Antivenom wanted

[Cradle of life]

I have tried contacting the antivenom producers via there website but have had no reponse. Does anyone know where i can get a hold of about 10 ampoules of polyvalent anti-venom and also maybe there are others for rattle snakes etc, available from a collector or simillar?

Regards
COL

[gaboon69]

Have a look at Bioclon Antivipmyn. I am in the process of ordering so you can join in Charles. Also look at Antivipmyn Africa. Chat soon.

[Cradle of life]

Have a look at Bioclon Antivipmyn. I am in the process of ordering so you can join in Charles. Also look at Antivipmyn Africa. Chat soon.

Thanks M

[adrianx]

Netcare Montana, Eugene Marais hospital and Unitas sells Polyvalent antivenom @ R800.00 per unit.
You can also buy a "Anitivenom Kit" from Unitas hospital. I just have no idea what the kit consists of...

[froot]

I've had no problems:

http://www.savp.co.za/ContactUs.htm

IIRC +/- R622 per vial polyvalent.

[Bushviper]

It is pretty easy to get antivenom. The trick is that you have to get an invoice from them, PAY THEM, and then they will send you the vials. They only put you on the list after you have paid for the serum. This is a mistake many vets make and then they cannot understand why the serum is never delivered.

[toxinologist]

I would be extremely dubious about the value of BioClon's Antivipmyn Africa for treating bites by ANY snake anywhere in Africa. While studies by the manufacturers and well paid consultants may appear glowing, the most recent independent study (Abubakar et al, 2010) found that the ED50 dose was so large, that EIGHTEEN (18) vials would be needed as an initial dose for a bite by Echis ocellatus (which has a venom yield of around 18-22 mg, maximum around 24.8mg). ED50 is the dose needed to rescue 50% of test animals exposed to a particular venom.

Given that Puff adders have an average yield of 100-350 mg and a reported maximum of up to 750 mg, and some cobras can produce similar yields, you are going to be very disappointed by this antivenom - which incidentally has NOT been subjected to clinical trials involving patients bitten by most of the 11 species it is made for ... trials by the manufacturer against Echis spp. in West Africa (and even in these, exact snake identification is lacking) do not in any way predict what will happen when this antivenom is used for someone bitten by Dendroaspis polylepis in South Africa or Swaziland or Kenya, nor for the poor bugger bitten by Naja nigricollis in Tanzania or Nigeria, or someone nailed by a decent sized Bitis arietans in South Africa, Botswana or Namibia...

The manufacturer is being very generous at the moment in giving some away (in the hope of growing their market in Africa = growing their profits), but the reality is that this is an untested, and in some jurisdictions, unregistered pharmaceutical. Even in countries where the manufacturer is registering this product the reality is that the National Regulatory Agencies are often so under-staffed, under-resourced and under-trained at evaluating antivenom product dossiers ... that even a vial of distilled water with a label on it could get a registration certificate.

Anyone who privately purchases this antivenom for use against bites by African snakes is taking their life in their hands.

The same applies to the Bharat ASNA-C African polyvalent made by Bharat in India, and to the SII African Polyvalent made by the Serum Institute of India (scarce now thankfully, because it had virtually the same case-fatality rate in southern Chad (Bregani et al, 2006), as for untreated patients!!). The Bharat product on the other hand is still being aggressively marketed in Africa, despite having been responsible for a 6-fold increase in case-fatality rates in Ghana (against bites by Echis ocellatus mostly), for which the manufacturers have been completely unrepentent (Visser et al, 2008; Warrell, 2008; Kanthawala, 2009; Visser et al, 2009; Warrell & Williams, 2009).

The only general polyvalent that may be of use (other than SAVP polyvalent made in South Africa) is the French-made FAV-Afrique produced by Sanofi-Pasteur and which sells for around €100 per vial ... with 5 vials being needed to effectively treat Echis bites in Ghana (for a case-fatality rate of about 1.8%). If it were me on the gurney with the IV line running, I would rather take my chances with SAVP polyvalent or FAV-Afrique, rather stick a virtual shotgun in my mouth and pull the trigger (by asking either the Mexican- or the Indian-made antivenoms).

Please consider your options carefully and take the time to actually research the products and seek independent expert advice.

