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This article was published in 1949
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INSTITUTE OF INSPECTORS OF STOCK OF N.S.W. YEAR BOOK.
Recent Advances in the Treatment of Internal Parasites
HUGH McL. GORDON, B.V.Sc., McMaster Animal Laboratory, Council for Scientific and Industrial Research.
INTRODUCTION.
Some of the general principles of the use of anthelmintics will be discussed, with particular reference to nematode parasites of sheep, and brief comments will be made on some of the "newer" anthelmintics themselves.
DEPENDENCE ON ANTHELMINTICS.
In the absence of precise, detailed and practical recommendations for control of the free-living stages of helminth parasites it was inevitable that anthelmintic medication should have become the basis for control of helminthiases. Knowledge of the bionomics of the free-living stages has increased tremendously in the last twenty years, and we do know what should be done to ensure pasture hygiene. However, animal and pasture management is inevitably a matter of compromise, and often in deciding on what is best for the pasture and best for the animal, it is not possible to achieve what is worst for the parasite. An efficient anthelmintic permits a compromise but should not obscure the needs for better animal husbandry in controlling parasitic diseases.
Further, the newer knowledge of the bionomics of the free-living stages stresses the importance of the host rather than the pasture as the reservoir of infestation. An efficient anthelmintic is one of the basic attacks on the contamination phase of the life-cycle. See Fig. 1 in Australian Veterinary Journal, Vol. 24, No, 2 (Feb. 1948).
NEED FOR A DIFFERENT POINT OF VIEW — PREVENTIVE RATHER THAN CURATIVE USE OF ANTHELMINTICS.
Control of helminth diseases of livestock is usually a matter of maintaining the worm burden at low levels. The conception of what constitutes a "low level" has changed since the economic effects of so-called sub-clinical infestations have been recognised. Eradication of helminth parasites is still a distant goal. Acceptance and adjustment to parasitism while biologically and academically attractive, are economically dangerous.
Maintenance of worm burdens at low levels calls for preventive use of anthelmintics based on knowledge of epidemiology. Preventative or strategic or tactical use of anthelmintics cannot wait upon diagnosis, but must be applied firstly according to the general ecological pattern of helminth diseases, which acknowledges that the majority of the herd or flock is infested, and that the parasites are contaminating the environment continuously; and secondly according to the special regional seasonal patterns of behaviour of helminths established by epidemiological studies.
GENERAL CONSIDERATIONS.
I. Multiple Infestations Require Multi-efficient Anthelmintics.
(a) The Composition of Parasitic Gastro-enteritis.
Parasitic Gastro-Enteritis is a rather general term for a very variable disease, the manifestations, epidemiology and control of which will vary according to the composition of the worm burden. A sheep harbouring 3,000 Haemonchus contortus and 3,000 Trichostrongylus spp. will present a clinical picture very different from that presented by a sheep harbouring 200 H. contortus and 30,000 Trichostiongylus spp., and while it to usual to find mixed infestations in flocks in the field, it is usual to find that one or two species or genera predominate and are largely responsible for the symptoms observed. It is important, therefore, to diagnose the disease, not simply as parasitic gastro-enteritis, but to determine which species predominate and include their names in the diagnosis. Unless this is done there often appears to be no rationale in the occurrence, symptoms or response to anthilmintics of outbreaks of parasitic diseases. Haemonchosis, trichoatrongylosis and oesophagostomiasis (0e. columbianum) are as distinct disease entities as entero-toxaemia, braxy and lamb dysentery.
In the application of anthelmintics in control two points should be emphasised:—(1) In general a multiple or mixed infestation will be present and the anthelmintic should be multi-effective, destroying at many species as possible; (2) There will be occasion, when treatment will be directed against one species,e.g., tactical treatments against H contortus in the warmer months of summer rainfall regions. For this use an anthelmintic such as carbon tetrachloride or the copper sulphate-arsenic mixtures may be employed rather than the much more expensive phenothiazine.
The wide range of efficiency of phenothiazine has simplified the selection of anthelmintics, but its expense is still a limiting factor. The economic aspects of parasite control always should be considered.
(b) Testing Drugs Against Individual Species.
