BRAVO: Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite
Study Details
Study Description
Brief Summary
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in subjects bitten by venomous snakes.
Approximately 110 male and female eligible subjects will be enrolled and randomized to receive active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio (approximately 36 per group). There will be no stratification by type of snakebite, though randomization will be stratified by age group (5 to 11 years, 12 to 17 years, and ≥ 18 years) and by the presence or absence of severe neurologic symptoms defined by yes/no neurologic system subscore of the snakebite severity score of ≥ 2.
Effective treatments for snakebite envenoming represents a deadly and unmet global medical need. While antivenoms comprise the SOC for treatment of snakebites, they suffer from several limitations including specificity of each antivenom for specific species of snake, limited access to antivenom in rural areas, practical storage requirements, and delays in administration. Treatment of snakebite envenoming with the small-molecule drug varespladib-methyl, which targets secreted phospholipase A₂ (sPLA₂) present in more than 95% of snake venoms, has the potential to overcome several limitations of serum-based antivenoms that underpin traditional SOC.
This study in the United States and India will provide coverage of a broad spectrum of venomous snake genera, including elapids, pit vipers, and potentially exotics such as vipers and colubrids if encountered over the course of the study. The study is designed to cover differing geographies and differing sPLA₂ structures. Study sites have been and will be selected based on demonstrated historical incidence of snake bites from species deemed relevant to this study, to ensure a broad range of envenoming toxins are expected to be encountered in potential study subjects.
The study design allows for both treatment arms (varespladib-methyl and placebo) to receive SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive emergency treatment in a timely manner while being evaluated for the potential clinical benefit associated with inhibition of venom sPLA₂ and inflammatory sPLA2s by varespladib-methyl.
Because subjects with severe snakebites are admitted to emergency departments, this study was designed to screen, enroll, and administer treatment in a single visit at the hospital upon admission. Because varespladib-methyl is administered orally, subjects who demonstrate substantial improvement and are eligible for discharge from the hospital may continue investigational product treatment in an outpatient setting.
Risks associated with the control (placebo) arm of this study include the same risks associated with SOC (antivenom).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Varespladib-methyl Varespladib-methyl is an immediate-release (IR), oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl are supplied as 50 mg IR capsules for oral administration. Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl (1 × 250 mg oral tablet) approximately 12 hours later, and subsequent twice daily (BID) dosing with 1 × 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period. Tablets may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. Pediatric subjects (5 to < 18 years) will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation. |
Drug: Varespladib Methyl
Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration.
Other Names:
Drug: Standard of care (SOC)
SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.
|
| Placebo Comparator: Placebo The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Placebo for scaled pediatric dosing is supplied as an immediate-release capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate. The dosing of placebo will match that of varespladib-methyl. |
Drug: Placebo
The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
Drug: Standard of care (SOC)
SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.
|
Outcome Measures
Primary Outcome Measures
- Change in the combined pulmonary, cardiovascular, hematologic, and nervous system subscores of the snakebite severity score (SSS) [Baseline to 6 and 9 hours after first dose]
Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, and nervous system subscores of the SSS. The values from each of these 4 subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.
Secondary Outcome Measures
- Area under the curve (AUC) of the pulmonary, cardiovascular, hematologic symptoms, renal, and nervous system sections of the SSS [Baseline through Day 7]
Absolute values and change from baseline (pre-dosing) through Day 7 in the AUC of the pulmonary, cardiovascular, hematologic symptoms, and nervous system sections of the SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.
- Complete SSS scores [Baseline through Day 7]
Absolute values and change from baseline (pre-dosing) through Day 7 in the complete SSS. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.
- Percent of patients with hematological abnormalities [Baseline through Day 7]
The percent of patients who had an SSS hematology score ≥ 2 at baseline with coagulation abnormalities from baseline (pre-dosing) through Day 7.
- Hemolysis markers: percent of patients for each visual hemolysis score level and abnormal lactate dehydrogenase (LDH) [Baseline through Day 3]
The percent of patients for each visual hemolysis score level and abnormal LDH from baseline (pre-dosing) through Day 3.
- Hemolysis markers: quantitative hemolysis score occurrence [Baseline through Day 3]
The quantitative hemolysis score occurrence (yes/no) and occurrence of abnormal LDH values (yes/no) from baseline (pre-dosing) through Day 3.
