INT173576
From wiki-pain
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Sentences Mentioned In
Key: | Protein | Mutation | Event | Anatomy | Negation | Speculation | Pain term | Disease term |
Significant differences in binding affinity to bone mineral have been found among the bisphosphonates in vitro, with a rank order of highest to lowest as follows: zoledronate > alendronate > ibandronate > risedronate.8,9 Similarly, the degree to which bisphosphonates reduce osteoclastic activity by inhibition of farnesyl pyrophosphate synthase also differs among them, with a rank of order from highest to lowest as follows: zoledronate > risedronate > ibandronate > alendronate.10,11 These differences are explained principally by the three-dimensional configuration of each bisphosphonate and, as a result, each bisphosphonate offers a unique combination of pharmacologic properties.7 As a class, bisphosphonates increase the bone mineral density (BMD), decrease the levels of biomarkers of bone resorption, and reduce the risk of osteoporotic fractures. | |||||||||||||||
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The model would benefit from further development in order to reduce variance in the startle response and FPS. | |||||||||||||||
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They also have two side chains which determine the affinity of the bisphosphonate for the calcium phosphate in hydroxyapatite crystals in bone tissue, and determine the extent to which the bisphosphonate inhibits the bone-resorbing activity of osteoclasts by selectively inhibiting the farnesyl pyrophosphate synthase (FPPS) enzyme, the key regulatory enzyme in the mevalonic acid pathway. | |||||||||||||||
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Earlier studies showed that the benzodiazepines oxazepam (15 and 30 mg) and diazepam (4, 10 and 15 mg) were not effective in reducing FPS in three different experiments (Baas et al. 2002a). | |||||||||||||||
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In the model originally introduced by Grillon et al. (1993), Riba and colleagues reported no effect of the benzodiazepine lorazepam (4 mg, even though baseline startle was affected substantially; Riba et al. 1999) and a decrease in FPS after administration of 1 mg of the benzodiazepine alprazolam (not 0.25 or 0.5 mg; Riba et al. 2001). | |||||||||||||||
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FPS was shown to be reduced with putative anxiolytic substances such as the glutamatergic substance LY354740 (Grillon et al. 2003) and testosterone (Hermans et al. 2006). | |||||||||||||||
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Zoledronic acid selectively inhibits the FPPS enzyme, which leads to a loss of prenylated proteins in osteoclasts and reduced bone resorbing activity.22 This is manifested by a reduced concentration of bone resorption markers in the serum and urine. | |||||||||||||||
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The binding affinity to hydroxyapatite determines attachment to bone and duration of effect, and the inhibition of FPP synthase determines antiresorptive potential. | |||||||||||||||
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In a study examining the potency of several nitrogen-containing bisphosphonates, a correlation has been found between the ability of bisphosphonates to inhibit FPP synthase in vitro and inhibit protein prenylation in cell-free extracts as well as in purified osteoclasts in vitro, and the ability to inhibit bone resorption in vivo (Dunford et al 2001). | |||||||||||||||
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Zoledronate is one of the most potent inhibitors of FPP synthase (Dunford et al 2001). | |||||||||||||||
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The order of potency in inhibiting FPP synthase (zoledronate > risedronate > ibandronate > alendronate) closely matched the order of antiresorptive potency (Russell 2007). | |||||||||||||||
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and atorvastatin in the presence or absence of mevalonate, FPP, and GGPP to determine whether atorvastatin inhibition of ENA-78 production was dependent on HMG-CoA reductase inhibition and subsequent downstream pathways. | |||||||||||||||
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For example, risedronate is a high-potent inhibitor of FPP synthase, but does not bind to hydroxyapatite as strongly as alendronate or zoledronate does (Dunford et al 2001; Nancollas et al 2006; Russell 2007). | |||||||||||||||
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The most potent anti-resorptive bisphosphonates such as zoledronic acid and risedronate are very potent inhibitors of FPP synthase, with IC50 values as low as 3 nM and 10 nM respectively. | |||||||||||||||
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Inhibition of FPP synthase prevents the formation of FPP and its derivative GGPP. | |||||||||||||||
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As expected, the former bisphosphonate is more active regardless of the calcium concentration, suggesting better cell penetration or a stronger inhibition of farnesyl diphosphate synthase (a key enzyme for protein prenylation). | |||||||||||||||
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The second class is more recent and includes nitrogen-containing bisphosphonates, such as alendronate, pamidronate, risedronate, ibandronate and zoledronic acid, which interfere with the mevalonate pathway, inhibiting the farnesyl diphosphate synthase and blocking the farnesylation and the geranylgeranylation of small GTPase proteins [15]. | |||||||||||||||
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Indeed, nitrogen-containing bisphosphonates are known to act as analogs of isoprenoid diphosphate lipids and to inhibit farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway [56,57]. | |||||||||||||||
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Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation). | |||||||||||||||
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The more potent nitrogen-containing bisphosphonates inhibit the farnesyl diphosphate synthase enzyme of the mevalonate pathway [38] that is responsible for producing cholesterol and isoprenoid lipids. | |||||||||||||||
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