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Igor Križaj - One of the best experts on this subject based on the ideXlab platform.
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Thrombocytopenic purpura following envenomation by the nose-horned viper (Vipera Ammodytes Ammodytes): Two case reports.
Medicine, 2018Co-Authors: Boris Lukšić, Svjetlana Karabuva, Joško Markić, Branka Polić, Tanja Kovačević, Julije Meštrović, Igor KrižajAbstract:RATIONALE Two clinical cases are reported of envenomation by the nose-horned viper (Vipera Ammodytes Ammodytes) venom of a 9-year-old boy and of an 84-year-old woman. PATIENT CONCERNS Both patients had been bitten on their extremities by such a snake in August near Split, a town in southern Croatia. DIAGNOSES Clinical manifestation of envenomation was severe in the case of the boy, being characterized by a severe coagulopathy. This was only just apparent in the case of the elderly woman, who suffered extensive local edema and hematoma at the site of the bite, together with a neurotoxic effect-bilateral ptosis. This was the first occasion of thrombocytopenic purpura being observed in patients envenomed by nose-horned viper venom. This unexpected clinical finding was characterized by an unusually profound thrombocytopenia of 5 and 10 × 10/L platelets of the respective patients on their admission to the hospital, together with purpura, observed on the face and thorax of both individuals. In the most serious cases, such pathology can be life threatening if not promptly recognized and treated. INTERVENTIONS The patients recovered quickly on receiving the specific antivenom along with all the usual supportive treatments. OUTCOMES No serious sequels were noticed at the moment of discharge. LESSONS Our finding constitutes an important message to clinicians to consider the possibility of such complications in the case of nose-horned viper envenomation.
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Ammodytin L is the main cardiotoxic component of the Vipera Ammodytes Ammodytes venom
Toxicon : official journal of the International Society on Toxinology, 2017Co-Authors: Svjetlana Karabuva, Adrijana Leonardi, Zorica Latinović, Boris Lukšić, Ivica Brizić, Igor KrižajAbstract:Abstract Venom of the nose-horned viper ( V. a. Ammodytes ) as also venoms of some related European viperids can induce also cardiotoxic effects in mammals. In this work we demonstrated that the protein in the V. a. Ammodytes venom acting on heart is a myotoxic secreted phospholipase A 2 analogue ammodytin L (AtnL). In the isolated perfused rat heart AtnL induced significant and irreversible cardiotoxicity characterized by atrioventricular (AV) blockade. This venom protein induced appearance of high levels of creatine kinase, lactate dehydrogenase, aspartate aminotransferase and troponin I in the sinus effluent of the isolated heart, indicative for myocardial damage, which is obviously the primary cause of its cardiotoxic action. Gel filtration chromatography subfractions C1 and C2 of the V. a. Ammodytes venom harboured most of the venom cardiotoxicity. As we showed, just these two subfractions contained also AtnL. Subfraction C1 in the final CF concentration 11.3 μg/mL (containing 3.1 μg/mL AtnL) induced a complete cardiac arrest while subfraction C2 in the final CF concentration 6.0 μg/mL (containing 0.8 μg/mL AtnL) and the pure AtnL (1.0 μg/mL) did not. Contrary to AtnL, subfraction C1 at 11.3 μg/mL was not able to induce the AV blockade. This exposed the only other cardiotoxic subfractions-specific venom protein, a cysteine-rich secretory protein (CRISP), as an additional venom component potentially involved in modulation of the heart activity. Cardiotoxicity reported in some cases of the adder ( V. berus ) venom and the asp viper ( V. aspis ) venom poisonings may be assigned to AtnL in these venoms.
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vipera Ammodytes bites treated with antivenom viperatab a case series with pharmacokinetic evaluation
Clinical Toxicology, 2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtovic, Damjan Grenc, Beata HalassyAbstract:AbstractContext: In clinical practice it is difficult to differentiate between V. berus and V. Ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. Ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus.Objective: To evaluate ViperaTAb® in V. a. Ammodytes envenomations.Materials and methods: This is a prospective case series of three consecutive patients envenomed by V. a. Ammodytes snakebite treated with ViperaTAb®. V. Ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out.Results: Three patients bitten by V. a. Ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. Ammodytes venom...
