Second vulture-safe veterinary painkiller identified! Tolfenamic Acid
In 2003, the veterinary use of diclofenac to treat cattle was discovered to be the cause of catastrophic vulture declines across South Asia. There was an urgent need to identify alternative, safe NSAIDs for veterinary use. The NSAID meloxicam was tested in 2006 and found to be both safe to vultures and effective in treating cattle. Unfortunately, various other NSAIDs have also been tested since then and so far all have been shown to be toxic to vultures. Therefore, it is hugely significant that a systematic safety testing study led by the Indian Veterinary Research Institute (IVRI) with the Bombay Natural History Society (BNHS) and the Royal Society for the Protection of Birds (RSPB) has identified tolfenamic acid as the second confirmed vulture-safe NSAID after meloxicam.
A total of 38 wild-caught Himalayan Griffon Vultures, along with single captive White-rumped and Long-billed Vultures from the conservation breeding population, were given doses of tolfenamic acid by oral gavage at the maximum possible level likely to be encountered by birds feeding on carcasses in the wild. This was calculated based on concentrations of diclofenac found in cattle carcasses in India, which showed that vets and livestock owners routinely give doses of this drug much higher than the recommended level. In addition, four Himalayan Griffons were also fed buffalo meat from animals given double the recommended dose of tolfenamic acid just prior to death. Although two of the Himalayan Griffons given the extremely high dose by gavage died, all other birds survived without an increase in uric acid levels in the blood, which is the usual sign of kidney failure caused by NSAID poisoning. These findings show that tolfenamic acid is safe to wild vultures at levels of the drug that they are likely to be exposed to.
IVRI and BNHS giving a vulture an oral dose. Chris Bowden, RSPB.
Dr Chandra Mohan, Scientist of IVRI and the lead investigator of the study said “Every painkiller available has slightly different properties, and the vets often complained of not having a second choice of NSAIDs. But we are very pleased to report that tolfenamic acid been found as a second safe NSAID drug.”
Dr Vibhu Prakash, Principal scientist and vulture programme Director of BNHS explained “by testing first on the less threatened Himalayan Griffon Vultures, we could establish the comparative safety of the drug. We then also tested it on the most threatened species held at the breeding centre at Pinjore, Haryana.”
The results of this study are reported in an IVRI report, while a pre-print publication, entitled “Experimental safety testing shows that the NSAID tolfenamic acid is not toxic to Gyps vultures in India at concentrations likely to be encountered in cattle carcasses” is freely available.
Dr A M Pawde, Incharge & Dr M. Karikalan, Scientist Centre for Wildlife, IVRI said “IVRI is particularly pleased to help identify this safe alternative for veterinarians, and it is important that this information is made available quickly, to avoid use of other more toxic alternatives (for the vultures) becoming popular in veterinary use.” They added “Tolfenamic acid does have certain properties which make it slightly more similar to diclofenac in its ability to reduce fever as well as inflammation, and this may be important in being taken up more widely by vets across the country.”
Dr. Triveni Dutt, the Director of ICAR-Indian Veterinary Research Institute commented “this is good news for vulture conservation and can help decision-makers to take important steps towards banning the NSAIDs which are proven to be toxic, such as aceclofenac and ketoprofen.”
Tolfenamic acid is already licensed and produced by a number of different Indian manufacturers, being out of patent, and similarly priced to other drugs.
Professor Rhys Green of Cambridge University UK, and Chair of the SAVE consortium said “After sixteen years and considerable effort in safety testing NSAIDs on vultures we have found a second vulture-safe NSAID for use on cattle. This is important and welcome news. It will reduce the pressure to use toxic alternatives such as aceclofenac, ketoprofen, flunixin and nimesulide, which are still available and legally used in the region. Veterinary use of all of these toxic drugs should be banned immediately.”
He added “So this is highly significant, and good news for vulture conservation, but only if it helps decision-makers to take more urgently needed action to remove licenses for similar drugs that are proven to be toxic, such as aceclofenac and ketoprofen. Neighbouring Bangladesh has earlier this year taken this important and commendable step to extend local ketoprofen bans to national bans, and if India can do this for aceclofenac and ketoprofen, this will be real progress.”
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Very good information and remarkable achievement by IVRI and BNHS team. Congratulations. Keep it up teammates
Highly informative research and useful for all veterinarians. Congratulations and good luck for the entire team..
