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Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

View Article: PubMed Central - PubMed

ABSTRACT

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

No MeSH data available.


Related in: MedlinePlus

Rats given lethal doses of M. fulvius venom subcutaneously (SC) were treated with a single dose of Varespladib 8 mg/kg intravenously (IV) or excipient (control). (a) Plot showing survival benefit (Excipient n = 6, Varespladib n = 12). Dose of venom indicated inside the red dots indicate 4 mg/kg and 8 mg/kg venom doses for which there was no apparent difference in time to death (287 ± 110 min vs. 240 ± 68, respectively; p = 0.32); (b) snake venom-induced rise in sPLA2 activity is suppressed by varespladib (N = 3 each group; * p < 0.001); time of varespladib addition post venom-addition is noted by “T =” for each group; (c) treatment with varespladib prevented intravascular hemolysis in the same 12 animals. Tubes shown are blood drawn at the 4 h time point.
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toxins-08-00248-f004: Rats given lethal doses of M. fulvius venom subcutaneously (SC) were treated with a single dose of Varespladib 8 mg/kg intravenously (IV) or excipient (control). (a) Plot showing survival benefit (Excipient n = 6, Varespladib n = 12). Dose of venom indicated inside the red dots indicate 4 mg/kg and 8 mg/kg venom doses for which there was no apparent difference in time to death (287 ± 110 min vs. 240 ± 68, respectively; p = 0.32); (b) snake venom-induced rise in sPLA2 activity is suppressed by varespladib (N = 3 each group; * p < 0.001); time of varespladib addition post venom-addition is noted by “T =” for each group; (c) treatment with varespladib prevented intravascular hemolysis in the same 12 animals. Tubes shown are blood drawn at the 4 h time point.

Mentions: We also tested the survival effect of varespladib in a rat model of lethal snake envenomation. Rats dosed with either 4 mg/kg or 8 mg/kg of M. fulvius venom were entirely rescued by intravenous administration of varespladib within 5 min of venom injection (Figure 4a). Varespladib suppressed the venom-induced rise in sPLA2 activity of both doses of venom (Figure 4b), as well as venom hemolysis (Figure 4c).


Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation
Rats given lethal doses of M. fulvius venom subcutaneously (SC) were treated with a single dose of Varespladib 8 mg/kg intravenously (IV) or excipient (control). (a) Plot showing survival benefit (Excipient n = 6, Varespladib n = 12). Dose of venom indicated inside the red dots indicate 4 mg/kg and 8 mg/kg venom doses for which there was no apparent difference in time to death (287 ± 110 min vs. 240 ± 68, respectively; p = 0.32); (b) snake venom-induced rise in sPLA2 activity is suppressed by varespladib (N = 3 each group; * p < 0.001); time of varespladib addition post venom-addition is noted by “T =” for each group; (c) treatment with varespladib prevented intravascular hemolysis in the same 12 animals. Tubes shown are blood drawn at the 4 h time point.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037474&req=5

toxins-08-00248-f004: Rats given lethal doses of M. fulvius venom subcutaneously (SC) were treated with a single dose of Varespladib 8 mg/kg intravenously (IV) or excipient (control). (a) Plot showing survival benefit (Excipient n = 6, Varespladib n = 12). Dose of venom indicated inside the red dots indicate 4 mg/kg and 8 mg/kg venom doses for which there was no apparent difference in time to death (287 ± 110 min vs. 240 ± 68, respectively; p = 0.32); (b) snake venom-induced rise in sPLA2 activity is suppressed by varespladib (N = 3 each group; * p < 0.001); time of varespladib addition post venom-addition is noted by “T =” for each group; (c) treatment with varespladib prevented intravascular hemolysis in the same 12 animals. Tubes shown are blood drawn at the 4 h time point.
Mentions: We also tested the survival effect of varespladib in a rat model of lethal snake envenomation. Rats dosed with either 4 mg/kg or 8 mg/kg of M. fulvius venom were entirely rescued by intravenous administration of varespladib within 5 min of venom injection (Figure 4a). Varespladib suppressed the venom-induced rise in sPLA2 activity of both doses of venom (Figure 4b), as well as venom hemolysis (Figure 4c).

View Article: PubMed Central - PubMed

ABSTRACT

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

No MeSH data available.


Related in: MedlinePlus