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Vipera Ammodytes bites treated with antivenoms Viperfav® and ViperaTAb®
2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtović, Damjan Grenc, Beata HalassyAbstract:Objective: Clinically Vipera berus and Vipera Ammodytes envenomation are difficult to differentiate. In the past this was not a concern, but due to the current shortage in European viper venom antiserum availability, V. Ammodytes venomous bites have recently been treated with ViperfavTM and ViperaTAb®. Viperfav contains polyvalent equine F(ab')2 fragments as an active principle against V. aspis, V. berus and V. Ammodytes, while ViperaTAb contains monospecific ovine Fab fragments against V. berus. ViperaTAb’s and Viperfav’s therapeutic convenience for use against V. Ammodytes venom- induced toxicity in humans has not been described, although protective efficacy has been proved preclinically. The aim of this study was to evaluate Viperfav and ViperaTAb in V. Ammodytes envenomations. Methods: A prospective case series of consecutive patients envenomed by V. Ammodytes treated with Viperfav and/or ViperaTAb in the University Medical Centre Ljubljana in 2015 and 2016. V. Ammodytes venom, neurotoxic ammodytoxins, and F(ab')2 and/or Fab fragments concentrations were determined in serum samples with a pharmacokinetic analysis of the antivenoms. Results: Ten patients bitten by V. Ammodytes were treated using Viperfav and/or ViperaTAb ; 5 received Viperfav, 4 ViperaTAb, and 1 patient received both. V. Ammodytes venom and antivenom concentrations were measured in 5 patients. V. Ammodytes venom was detected in serum of all 5 patients, but ammodytoxins were detected in only the most severely envenomed patient who developed neurological symptoms. Viperfav (4 mL) promptly reduced local swelling and improved systemic pathological signs, except recurrent thrombocytopenia. ViperaTAb (8 mL) reduced moderate swelling and temporarily improved systemic effects as well. However, this dose of ViperaTAb had no effect on neurological signs. ViperaTAb and Viperfav administration induced a decrease in V. Ammodytes venom serum concentrations, but only Viperfav affected the serum ammodytoxins concentration. Viperfav’s systemic clearance and elimination half-life were 1.64 (mL/h)/kg and 97 hours, while ViperaTAb’s were 4.3–13.4 (mL/h)/kg and 14.1– 55.4 hours, respectively. Conclusion: In patients bitten by V. Ammodytes, both Viperfav and ViperaTAb reduce local swelling and temporarily improve systemic effects. ViperaTAb did not affect neurological symptoms or the serum concentration of neurotoxic ammodytoxins. The recommended dose of Viperfav and ViperaTAb may be inadequate in serious cases of V. Ammodytes bites, therefore duplication and repetition of the treatment, with an adjustment of administration timing, should be considered. However, it should be pointed out that this study was the result of V. Ammodytes antivenom shortage and it emphasises the importance of the specific antivenom availability.
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venomics of vipera berus berus to explain differences in pathology elicited by vipera Ammodytes Ammodytes envenomation therapeutic implications
Journal of Proteomics, 2016Co-Authors: Zorica Latinović, Jernej Šribar, Adrijana Leonardi, Beata Halassy, Tamara Sajevic, Alenka Trampusbakija, Robert Frangež, Monika Cecilija žužek, Jože Pungercar, Igor KrižajAbstract:Abstract Vipera berus berus (Vbb) is the most widely distributed and Vipera Ammodytes Ammodytes (Vaa) the most venomous viper in Europe. In particular areas of the Old continent their toxic bites constitute a considerable public health problem. To make the current envenomation therapy more effective we have analysed the proteome of Vbb venom and compared it with that of Vaa. We found the proteome of Vbb to be much less complex and to contain smaller levels of particularly snaclecs and sPLA2s. Snaclecs are probably responsible for thrombocytopenia. The neurotoxic sPLA2s, ammodytoxins, are responsible for the most specific feature of the Vaa venom poisoning − induction of signs of neurotoxicity in patients. These molecules were not found in Vbb venom. Both venoms induce haemorrhage and coagulopathy in man. As Vaa and Vbb venoms possess homologous P-III snake venom metalloproteinases, the main haemorrhagic factors, the severity of the haemorrhage is dictated by concentration and specific activity of these molecules. The much greater anticoagulant effect of Vaa venom than that of Vbb venom lies in its higher extrinsic pathway coagulation factor-proteolysing activity and content of ammodytoxins which block the prothrombinase complex formation. Biological significance Envenomations by venomous snakes constitute a considerable public health problem worldwide, and also in Europe. In the submitted work we analysed the venom proteome of Vipera berus berus (Vbb), the most widely distributed venomous snake in Europe and compared it with the venom proteome of the most venomous viper in Europe, Vipera Ammodytes Ammodytes (Vaa). We have offered a possible explanation, at the molecular level, for the differences in clinical pictures inflicted by the Vbb and Vaa venoms. We have provided an explanation for the effectiveness of treatment of Vbb envenomation by Vaa antiserum and explained why full protection of Vaa venom poisoning by Vbb antiserum should not be always expected, especially not in cases of severe poisoning. The latter makes a strong case for Vaa antiserum production as we are faced with its shortage due to ceasing of production of two most frequently used products.
