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EFFICACY AND SAFETY OF PROBAN ® (cythioate)

Proban Scientific Information brochure
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Observations of Cythioate (Proban®) tick control for cats
Tick Paralysis: (antitoxin and vaccine, BF Stone, abridged)
Tick Paralysis (some issues, Atwell and Fitzgerald)
Tick Paralysis in Australia (Malik and Farrow)
Assessing the safety of long term cythioate therapy
Cythioate at 5 x or 10 x normal dose rate in dogs an evaluation
Safety of owner administration of Proban to dogs and cats
My clients object to household contamination and exposure to external insecticides
Reducing pet owner exposure to insecticides
Flea, tick (Rhipicephalus sanguineous) demodex and ear mites (Otodectes cynotis) control

Observations of Cythioate (Proban®) tick control for cats

Cythioate gave 100% control of paralysis tick, Ixodes holocyclus, on two young Burmese cats during the adult tick season at Toowoomba, Queensland. The product was used in a domestic situation, rather than as a formal trial, without thought originally of reporting results. Consequently, data on tick numbers is approximate.

The season for adult paralysis ticks on the Toowoomba escarpment was unusually severe, probably resulting from favourable weather conditions limiting normal mortality of earlier stages, and from an increased presence of bandicoots the nymphal stage was observed on the cats in August, 1988, with adult ticks appearing at the end of September, early October. Toowoomba is cooler than the coast in early Spring, with an elevation of 700 metres. The sibling cats were seven months old when treatment began in early October. Weight of cats during treatment was approximately 4kg. Dosage of Cythioate was doubled midway during the season with a change from the tablet formulation to the liquid formulation, the latter being easier to administer to cats resisting ingestion of the tablets. It was desirable also to try a higher dosage of Cythioate as some ticks which had inserted their mouthparts were still alive when removed, although they died within hours. It is assumed they would not have engorged at this lower dosage rate. In contrast, ticks which were free roaming on the cats fur were alive a week or more later.

The cats were searched daily and free roaming ticks as well as any ticks with mouthparts inserted, were removed. All ticks except two showed no evidence of engorgement. These two ticks appeared to be threequarters engorged and would have dropped off a previous host to transfer to one of the cats. Mouthparts were inserted but the ticks were dead. They were found when the higher rate of application of Cythioate was being used. As the cats were thoroughly searched each day these maturing paralysis ticks would have been present for less than a day. It is significant that these ticks were apparently killed by the Cythioate so quickly as they could have been producing dangerous quantities of paralysis toxin. The cats during treatment with Cythioate were wearing non-insecticidal collars. One or two fleas running over the coats of the cats were observed during Cythioate treatment. No dead fleas were seen.

Conclusion

There is little doubt that Cythioate was highly effective in killing paralysis ticks before engorgement. As previous studies have demonstrated a high tolerance of cats to Cythioate, the higher dosage of l51ng per 5kg bodyweight twice a week appears appropriate. This is double the present recommendation for cats for fleas. The adult tick season extends from August/September to Christmas at Toowoomba, but cats ,should be searched outside these times as occasional adult ticks could be present. The present label dosage rate for fleas when used after Christmas when flea activity is high in the hot weather should assure protection against possible late ticks.

Cats are difficult to treat orally; especially for older owners. The liquid formulation appears easier to apply orally. Application on food is ideal provided the cat is not finicky. This method may be difficult to control when two or more cats are in a household, for obvious reasons.

No adverse affects were observed on the cats which could be attributed to organophosphate poisoning.

Study, to evaluate the efficacy of Cythioate for control of I. holocyclus on dogs.

In this trial both immune dogs, dogs used for the production of tick serum and non immune dogs without previous known exposure to Ixodes holocyclus were divided into three groups. Each group consisted of immune and non immune dogs. The non immune untreated group were x-bred dogs.

Each group consisted of 4 immune and 4 non immune dogs. The control group received no Cythioate or other treatment and the other groups received either 2mg/kg or 3mg/kg Cythioate administered every 48 hours during the course of the trial.

Eight ticks were attached to each dog. Ticks attached and engorged on all dogs. In the treatment groups less ticks attached, they engorged more quickly and dropped off earlier than would be expected.

Of the 12 immune dogs used, one dog in the untreated group showed slight paralysis on day 6.

In the 12 non-immune group the 4 dogs in the 2mg/kg Cythioate treatment group showed no effect from the ticks. In the 3mg/kg group, one dog showed slight paralysis and recovered, one dog vomited on day 8. It recovered uneventfully without treatment. Of the 4 dogs in the untreated group 2 dogs dies on day 7 of tick paralysis, the other two being severely paralysed on day 5 were treated, all ticks with the exception of one tick were removed, cythioate at 6mg/kg together with tick serum was administered. On the following day the remaining tick dropped off, the dog recovered without further treatment over the next 48 hours (see table page 3).

Summary

It can be concluded from this experiment that cythioate gives a high degree of protection by preventing normal attachment and engorgement.

"Cythioate appears to interfere with the mature female Ixodes holocyclus preventing normal engorgement, reducing the time the tick is attached to the host. This possibly prevents or reduces the quantity of toxin injected into the canine during engorgement."

Frogley I; Siller R; Warner N & M. Trial to confirm the efficacy of cvthioate to prevent tick paralysis in doffs from Ixodes holocyclus - unpublished. 1989.

Percentage reduction of Ixodes holocyclus on dogs
		Immune Dogs			Non Immune Dogs
Days	Treatment	No Treatment	2mg/kg	3mg.kg	*No Treatment	2mg/kg	3mg/kg
13/6	T	100	100	100	100	100	100
14/6	NT	79	90.6	71.8	65.6	37.5	56.2
15/6	T	65.6	62.5	53.1	62.5	21.9	34.4
16/6	NT	59.4	53.1	46.9	0.0	12.5	9.4
17/6	T	59.4	9.4	31.3	0.0	0.0	0.0
18/6	NT	31.3	3.1	9.4	0.0	0.0	0.0
19/6	T	21.9	3.1	0.0	0.0	0.0	0.0
20/6	NT	21.9	3.1	0.0	0.0	0.0	0.0
21/6	T	0.0	0.0	0.0	0.0	0.0	0.0
T = Treatment days. NT = No Treatment days. 13/6 = Each dog loaded with eight adult female ticks. *Dogs suffered tick paralysis day 15/6-16/6. Dogs received treatment as indicated in trial protocol.

How to find ticks on a tick paralysed dog?

In the same trial the untreated non immune dogs suffered tick paralysis. Treatment consisted of removal of all ticks except one, administration of cythioate 6mg/kg and tick anti-serum. The following day the remaining tick dropped off the dogs, the dogs recovered in 48 hours.

Ticks on paralysed dogs may be missed in a body search. Long hair and skin folds may conceal ticks - snappy and savage dogs are difficult to search. Ticks in ears, inside the mouth or other inaccessible parts will be missed. Rinsing with an insecticidal wash is unsatisfactory due to incomplete coverage of the dog. Ticks remain susceptible to Proban wherever they attach to the dog.

Frogley J; Siller R; Warner N & M. Trial to confirm the efficacy of cythioate to prevent tick paralysis in dogs from Ixodes holocyclus - unpublished. 1989.

Tick Paralysis: Antitoxin and Vaccine. (B F Stone, Post Graduate Foundation in Veterinary Science - Perspective 3. abridged)

Introduction

All "hard" ticks (Family Ixodidae) and pre-adult "soft" ticks (Family Argasidae) have a lengthy attachment to hosts, allowing transfer during feeding, of organisms or toxins contained in tick oral secretions. Globally, there are up to seven "disease" toxicoses known or suspected to be due to toxins, including tick paralysis which is induced by up to 46 species of ticks.^1*

^*In this brief review, references have been kept to the minimum and the most recent review papers largely relied on to provide reader access to individual research papers

The Australian paralysis tick, I. holocyclus, the Tasmanian paralysis tick, 1. cornuatus, and Hirst's marsupial tick, I. hirsti, may cause paralysis. I. holocyclus is present along portions of the eastern coastal strip from north of Mossman in north Queensland to Lakes Entrance in Victoria. I. cornuatus and I. hirsti are of more limited importance and largely restricted to southern New South Wales, Victoria and Tasmania.

I. holocyclus causes serious losses of livestock and losses and distress to pets and their owners; there may be at least 20,000 domestic animals in Australia affected by tick paralysis per year including at least 10,000 companion animals referred to veterinarians for treatment. Livestock animals are also vulnerable and the deaths of calves in northern New South Wales alone may be about 10,000 per year.

