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NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties.

Kashfi K, Chattopadhyay M, Kodela R - Redox Biol (2015)

Bottom Line: Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted.Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding.These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, United States; Avicenna Pharmaceuticals Inc., New York, NY, United States. Electronic address: kashfi@med.cuny.edu.

No MeSH data available.


Related in: MedlinePlus

NOSH-sulindac is gastrointestinal safe. SUL and NOSH-SUL were administered orally at equimolar doses (0.56 mmol/kg; 200 mg/kg and 467 mg/kg for SUL and NOSH-SUL, respectively) and effects on the stomach were evaluated as indicated in Section 2.3. Panel A, shows the stomach of a vehicle-treated rat; Panel B, stomach of a SUL-treated rat showing ulceration and bleeding; Panel C, stomach of a NOSH-SUL-treated rat which is essentially devoid of ulcers. Panel D, gastric damage due to SUL, UI=135±15 mm (†P<0.01 compared to vehicle), NOSH-SUL was gastric damage-sparing, UI=10±1 mm (*P<0.01 compared to SUL). Photographs in Panels A–C are representative from 5 rats in each group. Results in Panel D are mean±SEM of 5 rats in each group.
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f0010: NOSH-sulindac is gastrointestinal safe. SUL and NOSH-SUL were administered orally at equimolar doses (0.56 mmol/kg; 200 mg/kg and 467 mg/kg for SUL and NOSH-SUL, respectively) and effects on the stomach were evaluated as indicated in Section 2.3. Panel A, shows the stomach of a vehicle-treated rat; Panel B, stomach of a SUL-treated rat showing ulceration and bleeding; Panel C, stomach of a NOSH-SUL-treated rat which is essentially devoid of ulcers. Panel D, gastric damage due to SUL, UI=135±15 mm (†P<0.01 compared to vehicle), NOSH-SUL was gastric damage-sparing, UI=10±1 mm (*P<0.01 compared to SUL). Photographs in Panels A–C are representative from 5 rats in each group. Results in Panel D are mean±SEM of 5 rats in each group.

Mentions: The rats receiving the vehicle (0.5% CMC solution) had a normal glandular region on the surface of their stomach, and no ulcerative damage (Fig. 2A and D). For these rats, the gastric damage score (also described in the literature as “ulcer index”, or UI), was zero (UI=0). Administration of SUL (200 mg/kg) resulted in extensive mucosal injury, UI=130 (Fig. 2B and D). NOSH-SUL (476 mg/kg) did not produce significant ulcerative damage (Fig. 2C and D), UI=10 compared to SUL at equimolar doses, which represents a remarkable reduction (P<0.01) in gastrointestinal toxicity. Thus, this modified sulindac which has been shown to releases NO and H2S [29] appears to be gastrointestinal safe. As alluded to in the introduction, SUL has extensively been utilized as a chemopreventive agent in patients with FAP [25–28]. However, a limiting factor in its long-term use is its GI toxicity. Based on the data presented here, NOSH-SUL would be an ideal drug candidate for development in such a setting.


NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties.

Kashfi K, Chattopadhyay M, Kodela R - Redox Biol (2015)

NOSH-sulindac is gastrointestinal safe. SUL and NOSH-SUL were administered orally at equimolar doses (0.56 mmol/kg; 200 mg/kg and 467 mg/kg for SUL and NOSH-SUL, respectively) and effects on the stomach were evaluated as indicated in Section 2.3. Panel A, shows the stomach of a vehicle-treated rat; Panel B, stomach of a SUL-treated rat showing ulceration and bleeding; Panel C, stomach of a NOSH-SUL-treated rat which is essentially devoid of ulcers. Panel D, gastric damage due to SUL, UI=135±15 mm (†P<0.01 compared to vehicle), NOSH-SUL was gastric damage-sparing, UI=10±1 mm (*P<0.01 compared to SUL). Photographs in Panels A–C are representative from 5 rats in each group. Results in Panel D are mean±SEM of 5 rats in each group.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556776&req=5

f0010: NOSH-sulindac is gastrointestinal safe. SUL and NOSH-SUL were administered orally at equimolar doses (0.56 mmol/kg; 200 mg/kg and 467 mg/kg for SUL and NOSH-SUL, respectively) and effects on the stomach were evaluated as indicated in Section 2.3. Panel A, shows the stomach of a vehicle-treated rat; Panel B, stomach of a SUL-treated rat showing ulceration and bleeding; Panel C, stomach of a NOSH-SUL-treated rat which is essentially devoid of ulcers. Panel D, gastric damage due to SUL, UI=135±15 mm (†P<0.01 compared to vehicle), NOSH-SUL was gastric damage-sparing, UI=10±1 mm (*P<0.01 compared to SUL). Photographs in Panels A–C are representative from 5 rats in each group. Results in Panel D are mean±SEM of 5 rats in each group.
Mentions: The rats receiving the vehicle (0.5% CMC solution) had a normal glandular region on the surface of their stomach, and no ulcerative damage (Fig. 2A and D). For these rats, the gastric damage score (also described in the literature as “ulcer index”, or UI), was zero (UI=0). Administration of SUL (200 mg/kg) resulted in extensive mucosal injury, UI=130 (Fig. 2B and D). NOSH-SUL (476 mg/kg) did not produce significant ulcerative damage (Fig. 2C and D), UI=10 compared to SUL at equimolar doses, which represents a remarkable reduction (P<0.01) in gastrointestinal toxicity. Thus, this modified sulindac which has been shown to releases NO and H2S [29] appears to be gastrointestinal safe. As alluded to in the introduction, SUL has extensively been utilized as a chemopreventive agent in patients with FAP [25–28]. However, a limiting factor in its long-term use is its GI toxicity. Based on the data presented here, NOSH-SUL would be an ideal drug candidate for development in such a setting.

Bottom Line: Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted.Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding.These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, United States; Avicenna Pharmaceuticals Inc., New York, NY, United States. Electronic address: kashfi@med.cuny.edu.

No MeSH data available.


Related in: MedlinePlus