Beata Halassy - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Preclinical Properties of Several Available Antivenoms in the Search for Effective Treatment of Vipera Ammodytes and Vipera berus Envenoming.
Toxins, 2021Co-Authors: Tihana Kurtović, Maja Lang Balija, Miran Brvar, Mojca Dobaja Borak, Sanja Mateljak Lukačević, Beata HalassyAbstract:Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera Ammodytes, Vipera berus, and Vipera aspis, immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. Ammodytes-specific F(ab')2 fragments. Viperfav is a polyspecific preparation based on F(ab')2 fragments against V. aspis, V. berus, and V. Ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus. In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. Ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. Ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. Ammodytes and V. berus venoms was above regulatory requirements.
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vipera Ammodytes bites treated with antivenom viperatab a case series with pharmacokinetic evaluation
Clinical Toxicology, 2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtovic, Damjan Grenc, Beata HalassyAbstract:AbstractContext: In clinical practice it is difficult to differentiate between V. berus and V. Ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. Ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus.Objective: To evaluate ViperaTAb® in V. a. Ammodytes envenomations.Materials and methods: This is a prospective case series of three consecutive patients envenomed by V. a. Ammodytes snakebite treated with ViperaTAb®. V. Ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out.Results: Three patients bitten by V. a. Ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. Ammodytes venom...
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Vipera Ammodytes bites treated with antivenoms Viperfav® and ViperaTAb®
2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtović, Damjan Grenc, Beata HalassyAbstract:Objective: Clinically Vipera berus and Vipera Ammodytes envenomation are difficult to differentiate. In the past this was not a concern, but due to the current shortage in European viper venom antiserum availability, V. Ammodytes venomous bites have recently been treated with ViperfavTM and ViperaTAb®. Viperfav contains polyvalent equine F(ab')2 fragments as an active principle against V. aspis, V. berus and V. Ammodytes, while ViperaTAb contains monospecific ovine Fab fragments against V. berus. ViperaTAb’s and Viperfav’s therapeutic convenience for use against V. Ammodytes venom- induced toxicity in humans has not been described, although protective efficacy has been proved preclinically. The aim of this study was to evaluate Viperfav and ViperaTAb in V. Ammodytes envenomations. Methods: A prospective case series of consecutive patients envenomed by V. Ammodytes treated with Viperfav and/or ViperaTAb in the University Medical Centre Ljubljana in 2015 and 2016. V. Ammodytes venom, neurotoxic ammodytoxins, and F(ab')2 and/or Fab fragments concentrations were determined in serum samples with a pharmacokinetic analysis of the antivenoms. Results: Ten patients bitten by V. Ammodytes were treated using Viperfav and/or ViperaTAb ; 5 received Viperfav, 4 ViperaTAb, and 1 patient received both. V. Ammodytes venom and antivenom concentrations were measured in 5 patients. V. Ammodytes venom was detected in serum of all 5 patients, but ammodytoxins were detected in only the most severely envenomed patient who developed neurological symptoms. Viperfav (4 mL) promptly reduced local swelling and improved systemic pathological signs, except recurrent thrombocytopenia. ViperaTAb (8 mL) reduced moderate swelling and temporarily improved systemic effects as well. However, this dose of ViperaTAb had no effect on neurological signs. ViperaTAb and Viperfav administration induced a decrease in V. Ammodytes venom serum concentrations, but only Viperfav affected the serum ammodytoxins concentration. Viperfav’s systemic clearance and elimination half-life were 1.64 (mL/h)/kg and 97 hours, while ViperaTAb’s were 4.3–13.4 (mL/h)/kg and 14.1– 55.4 hours, respectively. Conclusion: In patients bitten by V. Ammodytes, both Viperfav and ViperaTAb reduce local swelling and temporarily improve systemic effects. ViperaTAb did not affect neurological symptoms or the serum concentration of neurotoxic ammodytoxins. The recommended dose of Viperfav and ViperaTAb may be inadequate in serious cases of V. Ammodytes bites, therefore duplication and repetition of the treatment, with an adjustment of administration timing, should be considered. However, it should be pointed out that this study was the result of V. Ammodytes antivenom shortage and it emphasises the importance of the specific antivenom availability.
