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Biomedical subjects

L Binderup

Publications and source records attributed to L Binderup.

At least 91 records · Page 5Linked to original sources
PubMed1991

Calcipotriol (MC 903): pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OH)2D3.

Calcipotriol (MC 903) is a novel analogue of the physiologically active metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3]. MC 903 and 1,25(OH)2D3 have similar effects on cell proliferation and cell differentiation in vitro using the human histiocytic lymphoma cell line U 937, but in vivo MC903 has 100-200 times less effect on calcium metabolism. To elucidate this difference, the pharmacokinetic profiles after a single intravenous dose (50 micrograms/kg) of the two compounds to rats were compared. The area under the serum level/time curve (AUC) was more than 100 times higher for 1,25(OH)2D3 than for MC903 and the rate of clearance was more than 100 times higher for MC903 than for 1,25(OH)D3. Serum from MC903 or 1,25(OH)2D3 dosed rats (i.v. 10 micrograms/kg) was investigated for biological activities by incubation of U 937 cells with serum collected 0-24 hr after drug administration. Serum from MC903 dosed rats had an effect only when collected shortly after dosing, whereas serum from 1,25(OH)2D3 dosed rats had an effect when collected up to 4 hr after dosing. The biological effects on the U937 cells of the two major metabolites of MC903 (MC 1046 and MC 1080) were investigated. The metabolites had effects that were more than 100 times weaker than those of the parent compound. The effect of MC903 on proliferative disorders, its fast elimination and the formation of inactive metabolites makes MC903 suitable for topical treatment of psoriasis.

Animals↗
PubMed1991

Actions of calcipotriol (MC 903), a novel vitamin D3 analog, on human bone-derived cells: comparison with 1,25-dihydroxyvitamin D3.

The actions of a novel vitamin D3 analog calcipotriol (MC 903), on human bone-derived cells were compared to those of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Both calcipotriol and 1,25-(OH)2D3 inhibited the proliferation of human osteoblast-like cells in a dose-dependent manner (10(-10)-10(-6) M), an effect observed at different cell densities. Lower concentrations of either agent exerted no marked effect on the growth of the cells compared to untreated cultures. Calcipotriol and 1,25-(OH)2D3 were equipotent in stimulating the activity of alkaline phosphatase and the synthesis of osteocalcin in human osteoblast-like cells. The stimulation of alkaline phosphatase activity and osteocalcin synthesis by both compounds was evident by 24 h and was increased progressively up to 96 h in a dose-dependent manner over the concentration range of 10(-10)-10(-6) M. The increment in both proteins was dependent on cell density and was attenuated at higher cell densities. In contrast to these actions, neither calcipotriol nor 1,25-(OH)2D3 (10(-14)-10(-6) M) affected the synthesis of prostaglandin E2. These studies indicate that calcipotriol and 1,25-(OH)2D3 exhibit a similar spectrum of activity on human osteoblast-like cells in vitro.

Alkaline Phosphatase↗
PubMed1990

1,25(OH)2D3 and calcipotriol (MC903) have similar effects on the induction of osteoclast-like cell formation in human bone marrow cultures.

MC903 is a novel analogue of 1,25(OH)2D3 which exhibits similar inhibitory effects on cell proliferation and like, 1,25(OH)2D3, stimulates synthesis of osteoblast specific proteins by osteoblast-like cells in vitro. It is less active than 1,25(OH)2D3 in causing hypercalcemia in vivo. Since 1,25(OH)2D3 is known to stimulate bone resorption and increase the number of osteoclasts in several systems (in vivo and in vitro) we examined the effects of MC903 on the formation of osteoclast-like cells in vitro. As reported previously 1,25(OH)2D3 promoted the formation of multinucleated cells with phenotypic and functional characteristics of osteoclasts from adult human bone-marrow cultures at concentrations between 10(-8)M to 10(-12)M. Higher doses consistently suppressed multinucleated cell formation to values seen in the absence of 1,25(OH)2D3. Cells cultured in the presence of MC903 or for three weeks consistently induced the formation of multinucleated cells at concentrations 10(-8)M to 10(-12)M. As seen with 1,25(OH)2D3, MC903 also inhibited multinucleated cell formation at very high concentrations (10(-6)M). In two separate experiments MC903 appeared to be more potent than 1,25(OH)2D3 at lower concentrations (10(-10)M - 10(-12)M). From this study we conclude that MC903 is at least as potent as 1,25(OH)2D3 in inducing the formation human osteoclast-like cells in vitro. The decreased ability of MC903 to induce hypercalcemia in vivo is not therefore a result of a less marked effect than 1,25(OH)2D3 on the regulation of osteoclast formation.

