Snake Envenomation Gilliam, Lyndi L
The Veterinary clinics of North America. Equine practice
40, Številka:
1
Journal Article
Recenzirano
Snakebite envenomation (SBE) in horses can have devastating outcomes. Tissue damage, cardiotoxicity, coagulopathy, and neurotoxicity can be concerns with SBE. Understanding the actions of venom ...components is important in developing a successful treatment plan. Antivenom is the mainstay of treatment. Long-term deleterious effects can occur including cardiac dysfunction and lameness.
There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake's bite and as adjuncts to ...antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use.
The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by
(Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013.
14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming.
Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by
. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.
Background
Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra‐articular ...(IA) administration.
Hypothesis/Objectives
Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens.
Animals
Eight healthy neonatal foals.
Methods
Foals received 3 amikacin treatment protocols: (1) IV‐only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA‐only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility.
Results
Foal age was a significant variable. The IV‐only protocol met or exceeded the 30‐minute plasma concentrations considered therapeutic (mean μg/mL 95% confidence interval, CI) in 7‐ to 9‐day‐old (54.0 52.2‐56.9), 14‐ to 16‐day‐old (58.1 55.2‐61.0), and 21‐ to 23‐day‐old (66.6 63.7‐69.6) foals. Concurrent IV and IA protocol did not reach the 30‐minute concentration considered therapeutic in 7‐ to 9‐day‐old foals (46.5 43.6‐49.4) but did in 14‐ to 16‐day‐old (62.9 60.0‐65.8) and 21‐to 23‐day‐old (62.6 59.7‐65.6) foals.
Conclusions and Clinical Importance
Concurrent IV and IA administration of amikacin produces 30‐minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.
Background
Both obesity and metabolic syndrome are associated with hypercoagulability in people, increasing the risk of cardiovascular disease and thromboembolic events. Whether hypercoagulability ...exists in obese, insulin‐dysregulated horses is unknown.
Hypothesis/Objectives
To determine if coagulation profiles differ between healthy horses and those with obesity and insulin dysregulation.
Animals
Fifteen healthy horses (CON) and 15 obese, insulin‐dysregulated horses (OBID). Individuals were university or client owned.
Methods
Case‐control study. Obesity was defined as a body condition score (BCS) ≥7.5/9 (modified Henneke scale). Insulin dysregulation status was assessed by an oral sugar test (OST). Kaolin‐thromboelastography and traditional coagulation variables were compared between groups. The direction and strength of the association between coagulation variables and BCS and OST results were determined using Spearman's correlation.
Results
Thromboelastography variables MA (OBID: 69.5 ± 4.5 mm; CON: 64.8 ± 4.3 mm; P = .007) and G‐value (OBID: 11749 ± 2536 dyn/m2; CON: 9319 ± 1650 dyn/m2; P = .004) were higher in OBID compared to CON. Positive correlations between MA and BCS (R = 0.45, P = .01) and serum insulin (T0: R = 0.45, P = .01; T60: R = 0.39, P = .03), and G‐value and BCS (R = 0.46, P = .01), and serum insulin (T0: R = 0.48, P = .007; T60: R = 0.43, P = .02; T90: R = 0.38, P = .04) were present.
Conclusions and Clinical Importance
Obese, insulin‐dysregulated horses are hypercoagulable compared to healthy controls.
Background
Pregnancy toxemia is a common metabolic disease of periparturient small ruminants. Information on its effects on metabolism and perinatal adaptation of newborn lambs and kids is lacking.
...Objectives
Evaluate differences in morbidity, mortality, and common biochemical and hematologic variables between pregnancy toxemia kids (PT) and control kids (CON).
Animals
Sixteen kids born to does being treated at the hospital for pregnancy toxemia (blood beta‐hydroxybutyrate concentration BHB > 1.2 mmol/L) and 12 kids from healthy dams (dam BHB < 1.2 mmol/L) that kidded at the hospital.
Methods
In this cohort study, serial measurements of blood L‐lactate, glucose, and BHB concentrations, arterial blood gases, hematocrit, total protein concentrations, nonesterified fatty acids (NEFAs) concentrations, and body weight were compared between groups over the first 72 hours of life. Long‐term follow‐up was performed after 3 months.
Results
Pregnancy toxemia kids were more likely to require tube feeding at 0 and 12 hours (relative risk 7.7 1.13, 52.45 and 2.8 1.39, 5.65). Pregnancy toxemia kids were more acidemic (7.26 ± 0.069 vs 7.34 ± 0.079, P = .003) and hyperlactatemic (8.17 ± 2.57 vs 5.48 ± 2.71, P = .003) at birth than CON kids. Control kids were 1.1 1.01, 1.77 times more likely to survive to discharge and 2.2 1.15, 4.20 times more likely to survive to 3 months than PT kids.
Conclusions and Clinical Importance
Pregnancy toxemia kids had higher short‐ and long‐term mortality and were more likely to require perinatal intervention. Weight loss in the first few days could be a useful predictor of nonsurvival.
Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the ...rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan (
) subspecies in juvenile pigs (
). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg,
= 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg,
= 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from
envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data.
