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Transactions of the Royal Society of Tropical Medicine and Hygiene (2006) 100, 879884

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A randomized, double-blind, placebo-controlled trial of antivenom for local effects of green pit viper bites
Ponlapat Rojnuckarin a,,1, Walee Chanthawibun a,1, Jureeporn Noiphrom b, Narumol Pakmanee b, Tanin Intragumtornchai a
a b

Department of Medicine, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Patumwan, Bangkok 10330, Thailand Queen Saovabha Memorial Institute, Thai Red Cross Society, Rama IV Road, Patumwan, Bangkok 10330, Thailand

Received 30 July 2005; received in revised form 8 October 2005; accepted 10 October 2005 Available online 8 February 2006

KEYWORDS
Snakebite; Trimeresurus albolabris; Oedema; Crotalid venoms; Antivenom; Thailand

Summary Although systemic administration of antivenom can promptly reverse coagulopathy, efcacy on local effects of viper venom remains to be determined. Currently, there has been no proven specic treatment for snakebite patients with severe local effects. This study is a randomized, double-blind, placebo-controlled trial. Patients bitten by green pit vipers (Trimeresurus albolabris or T. macrops) with marked limb swelling, but no severe coagulopathy requiring antivenom, were randomized to receive either equine F(ab )2 antivenom, or placebo. Twentyeight cases were included, 14 in each group, and they had their limb circumferences measured on days 1, 2, 4 and 6 after interventions. The percentage reduction in limb circumference was signicantly better in the antivenom group compared with the placebo group (ANOVA, P = 0.03), especially in the rst 24 h (1.14 vs. 3.62%, in placebo and antivenom group, respectively, P = 0.014). The reduction in pain score was similar. The plasma venom levels were not different at presentation but lower in the antivenom group 24 h after intervention (P = 0.033). These data suggest that intravenous antivenom could accelerate local oedema resolution in humans. However, the degree is not clinically signicant, and, therefore, general use is not recommended. 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Viper snakebites still pose problems, both for public health and clinical management, worldwide. In Thailand, green pit vipers (Trimeresurus albolabris or T. macrops) account for 40% of all bites (Viravan et al., 1992). In addition, they are the most widely distributed of the vipers and comprise more than 95% of venomous snakebites in Bangkok (Mahasandana

Corresponding author. Tel.: +66 2256 4564x104; fax: +66 2253 9466. E-mail addresses: fmedprn@md2.md.chula.ac.th, porpiasod@hotmail.com (P. Rojnuckarin). 1 These authors contributed equally to this work.

0035-9203/$ see front matter 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2005.10.006

880 and Jintakune, 1990; Meemano et al., 1987). As we invaded their habitat, green pit vipers adapted to live with humans. Consequently, more than 400 new cases of bites come to the Chulalongkorn University Hospital each year. Most of them are bitten in Bangkok or nearby regions, despite extensive urbanization. Green pit viper venom causes systemic hypobrinogenaemia and thrombocytopenia (Mahasandana et al., 1980; Mitrakul, 1973). In addition, snake venom metalloproteinases can damage vessel walls, contributing signicantly to systemic bleeding (Gutierrez et al., 2005; Kamiguti et al., 1996). Furthermore, most patients also suffer from local effects of the venom: namely, limb swelling and pain. The symptoms might be so severe that, in some patients, absence from work is unavoidable. Skin blisters, resulting from dermo-epidermal separation, occur in 24.8% of victims and are signicantly related to subsequent dermal necrosis and super-infection (Rojnuckarin et al., 1998). Digital gangrene, which requires prolonged daily dressing and possible surgical dermotomy, also occurs in 6.6% of cases (Rojnuckarin et al., 1998). Without treatment, debrination syndrome following a green pit viper bite may be prolonged for over a week (Visudhiphan et al., 1981). Systemic antivenom can promptly reverse venom-induced coagulopathy within hours (Rojnuckarin et al., 1998). However, the efcacy of systemic administration of antivenom to alleviate these local symptoms remains to be determined. A subset of patients suffers from severe local effects without signicant coagulopathy. There is, currently, no proven treatment to be effective in these cases. As the commercially available antivenom has a risk of severe reactions, in our current practice its administration is withheld until severe coagulopathy is detectable, i.e.: (1) systemic bleeding; (2) Lee and White venous clotting time (VCT) over 30 min; or (3) platelet count less than 10 109 /l. Patients with normal VCT, but mildly prolonged prothrombin time, can be managed conservatively without antivenom. In our clinic, most patients do not receive antivenom, yet their oedema and pain after snakebites subsides progressively. Therefore, to denitely prove antivenom efcacy, a double-blind trial is required.