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venomics of vipera berus berus to explain differences in pathology elicited by vipera Ammodytes Ammodytes envenomation therapeutic implications
Journal of Proteomics, 2016Co-Authors: Zorica Latinović, Jernej Šribar, Adrijana Leonardi, Beata Halassy, Tamara Sajevic, Alenka Trampusbakija, Robert Frangež, Monika Cecilija žužek, Jože Pungercar, Igor KrižajAbstract:Abstract Vipera berus berus (Vbb) is the most widely distributed and Vipera Ammodytes Ammodytes (Vaa) the most venomous viper in Europe. In particular areas of the Old continent their toxic bites constitute a considerable public health problem. To make the current envenomation therapy more effective we have analysed the proteome of Vbb venom and compared it with that of Vaa. We found the proteome of Vbb to be much less complex and to contain smaller levels of particularly snaclecs and sPLA2s. Snaclecs are probably responsible for thrombocytopenia. The neurotoxic sPLA2s, ammodytoxins, are responsible for the most specific feature of the Vaa venom poisoning − induction of signs of neurotoxicity in patients. These molecules were not found in Vbb venom. Both venoms induce haemorrhage and coagulopathy in man. As Vaa and Vbb venoms possess homologous P-III snake venom metalloproteinases, the main haemorrhagic factors, the severity of the haemorrhage is dictated by concentration and specific activity of these molecules. The much greater anticoagulant effect of Vaa venom than that of Vbb venom lies in its higher extrinsic pathway coagulation factor-proteolysing activity and content of ammodytoxins which block the prothrombinase complex formation. Biological significance Envenomations by venomous snakes constitute a considerable public health problem worldwide, and also in Europe. In the submitted work we analysed the venom proteome of Vipera berus berus (Vbb), the most widely distributed venomous snake in Europe and compared it with the venom proteome of the most venomous viper in Europe, Vipera Ammodytes Ammodytes (Vaa). We have offered a possible explanation, at the molecular level, for the differences in clinical pictures inflicted by the Vbb and Vaa venoms. We have provided an explanation for the effectiveness of treatment of Vbb envenomation by Vaa antiserum and explained why full protection of Vaa venom poisoning by Vbb antiserum should not be always expected, especially not in cases of severe poisoning. The latter makes a strong case for Vaa antiserum production as we are faced with its shortage due to ceasing of production of two most frequently used products.
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A Single Dose of Viperfav TM May Be Inadequate for Vipera Ammodytes Snake Bite: A Case Report and Pharmacokinetic Evaluation
Toxins, 2016Co-Authors: Tihana Kurtović, Igor Križaj, Maja Lang Balija, Miran Brvar, Damjan Grenc, Beata HalassyAbstract:ViperfavTM is a commercial F(ab’)2 antivenom prepared against European vipers venom. It is safe and effective for treating envenomation caused by Vipera aspis and Vipera berus. Therapeutic efficacy for treating Vipera Ammodytes Ammodytes (V. a. Ammodytes) envenoming has not been yet described, although protective efficacy has been demonstrated in preclinical studies. We report on a 32-year-old man bitten by V. a. Ammodytes who was treated with Viperfav™. Viperfav™ promptly reduced local extension and improved systemic pathological signs, but 24 h after the incident a recurrence of thrombocytopenia occurred despite a favorable pharmacokinetic profile with systemic clearance (1.64 (mL·h−1)·kg−1) and elimination half-life (97 h) among the highest ever reported. The recommended dose of Viperfav™ for V. aspis and V. berus bites may be inadequate for serious V. a. Ammodytes envenomations. Following V. a. Ammodytes bite, serial blood counts and coagulation profiles should be performed to help guide Viperfav™ treatment, along with supplemental administration as indicated.
Maja Lang Balija - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Preclinical Properties of Several Available Antivenoms in the Search for Effective Treatment of Vipera Ammodytes and Vipera berus Envenoming.
Toxins, 2021Co-Authors: Tihana Kurtović, Maja Lang Balija, Miran Brvar, Mojca Dobaja Borak, Sanja Mateljak Lukačević, Beata HalassyAbstract:Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera Ammodytes, Vipera berus, and Vipera aspis, immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. Ammodytes-specific F(ab')2 fragments. Viperfav is a polyspecific preparation based on F(ab')2 fragments against V. aspis, V. berus, and V. Ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus. In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. Ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. Ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. Ammodytes and V. berus venoms was above regulatory requirements.