Objectives
To compare the efficacy of 2 equine‐origin antivenom products on correction of coagulation abnormalities noted on thromboelastography (TEG) caused by Crotalus atrox venom in vitro.
Design
...Prospective in vitro controlled study.
Setting
Veterinary teaching hospital.
Animals
Six healthy dogs.
Interventions
Blood from each dog was used for 4 separate kaolin‐activated TEG analyses: A negative control (blood–saline) and positive control (blood–Crotalus atrox venom) were used to assess the dog's normal coagulation and the effect of venom on TEG parameters. Thromboelastographic analyses were then run with blood, venom, and either Argentinian or North American antivenom. All TEG analyses from each dog were compared for efficacy.
Measurements and Main Results
The mean R values between the North American antivenom and negative controls were not significantly different (P = 0.681), but were significantly different (P = 0.024) between the Argentinian antivenom and negative controls. The mean fibrinolysis values measured 30 minutes after maximum amplitude achieved between the North American antivenom and negative controls were not significantly different (P = 0.198), but were significantly different (P < 0.001) between the Argentinian antivenom and negative controls. The mean K values between the Argentinian antivenom and negative controls were not significantly different (P = 0.274), but were significantly different (P = 0.043) between the North American antivenom and negative controls.
Conclusions
The North American antivenom normalized time to clot formation and fibrinolysis, while the Argentinian antivenom normalized rate of clot formation. Further studies in naturally envenomated patients are necessary to determine if these in vitro results would translate into different clinical outcomes.
OBJECTIVE To determine whether prophylactic administration of valacyclovir hydrochloride versus initiation of treatment at the onset of fever would differentially protect horses from viral ...replication and clinical disease attributable to equine herpesvirus type-1 (EHV-1) infection. ANIMALS 18 aged mares. PROCEDURES Horses were randomly assigned to receive an oral placebo (control), treatment at detection of fever, or prophylactic treatment (initiated 1 day prior to viral challenge) and then inoculated intranasally with a neuropathogenic strain of EHV-1. Placebo or valacyclovir was administered orally for 7 or 14 days after EHV-1 inoculation or detection of fever (3 horses/group). Effects of treatment on viral replication and clinical disease were evaluated. Plasma acyclovir concentrations and viremia were assessed to determine inhibitory concentrations of valacyclovir. RESULTS Valacyclovir administration decreased shedding of virus and viremia, compared with findings for control horses. Rectal temperatures and clinical disease scores in horses that received valacyclovir prophylactically for 2 weeks were lower than those in control horses. The severity of but not the risk for ataxia was decreased by valacyclovir administration. Viremia was decreased when steady-state trough plasma acyclovir concentrations were > 0.8 μg/mL, supporting the time-dependent activity of acyclovir. CONCLUSIONS AND CLINICAL RELEVANCE Valacyclovir treatment significantly decreased viral replication and signs of disease in EHV-1-infected horses; effects were greatest when treatment was initiated before viral inoculation, but treatment was also effective when initiated as late as 2 days after inoculation. During an outbreak of equine herpesvirus myeloencephalopathy, antiviral treatment may be initiated in horses at various stages of infection, including horses that have not yet developed signs of viral disease.
Snake envenomation can be a cause of significant morbidity in dogs and cats in North America. Being familiar with the venomous snakes in your area and understanding the mechanisms of action of their ...venom will allow for successful treatment of envenomation cases. Treatment of snake envenomation revolves around supportive care in mild to moderate cases and venom neutralization with antivenom in severe cases. Dogs and cats envenomated by North American snakes have a good prognosis if treated appropriately.
To evaluate the analgesic effects of orally administered gabapentin on horses with chronic thoracic limb lameness.
Randomized, crossover design.
A total of 14 adult horses with chronic thoracic limb ...lameness.
Following baseline measurement of lameness, horses were administered each of four treatments orally in grain: treatment G, gabapentin (20 mg kg
) twice daily for 13 doses; treatment F, firocoxib (171 mg once, then 57 mg once daily for six doses); treatment GF, gabapentin and firocoxib at previously stated doses and frequencies; or treatment C, grain only as a control. Treatments were administered in a randomized, crossover design, separated by 2 weeks. Subjective lameness score (SLS), inertial sensor vector sum (VS) calculations, peak vertical ground reaction force (PVGRF) measurements and vertical impulse (VI) calculations were determined immediately prior to each initial treatment dose and 2-4 hours after the final treatment dose for each treatment. Mean change in SLS, VS, PVGRF and VI for each treatment were compared among treatments.
The rank change in SLS of treatment GF was significantly greater than that of treatments C (p = 0.01) and G (p = 0.01) but not of treatment F (p = 0.08). No differences in VS (p = 0.4), PVGRF (p = 0.4) or VI (p = 0.1) were observed among treatments.
Gabapentin, as administered here, did not improve subjective or objective measures of lameness in horses with chronic thoracic limb musculoskeletal pain. Although subjective evaluation identified an improvement in lameness with treatment GF, it was not different from that observed with treatment F. Higher oral dosing and longer treatment regimens of gabapentin may be indicated for the treatment of chronic musculoskeletal pain in horses.
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