P. Rojnuckarin et al. joints from the biting sites (knee or elbow), but no bleeding, VCT under 30 min and platelet count over 10 109 /l; (2) age 15 years or older. The exclusion criteria were: (1) antivenom indicated for systemic coagulopathy during the course of follow-up; (2) severe systemic side effects during antivenom infusion, prohibiting at least half of the dose of antivenom administration and causing the intervention to be unblinded; (3) signicant underlying diseases, i.e. pulmonary, cardiac, renal or hepatic diseases. Because of the expected small sample size, we thought that exclusion of cases that could not receive the randomized treatments was necessary.

2.2. Methods
The Ethical Committee of the institution had approved the protocol of this study before enrolling the patients. The study was a randomized, double-blind, placebocontrolled clinical trial. Having signed informed consent forms, patients were admitted to a short-term ward. The nurses would then open a pre-randomized envelope and give each patient, accordingly, either two vials of horse-derived F(ab )2 green pit viper antivenom from Queen Saovabha Memorial Institute, Bangkok, Thailand (antivenom group) or the same volume of saline (placebo group) intravenous infusion over 60 min. Both solutions were colourless. The three-vial dose is recommended for treating systemic coagulopathy. We therefore chose a reduced dose for local effects. The investigator who examined the patients (W.C.) and the patients themselves were blinded for the treatment groups. The subjects were then followed-up on days 1, 2, 4 and 6 after interventions. Clinical examinations, complete blood count and VCT were performed. At every time point, venom level was also measured using a sandwich ELISA method as previously described (Rojnuckarin et al., 1999). A rabbit polyclonal antibody, adsorbed by venom from other species, and the horse antiserum (antivenin) for green pit vipers conjugated with peroxidase, were used for capture and detection antibodies, respectively. A known amount of T. albolabris venom, diluted serially in pooled normal plasma, was used to make a standard curve to determine venom levels in patient samples. The test could detect venom of both T. albolabris and T. macrops and was not cross-reactive with other Thai snake venoms, except for the Russells viper venom at a concentration over 100 ng/ml. This concentration is not found in clinical specimens (Hanvivatvong et al., 1997). The limit of detection was 1 ng/ml and the percent coefcient of variation (CV) was 6.18%. All patients were informed about the symptoms of serum sickness, i.e. fever, rashes and joint pain. The telephone number of the investigator was given to them to report these symptoms after day 6 and to make appointments for clinical examinations and treatments. The degree of oedema is dened by the differences in circumferences of the affected and unaffected sides of limbs, measured (in cm) at the same distances from nearby joints. The points with the maximal differences were chosen and marked for the next measurements. The main outcome is the percentage reduction in limb circumference, calculated as the reduction in limb circumference on each day after intervention, divided by the initial limb circumference, and multiplied by 100. Pain was scored by patients on a 010

2. Patients and methods


2.1. Study population
The study was conducted at the snakebite clinic, Chulalongkorn University Hospital, Bangkok, Thailand from September 2002 to March 2004. The patients were diagnosed as having been bitten by green pit vipers from the presence of fang marks, indicating a venomous snakebite, and one of the following: (1) bringing the snake for doctors identication as T. albolabris or T. macrops; (2) measurable green pit viper venom levels in the plasma; (3) patients clear recall of seeing a green snake with a red tail, the specic morphology for these two species, when combined with fang marks and biting location in Bangkok, as green pit vipers are responsible for almost 100% of venomous snakebites in this area (Meemano et al., 1987). The inclusion criteria were: (1) diagnosis of green pit viper bites with marked swelling, as dened by oedema reaching or going beyond the second

