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  • 1
    Electronic Resource
    Electronic Resource
    Bisphosphonates and Tetracycline: Experimental Models for Their Evaluation in Calcium-Related Disorders (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 606-613 
    Details
    ISSN: 1573-904X
    Keywords: bisphosphonates ; tetracycline ; calcification ; hydroxyapatite ; bone resorption ; synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This work was aimed at synthesizing novel bisphosphonates (BPs) and examining them in comparison to clinically used BPs such as pamidronate and alendronate, and to tetracycline, in order to evaluate their potential as anticalcification and antiresorption agents. The correlation between the various models was examined in order to establish facile experimental models for pre-screening of potential compounds. Methods. Nitrogen-containing heterocyclic, novel BPs such as 2-(3-methylimidazolio) ethylidene-l,l-bisphosphonic acid betaine (VS-5b), 2-(2-dimethylamino-4-pyrazinio)ethylidene-1,1 -bisphosphonic acid betaine (VS-6b), and 2-(2-α-pyridylethylthio) ethylidene-1,1-bisphosphonic acid (ISA-225), were synthesized and evaluated in comparison to clinically used BPs, in various experimental models of resorption and calcification. Results. The physicochemical properties of the novel compounds are slightly different than the BPs in clinical use: the pKa values are lower, the affinity for hydroxyapatite is lower and the solubilities of the calcium salts are higher. The anticalcification potencies of the novel compounds were high and ranked as follows: alendronate = pamidronate 〉 VS-6b = VS-5b = ISA-225 〉 tetracycline. The in vivo antiresorption activity of VS-5b and VS-6b in comparison to that of the clinically employed, pamidronate, was shown to be similar and higher, respectively. Conclusions. The anticalcification activity of the novel compounds as well as that of tetracycline was lower than that of alendronate. The antiresorption activity of VS-6b was similar to that of pamidronate. A good correlation between the different models was found, enabling the facile screening of novel compounds. The activities of tetracycline and EDTA highlight the distinct behavior of BPs as "crystal poison”. In addition, tetracycline was found to be a potent anticalcification agent in the ectopic calcification model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011990129437
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  • 2
    Electronic Resource
    Electronic Resource
    Bisacylphosphonates Inhibit Hydroxyapatite Formation and Dissolution in Vitro and Dystrophic Calcification in Vivo (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 143-148 
    Details
    ISSN: 1573-904X
    Keywords: bisphosphonates ; phosphonates ; acylphosphonates ; ketophosphonates ; calcification ; calcinosis ; hydroxy apatite
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Some geminal bisphosphonates are used clinically for a number of important bone/calcium related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bisacylphosphonates (e.g., adipoyl- and suberoylbisphosphonate). These compounds were found to inhibit significantly hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. These are the first instances of nongeminal bisphosphonates [P–(C)n– P, n ≥ 2] that have been reported to be active in calcium-related disorders. The reported bisacylphosphonates possess apparent lower toxicity, and their calcium complexes/salts have improved solubility properties. Therefore, they are of potential importance for clinical applications.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018956516640
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Structurally different bisphosphonates exert opposing effects on alkaline phosphatase and mineralization in marrow osteoprogenitors (1998)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 68 (1998), S. 186-194 
    Details
    ISSN: 0730-2312
    Keywords: osteoprogenitors ; marrow-stroma ; alkaline phosphatase ; bisphosphonates ; cell proliferation ; mineralization ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Bisphosphonates (BPs) are inhibitors of bone resorption and soft tissue calcification. The biological effects of the BPs in calcium-related disorders are attributed mainly to their incorporation in bone, enabling direct interaction with osteoclasts and/or osteoblasts through a variety of biochemical pathways. Structural differences account for the considerable differences in the pharmacological activity of BPs. We compared the effects of two structurally different compounds, alendronate and 2-(3′-dimethylaminopyrazinio)ethylidene-1,1-bisphosphonic acid betaine (VS-6), in an osteoprogenitor differentiation system. The BPs were examined in a bone marrow stromal-cell culture system, which normally results in osteoprogenitor differentiation. The drugs were present in the cultures from days 2 to 11 of osteogenic stimulation, a period estimated as being comparable to the end of proliferation and the matrix-maturation stages. We found that the two different BPs have opposing effects on specific alkaline phosphatase (ALP) activity, on stromal-cell proliferation, and on cell-mediated mineralization. These BPs differentially interact with cell-associated phosphohydrolysis, particularly at a concentration of 10-2 of ALP Km, in which alendronate inhibits whereas VS-6 did not inhibit phosphatase activity. VS-6 treatment resulted in similar and significantly increased mineralization at 10 and 1 μM drug concentrations, respectively. In contrast, mineralization was similar to control, and significantly decreased at 10 and 1 μM drug concentrations, respectively, under alendronate treatment. J. Cell. Biochem. 68:186-194, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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    Paper (German National Licenses)
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