Cheers


David

References cited:

Abubakar SB et al (2010) Toxicon 55(4): 719-723
Bregani ER et al (2006) Giornale Italiano de Medicina Tropicale 2(1-2) 25-28
Kanthawala T (2009) Transactions of the Royal Society of Tropical Medicine & Hygiene 103(9): 964
Visser LE et al (2008) Transactions of the Royal Society of Tropical Medicine & Hygiene 102(5): 445-450
Visser LE et al (2009) Transactions of the Royal Society of Tropical Medicine & Hygiene 103(9): 964-965
Warrell DA (2008) Transactions of the Royal Society of Tropical Medicine & Hygiene 102(5): 397-399
Warrell DA, Williams DJ (2009) Transactions of the Royal Society of Tropical Medicine & Hygiene 103(9): 965-966

[Bushviper]

Wow David that is scary. I see they are going to be doing some trials in Swaziland and hopefully it is still effective against Mamba and Mozambique spitter bites as these are the big problem children. Possibly the supply of raw venom is better for these species than for Echis which as we all know are not easy to identify and subsequently extract from.

I wonder how effective the SAVP antivenom is for Echis bites in North Africa considering I think they only extract from one species.

David just to give some perspective to Swaziland. If you had a choice between saline and Mexican antivenom I know which one I would go for. Either that or they give you some multivitamins and pain killers and send you home.

Has any independent laboratory (like some university) tried testing the effectiveness of the various antivenoms? That would be great for a quick thesis and then to even test it against similar species to see how cross sensitive it is. I know this will apply to mice but as least it would be a fair indication.

[toxinologist]

Bushviper,

I doubt it has anything to do with the quality of the venoms. It has to do with the absence of sufficient neutralising antibodies per vial. The product is raised against 11 venoms, contains very little protein (19-37 mg/ml, depending on whether you read the manufacturers paper, or the independent paper) and extremely low potency.

You might actually have an equivalent chance of survival with multivitamins and pain killers!

Handing out an untested, unregistered product in Swaziland is in my opinion the very height of irresponsibility and shows a complete lack of regard for any form of professional ethical conduct. Handing out the product simply because "nothing else is available" is not an excuse, especially when there ARE better products in the market. If Swaziland needs antivenom for mamba bites, then it should be supplied with either SAVP polyvalent or with French FAV-Afrique, there is no excuse for taking cheap, unproven alternative route. I would be particularly concerned for the people on the ground in Swaziland who hand out this antivenom, especially if all the patients who receive it die regardless. Knowing human nature, especially in tribal societies, fingers are very likely to end up being pointed... and since the overseas consultants will be long gone ... it will be the local people involved who could end up being targets.

There are a large number of very good preclinical and clinical antivenom studies in print (just search http://www.pubmed.org), but there are a number of manufacturers (in India for example) who are only too happy to make products to capitalise on perceived market opportunity without ever conducting or publishing any ethically conducted study data of any kind. Snake bite is a vastly under-funded public health problem, and to be honest antivenom, while it has an important place, is not a magic cure, nor is it the only aspect of dealing with the problem that needs resourcing. Sadly that situation will not change in a hurry.

Cheers..


David

[toxinologist]

On the topic of the Echis antivenom made by SAVP ... at last reporting the manufacturer had been using Echis ocellatus venom from Nigeria and Echis pyramidum venom from Ethiopia.

Echis venoms vary quite a bit from one species to another, and there are probably intraspecific differences as well between geographically disjunct populations.

Cheers


David

[CLSmith]

Thanks for that bit (huge) of scientific information toxinologist.

Would the quality (and quantity thereof) of anti-body protein have anything to do with the choice of anti-body producing hosts? Or is it just a case of inferior pharmaceutical procedures?

[toxinologist]

Hi,

From what I have read in the literature, Bioclon use venoms obtained from a very reputable venom producer (Latoxan in France). The big problem is that if you only have 19-32 mg protein in every millilitre of antivenom (and not all of that will be specific snake venom antibodies), there is not going to be a whole lot of specific antibody to any one particular species available. And if the antibodies that are present are not potent, then you are going to end up with a situation where you may as well give the patient nothing.

And the data that are available now for the Silanes Bioclon product clearly show that when compared to other antivenoms this product is simply very low in neutralising potency.

For example, Abubakar et al (2010) found that when 18-20 gram mice were challenged with the equivalent of 5x the LD50 dose of Echis ocellatus venom, the ED50 of the Silanes Bioclon (Mexico) product was 145 ul/mouse, compared to 13 ul/mouse for SAVP's Echis monovalent antivenom (South Africa), and a mere 8 ul/mouse for EchiTab G made by the Instituto Clodomiro Picado in Cost Rico. This means that the researchers had to use just over 11 times more Mexican antivenom per mouse than SAVP product, and over 18 times more Mexican antivenom than Costa Rican product.