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vipera Ammodytes bites treated with antivenom viperatab a case series with pharmacokinetic evaluation
Clinical Toxicology, 2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtovic, Damjan Grenc, Beata HalassyAbstract:AbstractContext: In clinical practice it is difficult to differentiate between V. berus and V. Ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. Ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus.Objective: To evaluate ViperaTAb® in V. a. Ammodytes envenomations.Materials and methods: This is a prospective case series of three consecutive patients envenomed by V. a. Ammodytes snakebite treated with ViperaTAb®. V. Ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out.Results: Three patients bitten by V. a. Ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. Ammodytes venom...
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Vipera Ammodytes bites treated with antivenoms Viperfav® and ViperaTAb®
2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtović, Damjan Grenc, Beata HalassyAbstract:Objective: Clinically Vipera berus and Vipera Ammodytes envenomation are difficult to differentiate. In the past this was not a concern, but due to the current shortage in European viper venom antiserum availability, V. Ammodytes venomous bites have recently been treated with ViperfavTM and ViperaTAb®. Viperfav contains polyvalent equine F(ab')2 fragments as an active principle against V. aspis, V. berus and V. Ammodytes, while ViperaTAb contains monospecific ovine Fab fragments against V. berus. ViperaTAb’s and Viperfav’s therapeutic convenience for use against V. Ammodytes venom- induced toxicity in humans has not been described, although protective efficacy has been proved preclinically. The aim of this study was to evaluate Viperfav and ViperaTAb in V. Ammodytes envenomations. Methods: A prospective case series of consecutive patients envenomed by V. Ammodytes treated with Viperfav and/or ViperaTAb in the University Medical Centre Ljubljana in 2015 and 2016. V. Ammodytes venom, neurotoxic ammodytoxins, and F(ab')2 and/or Fab fragments concentrations were determined in serum samples with a pharmacokinetic analysis of the antivenoms. Results: Ten patients bitten by V. Ammodytes were treated using Viperfav and/or ViperaTAb ; 5 received Viperfav, 4 ViperaTAb, and 1 patient received both. V. Ammodytes venom and antivenom concentrations were measured in 5 patients. V. Ammodytes venom was detected in serum of all 5 patients, but ammodytoxins were detected in only the most severely envenomed patient who developed neurological symptoms. Viperfav (4 mL) promptly reduced local swelling and improved systemic pathological signs, except recurrent thrombocytopenia. ViperaTAb (8 mL) reduced moderate swelling and temporarily improved systemic effects as well. However, this dose of ViperaTAb had no effect on neurological signs. ViperaTAb and Viperfav administration induced a decrease in V. Ammodytes venom serum concentrations, but only Viperfav affected the serum ammodytoxins concentration. Viperfav’s systemic clearance and elimination half-life were 1.64 (mL/h)/kg and 97 hours, while ViperaTAb’s were 4.3–13.4 (mL/h)/kg and 14.1– 55.4 hours, respectively. Conclusion: In patients bitten by V. Ammodytes, both Viperfav and ViperaTAb reduce local swelling and temporarily improve systemic effects. ViperaTAb did not affect neurological symptoms or the serum concentration of neurotoxic ammodytoxins. The recommended dose of Viperfav and ViperaTAb may be inadequate in serious cases of V. Ammodytes bites, therefore duplication and repetition of the treatment, with an adjustment of administration timing, should be considered. However, it should be pointed out that this study was the result of V. Ammodytes antivenom shortage and it emphasises the importance of the specific antivenom availability.
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A Single Dose of Viperfav TM May Be Inadequate for Vipera Ammodytes Snake Bite: A Case Report and Pharmacokinetic Evaluation
Toxins, 2016Co-Authors: Tihana Kurtović, Igor Križaj, Maja Lang Balija, Miran Brvar, Damjan Grenc, Beata HalassyAbstract:ViperfavTM is a commercial F(ab’)2 antivenom prepared against European vipers venom. It is safe and effective for treating envenomation caused by Vipera aspis and Vipera berus. Therapeutic efficacy for treating Vipera Ammodytes Ammodytes (V. a. Ammodytes) envenoming has not been yet described, although protective efficacy has been demonstrated in preclinical studies. We report on a 32-year-old man bitten by V. a. Ammodytes who was treated with Viperfav™. Viperfav™ promptly reduced local extension and improved systemic pathological signs, but 24 h after the incident a recurrence of thrombocytopenia occurred despite a favorable pharmacokinetic profile with systemic clearance (1.64 (mL·h−1)·kg−1) and elimination half-life (97 h) among the highest ever reported. The recommended dose of Viperfav™ for V. aspis and V. berus bites may be inadequate for serious V. a. Ammodytes envenomations. Following V. a. Ammodytes bite, serial blood counts and coagulation profiles should be performed to help guide Viperfav™ treatment, along with supplemental administration as indicated.