There are many other livestock areas along the east coast of Australia where I. holocyclus occurs and adult cattle may also be affected by somewhat heavier infestations as are adult horses, sheep, goats and deer. However, juveniles such as piglets, foals, kids, lambs, and fawns, are at greatest risk. Annually, 100,000 animals or more may be affected to some degree.¹(BF Stone, unpublished data).

The development by an ectoparasite of the ability to cause paralysis leading to possible death of its host, suggests an evolutionary accident but a paralysing toxin may well have a functional significance such as a local anaesthetic, an anticoagulant, a feeding stimulant or to temporarily immobilise a partially-immune host, allowing more attachments without killing the host.

However, the natural hosts of 1. holocyclus are not greatly inconvenienced by the paralysing toxin per se as the majority become immune to its effect, although there are some casualties among juveniles or even adults with insufficient immunity eg, koalas, possums, birds and other tree dwellers intermittently coming into contact with ground vegetation and leaf litter where ticks occur.²

The ground-dwelling northern brown bandicoot, Isoodon macrourus and the long-nosed bandicoot, Perameles nasuta which are regarded as principal hosts of I. holocyclus, are usually highly immune, at least as adults.

Toxin Characterisation

Throughout the world, attempts have been made to demonstrate paralysing toxins in various species of ticks, in eggs, salivary glands or saliva^3,4 but published reports have been largely restricted to those concerning the toxin which causes the syndrome induced by I. holocyclus. This has been named holocyclotoxin, is almost certainly secreted by identifiable cells in the salivary gland of the tick^3,5 and has been extracted from those glands and whole ticks.

It has also been recovered from an artificial feeding medium into which I. holocyclus females salivated following attachment to a silicon rubber membrane,³ thus confirming that the tick oral secretions contain the paralysing toxin.

The Symptoms of Tick Paralysis

The symptoms of 1. holocyclus are briefly listed: The initial symptoms of tick paralysis are loss of appetite and voice, incoordination, followed by ascending flaccid paralysis, ocular irritation, excessive salivation, asymmetric pupillary dilatation and vomiting. Full limb paralysis and respiratory distress may occur later, almost invariably followed by death in the absence of treatment.

An increase in blood pressure, a decrease in cardiac output and a dramatic decrease in heart rate in terminal stages may occur. Hyperexcitability, hypertension and emesis are often counteracted by acetylpromazine or phenoxybenzamine, an adrenergic alpha blocker.

Many aspects of motor paralysis may be explained on the basis of action at the neuromuscular junction without interference with conduction. A direct temperature-dependant inhibition of transmitter release at neuromuscular junctions during paralysis may result in muscles contracting more readily at lower than at higher temperatures.

Thus, the clinical practice in Australia of keeping the patient cool may have some scientific basis as it could be concluded from this research that even a very small drop in body temperature may partially reverse paralysis. Holocyclotoxin inhibition of transmitter release at neuromuscular junctions may occur via some intermediate step between depolarisation of the terminal membrane and release of acetylcholine.

Somewhat recently published research^7-9 on I. holocyclus paralysis concluded that the most prominent feature of the disease was dysfunction of the efferent motor system but some disturbance of afferent pathway and involvement of the autonomic nervous system occurred.

Histopathological Studies demonstrated moderate to sever congestion of the liver, kidney and lungs, and some pulmonary oedema, which although inexplicable, was regarded as contributing to death.⁷ Although acute ventilatory failure occurred in late stages, respiratory muscle paralysis may not have been the cause as dogs appeared capable of considerable respiratory effort even when ventilation was failing.

There was a progressive fall in respiratory rate, possibly due to central depression of the respiratory centre of the medulla oblongata, with no change in tidal volume. This was associated with prolonged expiratory time due to closure of vocal cords, which may assist re-expansion of collapsed portion of the lungs, and causes a "grunting" noise, characteristic of the disease.

Muscle may have been damaged as indicated by elevated blood phosphate levels; muscle cell lysis was suggested by elevation of creatine phosphokinase. Changes in individual blood biochemistry parameters such as elevated glucose, cholesterol and haemoglobin, and decreased potassium were difficult to interpret.

The combined effect was thought to represent a response to sympathetic stimulation of the adrenal medulla, either releasing adrenaline and noradrenaline or stimulating the adrenal cortex to release Corticosteroids.^7-9

Possible Implications of Forcible Tick Detacbment

This, possibly controversial matter, has been discussed recently¹⁰ but the following summary may be of interest:

I. holocyclus has a long hypostome penetrating l mm or more into skin; on attachment, mast cell degranulation and infiltration of dermis with basophil and eosinophil leucocytes help lesion formation. On feeding on a host, salivary proteins including allergens and holocclotoxin, being moderately large molecules, may tend to accumulate at the site of attachment of the tick, possibly bound to host cells and tissues surrounding the feeding lesion.

Salivary antigens tend to rapidly accumulate at the attachment site, being designed to remain there to assist feeding. Allergens start to accumulate immediately on attachment and holocyclotoxin may concentrate particularly during the rapid feeding phase of I. holocyclus on the fourth to sixth days. Excess feeding proteins such as the above would normally be slowly released for metabolism by the host or slowly relocated to sites of affinity or action eg, most cells, basophils in the case of allergens or neuromuscular junctions in the case of holocyclotoxin.

On forcible removal of the secreting tick and its hypostome, the stimulus for the inflammatory response (or "foreign body" reaction) is removed, with rapid dispersal away from the attachment site of possible carrier cells. This mechanism may assist in rapid transport of bound holocyclotoxin or allergens away from the attachment site.

Laceration of the wall of the lesion may well release more bound holocyclotoxin or allergens into the feeing lesion at the tip of the hypostome and thence rapidly into the vascular system. The physical removal of the live tick may also trigger off toxin release in some other unknown ways such as from more remote binding sites close to the critical site of actions.

The condition of an animal or a human affected by I. holocyclus usually worsens after the tick is physically removed or after it detaches naturally at the end of engorgement; where anaphylaxis develops in humans hypersensitive to tick allergens, it occurs immediately after physical removal of the live tick. The effect of an attached I. holocyclus, whether on a human or an animal, may be reduced by killing the tick in situ with a rapidly penetrating, rapidly-acting, "tickicidal chemical": suitable for use on animal or human skin (see ¹⁰ for more detail).

Stone B. Tick Paralysis: Antitoxin and Vaccine. Post Graduate Foundation in Veterinary Science - Perspective 3.

References:

1. Stone B F (1987). Toxicoses induced by ticks and reptiles in domestic animals, in: J B Harris (ed), Natural Toxins, Oxford University Press, Oxford, England, pp 56-71
2. Stone B F (1988). Tick paralysis, particularly involving Ixodes holocyclus and other Ixodes species. In: K F Harris (ed) Advances in Disease Vector Research, Vol 5, Springer-Verlag, New York, pp 61-85
3. Stone B F and Birmingham KC (1986). The paralyzing toxin and other immunogens of the tick I holocyclus and the role of the salivary gland in their biosyntheses, in: J R Sauer and J A Hair (eds), Morphology, Physiology and Behavioural Biology of Ticks, Ellis Horwood, Chichester, England, pp 75-99
4. Stone B P (1987). Research on tick paralysis, in: Proceedings No 103, Veterinary Clinical Toxicology, The Postgraduate Committee in Veterinary Science, The University of Sydney, pp 309-316
5. Stone B F, Binnington K C, Gauci M, and Aylward J H (1989). Tick-host interactions for Ixodes holocyclus: the role, effects, biosynthesis and nature of its toxic and allergenic secretions. Experimental and Applied Acarology, 7:59-69
6. "British Pharmacopoeia": (1973), Her Majesty's Stationery Office, London
7. Ilkiw J F., Turner D M, and Howlett C R (1987a). Infestation in the dog by the paralysis tick I holocyclus, 1. Clinical and histological findings, Aust Vet J 64: 137-139
8. Ilkiw J E, and Turner D M (1987b). Infestation in the dog by the paralysis tick 1 holocyclus, 2. Blood-gas and pH, haematological and biochemical findings, Aust Vet J 64: 139-142
9. Ilkiw J E, and Turner D M (1987c). Infestation in the dogs by the paralysis tick I holocyclus 3. respiratory effects, Aust Vet J 64: 142-144
10. Stone B F (1990). Tick paralysis - a suggestion. Aust Vet Practit 20: 30-39

Tick Paralysis (some issues, Atwell and Fitzgerald)

Cases of Tick Paralysis (TP) still cause concern to veterinarians in spite of the quantification of antisera and of the earlier work of the University of Sydney and CSIRO. There are still many areas of doubt or concern and many ideas, exposed in unrefereed publications, at this stage without firm scientific support. Some are genuine observations but proven explanations are usually limited. Outlined below are areas identified as in need of supportive explanatory research data. Hypotheses are offered but proof is lacking for most of these concepts.