What I find particularly interesting is that in a study by the Mexican manufacturer & collaborators (Ramos-Cerrillo et al, 2008), the LD50 of the Echis ocellatus venom tested was considerably less potent (28.3 ug/mouse) than that reported by independent investigators (Abubakar et al, 2010) who report an LD50 of 19.8 ug/mouse. That's about a third less toxic!

In their studies the manufacturers only use a 3x LD50 dose, compared to the 5x LD50 dose used by Abubakar et al (2010). The result is that using less potent Echis ocellatus venom, the manufacturer reports an ED50 of 49.7 ul/mouse for a 3x LD50 dose (compared to Abubakar's finding of 146 ul/mouse when more potent E. ocellatus venom is used at a dose of 5x LD50). Whether the lower potency of the venom completely explains the improved ED50 is hard to say. In any event, both the manufacturer's results and the Abubakar groups results show clearly that Antivipmyn Africa is far less potent than either the existing SAVP Echis monovalent (13 ug/mouse) or the new ICP EchiTab G monovalent (8 ug/mouse).

The manufacturer claims that each vial of Antivipmyn Africa will neutralise 17.1 mg (1.71 mg/ml) of Echis ocellatus. Disturbingly however, in a clinical trial conducted in Benin (Chippaux et al, 2007), 20% of patients in whom bleeding was reported had their first evolution of bleeding occur AFTER the antivenom had been given, and another 29% had recurrence of bleeding AFTER antivenom. Recurrence may be due to rapid clearance of antivenom from the body resulting in the product no longer being available in the circulation to neutralise more venom that may enter the circulation later due to what is sometimes called a venom depot effect. The first appearance of bleeding some time AFTER antivenom administration may be due to the same principle, but it may also indicate that the antivenom simply failed to effectively neutralise circulating venom toxins. And despite the manufacturer's laboratory-based study claim (Ramos-Cerrillo et al, 2008) indicating that 2 vials of antivenom would be sufficient, Chippaux et al (2007) reported that 23.5% needed 4 vials of antivenoms, and 23.9% of patients actually needed 6 vials or more!

By comparison (and of some relevance to South Africa and Swaziland) they claim that each vial of Antivipmyn Africa will neutralise 5.9 mg of Dendroaspis polylepis venom and 36.5 mg of Bitis arietans venom. They say each vial will neutralise 8.1 mg of Naja nigricollis venom. These are very low neutralising potencies, particularly for Dendroaspis polylepis and Naja nigricollis.

If the venom yield from Dendroaspis polylepis ranges from 50-120 mg (some references list a maximum yield of 400-450 mg) you would need somewhere between 9-21 vials to have a 50% chance of neutralising the venom present in the circulation, and for Naja nigricollis, which has a venom yield ranging from 200-350 mg somewhere between 25-44 vials are going to have to be used. For Bitis arietans if the manufacturers claims are right, then you will need somewhere between 3-10 vials to have a 50% chance of neutralising 100-350 mg of venom. These however are simplistic calculations and do not take into account the pharmocokinetics of either the venoms or the antivenom, nor does it take into account possible venom depot effects or a myriad of other factors that come into play when you start talking about putting venoms and antivenoms in human bodies.

For me the biggest problem however lies in accepting the reported potencies and neutralising potential of Antivipmyn Africa reported by Ramos-Cerrillo et al, in the face of (a) Abubakar's fresh data which strongly suggests that at least for Echis ocellatus, up to 3 times more antivenom will be needed than what the manufacturer has reported, and (b) the manufacturer's own clinical trial data (Chippaux et al 2007) which demonstrates that from 23.9% of patients treated for presumed Echis ocellatus bites, they did in fact need at least 3 times more antivenom.

Not to put too fine a point on it, but at the doses extrapolated from the manufacturers data, you will need 90-210 ml of antivenom for a Dendroaspis polylepis bite, 250-440 ml for a Naja nigricollis bite and 30-100 for a Bitis arietans bite ... if the truth is that doses up to 3 times higher might be needed ... well you guys can do the math ...

Cheers


David

Additional references cited:

Chippaux J-P et al (2007) American Journal of Tropical Medicine & Hygiene 77(3): 538-546.
Ramos-Cerrillo B., et al (2008) Toxicon 52: 881-888.

