title: Clinical and Pharmacological Investigation of Myotoxicity in Sri Lankan Russell's Viper (Daboia russelii) Envenoming.
abstract: Sri 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.
  
  
  
  Clinical 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.
  
  
  
  The 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.
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.|Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Saliyapura, Sri Lanka.|South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Anjana
authors.identifier: 0000-0002-9968-3707
authors.initials: A
authors.lastname: Silva
authors.affiliation: Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnston
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Kuruppu
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kneisz
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.|Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia.|Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Kalana
authors.initials: K
authors.lastname: Maduwage
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Oded
authors.initials: O
authors.lastname: Kleifeld
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: A Ian
authors.initials: AI
authors.lastname: Smith
authors.affiliation: Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Saliyapura, Sri Lanka.
authors.forename: Sisira
authors.initials: S
authors.lastname: Siribaddana
authors.affiliation: South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.|Clinical Pharmacology, University of Sydney, Sydney, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Buckley
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hodgson
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.|South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka.|Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Isbister
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002642:Chick Embryo; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D054467:Phospholipases A2 / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017840:Daboia / Q000502:physiology*; D012909:Snake Bites / Q000097:blood / Q000201:enzymology / Q000469:parasitology*; D013188:Sri Lanka; D014757:Viper Venoms / Q000737:chemistry / Q000201:enzymology / Q000633:toxicity*; D055815:Young Adult
chemical_list: D014757:Viper Venoms; D003402:Creatine Kinase; D054467:Phospholipases A2