Tick Variability

Seasons seem to vary, both between and within seasons for the numbers of the severity of TP cases. Presumably environmental factors influence tick survivability but are there ticks that are more toxic at different stages of each season or between seasons? People who breed ticks and produce antisera would believe so (Warne pets. comm., 1994) based on their observations of individual ticks, which seemed to have much more severe effects on immune dogs than did scores of other ticks similarly exposed to the same dog during the same season over a short period of time.

Additionally, there may be variability of dogs' susceptibility to the toxins and their individual immune status and responsiveness must also be variable.

Dog Variation

How does a dog's personality and response to stimuli affect their outcome in TP cases? It would seem possible that fearful dogs (but not necessarily all members of one breed) would be overstimulated by being paralysed, both from loss of limb control as well as pharyngeal paresis/ paralysis - the concept seen in people with Rabies where the knowledge of being unable to swallow or to remove secretions near to or in the glottis is reported to cause extreme anxiety. Are fearful dogs the same? Does the use of acetylpromazine have benefit in reducing responsiveness to such stimuli or does its benefit come from its antihypertensive effect via its effect on systemic vascular resistance (SVR). If the respiratory pattern alters quickly following its use, it would probably be the former, as reduced SVR would take some time to have a beneficial effect on pulmonary oedema and any associated respiratory signs.

Problems associated with tick intoxication, and their established and potential (p) therapies
Problem	Therapy - Established and Potential (p)
Paralysis	Tick antisera (TAS) with appropriate prophylactic pre-medication
Tick	in situ death, TAS at site
Vomiting	Anti-emetics (but is it regurgitation)
Distress	Anti-anxiety Sedation	a2 Agonists (p) pentobarbitone
	Reduced response to stimuli	acetylpromazine opioid (p)
Hypertension	Centrally mediated?	a2 Agonists (p)
Respiratory distress	Aspiration Pulmonary Vasodilators (p) Diuretics Phlebotomy Paralysis of respiratory muscle Central respiratory drive/respiratory support Muscle fatigue, water content	Very poor prognosis Confirmation? Acidity of material Antibiotics? Decrease pulmonary blood volume/venous pressure Venous and arterial, to reduce venous return and systemic vascular resistance, respectively. Reduce cardiac preload and afterload, as well as increasing pulmonary venous capacitance Venodilator function and to decrease circulating fluid volume Decrease central blood volume TAS Intubation, respirator, oxygen Bronchodilator (p)

Local Effects of Tick Attachment

Do ticks have a local effect due to local penetration of toxin? Could such toxin affect carotid sinus or carotid body function and/or local neurological (ie. ganglion or neuromuscular) function irrespective of systemic toxin levels? Local neurological dysfunction has been suggested for oesophageal dysfunction in TP but effects of such local toxin on cardiac rhythm or blood pressure setting by a direct effect on peripheral receptors in the neck (an area routinely involved in TP cases) have not been investigated. It could be that dogs that present with inspiratory dyspnoea could have some upper airway obstruction due to paralysis associated with local attachment.

Ticks and People

People report headaches and attachment areas that can be hyper or hypo-aesthetic and develop Type I hypersensitivity associated with tick detachment. Whether these conditions exist commonly or at all in the dog is not known, except perhaps for the local neurological dysfunction described above.

R Atwell1 and M Fitzgerald2 Companion Animal Medicine and Surgery The University of Queensland QLD 4072 2Alstonville Veterinary Hospital Alstonville NSW 2477

Tick Paralysis in Australia (Malik R and Farrow B. Veterinary Clinics of North America: Small Animal Practice- Vol. 21, No. 1. January 1991.)

Tick paralysis in Australia is a far more devastating disease than its counterpart in North America. Paralysis results from the engorgement of members of the Ixodes genus, whose normal hosts include bandicoots, brush-tailed possums, macropods, and koalas.^30,41,42,45 These native fauna appear to be relatively resistant to the toxins produced by paralysis ticks, and often carry heavy burdens of ticks without showing evidence of ill effect. Ixodes holocyclus is the most common species associated with tick paralysis, although Ixodes cornuatus and Ixodes hirsti are responsible for some paralysis cases.^30,41 The continuance of the life cycle of these ticks requires the presence of warmth and humidity, which restricts the distribution of the parasite to the bush and scrub country along a narrow strip of the east coast of Australia.^30,41Ticks are most numerous in spring and summer, and most clinical cases are seen during this period. Ixodes holocyclus has been reported to produce paralysis in a variety of species, including dogs, cats, sheep, calves, foals, pigs, chickens, and humans (principally infants)^{17,20,30,40-42} The disease usually occurs after infestation with adult female ticks, although heavy infestations with nymphs or larvae are capable of causing paralysis.⁴³

It is believed that physical findings in tick paralysis result from the action of various neurotoxins produced in the salivary glands of engorging ticks. ^42,45,47 Several toxic fractions have been isolated from the salivary glands of Ixodes holocclus, including a protein neurotoxin (holocyclotoxin) that causes paralysis and another toxin that is lethal but nonparalyzing.⁴⁷ Acetylcholine release at the motor end plate is reduced in tick paralysis, probably as a result of diminished calcium entry into motor nerve terminals, or interference with presynaptic excitation-secretion coupling.^8,9 The effects on neuromuscular transmission have been shown to be temperature dependent in vitro and are more pronounced at higher temperatures.^8,9 This corresponds with clinical and experimental observations that high ambient temperatures adversely affect the clinical course of the disease.^8,24 Axonal conduction is unaffected in paralysis caused by Ixodes holocyclus.⁸

Dysfunction in regions of the brain that influence the autonomic nervous system produces important physiologic derangements in many dogs with advanced tick paralysis. Overactivity of sympathetic vasomotor efferents causes intense peripheral vasoconstriction and arterial hypertension.²⁸ The resulting shift in blood volume from the systemic to the pulmonary vascular circuit gives rise to increased pulmonary capillary hydrostatic pressure, pulmonary congestion, and edema. ^1,23,28 This neurogenic pulmonary edema causes ventilation/perfusion mismatch and shunting, thereby contributing to the respiratory distress observed in affected animals. Sympathetic overactivity also may give rise to tachyarrhythmias (sinus tachycardia, ventricular tachycardia), or vagally mediated bradyarrhythmias as a result of activation of the baroreceptor reflex.²⁸ Increased sympathetic drive also is responsible for the pupillary dilation that is observed in advanced cases of tick paralysis. Central autonomic dysfunction presumably reflects the action of the salivary neurotoxins on central neurotransmission.

The severe respiratory impairment that is observed probably reflects intoxication of the respiratory centers in the medulla as well as paralysis of the diaphragm and intercostal muscles. The respiratory rate falls progressively as the disease develops.²⁶ The tidal volume, however, remains unchanged .²⁶ In advanced stages of tick paralysis, these changes cause a substantial reduction in the minute respiratory volume. The ensuing ventilatory failure is associated with hypoxia, hypercarbia, and respiratory acidosis.^25,26 These changes are compounded by the increased alveolar/arterial oxygen tension difference associated with pulmonary congestion and edema.²⁶

Clinical Findings

Clinical signs usually are observed 5 to 7 days after attachment of the tick.^8,29,42 However, the period preceding the onset of symptoms appears to depend on the rate of engorgement of the parasites rather than on a fixed time period. This period may be prolonged up to 2 weeks in cool weather.^30,42 Even with massive infestations, signs do not appear before the fourth day.⁴⁴ In some dogs, clinical signs may not be seen until all ticks have engorged and dropped off replete.³⁰

Although an alteration in the quality of the dog's bark can often be appreciated early in the course of the disease, the first consistent sign is a slight wobbliness of the hindquarters that rapidly worsens so that in a few hours the dog is unable to stand.^29,42 The motor paralysis rapidly ascends to involve the forelimbs so that the animal lies in lateral recumbency. Body temperature usually is normal at first, but animals can become hypothermic as the disease progresses.²⁹ The pupils are widely dilated and eventually fail to respond to light. Regurgitation or vomiting often occurs, sometimes as the first sign of tick intoxication, and may persist throughout the course of the disease.^29,42 Respiration becomes slow and labored, with a prolonged expiratory phase. A grunting respiratory noise is often present.^26,29,42 (This results from closure of the vocal cords during expiration.²⁶) Dyspnea becomes increasingly apparent and is accompanied by cyanosis and coarse crackles on auscultation as animals approach death.^27,29 Untreated dogs usually die within 24 to 48 hours of the onset of obvious clinical signs.^29,42