- Levels of myonecrosis marker, creatine kinase (CK) [Baseline through Day 3]
Absolute value and change from baseline in CK from baseline (pre-dosing) through Day 3. Only patients with ≥ 2× institutional reference range at Baseline and gross hemolysis at baseline will be included.
- Total antivenom requirement [Baseline through Day 28]
Total amount of antivenom given from baseline (pre-dosing) through Day 28.
- Patients requiring ventilatory support [Baseline through Day 28]
The percent of patients requiring ventilatory support from baseline (pre-dosing) through Day 28.
- Total duration of ventilatory support [Baseline through Day 28]
Total duration (days) of ventilatory support from baseline (pre-dosing) through Day 28.
- Total duration of Intensive Care Unit (ICU) stay [Baseline through Day 28]
Total duration (days) of ICU stay from baseline (pre-dosing) through Day 28.
- Total duration of hospitalization [Baseline through Day 28]
Total duration (days) of hospitalization from baseline (pre-dosing) through Day 28. Only hospitalization from baseline through Day 28 will be included.
- All-cause mortality [Baseline through Day 60]
The number of patients experiencing the event (death) and the number of patients censored from baseline (pre-dosing) through Day 60. The all-cause mortality will be censored at Day 60.
- Clinical Global Impression - Improvement (CGI-I) and Patient Global Impression of Change (PGIC) responders [Baseline through Day 7]
The proportion of patients with a score on the CGI-I and PGIC of 1: very much improved, or 2: much improved from baseline (pre-dosing) through Day 7. The CGI-I and PGIC are 7-point scales depicting a clinician's/patient's rating of overall improvement, with scores ranging from 1 (very much improved) to 7 (very much worse).
- Patient-Specific Functional Scale (PSFS) total score [Day 1 through Day 28]
Absolute values and change in the PSFS total score from Day 1 through Day 28. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties.
- Numeric Pain Rating Scale (NPRS) score [Baseline through Day 28]
Absolute values and change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28. The NPRS is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain).
- Kidney function markers: blood urea nitrogen (BUN) and creatinine [Baseline through Day 28]
Absolute values and changes from baseline (pre-dosing) through Day 28 in BUN and creatinine levels (mg/dL).
- Snakebite severity score [Baseline through day 3]
SSS neurologic system subscore
Other Outcome Measures
- Snakebite severity score [Baseline through Day 28 after first dose]
Absolute values and change from baseline (pre-dosing) through Day 28 in the SSS at 4, 6, and 9 hours, and on Days 2, 3, 7, 14, and 28 after the first dose of varespladib-methyl. The SSS is a tool used to measure the severity of envenoming based on 6 body categories: local wound, pulmonary, cardiovascular, gastrointestinal (graded at levels from Grade 0 to Grade 3), hematological, and nervous system effects (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms.
- Grip strength [Baseline through Day 28]
Absolute values and change from baseline (pre-dosing) through Day 28 in grip strength. The grip strength assessment is an objective measurement of hand function. The patient is asked to grip a dynamometer and squeeze with maximal force. The measurement is repeated for a total of 3 trials and the greatest value is recorded.
- Analgesic use [Baseline through Day 28]
The proportion of patients reporting any analgesic use from baseline (pre-dosing) through Day 28.
- PGIC scores through Day 28 [Baseline through Day 28]
Absolute values and changes from baseline (pre-dosing) through Day 28 in PGIC scores. The PGIC is a 7-point scale depicting a patient's rating of overall improvement, with scores ranging from 1 (very much improved) to 7 (very much worse).
- Kidney function markers: estimated glomerular filtration rate (eGFR) [Baseline through Day 28]
Absolute values and changes from baseline (pre-dosing) through Day 28 in eGFR (mL/min).
- Kidney function markers: urinalysis [Baseline through Day 28]
Number of patients with abnormal urinalysis results from baseline (pre-dosing) through Day 28.
- Complete blood count (CBC) [Baseline through Day 28]
Percentage of patients with CBC laboratory values below, within, or above the normal range by visit and in relation to baseline.
- Transfusion requirement [Enrollment through Day 28]
The percentage of patients with hemolysis at enrollment with a transfusion event from enrollment through Day 28.
- C-reactive protein (CRP) levels [Baseline through Day 14]
Absolute values and changes from baseline (pre-dosing) through Day 14 in CRP.
- D-dimer levels [Baseline through Day 14]
Number of patients with abnormal D-dimer levels from baseline (pre-dosing) through Day 14.