Antivenom for green pit viper bites

881

3. Results
3.1. Patients characteristics
During the study period, 656 new patients came to the snakebite clinic. Most of them had not been able to see the snakes clearly and/or showed only mild oedema. Approximately 5% required antivenom due to coagulopathy and were excluded. Thirty-ve patients tted the inclusion criteria. Thirty of them agreed to join the study and were randomized. Twenty-six were diagnosed by measurable plasma venom levels, one of which brought the snake for identication as T. albolabris. Four were bitten in Bangkok and could clearly recognize the snakes. One in the placebo group later developed severe coagulopathy (unclotted blood and a platelet count of 19 109 /l). Antivenom was thus given to this patient, and he showed a marked reduction in limb oedema. The other case, randomized to the antivenom group, suffered from bronchospasm and urticaria during antivenom infusion, requiring discontinuation, epinephrine and antihistamine injection. Antivenom was given at less than one-tenth of the intended dose. He showed no reduction in limb oedema at 24 h afterwards. Both of these cases were unblinded from the interventions and, hence, were excluded. Twenty-eight patients were included in the analysis. Half of these received antivenom. The mean age was 42.9 16.3 (mean SD), ranging from 17 to 85 years. Twelve of them (42.9%) were male. They presented on average at 21.6 h after bites (364 h). The differences between the affected and unaffected limbs ranged from 1.7 to 7.9 cm (4.36 1.74 cm). All had normal VCT. However, 11 (39.3%) were mildly thrombocytopenic at presentation and two more were so at follow-up (total of 46.4%). The baseline characteristics of the two treatment groups were similar (Table 1).

Figure 1 The effect of antivenom on percentage changes in limb circumference. The percentage reduction in limb circumference was calculated as: the reduction in limb circumference on each day after intervention, divided by the initial limb circumference, and multiplied by 100. The error bars represent standard errors of the mean. There was a signicant difference between the placebo and antivenom groups (ANOVA, P = 0.03). In addition, there were signicant differences on day 1 and day 2 (t test).

scale (no pain to worst pain) and recorded. The percentage reduction of pain scores compared with the scores at presentation was also calculated. Acetaminophen was the only medication prescribed to patients for use as needed.

2.3. Statistical methods


For descriptive purposes, data were expressed as means and standard deviations (SD), except that the error bars in Figure 1 were expressed as the standard error of the mean, as indicated. ANOVA (repeated measures) was used to test the effects of antivenom. Students t test was used to compare the numerical data between groups. The 2 test was used for the comparisons of categorical data. Pearsons correlation coefcients were utilized to examine data correlation. All statistical calculations were performed using the SPSS 12.0 for Windows software (SPSS Inc., Chicago, IL, USA).

3.2. Main outcome


The percentage reduction in limb circumference is shown in Figure 1. Antivenom could decrease limb circumferences signicantly better than the placebo (ANOVA, P = 0.03).

Table 1

Baseline characteristics of the study patientsa Placebo (n = 14) 48.36 18.37 3/11 3/11 10/4 2 (15.4%) 17.04 6.02 4.23 1.725 5.36 1.98 3 (21.4%) 2 (15.4%) 240.71 127.69 5 (35.7%) 103.50 79.15 Antivenom (n = 14) 37.5 12.25 9/5 6/8 9/5 3 (21.4%) 26.21 17.01 4.50 1.804 4.71 2.49 3 (21.4%) 2 (15.4%) 184.89 94.14 6 (42.9%) 90.50 63.34 P-value 0.077 0.054 0.225 0.696 0.075 0.692 0.457

Characteristic Age (years) Sex (no. male/female) Extremities (no. upper/lower) Side (no. right/left) Biting sites, ngers or toes Hours after bites Baseline oedemab (cm) Pain score Presence of ecchymosis Presence of blisters Platelet count (109 /l) Thrombocytopenia Venom-time (ng-h/ml)
a b

0.199 0.635

Data were expressed as mean SD. Oedema = the circumference of an affected side the circumference of an unaffected side of the same person.