Detailed neurologic testing demonstrates reduced muscle tone and diminished to absent myotatic reflexes early in the course of the disease.⁸ Although withdrawal reflexes are initially normal, they become progressively slower and weaker as the condition progresses.^8,29,42 Although proprioception and cutaneous sensation generally are thought to be preserved, diminished perception of noxious tactile stimuli occasionally has been noted in recent experimental studies.²⁹ The gag reflex is consistently depressed, and the inability to swallow results in drooling of saliva.²⁹

A rapid onset of signs tends to be associated with more severe disease and a higher likelihood of fatality.⁴² Similar clinical signs are seen in cats with tick paralysis; affected animals typically are distressed and agitated. Initially, there is often a change in voice, especially noticeable in Burmese and Siamese cats, which may be accompanied by retching or coughing. Pupillary dilation is prominent. Vomiting is rare in comparison to the dog.⁴¹

Some dogs with tick intoxication do not present with a straightforward ascending flaccid motor paralysis. Instead, they may present because of intractable vomition and loss of voice in the absence of significant appendicular weakness.^1,23 It is unclear whether true vomiting or regurgitation occurs in these cases. However, there is good evidence of laryngeal paresis, pharyngeal dysfunction, and megaesophagus in at least some of the reports.^1,31 Vomiting may result from a central action of tick toxin on the chemoreceptor region of the medulla, whereas regurgitation probably is referable to megaesophagus. Localized manifestations of tick paralysis, such as asymmetrical facial paralysis and anisocoria, have been reported in dogs and children.^2,17,20,40 The different manifestations of tick paralysis observed probably result from variations in the susceptibility of the host and the number and virulence of the ticks.

Diagnosis

The diagnosis often is unequivocal in classic cases of rapidly ascending flaccid motor paralysis associated with engorging female Ixodid ticks. The hoarse, husky type of bark referable to laryngeal paresis is suggestive of the disorder. The neurologic findings in most cases are characteristic and easily recognized by veterinarians who practice in areas where Ixodes holocyclus is endemic. These findings are especially likely to be recognized during the height of the tick season. Difficulties in diagnosis may be encountered early or late in the season, and in animals that present for regurgitation, vomiting and loss of voice in the absence of obvious appendicular weakness.^1,23,31 Therefore, in certain regions tick paralysis should be considered in the differential diagnosis of megaesophagus or unexplained vomiting.³¹

A definitive diagnosis of tick paralysis requires the demonstration of suitably engorged Ixodid ticks. This may pose problems in dogs with long coats or when the ticks have dropped off replete. Clipping the entire coat often is required to locate engorged ticks or the craters where they were recently attached.³⁰ The diagnosis is confirmed by recovery from paralysis after removal of the tick, administration of antitick serum, and symptomatic therapy. However, it must be remembered that the animal's condition may continue to deteriorate for 24 to 48 hours after tick removal, and some animals may die despite appropriate therapy.^23,24,42

Differential Diagnosis.

In Australia, tick paralysis must be differentiated from the same types of diffuse lower motor neuron diseases encountered in North America. The slow, labored respiratory pattern that is a prominent feature of many advanced cases is helpful in the differential diagnosis, because respiration tends to be rapid and shallow in other disorders that cause neuromuscular paralysis.²⁶ This contrasts with tick paralysis in which the respiratory rate is reduced (because of prolonged expiration) without any alteration in the tidal volume.²⁶ The presence of an expiratory grunting noise also suggests a diagnosis of tick paralysis.^30,41

Acute peripheral neurophathies and polyradiculoneuritis occur in Australia (even though racoons do not). However, along the coastal fringe of eastern Australia, these disorders are uncommon in comparison with tick paralysis. In inland areas, a history of a visit to the coast several days before the onset of paralysis should alert the clinician to the possibility of tick paralysis.

Envenomation by tiger and brown snakes also can result in a rapidly ascending flaccid paralysis associated with salivation, vomiting, and pupillary dilation.^3,21,22 However, systemic signs attributable to coagulopathy, intravascular hemolysis, or myonecrosis often are present in dogs that have been bitten by snakes, and the respiratory rate usually is increased. Affected animals may have hemoglobinuria (pink urine) or myoglobinuria (brown urine); the clotting time is invariably prolonged in dogs, and serum creatine kinase activity is elevated. ^3,21,22 In cats, the neuromuscular signs predominate. Definitive diagnosis in cats usually requires the use of a venom identification kit or a favourable response to the administration of antivenene, because bite wounds are not always found.^3,21,22

A diligent search for evidence of tick engorgement and response to therapy usually is all that is required to make a definitive diagnosis of tick paralysis. However, electrodiagnostic testing may be helpful in a minority of patients on which a tick can not be found and respiratory distress associated with pulmonary edema is not evident.

Electrodiagnosis

Neurophysiologic studies reveal no change in the size or latency of the CNAP, but there is a significant reduction in the amplitude of the CMAP, suggesting transmission failure at the motor end plate.^8,38 The reduction in CMAP amplitude is greater in the hindlimbs than in the forelimbs, which agrees with the physical findings.⁸ Conduction velocity and the CMAP response after repetitive nerve stimulation are normal in tick paralysis, whereas denervation potentials are not detected during electromyography.^8,38

Immunity

Animals acquire Immoral immunity after exposure to the toxin of Ixodes holocyclus,^45-47,50 and natural hosts of the tick, such as the bandicoot, probably survive heavy infestations as a result of acquired immunity rather than intrinsic species resistance. This acquired immunity is apparently short lived, because bandicoots carrying heavy Ixodes burdens when captured may succumb to a single adult female tick after being free of ticks in captivity for several months.⁴¹ The high incidence of tick paralysis observed in dogs and cats in late winter and early spring may be related to loss of the immunity that was acquired during the previous season.^30,41

Dogs can develop immunity to tick paralysis if a number of Ixodes ticks are allowed to engorge for short periods of time.^45,47 After 2 to 3 months of gradually increasing exposure, dogs can tolerate enormous numbers of ticks to full engorgement. The serum harvested from dogs prepared in this manner is commercially available for the treatment of tick paralysis.

Cutaneous immunity influences the occurrence of tick paralysis in cattle, in which the disease is restricted to young calves that have not yet developed sufficient resistance to tick attachment.

Treatment

There are three steps in the treatment of tick paralysis caused by Ixodes holocyclus: removal of the ticks, neutralization of circulating toxins, and initiation of symptomatic and supportive therapy.

After the diagnosis of tick paralysis is suspected, a thorough search of the animal's coat is indicated. Ticks can be found on any part of the animal, although they are most commonly attached to the head or neck in dogs. ^24,30 In cats, ticks usually are found in areas that are inaccessible to grooming, such as under the chin, on the neck, or between the shoulder blades.⁴¹ Although one tick may be found, the search should be thorough and complete, because even with treatment, the presence of other ticks prevents recovery. In longhaired dogs, clipping the coat often facilitates the detection of additional ticks, and this probably is preferable to the application of acaricidal solutions.

Ticks are best removed by sliding a pair of partially open scissors between the tick and the animal's skin. The tick can then be levered off with its mouthparts intact, thereby preventing further release of toxin into the patient. The tick should be scrutinized to ascertain if it is one of the species capable of producing paralysis. (Ixodes holocyclus is easily identified by the characteristic circle around its anus.)³⁰.

If the animal has not yet shown signs of tick paralysis, removal of the tick may prevent development of the disease. However, if the animal is showing any signs of intoxication, removal of the tick is not sufficient, because the disease is likely to progress for up to 48 hours in the absence of specific therapy. ^{2,20,24,40,42}

Therefore, in these animals, hyperimmune serum must be injected intravenously to neutralize circulating tick toxins. The placement of an indwelling cephalic catheter facilitates the slow intravenous injection of antitick serum and the subsequent administration of adjunctive drugs and maintenance fluid requirements. The efficacy of hyperimmune serum varies from manufacturer to manufacturer and from batch to batch, so it is difficult to give firm dosage recommendations. As a rule of thumb, 0.5 in L/kg body weight should be administered to dogs.²⁴ Generally, higher doses (1.0 mL/kg) are given to severely affected animals, and in these animals many veterinarians give as much antitick serum as the owners can afford. At least 0.5 mL of hyperimmune serum should be injected subcutaneously at and around the site of tick attachment.

