Indeed although the snake is the symbol of medicine, globally, medicine seems to have forgotten about snake bite
Procoagulant, anticoagulant enzymes (Viperidae): incoagulable blood Haemorrhagins: zinc metalloproteinase : spontaneous systemic haemorrhage Cytolytic or necrotic toxins : hyaluronidase, phospholipases A, polypeptide toxins : increase permeability Haemolytic and myolytic phospholipases A2: damage cell membranes and tissues Neurotoxins (pre or postsynaptic) Phosphodiesterase: decline of the blood pressure
Snake antivenoms, made of fragments of antibodies, are the only effective medecine in the treatment of snakebites
PARTICULARLY HIGH IN: The repartition of snake species vary from region to region. ASIAcomposition SOUTH AND EAST ,SUB S AHARAN The venom changes with different snake species.
General : nausea, vomiting, malaise Cardiovascular : hypotension, heart failure Haemostasis : haemorrhages
% deaths
4
2 0
CSL Limited 6
South African Vaccine Producers (SAVP)
Blood horse is next collected into an anticoagulant Third stage:Fractionation and purification
7
Whole IgG
Lyophilisation or not
Volume of Distribution
++ + ++ 10%
+ + + 30%
Tissue affinity
Rapid elimination
Hypersensitivity reactions
But theres no differences proven in the ability to neutralise the toxic effects of venoms in human
SAFETY OF ANTIVENOMS
Presence of bacteria
Contaminant proteins
EARs
Presence of protein aggregates
Total amount of protein administered
10
XxLD50
ED50 = dose of antivenom (l) saves 50% of mice Conversion en mg of venom neutralized per vial
QUANTITY OF ANTIVENOM
11
The rich countries Usa: The example of CroFab, marketed by Protherics Australia: Influence of CSL Limited
12
Man in rural areas less than 30 y.old Children represents 25% of the victims, more amputations than adult. During working activities During the rainy seasons
WHO estimates in 2 million DALYs (Disability Adjusted Life Years) per13 year for subsaharan africa
14
Bitis, Naja, Hemachatus, Dendroaspis Bitis, Naja, Hemachatus, Dendroaspis, Echis Echis ocellatus Bitis, Naja, Dendroaspis, Echis Bitis, Daboia, Dendroaspis, Echis
Behringwerke AG
National Health Laboratory Service (ex: SAIMR) Micropharm Ltd Sanofi Pasteur Serum Institute of India
Yes, >1000 per vial Yes, About 73,50 per vial Yes, but production stopped? About 30 per vial
The cost of snakebite treatment often represents a high portion of the yearly income of a rural worker
15
16
Cheaper antivenoms which are untested and ineffective, Fake antivenoms sold by unscrupulous marketors
17
No data available
Cost
US$139
US$36.75
18
70 % 60 50 40 30 20 10 0
1 dose 2 doses
3 doses
Probability of EARs
19
FAV-Afrique (Sanofi pasteur) N of patients N of initial ampoules N of repeat ampoules N total of ampoules Deaths Allergic reactions 278 3,9 5,3 5.2 5 (1,8%) 66
A six fold mortality increase after AV-C replaced FAV-A Asna Antivenom C was withdrawn from the market in February 2005
This illustrates the absolute need for regional pilot tests to assess the effectiveness of new antivenom
20
TO SIMPLIFYING
DISTRIBUTION
21
150000 100000
Cost (US$)
150000
100000 50000 0
Volume of plasma
50000 0
Whole IgG production provides a much higher yield of antibodies than F(ab) production 60% vs 30%
23
20
15 10 5 0 100 L 200 L
1000 L
Theres a need to: Find another markets for the manufacturer Have a collaboration between the countries to make antivenom 24 available in health centers
Constitute of a whole IgG Produced in Costa Rica (ammonium sulfate precipitation) or in Colombia (caprylic acid precipitation)
Naja 30%
collaboration
25
Polyvalent antivenoms
AHLS (SAIMR)
EchiTab (Micropharm Ltd)
Monovalent antivenoms
ED50 (l/challenge dose)
50
Strong neutralising potency against the venom of B. arietans Moderate potency against N. nigricollis venom
26
Purified lyophilized polyvalent equine (fab)2antivenom Obtained by immunization with the venoms of 11 species of African snakes
ED50 l
27
28
neutralization of Echis ocellatus venom activities Activity Hemorrhagic Defibrinogenating Pro-coagulant Neutralizing dose 15, 3l 12,5l 6,3l >15min
Necrotizing
19,2l
Choice of Benin: Safety: correct managment of snake bite Speed: high incidence of snakebite Economy: health center close to each other Including 11 health centers No comparative trial Main objective: to measure the early tolerance (incidence and severity of adverse effects)
30
Adverse effects are observed : in 13% of patients after the first injection in 19% of patients after all treatments
Study was made from september 2007 to january 2008 to specify minimal doses and to define protocol of administration of this antivenom Other study was made from february 2008 to june 2008 to observe the hematologic evolution
32
Each year 8000 venomous snake bites No more than 12 fatality cases reported/year
Coral snake of the micrurus of Elapidae family are responsible of a minority of snakebites in US
33
1954 Horse
IgG 18,9%
Use 4 Snakes venoms
Fab >85%
Result of the final combinaison of 4 monovalent antivenoms against:
34
EFFICACY OF CROFAB
Evolution of Snake Severity Score
4.5
Pilot Study n=11 As needed n=16
Scheduled n=15
3.5
2.5
2
Baseline After Crofab infusion Hour 1 Hour 4 or 6 Hour 12
35
Serum sickness
3% Treatment algorithm
Initial Dose (3 to 12 vials)
Dosing
Difficult to determine
dosereassessdosereassess
Time of reconstitution
90 min
40 min
36
The only available antivenom used to treat Crotaline snakebite in North America
31.5 27 19.3
20.4
2005
2006
2007
2008
Price : US$750.00/vial(10mL)
Recommended dose: 40 60mL
37
Antivipmyn
Animal source Type of fragment Production Cost
Coverage Species : All Crotalus and Bothrops species of the American continent
38
Enregistrement Enregistrement
Phase 3
39
SITUATION IN AUSTRALIA
o The incidence of snakebite is estimated 1000-3000 events/year
o It results in few deaths/year
In 2007,The Government has a four-year agreement with CSL for the manufacture of antivenom products at a cost of $15.1 million ($1.7 million in new funding)
40
Pseudechis australis
5 species
Pseudonaja textilis
Acanthophis antarcticus Ehnydrina schistosa Notechis scutatus Oxyuranus scutellatus Notechis scutatus
2 species
2 species 12 species One specie 7 species
Destinated for patients on whom the identification of the snake responsible is impossible
Elisa method Samples used: a bite site swab, the fangs, urine or blood Gives results in 20 min
42
Hypersensitivity reactions occurred in 25% of the patients. Mild reactions represent 14%. Severe reactions were uncommon (5%) and characterised mainly by hypotension. There were no deaths attributed to allergic reactions.
Mild
Moderate Severe
CONCLUSION
The market of snake antivenoms vary according to the different regions of the world and their ability to product their own antivenom or to buy foreign antivenoms
In USA and in Australia, effective snake antivenoms are available, but their cost are expensive Contrary to in developing countries where there is few effective antivenoms, the situation may improve by: Intervention of health agencies Close collaboration between the countries in need and with manufacturers in rich countries Financial contribution (Bill and Melinda Gates foundation)
44
THANK YOU
45
Be careful..
AMANDINE LADEN, THOMAS DUTERTE, (FRANOIS FLAMENT)