882
Table 2 Reduction in limb circumference and pain score after interventionsa Limb circumference reduction (cm) Placebo Day Day Day Day
a b

P. Rojnuckarin et al.

Pain score reduction (010) P-value 0.010 0.078 0.450 0.400


b

Antivenom 1.10 1.96 2.82 3.35 0.83 0.89 1.03 1.01

Placebo 1.93 2.93 3.21 4.36 1.73 2.76 2.67 1.99

Antivenom 2.00 2.50 3.36 4.14 1.41 2.47 1.87 2.38

P-valueb 0.906 0.669 0.871 0.978

1 2 4 6

0.37 1.31 2.37 2.95

0.49 0.98 1.19 1.29

Data were expressed as mean SD. Values were calculated by Students t test.

The mean values of the placebo and antivenom groups were 1.14 1.34% vs. 3.62 3.15% on day 1 (P = 0.014) and 3.84 2.74% vs. 6.18 2.69% on day 2 (P = 0.031). The percentage differences at the later time points were not statistically signicant. If we include two excluded cases that did not received assigned interventions as an intention-to-treat analysis, the difference between the placebo and antivenom group on day 1 remains signicant (P = 0.041, t test). However, the difference between the two groups using ANOVA becomes marginal (P = 0.058). To illustrate the magnitude of the effects, absolute reduction in limb circumference is shown in Table 2. From the average baseline increases in circumference of 45 cm, the antivenom group showed less than 1 cm faster resolution on day 1. Although it was statistically better, the differences were probably not clinically important. The absolute reduction in pain score is also displayed in Table 2. Both percentage and absolute reduction in pain scores were not different between the two groups (ANOVA). No patients reported the symptom of serum sickness. There was no signicant correlation between the percentage reductions in limb circumference at day 1 with patient ages, hours after bites or initial degrees of oedema. In addition, there was no signicant difference in percentage reduction in limb swelling between sexes.

placebo group still had detectable venom levels at day 6, but none of the antivenom group did so at that time. Initial platelet counts were not correlated with venom levels at presentation. They were signicantly correlated with the venom-time, the product of venom levels and time of specimen collections after bites. The Pearsons correlation coefcient is 0.48 (P = 0.01). However, neither venom levels nor venom-time at presentation were correlated with the initial degree of oedema. Two patients in the antivenom group who still had detectable venom in plasma 24 h after antivenom administrations showed good reductions in limb oedema (4.9 and 2.6%). Therefore, there is no detectable correlation between local effects and plasma venom parameters.

4. Discussion
Previous studies demonstrated that neutralization of the local effects of viper venoms by systemic antivenom was ineffective, although antivenom was administered very shortly after the venom (Ownby et al., 1984; Russell et al., 1973), or even before the venom in animal models (Gutierrez et al., 1998). In a clinical trial of ovine Fab antivenom against American pit vipers, the local effects were not promptly reversed by antivenom, although overall severity scores were markedly improved (Dart et al., 2001). This may be explained by the pathological changes of local effects of snake venoms, cell death and haemorrhage, processes that cannot be reversed quickly or at all (Gold et al., 2002). Nevertheless, antivenom was shown to be effective for local effects in some experimental models, including Bothrops insularis (Barbosa et al., 2003) and Crotalus viridis viridis (Evans and Ownby, 1999). In addition, clinical experience in countries where antivenom is given to all snakebite patients showed that limb oedema is stopped or decreased by antivenom (Dart and McNally, 2001; Lavonas et al., 2004).