Because hyperimmune serum is derived from dogs, there is some risk associated with its intravenous administration in other species, although anaphylaxis is said to be rare in cats receiving antitick serum for the first time.⁴¹ The authors administer intravenous hydrocortisone (30 mg/kg) routinely prior to the slow intravenous injection of antitick serum (5-l0mL) to seriously affected cats, and have epinephrine (1.0 mL of a 1:10,000 solution) available for injection in case of anaphylaxis. Other veterinarians give hyperimmune sera to cats by the intraperitoneal route or intravenously after premedication with acepromazine or an antihistamine. Canine hyper-immune serum probably should be initially withheld from mildly affected cats, pending their response to tick removal in hospital.

In mildly affected animals with a straightforward ascending paralysis, removal of ticks and administration of hyperimmune serum usually results in obvious clinical improvement within 24 to 48 hours, although there is often little change in the first 12 hours. ²⁷ Failure to respond to hyperimmune serum after an appropriate interval may suggest the presence of undetected ticks.

Animals with more advanced paralysis benefit from the administration of drugs that reduce peripheral vascular resistance, thereby relieving the respiratory distress associated with pulmonary congestion and edema.^24,27

The a-adrenoreceptor antagonist phenoxybenzamine (1 mg/kg diluted into at least 20 mL of 0.9% NaCl and repeated every 12-24 hours if necessary) and the phenothiazine tranquilizer acepromazine (0.05-0.10 mg/kg every 6-12 hours) given slowly intravenously have been used most frequently in this setting, and one of these vasodilators should be administered to animals with clinical signs referable to pulmonary congestion and edema. Both of these agents produce useful sedation as well as easing the respiratory distress. Afterload reducers, such as hydralazine and sodium nitroprusside, have not been evaluated clinically or experimentally in animals with tick paralysis. Furosemide also may be used to aid in removing fluid from the lungs. Animals with pulmonary edema may benefit from the administration of supplementary oxygen. In small patients, this is easily provided by piping 100% oxygen into a cat induction chamber through a disposable plastic nebulizer. However, care must be taken to avoid hyperthermia.

Some dogs develop ventilatory failure as a result of paralysis of the diaphragm and intercostal muscles (with or without, concomitant pulmonary edema), and these animals require intermittent positive pressure ventilation (IPPV) to survive. ^24,27 These animals are easy to intubate and maintain on IPPV because they have little jaw tone and do not tend to "fight" the ventilator. Using standard methods,³⁹ the authors have successfully ventilated a severely affected dog for 60 hours, by which time an acceptable minute respiratory volume could be generated.

Assiduous nursing care is vitally important in animals with tick paralysis.^24,27 Because stress of any type adversely affects the course of the disease, animals should be nursed with minimal interference in the quietest part of the hospital. Animals should be maintained in a cool, air conditioned environment, because the neuromuscular blockade has been shown to be exacerbated by high temperatures.^8,9 To minimize ventilation/perfusion mismatch, animals should be positioned in sternal recumbence on a well-padded surface by using towels and sandbags. The pharynx should be swabbed clean after episodes of vomiting or regurgitation to minimize the risk of aspiration.

Although it has been shown experimentally that dogs with tick paralysis do not become significantly dehydrated during the course of the disease, it is probably wise to provide submaintenance fluid requirements after the first day (0.45% NaCl containing 16 mmol KCl/L; 20-40 mL/kg/day), especially in animals in which recovery is prolonged. Fluids must be given slowly, preferably using an infusion pump, because of the propensity of affected animals to develop pulmonary congestion and edema.

Prophylactic antibiotics are inappropriate in tick paralysis, and atropine has been shown to be contraindicated.²⁷ Because cardiac arrhythmias directly or indirectly result from sympathetic overactivity, they tend to resolve after the administration of phenoxybenzamine or acepromazine and require no specific treatment.^27,28 Although high doses of glucocorticosteroids (0.5 mg/kg dexamethasone every 12 hours) have been shown to be of some value in advanced cases of tick paralysis ²⁷ their routine use is unwarranted because of the constant possibility of aspiration pneumonia. The role and effectiveness of antiemetics have not been adequately defined.

Animals should receive nothing by mouth while they are paralyzed, because pharyngeal dysfunction, megaesophagus, laryngeal paresis, and a weak cough all predispose the patient to the development of aspiration pneumonia. Food and water should be withheld until the patient is mobile and has not vomited for 24 hours. Water then can be given in small amounts, and food can be offered subsequently if there is no vomiting. After recovery, a period of convalescence should be imposed; exercise should be restricted, and high temperatures should be avoided. ^24,27 Violent exercise within a day of complete recovery from tick paralysis has resulted in collapse and sudden death, and extremes of heat may cause recovered animals to relapse into paralysis.^1,23

Prevention

Daily examination remains the least expensive and most effective form of prophylaxis, as the disease will not develop until ticks have been attached for at least 4 days. Weekly bathing with the organophosphorus compound coumaphos has been shown to prevent attachment of Ixodes holocyclus for 1 week. Collars impregnated with propoxur discourage tick attachment for 4 weeks.²⁴ The regular oral administration of cythioate (3 mg/kg every 3 days) [3mg/kg bodyweight every other day (48 hours)] can be used to prevent tick paralysis, because parasites receive a lethal dose of anticholinesterase when they begin to engorge. This product may be the treatment of choice in longhaired animals, especially those animals that belong to old, infirm, or inattentive clients. In the future, it may be possible to vaccinate dogs and cats using toxoids derived from the different toxins of Ixodes holocclus.⁵⁰

Malik R and Farrow B. Veterinary Clinics of North America: Small Animal Practice- Vol. 21, No. 1. January 1991.

