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The Toxic Mechanisms - some thoughts
Some of the Questions
Hard and Soft Facts
Examining the theoretical
possibilities
Some of the questions
What is the reason for the delay in toxicity?
Could the delay give clues as to how the toxin works?
Could the understanding of this help to improve treatment strategies?
Is the host response somehow responsible for the activation of the toxin?
This response might be a source of delay- if so is this a metabolic, physiologic or immunologic response?
How can one explain the local effects of the toxin? There seems to be local diffusion of toxin. Does the toxin cross tissue planes? How is the toxin carried and along what pathways- capillary, venous, arterial, lymphatic, neurological, fascial, lipid etc. Do ticks found on the neck have vagal effects? Does a tick on the head or neck increase the susceptibility to vomiting, dysphagia, laryngeal paralysis, cardiac or respiratory effects? Could there be a neurogenic pulmonary oedema, even vagally mediated pulmonary oedema?
Why is pulmonary oedema not described in tick poisoning in children?
Why, when an animal has been given antiserum for tick poisoning, does a second tick cause such a poor outcome given that antiserum is supposedly already present to inactivate any new toxin?
Hard and Soft Facts about the Toxicity
|
"Hard" facts |
"Soft" facts |
|---|---|
| causes paralysis, primarily of striated muscle | some early cases show ataxia without apparent loss of strength |
| causes pulmonary oedema in advanced cases | |
| affects most if not all warm blooded mammals and birds | |
| is slow to exert its effect in vivo | is slow to exert its effect in vitro (1 experiment) |
| canine antiserum contains substances which speed the rate of recovery | canine antiserum contains canine anti-tick IgG as the major beneficial antibody |
| the natural immunity is relatively short-lived | some individual dogs may have better immunity- either natural or acquired |
| in one small group treated with both antiserum and dexamethasone survival was improved | |
| smaller and younger mammals of a given species are more susceptible | |
| dogs are very susceptible to paralysis, nausea, drooling (striated oesophagus muscle), hypertension?, pulmonary oedema? | humans show more signs of respiratory failure through paralysis than through pulmonary oedema |
| the toxic effects are greatest at higher temperatures both in vivo and in vitro | |
| some animals appear to die suddenly after an apparent period of stability | is sudden death usually due to acute cardiac failure? eg chronic myocardial hypoxia, increased cardiac workload, direct cardiotoxicity? |
Examining the theoretical possibilities
The in vitro experiment suggests that humoral conveyance of the toxin (or its metabolite) is not the rate limiting effect.
If this is true what then is the delay from? Is there:
- a time delay for exisiting neurotransimtter to become exhausted?- No. Cooper's work suggests that ACh release is unable to be initiated because of a defect in depolarisation-secretion coupling. Spontaneous ACh release is not affected
- a time delay for diffusion of toxin into the neuron?
- a time delay for a slow metabolic process to activate the toxin?
- a time delay for a slow immunologic process to activate the toxin?
If there is an immunological process, then there must be at least some humoral component and perhaps also some cell-mediated component
Why is natural immunity so short-lved?
- is there too small a dose of toxin? This seems unlikely when one considers that even tick anti-serum producing dogs can develop tick poisoning when later exposed
- is there also a metabolic process of adaptation- hepatic, systemic enzymes?
- is there also a physiological process of adaptation- cardiovascular, neuro-endocrine?
Where does the toxin work?
- extracellularly? (or an initial effect may be extracellular but then a later step at 2 or 3)
- at the cell membrane?
- intracellularly?
If there is a metabolic adaptation involved is this in response to the toxic effects or to the degradation of the toxin itself?
If there were a physiological adaptation it would surely most likely be an adaptation to the toxic effects?
What are the metabolic and physiological differences or peculiarities that might make dogs in particular more susceptible to tick poisoning?-
- cardio-pulmonary physiology?
- striated oesophageal musculature?
- propensity to acquire ticks
- any breed related susceptibility differences that might provide clues?- German Shepherds?, myasthenia gravis?; brachycephalics?- airway disease?; Staffordshire Bull terriers, Maltese terriers?, Cavalier King Charles Spaniels? Coat length?, coat type?, behaviour?. NB the breeds mentioned are purely anecdotal - no statistical breed differences proven as yet.
If the toxin originally served a predatory role (as for spiders) - presumably for immobilising other small arthropods, annelids etc - what then was the physiological target receptor in these species- can the toxic effects be tested in arthropods etc? How does arthropod neurophysiology differ and equate with avian and mammalian neurophysiology?
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