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Vipera ammodites bites treated with antivenom ViperaTAb®: a case series and pharmacokinetic evaluation
2016Co-Authors: Tihana Kurtović, Igor Križaj, Maja Lang Balija, Miran Brvar, Damjan Grenc, Beata HalassyAbstract:In the southeastern parts of Europe Vipera a. Ammodytes and Vipera berus are the only medically important poisonous snakes. Differentiation of their bites based on clinical presentation is very difficult and unreliable. In the past this was not a concern, since snakebites were successfully treated with Viperfav™ (Aventis Pasteur, France) or European viper venom antiserum (Zagreb antivenom) (Institute of Immunology, Croatia) as formulations containing equine F(ab’)2 fragments that are either specific for both venoms, either clinically proved to be safe and effective for the treatment of V. a. Ammodytes and V. berus envenomings. However, due to current shortage in ViperfavTM and Zagreb antivenom availability, V. a. Ammodytes and V. berus bites have recently been treated with ViperaTAb® (MicroPharm Limited, United Kingdom) composed of ovine Fab fragments as active principle against the venom of V. berus only. Its therapeutical convenience for use against V. a. Ammodytes venom-induced toxicity in human has not been described yet, although neutralisation efficacy has been proved preclinically. In view of this for the first time we present cases of several V. a. Ammodytes snakebites treated with ViperaTAb® whose pharmacokinetics has been measured and correlated with clinical picture.
Valérie Choumet - One of the best experts on this subject based on the ideXlab platform.
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Sequences and structural organization of phospholipase A2 genes from Vipera aspis aspis, V. aspis zinnikeri and Vipera berus berus venom
FEBS Journal, 2003Co-Authors: Isabelle Guillemin, Christiane Bouchier, Thomas Garrigues, Anne Wisner, Valérie ChoumetAbstract:We used a PCR-based method to determine the genomic DNA sequences encoding phospholipases A2 (PLA2s) from the venoms of Vipera aspis aspis (V. a. aspis), Vipera aspis zinnikeri (V. a. zinnikeri), Vipera berus berus (V. b. berus) and a neurotoxic V. a. aspis snake (neurotoxic V. a. aspis) from a population responsible for unusual neurotoxic envenomations in south-east France. We sequenced five groups of genes, each corresponding to a different PLA2. The genes encoding the A and B chains of vaspin from the neurotoxic V. a. aspis, PLA2-I from V. a. zinnikeri, and the anticoagulant PLA2 from V. b. berus are described here. Single nucleotide differences leading to amino-acid substitutions were observed both between genes encoding the same PLA2 and between genes encoding different PLA2s. These differences were clustered in exons 3 and 5, potentially altering the biological activities of PLA2. The distribution and characteristics of the PLA2 genes differed according to the species or subspecies. We characterized for the first time genes encoding neurotoxins from the V. a. aspis and V. b. berus snakes of central France. Genes encoding ammodytins I1 and I2, described previously in Vipera Ammodytes Ammodytes (V. am. Ammodytes), were also present in V. a. aspis and V. b. berus. Three different ammodytin I1 gene sequences were characterized: one from V. b. berus, the second from V. a. aspis, V. a. zinnikeri and the neurotoxic V. a. aspis, and the third from the neurotoxic V. a. aspis. This third sequence was identical with the reported sequence of the V. am. Ammodytes ammodytin I1 gene. Genes encoding monomeric neurotoxins of V. am. Ammodytes venom, ammodytoxins A, B and C, and the Bov-B LINE retroposon, a phylogenetic marker found in V. am. Ammodytes genome, were identified in the genome of the neurotoxic V. a. aspis. These results suggest that the population of neurotoxic V. a. aspis snakes from south-east France may have resulted from interbreeding between V. a. aspis and V. am. Ammodytes.
