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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.


In vivo protection and rescue of V. berus envenomed mice by varespladib. (a) Venom and varespladib injected simultaneously into the subcutaneous space outlived controls (venom + excipient) N = 7 each group; (b) mice injected with lethal doses of venom just prior to SC administration of varespladib outlived controls (N = 7 each). Those injected with varespladib alone showed no signs of toxicity (N = 2); (c) varespladib administered SC or IV at a contract laboratory using the same lots of venom (8 mg/kg SC) and drug (8 mg/kg IV in lateral tail vein) following venom administration resulted in significant survival benefit with 5 of 5 IV treated animals surviving 24 h. 5 of 5 mice treated with SC varespladib outlived excipient only treated controls (N = 5 each group Survival: Controls 237 ± 92 min; Treated 1440 min. p < 0.001).
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toxins-08-00248-f003: In vivo protection and rescue of V. berus envenomed mice by varespladib. (a) Venom and varespladib injected simultaneously into the subcutaneous space outlived controls (venom + excipient) N = 7 each group; (b) mice injected with lethal doses of venom just prior to SC administration of varespladib outlived controls (N = 7 each). Those injected with varespladib alone showed no signs of toxicity (N = 2); (c) varespladib administered SC or IV at a contract laboratory using the same lots of venom (8 mg/kg SC) and drug (8 mg/kg IV in lateral tail vein) following venom administration resulted in significant survival benefit with 5 of 5 IV treated animals surviving 24 h. 5 of 5 mice treated with SC varespladib outlived excipient only treated controls (N = 5 each group Survival: Controls 237 ± 92 min; Treated 1440 min. p < 0.001).

Mentions: In pilot studies, mice injected with 100% lethal doses of Vipera berus venom outlived or were completely protected for 24 h from death when treated with varespladib administered subcutaneously (4 mg/kg unless stated otherwise) at the same time as or after venom administration (Figure 3a,b). All mice treated with IV varespladib following administration of venom survived 24 h, even when varespladib was administered after envenomation (Figure 3c). Mice injected with varespladib subcutaneously (SC) or intravenously (IV) alone showed no signs of toxicity. Venom only mice had subcutaneous hemorrhage, progressive paralysis and appeared to die from respiratory arrest. Treated mice had a similar, but unquantified degree of subcutaneous hemorrhage and initially had similar symptoms to controls for several hours before rallying such that it was difficult to distinguish control from treated animals with all appearing ill, initially after envenomation and up to roughly three h.


Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation
In vivo protection and rescue of V. berus envenomed mice by varespladib. (a) Venom and varespladib injected simultaneously into the subcutaneous space outlived controls (venom + excipient) N = 7 each group; (b) mice injected with lethal doses of venom just prior to SC administration of varespladib outlived controls (N = 7 each). Those injected with varespladib alone showed no signs of toxicity (N = 2); (c) varespladib administered SC or IV at a contract laboratory using the same lots of venom (8 mg/kg SC) and drug (8 mg/kg IV in lateral tail vein) following venom administration resulted in significant survival benefit with 5 of 5 IV treated animals surviving 24 h. 5 of 5 mice treated with SC varespladib outlived excipient only treated controls (N = 5 each group Survival: Controls 237 ± 92 min; Treated 1440 min. p < 0.001).
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toxins-08-00248-f003: In vivo protection and rescue of V. berus envenomed mice by varespladib. (a) Venom and varespladib injected simultaneously into the subcutaneous space outlived controls (venom + excipient) N = 7 each group; (b) mice injected with lethal doses of venom just prior to SC administration of varespladib outlived controls (N = 7 each). Those injected with varespladib alone showed no signs of toxicity (N = 2); (c) varespladib administered SC or IV at a contract laboratory using the same lots of venom (8 mg/kg SC) and drug (8 mg/kg IV in lateral tail vein) following venom administration resulted in significant survival benefit with 5 of 5 IV treated animals surviving 24 h. 5 of 5 mice treated with SC varespladib outlived excipient only treated controls (N = 5 each group Survival: Controls 237 ± 92 min; Treated 1440 min. p < 0.001).
Mentions: In pilot studies, mice injected with 100% lethal doses of Vipera berus venom outlived or were completely protected for 24 h from death when treated with varespladib administered subcutaneously (4 mg/kg unless stated otherwise) at the same time as or after venom administration (Figure 3a,b). All mice treated with IV varespladib following administration of venom survived 24 h, even when varespladib was administered after envenomation (Figure 3c). Mice injected with varespladib subcutaneously (SC) or intravenously (IV) alone showed no signs of toxicity. Venom only mice had subcutaneous hemorrhage, progressive paralysis and appeared to die from respiratory arrest. Treated mice had a similar, but unquantified degree of subcutaneous hemorrhage and initially had similar symptoms to controls for several hours before rallying such that it was difficult to distinguish control from treated animals with all appearing ill, initially after envenomation and up to roughly three h.

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.