Acid Phosphatase↗
PubMed1988

Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo.

MC 903 is a novel vitamin D analogue which has been tested for its effects on cell differentiation and cell proliferation in vitro using the human histiocytic lymphoma cell line U937, and on calcium metabolism in rats in vivo. In the present investigation MC 903 was compared to the natural metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] and to its synthetic analogue 1 alpha-hydroxycholecalciferol [1 alpha (OH)D3]. MC 903 was found to be a potent inducer of cell differentiation and to inhibit cell proliferation and DNA-synthesis in concentrations comparable to those observed with 1,25(OH)2D3. 1 alpha (OH)D3, which is only active after metabolic conversion to 1,25(OH)2D3, was more than 100 times less potent. Oral or intraperitoneal administration of MC 903 to rats showed that the compound was at least 100 times less active than 1,25(OH)2D3 and 1 alpha (OH)D3 in causing hypercalciuria, hypercalcemia and bone calcium mobilisation. The low vitamin D activity of MC 903 was further confirmed by administration of the compound to rachitic rats. The strong direct effects of MC 903 on cell proliferation and cell differentiation, coupled with its decreased activity as a classical vitamin D makes this compound an interesting candidate for studies in human proliferative disorders such as psoriasis.

Animals↗
PubMed1987

1 alpha(OH)D3 (ETALPHA) treatment and receptor studies in 16 patients with chronic and myeloproliferative disorders.

10 patients with CLL and 2 with CML were treated with gradually increasing doses of 1 alpha(OH)D3, up to 4 micrograms daily during 6 wk. 3 patients with preleukemia and 1 with myelofibrosis were treated with 2 micrograms daily of 1 alpha(OH)D3 for a prolonged period up to 17 wk. The treatment with 1 alpha (OH)D3 did not result in changes of disease parameters in any of the patients under study. Receptor studies for 1,25(OH)2D3 were performed in 8 CLL patients and revealed only 1 patient with increased specific receptor binding capacity. The maximum tolerable dose of 1 alpha(OH)D3 varied individually, but was in the range of 2-4 micrograms daily.

Humans↗
PubMed1986

Bone changes in rats with adjuvant arthritis: treatment with 1 alpha-hydroxycholecalciferol.

Adjuvant arthritis was induced in female Lewis rats by the injection of Mycobacterium butyricum in mineral oil in a hindpaw. Bone changes due to polyarthritis were evaluated in the tibia metaphyseal region of the noninjected hind leg. A decrease in bone mass and mineral content was observed in the affected bone. accompanied by a marked increase in bone resorption. Non-arthritic and arthritic rats were treated with the synthetic vitamin D analogue, 1 alpha-hydroxycholecalciferol (0.01 to 1.0 micrograms/kg/day orally) for 28 days. Treatment resulted in a small increase in bone weight and mineral content in the non-arthritic rats. Arthritic rats exhibited a larger increase in bone weight, hydroxyproline and calcium content. These beneficial effects were correlated with the ability of 1 alpha-hydroxycholecalciferol to increase extracellular calcium and phosphorus levels, as measured by the increased urinary excretion of calcium and inorganic phosphate and by the increase in serum calcium. Bone resorption and new bone formation were not affected by the treatment.

Alkaline Phosphatase↗
PubMed1985

Effects of isoprinosine in animal models of depressed T-cell function.

Isoprinosine--a new drug possessing immunostimulating properties--was investigated for its ability to influence cell-mediated immune responsiveness in animal models of deficient T-cell function. In vitro isoprinosine strongly increased T-cell mitogenesis in spleen cells from normal rats, with only modest increases in B-cell mitogenesis and no effects on unstimulated cells. In vivo isoprinosine (50 mg kg-1 day-1 orally) had no effects on spleen cell responsiveness when administered to normal rats for 4 or 14 days. However, when the same dose of isoprinosine was administered to rats immunosuppressed with cyclophosphamide (5 mg kg-1 day-1 orally) a partial restoration of T-cell mitogenesis was observed after 14 days of treatment. In rats with adjuvant arthritis treated with isoprinosine for 14 days, depressed T-cell responsiveness was completely restored to the level of the nonarthritic animals. The involvement of different cell types in the observed effects of isoprinosine was further studied in arthritic rats. Removal of monocytes/macrophages from the cell suspensions prior to culture did not affect the increased T-cell response in isoprinosine-treated rats, suggesting a direct stimulatory effect of isoprinosine on T-cell functions. T-suppressor cell function, impaired in arthritic rats, was not restored by treatment with isoprinosine. These results suggest that isoprinosine may exert selective effects on specific T-cell subsets, a finding that may increase the therapeutic interest of the drug.