3.3. Venom level determinations


Twelve of 14 in each group had measurable venom levels at the time of randomization (Table 3). Five (41.7%) in the placebo group cleared plasma venom on day 1 after the intervention. However, in 10 (83.3%) of the antivenom group plasma venom disappeared (P = 0.045). Venom levels at presentation were not signicantly different, but the venom levels of the antivenom group were signicantly lower at 24 h after the intervention (P = 0.033). Three (21.4%) of the

Table 3

Venom level determinationsa Placebo (n = 14) Antivenom (n = 14) 12 (85.7) 2 (14.3) 4.60 2.57 0.39 1.00 P-value NSb 0.045 0.29 0.02

Measurable plasma venom at baseline, n (%) Measurable venom at day 1, n (%) Venom level at baseline, ng/ml Venom level at day 1, ng/ml
a b

12 (85.7) 7 (50) 6.09 4.46 2.07 2.24

Data were expressed as mean SD. NS = not signicant.

Antivenom for green pit viper bites In this study, all the baseline characteristics of patients in the placebo and antivenom groups were similar, except that there was a trend towards more females in the placebo group. However, the difference is not statistically signicant and there has been no reported evidence that oedema resolution after snakebites is different between the sexes. In addition, there was no signicant difference in the percentage reduction of limb circumference between males and females in this study. Because venoms from the two Trimeresurus species were closely related, our ELISA test could not differentiate between the two. Trimeresurus albolabris causes more severe swelling and might be a cause of variability. However, as the initial degrees of oedema in both groups were similar (Table 1), it was unlikely that there was an unequal distribution of species. Our previous study has shown that the severity of the systemic envenomation is not associated with the venom level at presentation (Rojnuckarin et al., 1999). In an animal model, viper venom levels were highest close to the time of bite and then progressively declined (Audebert et al., 1994). This venomtime is signicantly associated with systemic coagulopathy, because it reects the accumulating effect of the venom (Hutton et al., 1990). In this study, the incidence of immediate reaction was 1 in 16 (6.3%). No recurrence of local oedema and no serum sickness were found in 15 patients receiving antivenom. Antivenom can modestly enhance the resolution of limb swelling. Other aspects, such as pain and functional activity, were not signicantly different between the two groups. There was only one case with dermal necrosis, which developed in the placebo group. The incidence was too low for statistical analysis. Therefore, the clinical signicance was not clear. Considering the possibility of hypersensitivity reactions and the cost, use of antivenom just for the alleviation of oedema is not appropriate. However, antivenom may be useful in cases with severe local effects, e.g. massive oedema or impending compartmental syndrome. Faster resolution of tissue swelling in these cases may be benecial. There was no correlation between the time from bite to antivenom administration and clinical response, and six patients in the antivenom group had been bitten more than 24 h earlier, suggesting that a long time after bite should not preclude antivenom use. In this study, oedema reduction was not signicantly enhanced at later time points, suggesting that additional dose(s) of antivenom may be benecial. Therefore, a different dose schedule may need further studies. Two possible explanations for the effect of antivenom on local tissue damage are: (1) antivenom neutralizes intravascular venom, accelerating its elimination and allowing venom redistribution into the intravascular space for clearance (Riviere et al., 1997); or (2) extravasation of the antivenom inhibits venom toxicities. We found no correlation between initial and subsequent venom parameters and local effects, suggesting the latter mechanism. Nevertheless, both mechanisms may operate together. There were two cases that still showed detectable plasma venom levels after antivenom administration. The use of higher doses of antivenom in order to clear systemic venom remains to be explored. The efcacy of antivenom on local tissue damage from snake venom depends on its capability to neutralize venom