[gaboon69]

Fantastic read. Thank you for the insight. I have heard and read different things about Tri antivipmyn after your extensive discussion. I am looking into obtaining ICP as an alternative. Much appreciated.

[Warren Klein]

Toxinologist- Thank you for this very informative response. I catch snakes in remote locations in Angola and have stocks of both SAVP polyvalent as well as the French-made FAV-Afrique. I was first a bit concerned about the effectiveness of the FAV- Afrique in Angola, but feel a bit more reassured now. Your insight is much appreciated here. Regards

[biochemist]

Toxinologist, you speculate a lot and you are very selective in your use of information. The Abubakar et al (2010) study you cite is a case in point. In it, according to you, they independently "prove" that Antivipmyn Africa is of low potency (18 vials as initial dose taking the maximum extractable venom as the amount to neutralize). Thus, not worth including in their highly questionable clinical study. Interestingly, using the "maximum extractable venom" criterion the authors selected 3 candidate antivenoms. You should remember (read the paper more carefully) that one of them (VacSera), while performing acceptably (according to the authors) in the preclinical screen, was shown to be quite inadequate in terms of clinical efficacy. So much for prediction of efficacy and, consequently, of inefficacy. Maybe the Antivipmyn Africa they excluded would have worked? Guess we will never know, especially with your science fictions.

Another detail about antivenom testing, that you should tell your audience, is that when the Abubakar team preclinically screened the antivenoms, the E. ocellatus venom they used to "independently test" was the same they used to make the two most "potent" antivenoms. Well, it is not altogether surprising that they would have the highest potency, considering that all venoms (E. ocellatus as well) show some regional variation. How would the SAVP, in case there was some around, perform against venoms from Benin, or Guinea? You should also remind your readers that severely envenomated patients were excluded from the Abubakar study, and ALL patients were treated in the Chippaux et al (2007) study, regardless of how ill they were on arrival. You know, antivenoms tend to work better when you select milder cases, and mortality is generally lower when you leave out the really severe cases from the study and/or calculations.

You also "forgot" to say that in the Ramos-Cerrillo et al (2008) study, they compared Antivipmyn Africa with the French FAV-Afrique using the same mice and venoms, and they found a comparable neutralizing potency against the same E. ocellatus venom [Antivipmyn-Africa: 39.7 mcl (29.8–53.0), FAV-Afrique: 57.1 mcl (46.8–69.7)] using 3xLD50 challenge, and when they used a challenge with 5xLD50 they found that the Antvipmyn Africa ED50 was 120.6 mcl (109.0–133.3) and FAV-Afrique's was 119.7 mcl (106.1–134.9). They also did this comparison with the strongly neurotoxic Naja melanoleuca venom, and found a comparable potency (60 mcl gave 100% asymptomatic survival for both of them using a 3XLD50 challenge). So, on the question of potency, how can you recommend one and so colorfully compare the other one to suicide or a placebo?

Your argument on the low protein content is quite irrelevant, as FAV-Afrique, which is made against 10 species, has only somewhat more than 46 mg/ml protein. Do you have actual evidence that TOTAL protein content and neutralizing potency are related, or are you just speculating for an impressionable gallery? If antibodies, or fragments thereof, are purer and relative venom binding content higher, neutralizing potency will go up as protein content goes down. Please, be a little more rigorous and finish your argument, honestly stating that it rests on the (unproven and largely speculative) premise that polyvalency means less neutralization. Other toxinologists have shown, for some Asian elapids at least, that polyvalency actually may add to neutralization potency. This is an old prejudice: it is better to have many monovalents than polyvalents. Please consult Raweerith & Ratanabanangkoon, 2005.

On the question of the dosages used by Chippaux et al (2007), they specifically state, and I quote, that "Thus, assessment of efficacy of the antivenom as a function of doses is speculative, and circumstances described constitute an important potential bias that limits evaluation of a minimal therapeutic dose." So, have YOU (or others) conducted any (reported) experiments to support your statement that "These are very low neutralising potencies, particularly for Dendroaspis polylepis and Naja nigricollis."? Or are you just speculating on what would happen in your world?

You know, you may be right. But then again, you may be wrong. We do not know, and that includes YOU. Presenting your simplistic (as you yourself recognize) calculations as being predictive of efficacy, or anything else for that matter, is really intellectually dishonest and will only add to the paralyzing confusion in the field.

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Immunochemical and biochemical comparisons of equine monovalent and polyvalent snake antivenoms, Rutai Raweerith, Kavi Ratanabanangkoon, Toxicon 45 (2005) 369–375.