References

1. Allan GS, Pursell RT: Pulmonary involvement and other sequelae of tick poisoning. Australian Veterinary practitioner 1:39, 1971
2. Ban field JF: Tick bites in man. Med J Aust 2:600, 1966
3. Barr SC: Clinical features and epidemiology of tiger snake bite in dogs and cats. Aust Vet J 61:208, 1984
4. Barsanti JA, Walser M, Hatheway CL, et al: Type C botulism in American foxhounds. J Am Vet Med Assoc 1972:809, 1978
5. Cherington M, Snyder RD: Tick paralysis: Neurophysiological studies. N Engl J Med 278:95, 1968
6. Chrisman (:L: Differentiation of tick paralysis and acute idiopathic polyradiculoneuritis in the dog using electromyography. J Am Anim Hosp Assoc 11:455, 1975
7. Chrisman CL: peripheral nerve disorders. In Ettinger SJ: Textbook of Veterinary Internal Medicine, ed 3. Philadelphia, WB Saunders, 1989, p 727
8. Cooper BJ: Studies on the pathogenesis of tick paralysis [thesis]. Sydney, Australia, The University of Sydney, 1976
9. Cooper BJ, Spence I: Temperature-dependent inhibition of evoked acetylcholine release in tick paralysis. Nature 263:693, 1976
10. Cork LC, Griffin JW, Munnel JF, et al: Hereditary canine spinal muscular atrophy. J Neuropathol Exp Neurol 38:209, 1979
11. Cummings JF, Haas DC: Coonhound paralysis: An acute idiopathic polyradiculoneuritis in dogs resembling the Landry-Guillain-Barre syndrome. J Neurol Sci 4:51, 1967
12. de Lahunta A: Veterinary Neuroanatomy and Clinical Neurology. Philadelphia, WB Saunders, 1983, p 68
13. Dow SW, LeCouteur RA, Fettman MJ, et al: Potassium depletion in cats: Hypokalemic polymyopathy. J Am Vet Med Assoc 191:1563, 1987
14. Emmons I? McLennan H: Failure of acetylcholine release in tick paralysis. Nature 183:474, 1959
15. Emmons I? McLennan H: Some observations on tick paralysis in marmots. Exp Biol 37:355, 1960
16. Farrow BRH, Murrel WG, Revington ML, et al: Type C botulism in young dogs. Aust Vet J 60:374, 1983
17. Foster B: A tick in the auditory meatus. Med J Aust 2:15, 1931
18. Gothe R, Kunze K, Hoogstraal H: The mechanisms of pathogenicity in the tick parlyses. J Med Entomol 16:537, 1979
19. Griffiths IR, Duncan I: Distal denervating disease: A degenerative neuropathy of the distal motor axon in dogs. Journal of Small Animal Practice 20:579, 1979
20. Hamilton DG: Tick paralysis: A dangerous disease in children. Med J Aust 1:759, 1940
21. Hill FWG: Snake bite in dogs. Aust Vet J 55:82, 1979
22. Hill FWG, Campbell T: Snake bite in cats. Aust Vet J 54:437, 1978
23. Hindmarsh WL, Rummell RT: Tick paralysis of dogs: Mortality after serum treatment. Aust Vet J 11:229, 1935
24. Ilkiw JE: Tick paralysis in Australia. In Kirk RW: Current Veterinary Therapy 9: Small Animal Practice. Philadelphia, WB Saunders, 1983, p 691
25. Ilkiw JE, Turner DM: Infestation in the dog by the paralysis tick Ixodes holocyclus: 2. Blood-gas and pH, haematological and biochemical findings. Aust Vet 164:139, 1987
26. Ilkiw JE, Turner DM: Infestation in the dog by the paralysis tick Ixodes holocyclus: 3. Respiratory effects. Aust Vet J 64:142, 1987
27. Ilkiw JE, Turner DM: Infestation in the dog by the paralysis tick Ixodes holocyclus: 5. Treatment Aust Vet J 65:236, 1988
28. Ilkiw JE, Turner DM, Goodman AH: Infestation in the dog by the paralysis tick Ixodes holocyclus-. 4. Cardiovascular effects. Aust Vet J 65:232, 1988
29. Ilkiw JE, Turner DM, Howlett CR: Infestation in the dog by the paralysis tick Ixodes holocyclus-. 1. Clinical and histological findings. Aust Vet J 64:137, 1987
30. Kelly JD: Canine Parasitology. Sydney, Australia, Postgraduate Foundation in Veterinary Science, 1977, p 58
31. Malik R, King J, Allan GS: Megaoesophagus associated with tick paralysis in three dogs. Australian Veterinary Practitioner 18:156, 1988
32. Morris HM: Tick paralysis: Electrophysiologic measurements. South Med J 70:121,1977
33. Murnaghan ME: Neuro-anatomical site in tick paralysis. Nature 181:131, 1958
34. Murnaghan MF: Site and mechanism of tick paralysis. Science 131:418, 1959
35. Nafe LA: Selected neurotoxins. Vet Clin North Am Small Anim Pract 18:593, 1988
36. Northington JW, Brown MJ, Farnbach GC, et al: Acute idiopathic polyneuropathy in the dog. J Am Vet Med Assoc 179:375, 1981
37. Oliver JE, Lorenz MD: Handbook of Veterinary Neurologic diagnosis. Philadelphia, WB Saunders, 1983, p 207
38. Ouvrier RA: Neurophysiological studies in tick paralysis. Aust Paediatr J 10:239, 1974
39. Pascoe PJ: Short term ventilatory support. In Kirk RW: Current Veterinary Therapy 9: Small Animal Practice. Philadelphia, WB Saunders, 1986, p 269
40. Pearn J: The clinical features of tick bite. Med J Aust 2:313, 1977
41. Prescott CW: Parasitic diseases of the cat in Australia. Sydney, Postgraduate Foundation in Veterinary Science, 1972, p 27
42. Ross IC: An experimental study of tick paralysis in Australia. Parasitology 18:410, 1926
43. Ross IC: Tick paralysis in the dog caused by nymphs of Ixodes holocyclus. Aust Vet J 8:102, 1932
44. Ross IC: Tick paralysis in the dog. Period elapsing between attachment of tick and onset of symptoms. Aust Vet J 10:182, 1934
45. Ross IC: Tick paralysis: A fatal disease of dogs and other animals in eastern Australia. Journal of the Council of Scientific and Industrial Research 8:8, 1935
46. Stone BF, Binnington KC: The paralysing toxin and other immunogens of the tick Ixodes holocyclus and the role of the salivary gland in their biosynthesis. In Sauer JR, Hair JA (eds): Morphology, physiology and behavioral biology of ticks. New York, Ellis Horwood, 1986, p 75
47. Stone BF, Neish AL, Wright IG: Tick (Ixodes holocyclus) paralysis in the dog: Quantitative studies on immunity following artificial infestation with the tick. Aust Vet J 60:65, 1983
48. Swift TR, Ignacio OJ: Tick paralysis: Electrophysiologic studies. Neurology 25:1130, 1975
49. Van Nes JJ, Van Der Most Van Spijk D: Electrophysiological evidence of peripheral nerve dysfunction in six dogs with botulism type C. Research in Veterinary Science 40:372, 1986
50. Wright IG, Stone BF, Neish AL: Tick (Ixodes holocyclus) paralysis in the dog: Induction of immunity by injection of toxin. Aust Vet J 60:69, 1983

 

Assessing the safety of long term cythioate therapy

Safety of Cythioate administered to dogs for 52 consecutive weeks

Fifteen males and female dogs of mixed breed with a weight range of 628 kg were used, Cythioate was administered twice a week or at three or four day intervals. Fifteen dogs received treatment for 26 weeks and five dogs for 52 weeks.

Cythioate as liquid or tablets was administered at 1 x or 3 x the standard dose rate.

Pre treatment blood samples for analysis of serum chemistry and haematologic values were taken. Post treatment analysis was conducted at five week intervals.

Evaluating the results

Appetites appeared to be normal among all dogs in the study. Treatments had no adverse effect on body weight.

No clinically significant signs were observed to indicate organophosphate toxicosis. Some minor, transient signs of diarrhoea and vomiting occurred sporadically in all groups. However, these problems are not unusual in animals confined for 52 weeks within a kennel environment.

Oestrus was observed in animals from all treatment groups. Two animals were in early pregnancy at the time the study was initiated. Both bitches whelped and nursed their puppies in a normal manner.

Slight changes were observed in the chemistry/haematologic parameters, which were measured every four weeks. No trends indicated damage had been done to essential organs or haematologic dysfunction; no dose-related effects occurred.

Depression of plasma cholinesterase values was dose-related.

The findings of this study, evaluating overdoses for up to 52 consecutive weeks, indicate an adequate safety margin for longterm use of cythioate formulations in dogs. Parameters supporting this conclusion are based upon observations for clinical signs, monitoring of clinical chemistry/haematologic parameters, monitoring of erythrocyte/plasma/whole-brain cholinesterase values, and histologic evaluations.

James A. Shmidl, DVM, MS
Mary L. Kohlenberg, BS
Gerald L. Johnson, DVM
Samuel M. Kruckenberg, DVM, PhD.
Veterinary Medicine-September 1984

Cythioate at 5 x or 10 x normal dose rate in dogs an evaluation

Summary

A mild transient effect on erythrocyte cholinesterase values (89% of normal) followed a single use rate treatment of dogs with tablet or liquid formulations of cythioate. Plasma levels were moderately (60% of normal) affected with regeneration to normal occurring within 72 hours.

Dogs showed no critical signs of toxicosis. Signs occurring in some dogs primarily during the first six hours after excessive treatments included salivation, coughing, vomiting, diarrhoea, trembling, and sedation. All dogs appeared essentially normal at 24 hours post treatment. Erythrocyte cholinesterase values were depressed to 24% of normal after the 10 times over dose, with plasma cholinesterase values at 188% of normal. Regeneration of enzyme values followed an anticipated pattern. Serum chemistry profiles and haematology failed to demonstrate adverse reactions to the formulations.

James A. Shmidl, DVM, MS Mary L. Kohlenberg, BS Gerald L. Johnson, DVM Evaluation of cholinesterase values in dogs treated with cythioate formulations Veterinary Medicine and Small Animal Clinician - October 1983 Vol 78, No. 10

 

Web Author's Note: in neither trial was cythioate tested by adminstration on every 2nd day, as is usually done in prevention of tick paralysis in Australia.

Safety of owner administration of Proban to dogs and cats

Proban liquid or tablets was administered by owners to: 900 dogs weighing from 0.5 kg to 40 kg and ranging in age from 2 months to 15 years, cythioate mixed in the food at a dosage of 1 mL/4.5 kg every third day.

750 cats and kittens ranging in age from 4 weeks to 15 years were treated regularly with 1.6% cythioate liquid in food at a dosage of 0.5 mL/4.5 kg.

When given as directed, cythioate was found to be a non-toxic, highly effective compound for treating and controlling external parasites on dogs and cats.

We discovered that most incidence of toxicity resulted from accidental overdosing by owners.

Adverse reactions were reported in only 0.5% of the animals. When clients inadvertently overdosed their pets or used another organophosphate compound in conjunction with cythioate, typical signs of cholinesterase inhibition were observed. These were quickly reversed with atropine. No other toxic signs were reported.