883 components responsible for the effects. Both catalytically active (Asp49) and inactive (Lys49) classes of phospholipases A2 (PLA2 s) in snake venoms have been shown to induce local oedema in animals (Liu et al., 1991; Lomonte et al., 1993). The effects of active PLA2 s are mediated by releases of histamine and other pro-inammatory cytokines (Barbosa et al., 2003; Lloret and Moreno, 1993). However, Lys49 PLA2 s cause membrane damage through their C-terminal basic and hydrophobic residues (Lomonte et al., 2003). Furthermore, snake venom metalloproteases (haemorrhagins) can destroy vascular wall, resulting in uid leakage into the interstitial space. Neutralization of haemorrhagin has been proposed to be the mechanism of action of antivenom (Evans and Ownby, 1999). Production of antibody specic to these components may be able to enhance antivenom efcacy. Furthermore, a synergy of antivenom and a PLA2 enzyme inhibitor, parabromophenacyl bromide, has been found to markedly reduce the local effects of Agkistrodon contortrix laticinctus venom in an animal model (Evans and Ownby, 1999). Therefore, inhibition of these toxins using chemical means is another attractive adjunctive approach. In conclusion, we have demonstrated the efcacy of the systemic antivenom in reducing limb oedema after green pit viper bites in humans. However, the effect was not strong enough to recommend clinical use in most cases. Conicts of interest statement The authors have no conicts of interest concerning the work reported in this paper.

Acknowledgements
This study was supported by the Asahi Glass Foundation, overseas research grant 2002 and the Thai Association of Hematology research fund. We are grateful to all the snakebite patients, the nursing staff of the research ward, the staff of the snakebite clinic, and Dr Supat Chamnarnchanan for their great help in this study.

References
Audebert, F., Urtizberea, M., Sabouraud, A., Scherrmann, J.M., Bon, C., 1994. Pharmacokinetics of Vipera aspis venom after experimental envenomation in rabbits. J. Pharmacol. Exp. Ther. 268, 15121517. Barbosa, A.M., do Amaral, R.O., Teixeira, C.F., Hyslop, S., Cogo, J.C., 2003. Pharmacological characterization of mouse hind paw oedema induced by Bothrops insularis (jararaca ilhoa) snake venom. Toxicon. 42, 515523. Dart, R.C., McNally, J., 2001. Efcacy, safety, and use of snake antivenoms in the United States. Ann. Emerg. Med. 37, 181188. Dart, R.C., Seifert, S.A., Boyer, L.V., Clark, R.F., Hall, E., McKinney, P., McNally, J., Kitchens, C.S., Curry, S.C., Bogdan, G.M., Ward, S.B., Porter, R.S., 2001. A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch. Intern. Med. 161, 20302036. Evans, J., Ownby, C.L., 1999. Neutralization of edema, hemorrhage and myonecrosis induced by North American crotalid venoms in simulated rst-aid treatments. Toxicon. 37, 633650. Gold, B.S., Dart, R.C., Barish, R.A., 2002. Bites of venomous snakes. N. Engl. J. Med. 347, 347356.

884
Gutierrez, J.M., Leon, G., Rojas, G., Lomonte, B., Rucavado, A., Chaves, F., 1998. Neutralization of local tissue damage induced by Bothrops asper (terciopelo) snake venom. Toxicon. 36, 15291538. Gutierrez, J.M., Rucavado, A., Escalante, T., Diaz, C., 2005. Hemorrhage induced by snake venom metalloproteinases: biochemical and biophysical mechanisms involved in microvessel damage. Toxicon. 45, 9971011. Hanvivatvong, O., Mahasandana, S., Karnchanachetanee, C., 1997. Kinetic study of Russells viper venom in envenomed patients. Am. J. Trop. Med. Hyg. 57, 605609. Hutton, R.A., Looareesuwan, S., Ho, M., Silamut, K., Chanthavanich, P., Karbwang, J., Supanaranond, W., Vejcho, S., Viravan, C., Phillips, R.E., Warrell, D.A., 1990. Arboreal green pit viper (genus Trimeresurus) of Southeast Asia: bites by T. albolabris and T. macrops in Thailand and a review of the literature. Trans. R. Soc. Trop. Med. Hyg. 84, 866874. Kamiguti, A.S., Hay, C.R., Theakston, R.D., Zuzel, M., 1996. Insights into the mechanism of haemorrhage caused by snake venom metalloproteinases. Toxicon. 34, 627642. Lavonas, E.J., Gerardo, C.J., Omalley, G., Arnold, T.C., Bush, S.P., Banner Jr, W., Steffens, M., Kerns 2nd, W.P., 2004. Initial experience with Crotalidae polyvalent immune Fab (ovine) antivenom in the treatment of copperhead snakebite. Ann. Emerg. Med. 43, 200206. Liu, C.S., Chen, J.M., Chang, C.H., Chen, S.W., Teng, C.M., Tsai, I.H., 1991. The amino acid sequence and properties of an edemainducing Lys-49 phospholipase A2 homolog from the venom of Trimeresurus mucrosquamatus. Biochim. Biophys. Acta 1077, 362370. Lloret, S., Moreno, J.J., 1993. Oedema formation and degranulation of mast cells by phospholipase A2 puried from porcine pancreas and snake venoms. Toxicon. 31, 949956. Lomonte, B., Tarkowski, A., Hanson, L., 1993. Host response to Bothrops asper snake venom: analysis of edema formation, inammatory cells, and cytokine release in a mouse model. Inammation 17, 93105. Lomonte, B., Angulo, Y., Calderon, L., 2003. An overview of lysine49 phospholipase A2 myotoxins from crotalid snake venoms and their structural determinants of myotoxic action. Toxicon. 42, 885901. Mahasandana, S., Jintakune, P., 1990. The species of green pit viper in Bangkok. Southeast Asian J. Trop. Med. Public Health 21, 225230.