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toxicity evolution of vipera aspis aspis venom identification and molecular modeling of a novel phospholipase a2 heterodimer neurotoxin1
FEBS Letters, 2002Co-Authors: Rachid C Maroun, A Robbevincent, Luc De Haro, Valérie ChoumetAbstract:We report the simultaneous presence of two phospholipase A2 (PLA2) neurotoxins in the venom of Vipera aspis aspis, the first such observation. One is monomeric and identical to ammodytoxin B of Vipera Ammodytes Ammodytes. Its presence may result from gene flux after interbreeding between V. aspis aspis and V. Ammodytes Ammodytes. The second, a novel heterodimer named vaspin, is very similar to vipoxin of Vipera Ammodytes meridionalis and to PLA2-I of Vipera aspis zinnikeri. It may result from expression of preexisting genes, the acidic subunit evolving from an ancestor common to ammodytin I2 from V. Ammodytes Ammodytes, which we also found in V. aspis aspis.
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Comparison of Preclinical Properties of Several Available Antivenoms in the Search for Effective Treatment of Vipera Ammodytes and Vipera berus Envenoming.
Toxins, 2021Co-Authors: Tihana Kurtović, Maja Lang Balija, Miran Brvar, Mojca Dobaja Borak, Sanja Mateljak Lukačević, Beata HalassyAbstract:Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera Ammodytes, Vipera berus, and Vipera aspis, immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. Ammodytes-specific F(ab')2 fragments. Viperfav is a polyspecific preparation based on F(ab')2 fragments against V. aspis, V. berus, and V. Ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus. In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. Ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. Ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. Ammodytes and V. berus venoms was above regulatory requirements.
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Vipera Ammodytes bites treated with antivenoms Viperfav® and ViperaTAb®
2017Co-Authors: Miran Brvar, Igor Križaj, Maja Lang Balija, Tihana Kurtović, Damjan Grenc, Beata HalassyAbstract:Objective: Clinically Vipera berus and Vipera Ammodytes envenomation are difficult to differentiate. In the past this was not a concern, but due to the current shortage in European viper venom antiserum availability, V. Ammodytes venomous bites have recently been treated with ViperfavTM and ViperaTAb®. Viperfav contains polyvalent equine F(ab')2 fragments as an active principle against V. aspis, V. berus and V. Ammodytes, while ViperaTAb contains monospecific ovine Fab fragments against V. berus. ViperaTAb’s and Viperfav’s therapeutic convenience for use against V. Ammodytes venom- induced toxicity in humans has not been described, although protective efficacy has been proved preclinically. The aim of this study was to evaluate Viperfav and ViperaTAb in V. Ammodytes envenomations. Methods: A prospective case series of consecutive patients envenomed by V. Ammodytes treated with Viperfav and/or ViperaTAb in the University Medical Centre Ljubljana in 2015 and 2016. V. Ammodytes venom, neurotoxic ammodytoxins, and F(ab')2 and/or Fab fragments concentrations were determined in serum samples with a pharmacokinetic analysis of the antivenoms. Results: Ten patients bitten by V. Ammodytes were treated using Viperfav and/or ViperaTAb ; 5 received Viperfav, 4 ViperaTAb, and 1 patient received both. V. Ammodytes venom and antivenom concentrations were measured in 5 patients. V. Ammodytes venom was detected in serum of all 5 patients, but ammodytoxins were detected in only the most severely envenomed patient who developed neurological symptoms. Viperfav (4 mL) promptly reduced local swelling and improved systemic pathological signs, except recurrent thrombocytopenia. ViperaTAb (8 mL) reduced moderate swelling and temporarily improved systemic effects as well. However, this dose of ViperaTAb had no effect on neurological signs. ViperaTAb and Viperfav administration induced a decrease in V. Ammodytes venom serum concentrations, but only Viperfav affected the serum ammodytoxins concentration. Viperfav’s systemic clearance and elimination half-life were 1.64 (mL/h)/kg and 97 hours, while ViperaTAb’s were 4.3–13.4 (mL/h)/kg and 14.1– 55.4 hours, respectively. Conclusion: In patients bitten by V. Ammodytes, both Viperfav and ViperaTAb reduce local swelling and temporarily improve systemic effects. ViperaTAb did not affect neurological symptoms or the serum concentration of neurotoxic ammodytoxins. The recommended dose of Viperfav and ViperaTAb may be inadequate in serious cases of V. Ammodytes bites, therefore duplication and repetition of the treatment, with an adjustment of administration timing, should be considered. However, it should be pointed out that this study was the result of V. Ammodytes antivenom shortage and it emphasises the importance of the specific antivenom availability.
