical; Edema; Immunosuppressive Agents; Inflammation; Lymphocyte Activation; Male; Microscopy, Electron, Scanning; Osteoclasts; Rats; Rats, Inbred Lew; Spiro Compounds; Spleen; T-Lymphocytes, Regulatory
PubMed: 8006892
DOI: No ID Found -
Transplantation Jun 1993SK&F 105685 is a novel azaspirane with immunosuppressive activity in animal models of autoimmune disease. This study evaluates the efficacy and mechanism of action of...
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.
SK&F 105685 is a novel azaspirane with immunosuppressive activity in animal models of autoimmune disease. This study evaluates the efficacy and mechanism of action of the compound in rat recipients of cardiac allografts. Short-term SK&F 105685 therapy (20 mg/kg/day by gavage) proved effective both in the pretreatment (days -14 to -8 or -7 to -1; allograft at day 0) and treatment (days 0 to 6) protocols, with cardiac allograft survival prolonged to 14-17 days (acute rejection = 7 days; P < 0.001). SK&F 105685 pretreatment exerted at least additive effects with subtherapeutic CsA (1.5 mg/kg/day x 7 days i.m.) given after transplantation, with 50% of allografts surviving > 50 days. 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. These correlated with normal frequency of CD4, CD5, CD8 phenotype subsets and B cells in recipient lymphoid organs, as shown by flow microfluorimetry. Adoptive transfer of untreated or x-irradiated (2000 rads) spleen cells from SK&F 105685-modulated hosts significantly prolonged the survival of donor-specific or third-party test cardiac allografts to 10-15 days, suggesting the presence of nonspecific x-irradiation-resistant suppressor cells in the transferred inoculum. Their activity could be enriched by Percoll density centrifugation and screened by the ability to inhibit Con A-driven proliferation of normal cells in the coculture assay. The light-density x-irradiation-resistant spleen cell fraction (1.07 g/ml) was consistently and significantly more suppressive than the heavy-density (1.09 g/ml) interface, or the corresponding unseparated cells. Thus SK&F 105685 therapy abrogates rejection response and significantly prolongs the survival of vascularized cardiac allografts in rats. This effect is associated with selective depression of host alloreactivity/immune activation at the graft site, and simultaneous induction of suppressor cells in recipient spleen, comparable to natural or nonspecific suppressor cells generated by TLI. This unique activity profile is consistent with the concept that SK&F 105685 should be considered as a critical chemical adjunct in novel therapeutic strategies representing TLI-equivalent.
Topics: Animals; Graft Rejection; Graft Survival; Heart Transplantation; Immunization, Passive; Male; Rats; Rats, Inbred Strains; Spiro Compounds; T-Lymphocytes, Regulatory; X-Rays
PubMed: 8516808
DOI: No ID Found -
Clinical and Experimental Rheumatology 1993SK&F 105685, methotrexate (MTX) and chloroquine (CHL) were examined for their ability to inhibit paw inflammation in the adjuvant arthritic rat (AA) and for their... (Comparative Study)
Comparative Study
SK&F 105685, methotrexate (MTX) and chloroquine (CHL) were examined for their ability to inhibit paw inflammation in the adjuvant arthritic rat (AA) and for their ability to induce non-specific suppressor cells (SC) in the spleens of these animals. Compared to SK&F 105685 (84-90%) inhibition and MTX (91% inhibition) CHL, at the maximally tolerated dose, only inhibited paw lesions by 29%. MTX did not induce splenic SC activity and, despite the structural similarities between CHL and SK&F 105685, only the latter induced suppressor cells.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Chloroquine; Methotrexate; Rats; Rats, Inbred Lew; Spiro Compounds; T-Lymphocytes, Regulatory
PubMed: 8324933
DOI: No ID Found -
Journal of Medicinal Chemistry Jan 1964
Topics: Anesthetics; Anesthetics, Local; Central Nervous System; Central Nervous System Stimulants; Chemistry, Pharmaceutical; Ganglionic Blockers; Hypnotics and Sedatives; Pharmacology; Rats; Research; Seizures; Spiro Compounds; Toxicology