P. Rojnuckarin et al.
Mahasandana, S., Rungruxsirivorn, Y., Chantarangkul, V., 1980. Clinical manifestations of bleeding following Russells viper and green pit viper bites in adults. Southeast Asian J. Trop. Med. Public Health 11, 285293. Meemano, K., Pochanugool, C., Limthongkul, S., 1987. Incidence of snakebites at Chulalongkorn hospital, in: Gopalakrishnakone, P., Tan, C.K. (Eds), Progress in Venom and Toxin Research. National University of Singapore, Singapore, pp. 36 40. Mitrakul, C., 1973. Effects of green pit viper (Trimeresurus erythrurus and T. popeorum) venoms on blood coagulation, platelets and the brinolytic enzyme systems: studies in vivo and in vitro. Am. J. Clin. Pathol. 60, 654662. Ownby, C.L., Colberg, T.R., Claypool, P.L., Odell, G.V., 1984. In vivo test of the ability of antiserum to myotoxin a from prairie rattlesnake (Crotalus viridis viridis) venom to neutralize local myonecrosis induced by myotoxin a and homologous crude venom. Toxicon. 22, 99105. Riviere, G., Choumet, V., Audebert, F., Sabouraud, A., Debray, M., Scherrmann, J.M., Bon, C., 1997. Effect of antivenom on venom pharmacokinetics in experimentally envenomed rabbits: toward an optimization of antivenom therapy. J. Pharmacol. Exp. Ther. 281, 18. Rojnuckarin, P., Mahasandana, S., Intragumthornchai, T., Sutcharitchan, P., Swasdikul, D., 1998. Prognostic factors of green pit viper bites. Am. J. Trop. Med. Hyg. 58, 2225. Rojnuckarin, P., Intragumtornchai, T., Sattapiboon, R., Muanpasitporn, C., Pakmanee, N., Khow, O., Swasdikul, D., 1999. The effects of green pit viper (Trimeresurus albolabris and Trimeresurus macrops) venom on the brinolytic system in human. Toxicon. 3, 743755. Russell, F.E., Ruzic, N., Gonzalez, H., 1973. Effectiveness of antivenin (Crotalidae) polyvalent following injection of Crotalus venom. Toxicon. 11, 461464. Viravan, C., Looareesuwan, S., Kosakarn, W., Wuthiekanun, V., McCarthy, C.J., Stimson, A.F., Bunnag, D., Harinasuta, T., Warrell, D.A., 1992. A national hospital-based survey of snakes responsible for bites in Thailand. Trans. R. Soc. Trop. Med. Hyg. 86, 100106. Visudhiphan, S., Dumavibhat, B., Trishnananda, M., 1981. Prolonged debrination syndrome after green pit viper bite with persisting venom activity in patients blood. Am. J. Clin. Pathol. 75, 65 69.

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