Thank you Dr Swarup. And greatly appreciate your help in passing this story to relevant outlets – eg
I hope others can help in such ways to disseminate this news, Chris Bowden
Jürgen Dämmgen, Germany,
this is really good news after many years of hard work and frustration. Congratulations to a great team and good luck for the vultures of the world!
Many thanks! And thank you for your ongoing support to this cause!
Very glad news .
Very good news to see this joint research and development and another safe drug to support vulture conservation. Congratulations to all involved.
Interesting News, Best wishes for the work.
Recently I wrote this poem, hope the message to protect vultures will reach wider audiences. https://sciencenextdoorcom.wordpress.com/2021/09/02/vultures-natures-winged-avengers/
Many thanks Nishand, and indeed for your willingness to incorporate feedback. We will be pleased to post this on our SAVE Facebook page, and I hope you can reach other audiences with these messages and further awareness.
Great news.We the Veterinarians at People for Animals Wildlife hospital and conservation center in Bangalore,extensively use Meloxicam and have found no toxic effects.
Dear Col Dr Navaz, Manythanks for this feedback, and indeed my understanding is that many vets (including in Europe) are already perfectly happy with using meloxicam, which we have known to be safe for vultures since 2005. Having one more option (tolfenamic acid) available to vets (with more anti-pyretic properties, so perhaps more similar to diclofenac in that way) is something that some vets have been asking for. But if meloxicam already covers the needs for you, then this is ideal and no need to change. Further feedback on this point will be welcome.
Very inspiring/refreshing news after devastation of vulture population. The coordinated approach is most appreciated. Meloxicam and tolfenamic acid have giver good results, pharmacovigilence should continue.
With thanks for your support and IVRI’s role in this work. Fully agreed that extending the pharmacovigilence on this and all NSAIDs in veterinary use is definitey both extremely important and urgent. Warm regards.
Congrats Team IVRI. Proud of you.
I’m pretty stunned that a 5% (2/38) mortality rate is considered safe.
John Mallord (co-author) has just passed me his response to post here: Many thanks for your comment. It was of concern to us that two of the birds died during this experiment. However, based on the reasons we detailed in the manuscript; we believe that this does not indicate that tolfenamic acid is likely to be toxic to wild vultures at levels of the drug that they are will encounter when feeding on cattle carcasses. The main point to note is the very large dose that was given to all the birds as part of a precautionary approach, because the levels of tolfenamic acid in cattle carcasses available to vultures in India are unknown at the moment. As explained in the online Supplementary Information, we used a dose for the experiments based on the degree to which concentrations of diclofenac found in the carcasses of dead cattle in India exceed those expected from experiments in which cattle were given the recommended dose of that drug. Those results showed that diclofenac was given to some cattle by vets and practitioners at far above the recommended levels. We made the worst-case assumption that this overdosing would also be the case for tolfenamic acid, but concentrations of TA in cattle carcasses are not currently available so we do not know if it is given in doses that are too large. We do know that some drugs are not overused in this way. The NSAID meloxicam is present in cow carcasses in India at about the concentration you would expect if users administered the recommended veterinary dose. We also chose to use the 95th percentile of the distribution of expected concentration of the drug if it was overdosed, rather than the mean or a lower percentile. So the dose of tolfenamic acid we used would not be encountered by anything more than a tiny proportion of wild vultures and probably not by any.
Due to the deaths of these two birds, it was very important that more birds were tested, and this was done. A further seventeen Himalayan Griffons were given the same highly elevated dose after the deaths, with all of them surviving. Importantly, none of the other birds showed the marked increase in uric acid levels in the blood observed for the birds that died and which is also seen in vultures treated with the toxic drug diclofenac. In addition, two White-rumped and Indian Vultures were also dosed by gavage with no negative effects. When four Himalayan griffons were fed meat from water buffaloes given double the standard veterinary dose of tolfenamic acid there was no sign of negative effects. So, even with overdosing, the meat of treated animals did no harm.
In conclusion, , we think that the evidence indicates that tolfenamic acid is likely to be safe for vultures at the doses they encounter when feeding on carcasses of animals that died soon after being treated with the drug. Unlike diclofenac, tolfenamic acid is unlikely to have a significant negative impact either on individual vultures or on their population trends.