{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:27:00Z","timestamp":1787009220743,"version":"build-2736575974"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"11-12","funder":[{"DOI":"10.13039\/100009898","name":"Defense Health Agency","doi-asserted-by":"publisher","award":["G1716"],"award-info":[{"award-number":["G1716"]}],"id":[{"id":"10.13039\/100009898","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Warfighters are exposed to life-threatening injuries daily and according to the Joint Trauma System Military Clinical Practice Guideline\u2014Global Snake Envenomation Management snakebites are a concerning threat in all theaters of operation. Snake venom is a complex mixture of toxins including phospholipases A2 (PLA2) and snake venom metalloproteinases (SVMP) that produce myotoxic, hemotoxic, and cytotoxic injuries. Antibody-based antivenom is the standard of care but new approaches including small-molecule inhibitors have gained attention in recent years. Doxycycline is an effective inhibitor of human metalloproteinases and PLA2. The enzymatic activities of 3 phylogenetically distinct snakes: Agkistrodon piscivorus, Naja kaouthia, and Daboia russelii were tested under inhibitory conditions using doxycycline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Enzymatic activity of PLA2 and SVMP was measured in N. kaouthia, D. russelii, and A. piscivorus venom alone and with doxycycline using EnzChek Phospholipase A2 and Gelatinase Assay Kits. A 1-way ANOVA with Tukey\u2019s post-hoc test was used to conduct comparative analysis. The median lethal dose of the venoms, the effective dose of doxycycline, and creatine kinase (CK) inhibition levels were measured in a murine model with adult Bagg Albino (BALB\/c) mice using intramuscular injections. Median lethal and effective doses were determined using Spearman-Karber\u2019s method and a 1-way ANOVA with Tukey\u2019s post-hoc test was used to compare CK inhibition levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Phospholipases A2 activity was reduced to 1.5% to 44.0% in all 3 venoms in a dose-dependent manner using 0.32, 0.16, and 0.08\u2009mg\/mL doxycycline when compared to venom-only controls (P\u2009&amp;lt;\u2009.0001) (Fig.\u00a01A). Snake venom metalloproteinases activity was reduced to 4% to 62% in all 3 venoms in a dose-dependent manner using 0.32, 0.16, and 0.08\u2009mg\/mL doxycycline (P\u2009&amp;lt;\u2009.0001) (Fig.\u00a01B). The lethal dose (LD50) values of the venoms in the murine model were calculated as follows: A. piscivorus\u2009=\u200920.29\u2009mg\/kg (Fig.\u00a02A), N. kaouthia\u2009=\u20090.38\u2009mg\/kg (Fig.\u00a02B), and D. russelii\u2009=\u20097.92\u2009mg\/kg (Fig.\u00a02C). The effective dose (ED50) of doxycycline in A. piscivorus was calculated to be 20.82\u2009mg\/kg and 72.07\u2009mg\/kg when treating D. russelii venom. No ED50 could be calculated when treating N. kaouthia venom (Fig.\u00a03). Creatine kinase activity was significantly decreased in all 3 venoms treated with doxycycline (P\u2009&amp;lt;\u2009.0001) (Fig.\u00a04).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Doxycycline reduced PLA2- and SVMP-related lethality, particularly in A. piscivorus envenomings and in a limited capacity with D. russelii revealing its promise as a treatment for snakebites. In addition, CK activity, a common indicator of muscle damage was inhibited in mice that received doxycycline-treated venom. The doxycycline concentrations identified in the ED50 studies correspond to 1,456 to 5,061\u2009mg dosages for a 70\u2009kg human. Factors including venom yield and snake species would affect the actual dosage needed. Studies into high-dose doxycycline safety and its effectiveness against several snake species is needed to fully translate its use into humans. Based on this work, doxycycline could be used as a treatment en route to higher echelons of care, providing protection from muscle damage and reducing lethality in different snake species.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/milmed\/usae184","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T18:27:00Z","timestamp":1711996020000},"page":"e2430-e2438","source":"Crossref","is-referenced-by-count":10,"title":["Doxycycline-Mediated Inhibition of Snake Venom Phospholipase and Metalloproteinase"],"prefix":"10.1093","volume":"189","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9812-149X","authenticated-orcid":false,"given":"Daniel K","family":"Arens","sequence":"first","affiliation":[{"name":"Maxillofacial Injury and Disease, Naval Medical Research Unit San Antonio , JBSA FT Sam Houston, TX 78234,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meaghan 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