Bowen PM, DVM; Caldwell N J, DVM; Use of Cythioate to Control External Parasites on Cats and Dogs

My clients object to household contamination and exposure to external insecticides

Flea allergy dermatitis is one of the most prevalent dermatologic problems that practitioners are asked to treat. Treating the patient with corticosteroids is palliative and may be acceptable in geographic regions where flea infestation is seasonal, but in those climates where fleas are present year round, resolving the problem depends upon a flea control programme. A successful programme involves treatment of the animal and its environment.' If fleas are to be controlled, a fenced yard is essential to confine the pet to a manageable area. This is not always possible; and even when it is, neighbours' pets and feral animals will often repopulate the area with fleas. Even the daily walk of an apartment dwelling pet may provide an opportunity for reinfestation. Although not always practical, clients that keep their pets indoors are advised to reduce carpeted areas in the home.

Clients whose pets suffer from flea allergy dermatitis need to be informed that their home, pet, and the outside environment must be treated repeatedly, often at considerable expense. If clients follow this advice without satisfactory results, it becomes a frustrating and difficult experience for the practitioner, client, and pet.

Many clients and veterinarians object to repeated use of insecticide fogs and sprays within homes. This is especially true when infants, elderly people, and persons with respiratory problems and allergies are living in the homes.

As these problems become more prevalent, flea control for many clients becomes a dilemma. My clients objected to an increasing frequency of exposure to pesticides, ongoing exterminating and grooming expense, and excessive use of corticosteroids in their pets. In extreme cases, some pet owners considered euthanatizing their pets. This forced me to consider alternative flea control program to programmes

Finding a means of residual flea control without further contaminating the environment seemed the most logical course to follow. Oral cythioate (Proban) had always been a consideration. Clients constantly requested the product, but I had refused to dispense it, considering the oral administration of organophosphate pesticides unacceptable. Conversely, because some clients considered euthanatising their pets, cythioate was a valid alternative. Another fact that influenced my decision was that pesticide use within the home would be decreased or eliminated (providing the external environment was adequately treated).

I found that cythioate was helpful in flea control, and consequently, in treatment for flea allergy dermatitis.

It should be made clear that cythioate is an ancillary aid in a total flea control programme. Client education, effective communication, and the client's willingness to participate in a flea control programme are essential for successful management of the flea problem.

*Bledsoe, B. et al: Current Therapy and New Developments in Indoor Flea Control. JAAHA 18(3):415-422; 1982 Designing a long term flea control programme Paul Fenster, VMD South Dade Animal Hospital 6380 South Dixie I lighway Miami, Florida 33143

Reducing pet owner exposure to insecticides

The use of cythioate reduces human exposure to insecticides, as compared to collars, sprays, and powders. Treatment with cythioate also eliminates the dangers of flea collars to pets (eg sensitive reaction, strangulation).

When given as directed, cythioate was found to be a nontoxic, highly effective compound for treating and controlling external parasites on dogs and cats.

Bowen PM, DVM Caldwell N J, DVM Use of Cythioate to Control External parasites on Cats and Dogs Veterinary Medicine / Small Animal Clinician Jan 1982 pp 79-80

Flea, tick (Rhipicephalus sanguineous) demodex and ear mites (otodectes cynotis) control

Cythioate provided excellent control of fleas, ticks, and ear mites in 300 cats and 900 dogs. The 300 cats we treated ranged in age from 2 months to 15 years and weighed from 0.5 kg to 7 kg. They were treated with cythioate liquid mixed in food at a dosage of 0.5mL/4.5kg every third day or twice a week. Acceptance by both cars and kittens was excellent. Within seven davs after the start of treatment, the animals were free of fleas. Reinfestation did not occur during treatment.

Ear mite infections were treated topically with half the recommended dose of cythioate in each ear. Nearlv 100% of the cats were free of living mites after the second treatment. We do not recommend that owners try this treatment because cats tend to shake the medication out of their ears.

In 900 dogs weighing from 0.5 kg to 40 kg and ranging in age from 2 months to 15 years, cythioate mixed in the food at a dosage of 1 mL/4.5 kg every third day provided excellent control of fleas. The medicated food was well accepted by both adult dogs and puppies. Response was noted in all dogs within seven days after the start of therapy.

Some of these dogs were also infected with ticks of the species Rhipicephalus sanguineous.

Cythioate also aided in treatment and control of demodectic mange. In these trials, 40 infected dogs were given oral cythioate at a dosage of 1.5 mg/0.5 kg every third day. Good to excellent response was achieved in 28 of the dogs (Table 1).

A few of the animals that did not respond well at this dosage were then given 3 mg/0.5 kg every three days. Improvement was noted in about half of these cases.

Table 1: Evaluation of Cythioate* for the Treatment of Demodex Canis in Dogs
Age of dogs (Years)	No. of Dogs	Average Duration of Infection Before Treatment	Average Duration of Treatment	Degree of Control Excellent	Good	Fair	Poor
0-1	24	4 weeks	6 weeks	12	6	2	4
1-6	10	3-4 weeks	2 months	4	4	1	1
6-15	6	6 months-2 years	2-4 months	0	2	1	3
*Oral dosage - 1.5mg/0.5kg every 3rd day.

We formed a joint practice in Ohio and established a parasitic programme using Proban on an out patient basis during the parasite season. Client participation was excellent. 750 cats and kittens ranging in age from 4 weeks to 15 years were treated regularly with 1.6'% cythioate liquid in food at a dosage of 0.5 mL/4.5 kg, nearly 100% flea control was achieved. No cases of ear mite infection occurred. Small cats were given 1 drop of cythioate/0.5 kg twice weekly.

Animals already infected with ear mites were treated in the clinic with 3 to 5 drops of cythioate in each ear. No living mites were observed after the second treatment.

Cythioate controlled flea infestations in 1,200 dogs of various breeds, with the exception of greyhounds, for which cythioate is not recommended. The dogs ranged in age from 4 weeks to 15 years. They were treated orally during the flea season with either 30 mg cvthioate tablets or oral liquid at the recommended dosage. The compound was particularly effective in longhaired dogs where cellars, sprays, and powders had not been producing satisfactory control.

If a dog is severely infested with fleas, the normal dosage of Proban can be given every second day until the problem is controlled. For continued flea control, the drug is given every third day.

Conclusions

Owners must administer cythioate treatments faithfully and should he reminded to continue treatments as long as fleas and ticks arc in the pets environment. To avoid accidental overdosing, clients must he thoroughly instructed in the dosage and administration of the compound.

Cythioate is highly palatable when mixed in food and is well accepted by pets of all ages and weights. It can easily be administered on an outpatient basis. When given as directed, cythioate was found to be a nontoxic, highly effective compound for treating and controlling external parasites on dogs and cats.

Bowen PM, DVM
Caldwell NJ, DVM
Use of Cythioate to Control External Parasites on Cats and Dogs
Veterinary Medicine/Small Animal Clinician Jan 1982 pp 79-80

Evaluating Cythioate for control of fleas on dogs

The purpose of the clinical trial reported here was to evaluate cythioate l.6% oral liquid and 30 mg tablets (Proban®) when used to kill fleas on dogs. The safety and efficacy of cythioate for flea control in clogs already has been established.

Materials and methods

Investigators (veterinarians and entomologists) from six geographic regions with abundant natural flea populations participated in the clinical trials, which were conducted from May to September 1987. The dogs used in these trials were all client owned, and included various breeds and sizes. Also, the housing conditions and number of pets per household varied.

Before a dog was included in the study, its general health was evaluated and fleas were counted using a standardized hand counting procedure. The animal's hair was parted against the grain across the entire body, paying special attention to the neck, shoulders, axillary and pelvic regions, legs, abdomen, and base of the tail. The examiner made every effort to move efficiently across the dog's body so that fleas were counted only once.

Each dog was then placed in one of four flea infestation categories: 1-5 fleas = very light; 6-15 = light; 1 <-50 = medium, and > 50 = heavy. The dogs in each infestation level were then divided into two treatment groups according to a preassigned randomization schedule: Group 1 would receive 1.6% cythioate oral liquid; Group 2 would receive 30 mg cythioate tablets.

Each dog was weighed before treatment to determine the appropriate dosage of medication. Cythioate treatments were administered in accordance with the produce labels: 1 mL/4.5 kg for the 1.6% oral liquid and one 30 mg tablet/9 kg, rounded to the nearest half tablet. (The target dose for cythioate is 3.3 mg/kg). Because the dogs were owned by clients, an untreated control group was not used.

