Re-positioning of the PAPP antidote

In the initial development of PAPP baits it was hoped that a failsafe antidote in all circumstances would make the baits safer for working and pet dogs. While it remains true that there is a way to overcome the immediate effects of PAPP, the story is more complicated and some additional precautions are needed.

While the antidote, methylene blue dye (MB), does reduce methaemoglobin back to normal haemoglobin (thus reversing the effects of PAPP) there are some important caveats that need to be emphasised.

  1. PAPP acts very fast to cause methemoglinaemia, so death can occur within 1-2 hrs of a bait being taken. Thus, if the antidote is not administered within this time frame an animal will not be saved. This is a problem in areas that are distant from a vet, but may also be a problem if the symptoms are not noticed. Since the initial symptoms are lethargy, an affected animal may be mistaken for a resting animal. Having said this, even as later indications such as cyanotic tongue/gums and ataxia become apparent (anoxeamia), it is still possible for the animal to be saved.
  2. The only antidote treatment that has been shown to work reliably to date is by intravenous (IV) administration. Some dogs have been successfully treated with an oral dose form but several administrations were required and the antidote is not well accepted by the dog. Attempts to achieve a simple formulation suitable for an oral dose or suppository have not been successful, so an on-farm option is not yet available. In addition to giving the MB antidote, an advisory sheet has been developed by the AVA and IA-CRC that now includes a suite of therapies including use of charcoal absorbent, oxygen therapy and inducing vomiting that may support the poisoned dog while the MB antidote takes effect.
  3. The commercially available MB solution in water is not isotonic (MB does not dissolve well in physiological saline). A non-isotonic solution is potentially able to cause immediate lysis (rupture) of red blood cells, so the MB solution must be administered slowly to avoid red cell damage.
    These messages all have already been emphasised in the previous ACTA communications and booklets. However, in the process of the CRC preparing its clinical guide sheets in conjunction with AVA, three additional issues were uncovered.
  4. Methylene blue dye can be toxic if overdoses are administered. One of the effects of MB overdose can be to cause Heinz body formation in red blood cells that may even exacerbate the problems of oxygen transport and methaemoglobinaemia.
    As with many useful drugs there is a ‘therapeutic window’ for safe use. For MB, the cumulative maximum safe dose is below 10mg/kg bodyweight but even doses over 5mk/kg may require clinical monitoring during and after administration. During trials one dog given 15mg/kg was killed by the antidote. The toxic effects of MB overdose may develop over several days so monitoring and observation post treatment is recommended, especially if high doses of antidote are given. In human use where less severe methaemoglobinaemia is being treated, the maximum dose is set at 2mg/kg bodyweight.
    The critical issue here is that if a working dog receives a dog bait dose of PAPP (1000mg) there is a risk that insufficient antidote can be given safely to reverse the PAPP. The data is confounded by the fact that some dogs in antidote trials vomited at the time of treatment (probably reducing the absorbed PAPP dose). It should also be noted that during trials of the antidote the animals had immediate access to the vet.
    Added to this we have been advised that the response to the MB is sometimes not immediate. This means there is some risk that additional MB is given when it is not needed and this exacerbates the potential for inadvertent overdose.
    The situation may be somewhat better for 400mg fox bait dose of PAPP where all MB treated dogs have recovered in clinical trials and where 5/6 dogs were successfully treated in the NSW Goonoo project field study. This is partly due to the fox bait PAPP dose being perhaps more marginal for a large dog and also because less antidote is likely to be needed to reverse the lower dose PAPP effects. All registered vets are now being thoroughly briefed on these issues so that appropriate care is applied.
  5. It has been found that there are two forms of methylene blue dye. One is called methylene blue and is the antidote tested. The other is called “new methylene blue”. New MB is a closely related dye used for staining tissue sections, but has not been tested for use as a methaemoglobin antidote. Moreover, there is a third dye with a similar name called “methyl blue” that has a different structure. We raise this so that our readers are aware that there is potential for confusion.
  6. Methylene Blue Injection is the name of the antidote and it is only manufactured currently by PHEBRA in Sydney who already provide sterilised vials for human use. The APVMA have issued a permit to allow PHEBRA to relabel their human registered product so it can be used as an antidote. The IA-CRC is working with Phebra to seek full veterinary registration. Registration regulations mean that only registered vets can purchase and use this product to treat animals.
    MB vials contain 5ml of 10mg/ml solution, so just one vial would approach the toxic threshold of 10mg/kg for a 5 kg dog. However, several vials may be needed to effectively treat a larger dog. Vets can purchase the vials from their normal veterinary medicines wholesaler or directly from PHEBRA. Retail cost of MB is uncertain but, with the need for qualified veterinary intervention and potential follow-up monitoring and use of several vials, a treatment may be several hundred dollars, especially if additional observations are needed.