PubMed: 14186032
DOI: 10.1021/jm00331a018 -
Leukemia Research Jan 2007
Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Spiro Compounds; Tretinoin
PubMed: 16860863
DOI: 10.1016/j.leukres.2006.06.007 -
Journal of Clinical Oncology : Official... May 1983Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation... (Comparative Study)
Comparative Study
Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation of clinical antitumor activity and lack of myelosuppression prompted us to investigate further the clinical effects of spirogermanium administered on various schedules. A total of 52 patients with advanced metastatic tumors refractory to standard therapy were treated with spirogermanium. Three different schedules of drug administration were evaluated. Initially, a short daily IV infusion for 5 days every week was evaluated, starting with a dose of 30 mg/m2/day. A total of 22 patients received 69 courses with a dose range of 30-120 mg/m2/day for 5 days every week. The maximum tolerated dose was 100 mg/m2/day IV over 1 hr and 120 mg/m2 over 2-3 hr. In the second phase of the study, 12 patients received 41 courses of spirogermanium as a 24-hr continuous infusion for 5 days/wk at a dose of 150-375 mg/m2/day. The maximum tolerated dose was 200 mg/m2/day for 5 days. In the third phase of the study, 18 patients received spirogermanium as a continuous infusion daily for a median of 30 days (range 6-77 days) in a dose range of 100-200 mg/m2/day. The maximum tolerated dose was 150 mg/m2/day. Of the 44 assessable patients, 3 demonstrated a partial response and 3 had minor tumor regression; all responses occurred in lymphoma patients. The dose-limiting toxicity of spirogermanium was neurologic; other side effects consisted of mild anorexia, nausea and vomiting, and possible lung toxicity. There was no clear evidence of cumulative toxicity despite daily administration of spirogermanium. Our data suggest that spirogermanium can be administered daily by several different schedules, and the optimum dose depends on the infusion time and the duration of therapy. The delivery of drug by continuous infusion permitted administration of twofold higher dose levels compared to the standard IV schedules used in previous studies.
Topics: Adult; Aged; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Lymphoma; Male; Middle Aged; Nausea; Nervous System Diseases; Organometallic Compounds; Ovarian Neoplasms; Spiro Compounds
PubMed: 6668504
DOI: 10.1200/JCO.1983.1.5.331 -
Journal of Medicinal Chemistry Jul 1963
Topics: Antineoplastic Agents; Biomedical Research; Chemistry, Pharmaceutical; Neoplasms; Neoplasms, Experimental; Pharmacology; Rats; Research; Sarcoma; Spiro Compounds
PubMed: 14191387
DOI: 10.1021/jm00340a012 -
Cancer Treatment Reports 1980Spirogermanium is a new azaspirane antitumor agent, with the metal germanium substituted for a one-carbon moiety in the ring structure. This drug inhibits DNA and RNA...
Spirogermanium is a new azaspirane antitumor agent, with the metal germanium substituted for a one-carbon moiety in the ring structure. This drug inhibits DNA and RNA synthesis in HeLa cells, is cytotoxic in vitro, and has curative in vivo antitumor activity against the ascitic Walker 256 carcinosarcoma in rats. No hematologic toxicity was recorded during the preclinical toxicologic evaluation. The principal clinical toxic effects observed in this phase I trial were neurologic, manifested as lethargy, dizziness, and ataxia, while a grand mal seizure was produced after an accidental overdose. There was no evidence of hematologic, renal, or hepatic toxicity. A partial response was achieved in a patient with a well-differentiated lymphocytic lymphoma. We recommend that phase II trials be conducted with a twice or thrice weekly dose of 50-80 mg/m2, administered in a 30-minute iv infusion.
Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Evaluation; Female; Germanium; HeLa Cells; Humans; Male; Middle Aged; Neoplasms; Nervous System Diseases; Organometallic Compounds; Spiro Compounds
PubMed: 7459890
DOI: No ID Found