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Blank, Marion; Ems, Beth L.; Gibson, George W.; Myers, William; Berman, S. Kim; Phipps, Roger J.; Smith, Paige N.

doi:10.1023/a:1018849415297

Cited by 64 publications

(6 citation statements)

References 8 publications

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“…These effects were not attributable to changes in gastric acid secretion or prostaglandin synthesis, but are thought to be due to a topical irritant effect. Similar effects were reported with etidronate, risedronate, and tiludronate when given at pharmacologically equivalent doses 13,21–23…”

Section: The Different Drug Classes: Mechanisms Of Actionsupporting

confidence: 73%

Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

Cavalli¹,

Brandi

2012

TCRM

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Denosumab is a breakthrough biological drug approved by the Food and Drug Administration and European Medicines Agency for the treatment of osteoporosis in 2010. It is a fully human monoclonal antireceptor activator of nuclear factor kappa-B ligand antibody, which inhibits the activity of osteoclasts, resulting in an antiresorptive effect with a significant increase in bone mineral density. The FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial, comparing denosumab with no treatment in 7868 women with postmenopausal osteoporosis, showed an important reduction of fracture risk at hip, vertebral, and nonvertebral sites in the treated group, while no statistically significant difference in the incidence of adverse events was detected between denosumab and placebo groups. The specific action of denosumab directed against a key regulator of osteoclasts makes it a valuable tool in preventing the occurrence of skeletal events caused by bone destruction in patients with advanced malignancies. The drug was approved for postmenopausal osteoporosis in women at increased risk of fracture and for the treatment of bone loss associated with androgen deprivation therapy in men with prostate cancer.

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Section: The Different Drug Classes: Mechanisms Of Actionsupporting

confidence: 73%

Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

Cavalli¹,

Brandi

2012

TCRM

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“…Among the various bisphosphonates used clinically, those with primary amino side chains, such as alendronate (ALD) and pamidronate, may also have increased potential for causing gastric damage (1- 4). …”

Section: Introductionmentioning

confidence: 99%

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

Nicolau

Silva

Damasceno

et al. 2013

Braz J Med Biol Res

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Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels.

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“…(3) These results were interpreted as reflecting the inhibition of prostaglandin (PG) synthesis and the consequent impedance of the usual epithelial defense mechanisms. (1,2,4,5) …”

Section: Introductionmentioning

confidence: 99%

Bisphosphonate-induced gastrointestinal mucosal injury is mediated by mitochondrial superoxide production and lipid peroxidation

Nagano

Matsui

Shimokawa

et al. 2012

J. Clin. Biochem. Nutr.

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Bisphosphonates such as alendronate and risedronate are commonly used for the treatment of postmenopausal osteoporosis. They have the gastrointestinal adverse effects such as erosions and ulcers in stomach and small intestine. However, the detailed biological mechanism remains to be elucidated. Since alendronate is suggested to increase the risk of non-steroidal anti-inflammatory drug-related gastropathy, we hypothesized that bisphosphonates and non-steroidal anti-inflammatory drugs have the same pathophysiological mechanisms in gastrointestinal mucosa: Bisphosphonates may induce cellular lipid peroxidation by inducing the production of mitochondrial superoxide. We also hypothesized that geranylgeranylacetone, an antiulcer drug, may prevent lipid peroxidation by reducing superoxide production. We treated gastric RGM1 cells and small intestinal IEC6 cells with alendronate or risedronate, and examined cellular injury, lipid peroxidation and superoxide production with specific fluorescent dyes, and underwent electron paramagnetic resonance spectroscopy to detect the production of superoxide in vitro. The results indicated that bisphosphonates indeed induced cellular injury, cellular lipid peroxidation, and superoxide production. We also demonstrated that the pretreatment of geranylgeranylacetone decreased superoxide production and prevented cellular lipid peroxidation. These results suggested that bisphosphonates, like non-steroidal anti-inflammatory drugs, induce lipid peroxidation by producing mitochondrial superoxide, which was prevented by geranylgeranylacetone.

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Cited by 64 publications

References 8 publications

Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

Bisphosphonate-induced gastrointestinal mucosal injury is mediated by mitochondrial superoxide production and lipid peroxidation

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