INT173576

Context Info Confidence 0.57 First Reported 2003 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 25 Total Number 26 Disease Relevance 8.42 Pain Relevance 1.91

cytosol (FDPS) mitochondrion (FDPS) small molecule metabolic process (FDPS) nucleolus (FDPS) nucleus (FDPS) cytoplasm (FDPS)

Anatomy Link Frequency osteoclasts 4 FDPS (Homo sapiens)

Pain Link Frequency Relevance Heat Potency 69 99.92 Inflammation 424 97.68 Arthritis 75 75.48 metalloproteinase 72 69.96 antagonist 29 65.80 Lasting pain 7 61.36 Inflammatory response 56 57.88 pregabalin 156 50.00 Pain 77 22.64 Bioavailability 5 20.28

Disease Link Frequency Relevance Heat Anxiety Disorder 556 100.00 Hypercalcemia 202 99.92 Osteoporosis 681 99.74 INFLAMMATION 514 97.68 Disease 223 89.76 Solid Tumor 1 89.44 Breast Cancer 102 88.80 Metastasis 26 88.80 Multiple Myeloma 62 87.96 Malignant Neoplastic Disease 40 87.24

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Mutation

Event

Anatomy

Negation

Speculation

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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.

Negative_regulation (inhibition) of farnesyl pyrophosphate synthase associated with osteoporotic fractures, hypercalcemia and osteoporosis

1) Confidence 0.57 Published 2010 Journal Therapeutics and Clinical Risk Management Section Body Doc Link PMC2909499 Disease Relevance 0.66 Pain Relevance 0.06

The model would benefit from further development in order to reduce variance in the startle response and FPS.

Negative_regulation (reduce) of FPS associated with anxiety disorder

2) Confidence 0.40 Published 2009 Journal Psychopharmacology (Berl) Section Body Doc Link PMC2695548 Disease Relevance 0.54 Pain Relevance 0

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.

Negative_regulation (inhibiting) of farnesyl pyrophosphate synthase in osteoclasts

3) Confidence 0.34 Published 2010 Journal Drug Design, Development and Therapy Section Body Doc Link PMC2998805 Disease Relevance 0.21 Pain Relevance 0

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).

Negative_regulation (reducing) of FPS

4) Confidence 0.30 Published 2009 Journal Psychopharmacology (Berl) Section Body Doc Link PMC2695548 Disease Relevance 0.63 Pain Relevance 0

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).

Negative_regulation (decrease) of FPS

5) Confidence 0.30 Published 2009 Journal Psychopharmacology (Berl) Section Body Doc Link PMC2695548 Disease Relevance 0.66 Pain Relevance 0

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).

Negative_regulation (reduced) of FPS associated with anxiety disorder

6) Confidence 0.30 Published 2009 Journal Psychopharmacology (Berl) Section Body Doc Link PMC2695548 Disease Relevance 0.45 Pain Relevance 0

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.

Negative_regulation (inhibits) of FPPS enzyme in osteoclasts associated with hypercalcemia

7) Confidence 0.25 Published 2010 Journal Drug Design, Development and Therapy Section Body Doc Link PMC2998805 Disease Relevance 0.54 Pain Relevance 0.05

The binding affinity to hydroxyapatite determines attachment to bone and duration of effect, and the inhibition of FPP synthase determines antiresorptive potential.

Negative_regulation (inhibition) of FPP synthase

8) Confidence 0.08 Published 2008 Journal Clinical Interventions in Aging Section Body Doc Link PMC2546473 Disease Relevance 0.06 Pain Relevance 0.18

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).

Negative_regulation (inhibit) of FPP synthase in osteoclasts associated with hypercalcemia and potency

9) Confidence 0.08 Published 2008 Journal Clinical Interventions in Aging Section Body Doc Link PMC2546473 Disease Relevance 0.09 Pain Relevance 0.22

Zoledronate is one of the most potent inhibitors of FPP synthase (Dunford et al 2001).

Negative_regulation (inhibitors) of FPP synthase

10) Confidence 0.08 Published 2008 Journal Clinical Interventions in Aging Section Body Doc Link PMC2546473 Disease Relevance 0.20 Pain Relevance 0.03

The order of potency in inhibiting FPP synthase (zoledronate > risedronate > ibandronate > alendronate) closely matched the order of antiresorptive potency (Russell 2007).

Negative_regulation (inhibiting) of FPP synthase associated with potency

11) Confidence 0.08 Published 2008 Journal Clinical Interventions in Aging Section Body Doc Link PMC2546473 Disease Relevance 0.10 Pain Relevance 0.23

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.

Negative_regulation (absence) of FPP

12) Confidence 0.06 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2518836 Disease Relevance 0 Pain Relevance 0

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).

Negative_regulation (inhibitor) of FPP synthase

13) Confidence 0.06 Published 2008 Journal Clinical Interventions in Aging Section Body Doc Link PMC2546473 Disease Relevance 0.11 Pain Relevance 0.14

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.

Negative_regulation (inhibitors) of FPP synthase

14) Confidence 0.06 Published 2007 Journal Immun Ageing Section Body Doc Link PMC1845171 Disease Relevance 0 Pain Relevance 0.09

Inhibition of FPP synthase prevents the formation of FPP and its derivative GGPP.

Negative_regulation (Inhibition) of FPP synthase

15) Confidence 0.06 Published 2007 Journal Immun Ageing Section Body Doc Link PMC1845171 Disease Relevance 0 Pain Relevance 0.09

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).

Negative_regulation (inhibition) of farnesyl diphosphate synthase

16) Confidence 0.06 Published 2008 Journal Breast Cancer Res Section Body Doc Link PMC2374955 Disease Relevance 0.15 Pain Relevance 0.04

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].

Negative_regulation (inhibiting) of farnesyl diphosphate synthase

17) Confidence 0.06 Published 2008 Journal Breast Cancer Res Section Body Doc Link PMC2374955 Disease Relevance 0.23 Pain Relevance 0

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].

Negative_regulation (inhibit) of farnesyl pyrophosphate synthase

18) Confidence 0.05 Published 2006 Journal Breast Cancer Res Section Body Doc Link PMC1413981 Disease Relevance 0.15 Pain Relevance 0.03

Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation).

Negative_regulation (inhibited) of diphosphate synthase

19) Confidence 0.05 Published 2007 Journal Immun Ageing Section Body Doc Link PMC1845171 Disease Relevance 0.06 Pain Relevance 0.12

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.

Negative_regulation (inhibit) of farnesyl diphosphate synthase enzyme

20) Confidence 0.05 Published 2003 Journal Arthritis Res Ther Section Body Doc Link PMC154424 Disease Relevance 0.49 Pain Relevance 0

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