We feel that, given the initial publicity around the antidote and a widely held conception that it was cheap, readily available and effective, that it is necessary to better explain the strengths and weakness, now that we have a better understanding of the IA-CRC work and the implications from the testing results.

However, despite these caveats, it remains true that MB can be used to overcome the effects of PAPP and in this regard it does provide a measure of comfort compared with alternate toxins. This is not however a ‘bullet proof’ safety case, given the now known limitations, so we take this opportunity to again stress the normal precautions when using poison baits.

Use restraints and muzzles:

The clear advice to all users, that is stated in the booklets, is that collars and name tags do not protect working dogs. It remains appropriate to use all precautions including restraints and muzzles to prevent against exposure of valuable dogs to PAPP baits.

Low risk of secondary exposure:

One final point here is that there is no significant risk to any animals from secondary poisoning if a PAPP killed carcass is scavenged. This is because PAPP has only a short half-life in the affected animals. Also PAPP does not reach high levels in tissues, so a scavenger can simply not eat enough fast enough for the PAPP residues to give the acute dose required for a high risk.

Scat Marker Beads

ACTA has individual plastic marker beads in both PAPP (yellow/orange beads) and 1080 baits (red beads) as an aid for vets presented with any non-target animal suspected of taking baits. This aids in correct treatment and also helps exclude baits if there has been a snake bite.

PAPP baits have yellow/orange beads

Yellow/orange marker beads are incorporated into PAPP baits

1080 baits have red beads

Red scat marker beads are incorporated into 1080 baits

To report an adverse event associated with the use of Phebra methylene Blue for injection, please contact Poonam Kamboj Pharmacovigilance & Medical Information Manager
P: +61 (0)2 9420 9199 (ext 926)
F: +61 (0)2 9091 2342

Low direct risk to non target species

Adapted from Fisher (2008)
Dog (Canis familiaris) Not reported 7.5 Coleman et al., 1960 reported from handbook of toxicology
Coyote (Canis latrans) Cod liver oil 5.6 Savarie et al., 1983
Kit fox (Vulpes velox) 0.05% Carbopol 914 14 Savarie et al., 1983
Red fox (Vulpes vulpes) DMSO* and sweetened condensed milk 25.2 (estimate from non-lethal model) Marks et al., 2004
Cat (Felis libyca domestica) 0.05% Carbopol 914 5.6 Savarie et al., 1983
Bobcat (Lynx rufus) 0.05% Carbopol 914 10 Savarie et al., 1983
North American badger (Taxidea taxus) 0.05% Carbopol 914 100 Savarie et al., 1983
Raccoon (Procyon lotor) 0.05% Carbopol 914 142 Savarie et al., 1983
Striped skunk (Mephitis mephitis) 0.05% Carbopol 914 400 Savarie et al., 1983
Stoat (Mustela erminea) PAPP-HCl monopropylene glycol 9.3 Fisher et al., 2005
Ferret (Mustela furo) PAPP-HCl monopropylene glycol 15.52 Fisher and O’Connor, 2007
Guinea pig (female) (Cavellio porcinus) DMSO solvent 1,020 Scawin et al., 1984
Mouse (albino) Propylene glycol 223 Savarie et al., 1983
Mouse (female) DMSO solvent 5,000 Scawin et al., 1984
Mouse (male) (Swiss Webster strain) Propylene glycol 168 Pan et al., 1983
Rat (female) (Porton Wistar strain) DMSO solvent 223 Scawin et al., 1984
Rat (male) DMSO solvent 475 Scawin et al., 1984
Rat Propylene glycol 177 Savarie et al., 1983
Rat (male) (Sprague-Dawley) Propylene glycol 221 Pan et al., 1983
Golden eagle (Aquila chrysaetos) Propylene glycol 50 Savarie et al., 1983
Coturnix quail (Coturnix coturnix) Propylene glycol 316 Savarie et al., 1983
Starling (Sturnus vulgaris) Propylene glycol 316 Savarie et al., 1983
Red-winged Blackbird (Agelaius phoenicus) Propylene glycol 133 Savarie et al., 1983
Black-billed Magpie (Pica pica) Propylene glycol 178 Savarie et al., 1983
Common Crow (Corvus brachyrhynchos) Propylene glycol 178 Savarie et al., 1983

Fisher et al. (2008) reviewed oral lethal dose (LD50) values for PAPP. The table above is adapted from this citation to demonstrate relative species sensitivities.

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