- Levels of myonecrosis marker (CK) [Baseline through Day 3]
Absolute values and change from baseline in CK from baseline (pre-dosing) through Day 3 in patients presenting with and without tourniquets at enrollment. Only patients with ≥ 2× institutional reference range at Baseline and gross hemolysis at baseline will be included.
- Secretory phospholipase A₂ (sPLA₂) activity in serum [Days 1 to 7]
Absolute value and change from baseline in sPLA₂ activity in serum from baseline (pre-dosing) through Day 7.
- Pharmacokinetic (PK) parameters of varespladib-methyl in plasma: area under the curve [Days 1, 3, and 7]
Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable plasma concentration (AUC0-t), and area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.
- PK parameters of varespladib-methyl in plasma: maximum serum plasma concentration [Days 1, 3, and 7]
The rate of absorption using the maximum serum plasma concentration (Cmax). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.
- PK parameters of varespladib-methyl in plasma: time of Cmax (Tmax) [Days 1, 3, and 7]
Tmax, the time of Cmax. PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.
- PK parameters of varespladib-methyl in plasma: apparent first order terminal elimination half-life (t1/2) [Days 1, 3, and 7]
The apparent first order terminal elimination half-life (t1/2). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.
- PK parameters of varespladib-methyl in plasma: apparent terminal phase rate constant (λz) [Days 1, 3, and 7]
The apparent terminal phase rate constant (λz). PK samples will be taken from a subset of adult and pediatric patients on Days 1 and 3, and from all patients on Day 7 at the following timepoints: Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, and 12 (pre-second dose) hours post-dose; Day 3: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose; Day 7: pre-dose.
- Incidence and severity of adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation of Investigational Product (IP) [After obtaining informed consent until 28 days after the last day of study participation]
- Number of reported treatment-emergent adverse events (TEAEs) [Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28]
- Rates of reported TEAEs [Beginning of treatment until last Follow-Up Visit at Day 28]
- Number of patients with a treatment-related SAE [Beginning of treatment until last Follow-Up Visit/Telephone call at Day 28]
The Investigator will assess each AE's relationship to the IP and categorize as either: Likely related: a reasonable possibility exists of a relationship between the AE and IP. Unlikely related: no reasonable possibility exists of a relationship between the AE and IP.
- Clinical laboratory evaluations [Baseline through Day 28]
Number of patients with clinically significant abnormal laboratory values for CBC, urinalysis, liver function tests, renal function tests (albumin, creatinine, blood urea nitrogen, and estimated glomerular filtration rate) from baseline (pre-dosing) through Day 28.
- 12-lead electrocardiogram (ECG) [Baseline through Day 28]
The number of patients with normal and abnormal ECGs from baseline (pre-dosing) through Day 28.
- Concomitant medications and analgesics [Baseline through Day 28]
The number of patients using concomitant medications and analgesics from baseline (pre-dosing) through Day 28.
- Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline through Day 28]
Absolute values and change from baseline (pre-dosing) or at the earliest time point clinically allowable (ideally Day 1) and then at every study visit through Day 28. The C-SSRS is a questionnaire used for assessment of suicidal ideation and behavior with the following scale: 0: no ideation present; 1: wish to be dead; 2: non-specific active suicidal thoughts; 3: active suicidal ideation with any methods (not plan) without intent to act; 4: active suicidal ideation with some intent to act, without specific plan; 5: active suicidal ideation with specific plan and intent; 6: preparatory acts or behavior; 7: aborted attempt; 8: interrupted attempt; 9: actual attempt (non-fatal); 10: completed suicide.
- Snakebite Severity score [Baseline through day 7]
SSS neurologic system subscore Baseline through Day 7
Eligibility Criteria
Criteria
Inclusion Criteria:
- Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of
-
2 points in any SSS category other than gastrointestinal and 1 or more additional points in any other SSS category other than gastrointestinal or
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≥ 3 in any SSS category other than gastrointestinal.
SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion.
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Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment.
-
Must meet one of two categories of inclusion criteria:
Category 1: The patient has not yet completed first dose of antivenom:
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system.
OR
Category 2: The patient has completed an initial dose of antivenom:
SSS inclusion score* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very much worse).
- Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures.
Exclusion Criteria:
-
Has received antivenom treatment for envenoming prior to enrollment in this study.
