Clinical and Pharmacological Investigation of Myotoxicity in Sri Lankan Russell’s Viper (Daboia russelii) Envenoming

Abstract

BackgroundSri Lankan Russell’s viper (Daboia russelii) envenoming is reported to cause myotoxicity and neurotoxicity, which are different to the effects of envenoming by most other populations of Russell’s vipers. This study aimed to investigate evidence of myotoxicity in Russell’s viper envenoming, response to antivenom and the toxins responsible for myotoxicity.Methodology and FindingsClinical features of myotoxicity were assessed in authenticated Russell’s viper bite patients admitted to a Sri Lankan teaching hospital. Toxins were isolated using high-performance liquid chromatography. In-vitro myotoxicity of the venom and toxins was investigated in chick biventer nerve-muscle preparations. Of 245 enrolled patients, 177 (72.2%) had local myalgia and 173 (70.6%) had local muscle tenderness. Generalized myalgia and muscle tenderness were present in 35 (14.2%) and 29 (11.8%) patients, respectively. Thirty-seven patients had high (>300 U/l) serum creatine kinase (CK) concentrations in samples 24h post-bite (median: 666 U/l; maximum: 1066 U/l). Peak venom and 24h CK concentrations were not associated (Spearman’s correlation; p = 0.48). The 24h CK concentrations differed in patients without myotoxicity (median 58 U/l), compared to those with local (137 U/l) and generalised signs/symptoms of myotoxicity (107 U/l; p = 0.049). Venom caused concentration-dependent inhibition of direct twitches in the chick biventer cervicis nerve-muscle preparation, without completely abolishing direct twitches after 3 h even at 80 μg/ml. Indian polyvalent antivenom did not prevent in-vitro myotoxicity at recommended concentrations. Two phospholipase A2 toxins with molecular weights of 13kDa, U1-viperitoxin-Dr1a (19.2% of venom) and U1-viperitoxin-Dr1b (22.7% of venom), concentration dependently inhibited direct twitches in the chick biventer cervicis nerve-muscle preparation. At 3 μM, U1-viperitoxin-Dr1a abolished twitches, while U1-viperitoxin-Dr1b caused 70% inhibition of twitch force after 3h. Removal of both toxins from whole venom resulted in no in-vitro myotoxicity.ConclusionThe study shows that myotoxicity in Sri Lankan Russell’s viper envenoming is mild and non-life threatening, and due to two PLA2 toxins with weak myotoxic properties.

Non-neurotoxic activity of Malayan krait (Bungarus candidus) venom from Thailand

“…In the present study, CK elevation did not reach maximum value within 6 h as seen for viperid myotoxins or coral snake venoms [ 9 , 25 ]. This result is in agreement with a recent study indicating no significant elevation of CK level following Sri Lankan Russell’s viper envenoming at the 6 h time point [ 19 ]. The variation in CK levels following venom administration could be attributed to differences in either the pharmacokinetics of venom distribution or method of administration.…”

“…Systemic myotoxicity is observed following envenoming by sea snake, some viperids and elapids [ 7 , 19 , 20 ]. Clinical outcomes following systemic venom-induced myotoxicity include widespread muscle injury with associated myalgia, elevation of plasma CK level, myoglobinuria and hyperkalemia due to extensive muscle cell damage [ 9 , 21 ].…”

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

“…In two animals, attempts were made to assess whether the neurotoxic effect was due to alpha-neurotoxins acting at the cholinergic receptor of the motor end-plate of muscle fibers; a combination of edrophonium (1 mg/kg) and atropine (0.02 mg/kg) combined in the same syringe was administered slowly intravenously over one minute in two animals receiving a lethal dose of the venom. No clinically observable improvement in strength occurred, suggesting, but not proving, the absence of any contribution by post-synaptically acting alpha-neurotoxins [ 35 , 36 ]. Notably, no animal in the study required any additional analgesia more than the mandatory two initial doses required by protocol (see Materials and Methods Detail, Section 5 ).…”

“…It may simply be that the high affinity of the alpha toxins towards the nAChR cannot be overcome by anticholinesterases. One straightforward method of showing this in other models is the isolated chick-biventer nerve-muscle preparation, which differentiates pre-synaptic from post-synaptic neurotoxicity [ 35 , 36 ]. However, this was not part of the present study, which was conducted on pigs.…”

Evaluation of the geographical utility of Eastern Russell’s viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity

“…Envenoming by snakes of the genus Daboia manifest in a variety of clinical outcomes. For example, in Sri Lanka, some bites by D. russelii russelii have been reported to cause neurotoxicity characterized by flaccid paralysis, myotoxicity associated with skeletal muscle breakdown, and coagulopathy [30, 31]. In the case of D. siamensis , two of the most severe and common clinical outcomes observed following envenoming by this species are systemic coagulopathy and acute renal failure [7, 32].…”