Table 2: Outline of the Study Schedule
Day	Activitiy
0	Pretreatment flea counts for all dogs; assign dogs to treatment groups; and administer first treatment to all dogs
1	First post-treatment flea counts for both cythioate groups
3 or 4	Treatment No. 2 for both cythioate groups
7	Treatment No. 3 for both cythioate groups
10 or 11	Treatment No. 4 for both cythioate groups
14	Treatment No. 5 for both cythioate groups
15	Second post-treatment flea count for both cythioate groups
17 or 18	Treatment No. 6 for both cythioate groups
21	Treatment No. 7 for both cythioate groups
24 or 25	Treatment No. 8 for both cythioate groups
28	Treatment No. 9 for both cythioate groups
29	Third post-treatment flea count for both cythioate groups

 

Table 3: Summary of Pretreatment Flea Counts by Infestation Level*
	No. of fleas (%) in Each Flea Infestation Level
Investigator Location	Very Light (1-5 fleas)	Light (6-15 fleas)	Medium (16-50 fleas)	Heavy (> 50 fleas)
Florida	20 (50)	8 (20)	9 (22.5)	3 (7.5)
Arkansas	4 (5.6)	10 (14.1)	15 (21.1)	42 (59.2)
Kansas	13 (35.1)	9 (24.3)	11 (29.8)	4 (10.8)
Texas	20 (16.1)	25 (20.2)	34 (27.4)	45 (36.3)
Georgia	10 (17.2)	14 (24.2)	24 (41.4)	10 (17.2)
California	0	23 (20)	78 (67.8)	14 (12.2)
Total	67 (15.1)	89 (20)	171 (38.4)	118 (26.5)
*Data based on 445 correctly completed case reports.

Cythioate treatments were administered orally (tablets by mouth, liquid added to food) every third day or twice weekly for a four week period.

An outline of the study schedule is shown in Table 2. In most cases, the investigator administered the first treatment and dispensed medication to the owner for subsequent treatments.

The owner was asked to closely observe the dog after each treatment for any side effects such as excessive salivation, vomiting, or diarrhoea.

Three different environmental flea control products were also used in the study, depending on how the dog was housed. A yard and kennel insecticide (Duratrol® Yard and Kennel Spray- 3M) was provided for dogs housed outside, a household premise insecticide (Para-PremiseTM - Haver) and room fogger (Siphotrol® Plus Fogger - VetKem) were provided for dogs housed inside, and all three products were provided for dogs housed both inside and outside. The owners were instructed to follow label directions when applying these products and to record the dates of application. The dogs were not bathed during the study and no other flea control products were used.

After the treatments were begun, each dog was returned to the investigator at three designated intervals for post treatment flea counts. To minimize bias, the person counting fleas was unaware of the treatment each dog had received. For cythioate treated dogs, fleas were counted one day after the first, fifth, and ninth treatments.

Total flea counts were compared among treatment groups using an analysis of variance model that included location, treatment, and location by treatment interaction effect ( a measure of how consistent treatment efficacy is among different locations). Fisher's sign test was used to compare pre and post treatment flea counts within each location and treatment group. Statistical comparisons were deemed significant if the p value was less than 0.05.

At the end of the study, the investigators gave written evaluations of the overall safety and efficacy of the treatment for each dog, based on their clinical judgment and considering the degree of flea reduction and any side effects attributable to treatment.

Results

The pretreatment flea counts by infestation level at each location are summarized in Table 3. There was a statistically significant (p > 0.01) difference in pretreatment flea counts among the trial locations (location effect). The lowest pretreatment flea infestation levels were encountered at the Florida location (50% of the dogs had very light flea infestation levels) whereas the highest infestation levels were encountered at the Arkansas location (59.2% of the dogs had heavy flea infestation). Overall, the largest portion of dogs (38.4%) in the study harboured medium flea infestations whereas heavy, light and yew light infestations accounted cases, respectively.

A total of 304 dogs (Table 4) were treated: 152 with cythioate oral liquid, 152 with cythioate tablets, two dogs in each of the groups were not treated according to the prescribed schedule. Therefore, data from these cases were not included in the calculation of flea control efficacy.

During the study, 1,368 cythioate oral liquid treatments and 1,368 tablet treatments were administered (nine treatments for each of 152 dogs in each treatment group). Three observations of vomiting were reported for the cythioate treated dogs: one given the liquid vomited on the day after first treatment, and one dog given tablets vomited twice, once the day of the first treatment and once on the day of the second treatment.

The investigator regarded these observations as slightly significant. Therefore, in this study, the occurrences of vomiting following individual treatments with cythioate oral liquid and cythioate tablets were 0.073% and 0.146%, respectively.

Table 4: Number of Dogs Included in Clinical Field Studies to Evaluate the Safety and Efficacy of Cythioate
	No. of Dogs Treated
Investigator Location	Cythioate Liquid	Cythioate Tablets	Total
Florida	15	14	29
Arkansas	23	24	47
Kansas	14	13	27
Texas	41	42	83
Georgia	19	20	39
California	40	39	79
Total	152	152	304

 

Table 5: Median Flea Counts by Treatment Group and a Statistical Comparison by Location and Treatment
	Cythioate Liquid				Cythioate Tablet
Investigator Location	Pre- Treatment	Post- Treatment 1	2	3	Pre- Treatment	Post- Treatment 1	2	3
Florida	6	2a	1a	1a	11.5	1.5a	0.5a	1.5a
Arkansas	82	18a	15a	14a	68.5	13a	8.5a	12a
Kansas	10.5	4.5a	1a	0a	7	3a	2a	2.5a
Texas	38	10a	4a	2ab	25	9.5a	8a	5a
Georgia	21	19	12a	8a	16	20a	14.5	9a
California	32.5	15a	0a	0a	25	13a	0a	0a
a This post-treatment count is significantly less than the pretreatment count (Fisher's sign test, p,0.05). b This is significantly less than cythioate tablet group (ANOVA, p<0.05).

 

One or more of the three environmental flea control products were used in conjunction with the dog's treatment. The dog owners recorded the dates of application of each product, but it was not possible to quantify the amount of each product used.

The statistics comparing pretreatment and post treatment flea counts appear in Table 5. At four of the six locations, all median post treatment flea counts were significantly lower than pre treatment median counts for the three treatment groups. In Georgia, the median of the first and third flea counts after treatment with cythioate liquid, the first and second counts after treatment with cythioate tablets did not decrease significantly from the pre treatment median flea counts.

Statistical comparisons among treatment groups are also summarized in Table 5. Although the location effect remained statistically significant (p > 0.01) throughout the study, there was no overall significant difference among treatment groups. At the Texas location, the third post treatment flea count for the cythioate liquid group was significantly less (p > 0.05) than that for the cythioate tablet group.

Figure 1 illustrates the reductions in overall median flea counts. For dogs treated with the cythioate liquid, the median count dropped from a pre treatment level of 23 fleas per dog to 11.5, three, and two fleas per dog at the three post treatment flea counts. (This corresponds to a 56%, 87% and 94% median reduction, respectively.) For dogs receiving the cythioate tablets, the overall median pre treatment count of 21 fleas per dog was reduced to ! 1, four, and three fleas per dog at the three post treatment flea counts. (This corresponds to a 41%, 80% and 88% median reduction, respectively.)

Discussion

The evaluation of flea control products is frequently confined to the laboratory or simulated field conditions involving a limited number of dogs, a controlled environment, and laboratory reared fleas. Such studies provide basic information on product's ability to kill or repel fleas, but information about the product's performance under actual use conditions is necessarily limited. This study was designed to incorporate a large population of privately owned dogs that lived under a wide range of housing conditions and were exposed to various natural flea populations. This type of study required pet owners to comply with instructions to treat the dog according to the prescribed schedule.

Environmental flea control products are essential in any complete flea control programme. The investigators tried to ensure that the owners were using the environmental products in a uniform manner, but also in a manner consistent with each dog's housing. How much these products contributed to the reduction of fleas on the dogs could not be directly evaluated in this study.

Cythioate liquid and tablets contributed to the sequential reduction in fleas when used according to labelled dosages in a four week flea control programme. Most of the dogs entered the study during late spring and early summer when their owners first recognized the flea problem and subsequently presented the dogs for treatment. The results indicate that the treatment programmes helped reduce flea burdens on the dogs even though seasonal conditions were conducive to increasing flea populations.

The flea control provided by the cythioate liquid and tablet treatments was similar to the control described in other reports.

Only a few minor side effects were observed in this study, which reflects the safety margins reported for the products when used at the recommended dosage.

Arthur RG, Cox DD, McCurdy HD, Schmidl JA:Vet. Med.5.89

 

 

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