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Is considered by the investigator to have a clinically significant upper GI bleed evidenced by hematemesis, "coffee-ground" emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract.
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Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
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Has known history of inherited bleeding or coagulation disorder.
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Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine or another anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or other low molecular weight heparin or antiarrhythmic drugs within 14 days prior to treatment.
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Has a history of chronic liver disease such as chronic active viral hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, or autoimmune hepatitis.
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Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration).
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Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds.
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Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns.
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Is pregnant, has a positive serum human chorionic gonadotropin (hCG) pregnancy test or not willing to use a highly effective method of contraception for 14 days after initial treatment, or is breast-feeding.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona | Tucson | Arizona | United States | 85724 |
| 2 | Loma Linda University Medical Center | Loma Linda | California | United States | 92354 |
| 3 | University of Florida Health | Jacksonville | Florida | United States | 32209 |
| 4 | Agusta University Medical Center | Augusta | Georgia | United States | 30912 |
| 5 | University of Kentucky Chandler Medical Center | Lexington | Kentucky | United States | 40536 |
| 6 | LSU LA Poison Control Center | Shreveport | Louisiana | United States | 71103 |
| 7 | University of Mississippi Medical Center - Jackson | Jackson | Mississippi | United States | 39216 |
| 8 | Duke University Hospital Durham, NC | Durham | North Carolina | United States | 27710 |
| 9 | Government medical College | Kozhikode | Calicut | India | |
| 10 | Father Muller medical College Hospital | Mangalore | Karnataka | India | 575002 |
| 11 | K R Hospital Mysore medical College and Research Institute | Mysore | Karnataka | India | |
| 12 | Jubilee Mission Medical College and Research Institute | Thrissur | Kerala | India | |
| 13 | Jawaharlal Institute of Postgraduate Medical Education & Research | Pondicherry | Puducherry | India | |
| 14 | S.P. Medical College Snakebite Research Cell | Bikaner | Rajasthan | India | |
| 15 | Calcutta National Medical College | Kolkata | West Bengal | India | |
| 16 | Postgraduate Institute of Medical Education and Research | Chandigarh | India |
Sponsors and Collaborators
- Ophirex, Inc.
- Premier Research Group plc
Investigators
- Principal Investigator: Matthew Lewin, MD, PhD, Ophirex, Inc.
- Principal Investigator: Timothy F Platts-Mills, MD, MSc, Ophirex, Inc.
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Alangode A, Rajan K, Nair BG. Snake antivenom: Challenges and alternate approaches. Biochem Pharmacol. 2020 Nov;181:114135. doi: 10.1016/j.bcp.2020.114135. Epub 2020 Jul 3. Review.
- Albulescu LO, Xie C, Ainsworth S, Alsolaiss J, Crittenden E, Dawson CA, Softley R, Bartlett KE, Harrison RA, Kool J, Casewell NR. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun. 2020 Dec 15;11(1):6094. doi: 10.1038/s41467-020-19981-6. Erratum in: Nat Commun. 2021 Jun 24;12(1):4027.
- Anderson BO, Moore EE, Banerjee A. Phospholipase A2 regulates critical inflammatory mediators of multiple organ failure. J Surg Res. 1994 Feb;56(2):199-205. Review.
- Arce-Bejarano R, Lomonte B, Gutiérrez JM. Intravascular hemolysis induced by the venom of the Eastern coral snake, Micrurus fulvius, in a mouse model: identification of directly hemolytic phospholipases A2. Toxicon. 2014 Nov;90:26-35. doi: 10.1016/j.toxicon.2014.07.010. Epub 2014 Aug 1.
- Bittenbinder MA, Zdenek CN, Op den Brouw B, Youngman NJ, Dobson JS, Naude A, Vonk FJ, Fry BG. Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). Toxins (Basel). 2018 Dec 4;10(12). pii: E516. doi: 10.3390/toxins10120516.
- Bryan-Quirós W, Fernández J, Gutiérrez JM, Lewin MR, Lomonte B. Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A(2). Toxicon. 2019 Jan;157:1-7. doi: 10.1016/j.toxicon.2018.11.292. Epub 2018 Nov 14.
- Bulfone TC, Samuel SP, Bickler PE, Lewin MR. Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite. J Trop Med. 2018 Jul 30;2018:4320175. doi: 10.1155/2018/4320175. eCollection 2018. Review.