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A Single Dose of Viperfav TM May Be Inadequate for Vipera Ammodytes Snake Bite: A Case Report and Pharmacokinetic Evaluation
Toxins, 2016Co-Authors: Tihana Kurtović, Igor Križaj, Maja Lang Balija, Miran Brvar, Damjan Grenc, Beata HalassyAbstract:ViperfavTM is a commercial F(ab’)2 antivenom prepared against European vipers venom. It is safe and effective for treating envenomation caused by Vipera aspis and Vipera berus. Therapeutic efficacy for treating Vipera Ammodytes Ammodytes (V. a. Ammodytes) envenoming has not been yet described, although protective efficacy has been demonstrated in preclinical studies. We report on a 32-year-old man bitten by V. a. Ammodytes who was treated with Viperfav™. Viperfav™ promptly reduced local extension and improved systemic pathological signs, but 24 h after the incident a recurrence of thrombocytopenia occurred despite a favorable pharmacokinetic profile with systemic clearance (1.64 (mL·h−1)·kg−1) and elimination half-life (97 h) among the highest ever reported. The recommended dose of Viperfav™ for V. aspis and V. berus bites may be inadequate for serious V. a. Ammodytes envenomations. Following V. a. Ammodytes bite, serial blood counts and coagulation profiles should be performed to help guide Viperfav™ treatment, along with supplemental administration as indicated.
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Vipera ammodites bites treated with antivenom ViperaTAb®: a case series and pharmacokinetic evaluation
2016Co-Authors: Tihana Kurtović, Igor Križaj, Maja Lang Balija, Miran Brvar, Damjan Grenc, Beata HalassyAbstract:In the southeastern parts of Europe Vipera a. Ammodytes and Vipera berus are the only medically important poisonous snakes. Differentiation of their bites based on clinical presentation is very difficult and unreliable. In the past this was not a concern, since snakebites were successfully treated with Viperfav™ (Aventis Pasteur, France) or European viper venom antiserum (Zagreb antivenom) (Institute of Immunology, Croatia) as formulations containing equine F(ab’)2 fragments that are either specific for both venoms, either clinically proved to be safe and effective for the treatment of V. a. Ammodytes and V. berus envenomings. However, due to current shortage in ViperfavTM and Zagreb antivenom availability, V. a. Ammodytes and V. berus bites have recently been treated with ViperaTAb® (MicroPharm Limited, United Kingdom) composed of ovine Fab fragments as active principle against the venom of V. berus only. Its therapeutical convenience for use against V. a. Ammodytes venom-induced toxicity in human has not been described yet, although neutralisation efficacy has been proved preclinically. In view of this for the first time we present cases of several V. a. Ammodytes snakebites treated with ViperaTAb® whose pharmacokinetics has been measured and correlated with clinical picture.
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Identification of proteins interacting with ammodytoxins in Vipera Ammodytes Ammodytes venom by immuno-affinity chromatography
Analytical and Bioanalytical Chemistry, 2014Co-Authors: Marija Brgles, Lidija Kovačič, Igor Križaj, Gunter Allmaier, Tihana Kurtović, Miloš Barut, Martina Marchetti-deschmann, Maja Lang-balija, Beata HalassyAbstract:In order to perform their function, proteins frequently interact with other proteins. Various methods are used to reveal protein interacting partners, and affinity chromatography is one of them. Snake venom is composed mostly of proteins, and various protein complexes in the venom have been found to exhibit higher toxicity levels than respective components separately. Complexes can modulate envenomation activity of a venom and/or potentiate its effect. Our previous data indicate that the most toxic components of the Vipera Ammodytes Ammodytes ( Vaa ) venom isolated so far—ammodytoxins (Atxs)—are contributing to the venom’s toxicity only moderately; therefore, we aimed to explore whether they have some interacting partner(s) potentiating toxicity. For screening of possible interactions, immuno-affinity chromatography combined with identification by mass spectrometry was used. Various chemistries (epoxy, carbonyldiimidazole, ethylenediamine) as well as protein G functionality were used to immobilize antibodies on monolith support, a Convective Interaction Media disk. Monoliths have been demonstrated to better suit the separation of large biomolecules. Using such approach, several proteins were indicated as potential Atx-binding proteins. Among these, the interaction of Atxs with a Kunitz-type inhibitor was confirmed by far-Western dot-blot and surface plasmon resonance measurement. It can be concluded that affinity chromatography on monolithic columns combined with mass spectrometry identification is a successful approach for screening of protein interactions and it resulted with detection of the interaction of Atx with Kunitz-type inhibitor in Vaa venom for the first time.