Limits...
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

Pretreatment with varespladib protects against M. fulvius envenomation. (a) Five of 5 (100%) of mice given 4 mg/kg SC injections of M. fulvius venom died quickly with previously described paralytic and hemorrhagic complications. Zero of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) several minutes before venom injection died within 8 h; (b) from a different experiment with methyl-varespladib, but exemplary of coral snake bite syndrome and effect of the study treatments: Left, untreated mouse 2 h after venom administration showing effects of venom including (i) postural weakness; (ii) vasodilation (ears) and (iii) ptosis; Right, methyl-varespladib treated mouse. Both mice have piloerection.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5037474&req=5

toxins-08-00248-f002: Pretreatment with varespladib protects against M. fulvius envenomation. (a) Five of 5 (100%) of mice given 4 mg/kg SC injections of M. fulvius venom died quickly with previously described paralytic and hemorrhagic complications. Zero of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) several minutes before venom injection died within 8 h; (b) from a different experiment with methyl-varespladib, but exemplary of coral snake bite syndrome and effect of the study treatments: Left, untreated mouse 2 h after venom administration showing effects of venom including (i) postural weakness; (ii) vasodilation (ears) and (iii) ptosis; Right, methyl-varespladib treated mouse. Both mice have piloerection.

Mentions: Based on their surprising in vitro anti-sPLA2 activity (Figure 1 and Table 1) we pilot tested the survival effect of varespladib in a mouse model of lethal snake envenomation. Eastern coral snake (Micrurus fulvius) has well-characterized venom causing both hemo- and neurotoxic effects in normal prey and human victims [33,34,35] and had the most potent sPLA2 activity in vitro (Table 1 and Figure 1j), thus it was chosen for the first experiments. Mice receiving subcutaneous injections of M. fulvius venom at ~4 times the expected LD50 (0.1 mg M. fulvius venom/animal for approximate dose of ~4 mg/kg) survived when pretreated with 4 mg/kg varespladib subcutaneously while 0 of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) died within 8 h. The 5 (100%) of sham treated envenomed mice died at an average of 63 min, compared to 1140 min for varespladib treatment group (Figure 2a). Only one varespladib-treated mouse showed any evidence of hemorrhage on necropsy, but this was significantly less than the controls. The remaining mice showed no overt evidence of coagulopathy or hemorrhage at death.


Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation
Pretreatment with varespladib protects against M. fulvius envenomation. (a) Five of 5 (100%) of mice given 4 mg/kg SC injections of M. fulvius venom died quickly with previously described paralytic and hemorrhagic complications. Zero of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) several minutes before venom injection died within 8 h; (b) from a different experiment with methyl-varespladib, but exemplary of coral snake bite syndrome and effect of the study treatments: Left, untreated mouse 2 h after venom administration showing effects of venom including (i) postural weakness; (ii) vasodilation (ears) and (iii) ptosis; Right, methyl-varespladib treated mouse. Both mice have piloerection.
© Copyright Policy
Related In: Results  -  Collection

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

toxins-08-00248-f002: Pretreatment with varespladib protects against M. fulvius envenomation. (a) Five of 5 (100%) of mice given 4 mg/kg SC injections of M. fulvius venom died quickly with previously described paralytic and hemorrhagic complications. Zero of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) several minutes before venom injection died within 8 h; (b) from a different experiment with methyl-varespladib, but exemplary of coral snake bite syndrome and effect of the study treatments: Left, untreated mouse 2 h after venom administration showing effects of venom including (i) postural weakness; (ii) vasodilation (ears) and (iii) ptosis; Right, methyl-varespladib treated mouse. Both mice have piloerection.
Mentions: Based on their surprising in vitro anti-sPLA2 activity (Figure 1 and Table 1) we pilot tested the survival effect of varespladib in a mouse model of lethal snake envenomation. Eastern coral snake (Micrurus fulvius) has well-characterized venom causing both hemo- and neurotoxic effects in normal prey and human victims [33,34,35] and had the most potent sPLA2 activity in vitro (Table 1 and Figure 1j), thus it was chosen for the first experiments. Mice receiving subcutaneous injections of M. fulvius venom at ~4 times the expected LD50 (0.1 mg M. fulvius venom/animal for approximate dose of ~4 mg/kg) survived when pretreated with 4 mg/kg varespladib subcutaneously while 0 of 5 (0%) of mice pre-treated with varespladib (4 mg/kg) died within 8 h. The 5 (100%) of sham treated envenomed mice died at an average of 63 min, compared to 1140 min for varespladib treatment group (Figure 2a). Only one varespladib-treated mouse showed any evidence of hemorrhage on necropsy, but this was significantly less than the controls. The remaining mice showed no overt evidence of coagulopathy or hemorrhage at death.

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