- Chippaux JP. Estimate of the burden of snakebites in sub-Saharan Africa: a meta-analytic approach. Toxicon. 2011 Mar 15;57(4):586-99. doi: 10.1016/j.toxicon.2010.12.022. Epub 2011 Jan 9.
- Fernández ML, Quartino PY, Arce-Bejarano R, Fernández J, Camacho LF, Gutiérrez JM, Kuemmel D, Fidelio G, Lomonte B. Intravascular hemolysis induced by phospholipases A(2) from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms. Toxicol Lett. 2018 Apr;286:39-47. doi: 10.1016/j.toxlet.2017.11.037. Epub 2017 Nov 29.
- Fontana Oliveira IC, Gutiérrez JM, Lewin MR, Oshima-Franco Y. Varespladib (LY315920) inhibits neuromuscular blockade induced by Oxyuranus scutellatus venom in a nerve-muscle preparation. Toxicon. 2020 Nov;187:101-104. doi: 10.1016/j.toxicon.2020.08.023. Epub 2020 Sep 2.
- Gerardo CJ, Vissoci JRN, Evans CS, Simel DL, Lavonas EJ. Does This Patient Have a Severe Snake Envenomation?: The Rational Clinical Examination Systematic Review. JAMA Surg. 2019 Apr 1;154(4):346-354. doi: 10.1001/jamasurg.2018.5069.
- Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA. Snakebite envenoming. Nat Rev Dis Primers. 2017 Sep 14;3:17063. doi: 10.1038/nrdp.2017.63. Review. Erratum in: Nat Rev Dis Primers. 2017 Oct 05;3:17079.
- Gutiérrez JM, Lewin MR, Williams DJ, Lomonte B. Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. Toxins (Basel). 2020 Feb 20;12(2). pii: E131. doi: 10.3390/toxins12020131.
- Halilu S, Iliyasu G, Hamza M, Chippaux JP, Kuznik A, Habib AG. Snakebite burden in Sub-Saharan Africa: estimates from 41 countries. Toxicon. 2019 Mar 1;159:1-4. doi: 10.1016/j.toxicon.2018.12.002. Epub 2018 Dec 27.
- Kazandjian TD, Petras D, Robinson SD, van Thiel J, Greene HW, Arbuckle K, Barlow A, Carter DA, Wouters RM, Whiteley G, Wagstaff SC, Arias AS, Albulescu LO, Plettenberg Laing A, Hall C, Heap A, Penrhyn-Lowe S, McCabe CV, Ainsworth S, da Silva RR, Dorrestein PC, Richardson MK, Gutiérrez JM, Calvete JJ, Harrison RA, Vetter I, Undheim EAB, Wüster W, Casewell NR. Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science. 2021 Jan 22;371(6527):386-390. doi: 10.1126/science.abb9303.
- Le Geyt J, Pach S, Gutiérrez JM, Habib AG, Maduwage KP, Hardcastle TC, Hernández Diaz R, Avila-Aguero ML, Ya KT, Williams D, Halbert J. Paediatric snakebite envenoming: recognition and management of cases. Arch Dis Child. 2021 Jan;106(1):14-19. doi: 10.1136/archdischild-2020-319428. Epub 2020 Oct 28. Review.
- Lewin M, Samuel S, Merkel J, Bickler P. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins (Basel). 2016 Aug 25;8(9). pii: E248. doi: 10.3390/toxins8090248.
- Lewin MR, Gilliam LL, Gilliam J, Samuel SP, Bulfone TC, Bickler PE, Gutiérrez JM. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins (Basel). 2018 Nov 17;10(11). pii: E479. doi: 10.3390/toxins10110479.
- Lewin MR, Gutiérrez JM, Samuel SP, Herrera M, Bryan-Quirós W, Lomonte B, Bickler PE, Bulfone TC, Williams DJ. Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins (Basel). 2018 Sep 20;10(10). pii: E380. doi: 10.3390/toxins10100380.
- Longbottom J, Shearer FM, Devine M, Alcoba G, Chappuis F, Weiss DJ, Ray SE, Ray N, Warrell DA, Ruiz de Castañeda R, Williams DJ, Hay SI, Pigott DM. Vulnerability to snakebite envenoming: a global mapping of hotspots. Lancet. 2018 Aug 25;392(10148):673-684. doi: 10.1016/S0140-6736(18)31224-8. Epub 2018 Jul 17.
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