Animals↗
PubMed1984

Effects of the H2-receptor agonist dimaprit on lymphocyte responsiveness in vitro.

The histamine H2-agonist dimaprit was found to increase the response of rat spleen cells to the T-cell mitogen Concanavalin A, when present at concentrations of 10(-5) and 10(-4)M. Higher concentrations of dimaprit were cytotoxic. The enhanced response seemed to be associated with an inhibitory effect of dimaprit on T-suppressor cell activity rather than with a direct mitogen-like stimulation of lymphocyte proliferation or with an interference with monocyte/macrophage functions. The stimulatory effects of dimaprit were not reversed by the H2-receptor antagonist, cimetidine, nor by the beta-receptor antagonists metoprolol and H 35/25. Addition of the H1-receptor antagonist, mepyramine, further increased the stimulatory effect of dimaprit on lymphocyte responsiveness.

Animals↗
PubMed1983

Lymphocyte-macrophage co-operation during induction of T-suppressor cell activity in rats with adjuvant arthritis.

The role of macrophages and of macrophage-lymphocyte co-operation in the induction of T-suppressor cell activity in rats with adjuvant arthritis was investigated. Macrophages from arthritic rats had no direct effect on the induction of T-suppressor cells, but, in the presence of arthritic rats' lymphocytes or supernatants from such lymphocytes, macrophages inhibited the induction of T-suppressor cell activity. Addition of indomethacin during the induction of T-suppressor cells reduced the inhibitory effects, suggesting that prostaglandins released from lymphocyte-activated macrophages might be involved in the defective induction of T-suppressor cell activity in rats with adjuvant arthritis.

Animals↗
PubMed1983

Decreased T-suppressor cell activity in rats with adjuvant arthritis.

Concanavalin-A-induced T-suppressor cell activity was decreased in spleen cell suspensions from Lewis rats with adjuvant arthritis. This decreased activity was evident on day 10 after the induction of the disease, just before the development of the polyarthritic lesions, and persisted during the period of active inflammatory and immunological disease. The extent of the impairment of T-suppressor cell activity was positively correlated with the severity of the arthritic lesions. Removal of phagocytic cells prior to induction of T-suppressor cells abolished the observed decrease in suppressor cell activity. It is suggested that this model may be of value for the investigation of suppressor cell function in immunologically mediated disorders.

Animals↗
PubMed1982

Captopril(SQ 14,225): in vitro and in vivo influence on the proliferative response of rat lymphocytes.

Captopril in vitro (50-500 micrograms/ml) increased 3H-TdR incorporation in unstimulated and mitogen-stimulated cultures of rat lymphocytes. Unseparated spleen and lymph node cells of rats orally treated with captopril (50 mg/kg/day x 4)) showed decreased basal and mitogen stimulated 3H-TdR incorporation. The removal of macrophages abrogated this inhibitory effect. Leucine aminopeptidase activity of macrophages was reduced - in vivo and in vitro - by captopril.

Animals↗
PubMed1982

Antirheumatic drugs and macrophage function: effects on tumour cell growth in vitro.

The ability of the antirheumatic drugs D-penicillamine, chloroquine and levamisole to modify macrophage-mediated inhibition of tumour cell growth in vitro was investigated. Increasing numbers of rat peritoneal macrophages were cocultured with a fixed number of ascites hepatoma AH-13 rat tumour cells. Tumour cell growth was assessed as the uptake of 3H-thymidine (3H-TdR) by AH-13 cells at the end of a 24 h period of coculture with macrophages treated in vitro or in vivo with the various drugs. In vitro, preincubation of macrophages with D-penicillamine or chloroquine (50 - 250 micrograms/ml) increased tumour cell 3H-TdR incorporation, compared to cultures with untreated macrophages. Macrophages from rats treated with D-penicillamine or chloroquine (50 mg/kg/day orally) for 4 days similarly increased tumour cell 3H-TdR incorporation, compared to cultures with macrophages from untreated rats. These effects persisted for at least 3 to 4 weeks of treatment. Preincubation with levamisole (10 - 100 micrograms/ml) in vitro had no effect on macrophage-mediated inhibition of tumour cells, whereas increased tumour cell 3H-TdR incorporation was observed in cultures with macrophages from rats treated with levamisole (5 mg/kg/day orally) in vivo. Macrophages from rats with experimentally induced chronic inflammation, i.e. adjuvant arthritis, were found to increase tumour cell 3H-TdR incorporation, compared to macrophages from nonarthritic rats. This trend was further enhanced by treatment with D-penicillamine, chloroquine or levamisole.

Animals↗
PubMed1982

The effect of some antirheumatic drugs in vivo on the response of spleen cells to concanavalin A in rats with chronic inflammation.

During the course of adjuvant arthritis in rats adherent spleen cells inhibited the response of spleen lymphocytes to the T-cell mitogen concanavalin A (Con A). The effects of 14 days treatment with various antirheumatic drugs on spleen cell responsiveness to Con A were investigated. Two nonsteroidal anti-inflammatory drugs, indomethacin (1 mg/kg/day p.o.) and acetylsalicylic acid (200 mg/kg/day p.o.) did not modify the spleen cell response, whereas treatment with chloroquine (50 mg/kg/day p.o.) or levamisole (5 mg/kg/day p.o.) further increased the inhibitory effects of the adherent suppressive spleen cells. On the contrary, treatment with sodium aurothiomalate (10 mg/kg/day i.m.), D-penicillamine (50 mg/kg/day p.o.) or pyritinol (50 mg/kg/day p.o.) significantly enhanced the response of the lymphocytes to Con A. In addition to the effects on spleen cell responsiveness, the ability of the various drug treatments to modify the polyarthritic lesions of the disease was investigated. It is suggested that this model may provide a valuable approach for evaluating the effects of antirheumatic drugs in vivo on immunological responsiveness during chronic inflammatory disease.

Animals↗
PubMed1981

An unusual profile of activity of a new basic anti-inflammatory drug, timegadine.

Timegadine (SR 1368, N-cyclohexyl-N"-4-(2-methylguinolyl)-N'-2-thiazolylguanidine) dose-dependently inhibited carrageenan-, nystatin-, and concanavalin A-induced edema. Detailed studies in adjuvant arthritic rats showed: (a) long dosing regimen with timegadine inhibited primary and secondary lesions, leukocytosis and hyperfibrinogemia, (b) timegadine was significantly active in reducing the severity of the already established disease, (c) a short course of dosing with timegadine at the time of adjuvant injection permanently prevented the development of secondary lesions. The tuberculin hypersensitivity reaction was enhanced by timegadine in both adjuvant arthritic and normal rats. Experimental allergic encephalomyelitis in rats and guinea pigs was not affected. It is concluded that timegadine has a profile or activity which differs from that of known anti-inflammatory drugs.

Analgesics↗
PubMed1980

Inhibition of adjuvant arthritis by intraperitoneal administration of low doses of silica.

Daily intraperitoneal administration from day 3 to day 10 post-adjuvant of crystalline silica in doses 1.5-3.1 mg/kg per day or of amorphous silica in doses of 12.5 mg/kg per day inhibited the development of adjuvant arthritis mostly suppressing the swelling of the non-injected paw. These doses of silica did not impair the carbon clearance. Higher doses of silica (25 mg/kg per day of the crystalline form and 50 mg/kg of the amorphous form) administered from day 17 to day 24 post-adjuvant had no effect on the already established disease.

Animals↗
PubMed1980

Macrophages from adjuvent arthritic rats preferentially synthetize prostacyclin.

Peritoneal macrophages obtained from rats 21 days after induction of adjuvant arthritis and maintained in culture for 20 h in presence of [14C]-arachidonic acid and 10% foetal calf serum were found to have increased capacity for synthetizing prostacyclin and diminished capacity for synthetizing PGE2 compared with macrophages from normal rats. Similar results were obtained when foetal calf serum was replaced by either normal or arthritic rat serum. Orally administered indomethacin inhibited the increased synthesis of prostacyclin.

Animals↗