Testing the precise efficiency of anthelmintics against mixed infestations is difficult and generally unsatisfactory. The various species have very different habits and habitat which may influence their reactions to drugs. The various species produce eggs at varying rates, so that assessment of anthelmintic efficiency is impossible by means of egg counts unless differential egg or larval counts are made. In trials in which changes in count, of "strongyle" or "strongyloid" eggs are recorded, results may be difficult to interpret, and even misleading.
While it is essential to test anthelmintics against individual species in order to assess their efficiency precisely, field tests also ara required, and in these the economics of the operation should be considered as one of the criteria of efficiency.
(c) The Resistance of Immature Worms.
In general, immature H. contortus and Trichostrongylus spp. are more resistant to the actions of anthelmintics than the mature worms. If the dose of phenothiazine is increased a high degree of efficiency may he obtained against immature worms. In one trial young sheep were dosed with 40,000 Trichostrongylus spp. larvae each. One group was treated with the usually prescribed dose of phenothiazine (15 gr.) when the worms were 12 days old and showed a mean egg count of 1550 eggs per gramme 30 days after the infecting dose of larvae. A second group treated with a 40 gr. dose showed a mean count of 150 eggs per gramme at the 30th day. Controls showed a mean count of 3,200 eggs per gramme.
The differential efficiency against immature and mature worms is of considerable importance in trials carried out to assess the efficiency of anthelmintics and in the application of anthelmintics in control of helminthiases. In the tactical use of anthelmintics in the field following the occurrence of condtions which favour the acquisition of infestations, treatment should be timed to avoid immature worms. For example, where an infestation is acquired as a result of wet weather, the anthelmintic should be administered about three weeks later, by which time the worms will have just reached maturity.
(d) Outbreaks.
The object of control measures should be not only to prevent outbreaks, but to restrict the worm population to lower than "sub-clinical" levels. Nevertheless, from time to time there are tremendous increases in the parasite population leading to outbreaks of disease. The trial of anthelmintics during an outbreak provides a salutary lesson regarding the general efficiency of their curative use. Results of one trial have been published. (Year Book of the Institute for 1944).
The reasons fur the general failure of anthelmintics during outbreaks include the following:—(i) Low degree of efficiency against immature worms; (ii) Lack of a "preventive" degree (i.e., a very high degree) of efficiency; (iii) Complete failure of anthelmintics which depend initially on the oesophageal groove reflex (copper sulphate and its mixtures with sodium arsenite) in a proportion of sheep; (iv) Rapid reinfestation from larvae on unspelled pastures.
Some comments may be made on (ii) at this stage, supported by semi-hypothetical figures. If a sheep harbours 10,000 worms, an anthelmintic which removes 80 per cent. of them leaves a residue of 2,000 which may be a sufficient "burden" to retard recovery, and which will disseminate ample eggs to cause re-infestation. If the worms are H. contortus and assuming that half of them are females, the post-treatment egg output is in the vicinity of 5 to 10 million eggs per day! From the purely curative aspect it is clear that the heavier the infestation the greater the degree of efficiency required to leave a harmless residual worm burden. This may he illustrated by an example. If a sheep "A" harbours 10,000. and sheep "B" harbours 60,000 Trichostrongylus spp., an anthelmintic which 80 per cent. efficient will leave residual worm burdens of 2000 and 12,000 worms respectively. Sheep "A" will recover from the disease, sheep "B" may not. An efficiency of 96.6 per cent. is required to reduce the worm burden in sheep "B" to 2,000. In a series of experiments no evidence was found that efficiency increased with increasing worm burdens.
2. Epidemiological Use of Anthelmintics Requires High Efficiency.
(a) Effects on Population Dynamics.
There are seasonal trends in population changes which provide indications for the timing of strategic and tactical preventive use of anthelmintics to forestall anticipated increases in numbers. Data is to be sought on comparative rates of increase in worm populations beginning with different initial levels in the flocks in the hope that a harmless low level, from which the chances of the population increasing to danger levels are remote, may he defined. It is clear already, however, that severe infestations may develop quite rapidly from relatively low initial infestations.
In a field trial the level of H. contortus infestation late in the winter (13th August) in a flock of 40 young sheep was expressed by a mean count of 375 eggs per gramme of faeces (range from 35 epg to 1900 epg). The rapid increase in spring is shown in Table 1.
TABLE 1.
Increasing Population a H. contortus in a Flock of 40 Sheep.
| Date | Mean No. Eggs per Gramme of Faeces | Mean Total Egg Output per Sheep per day* |
|---|---|---|
| 13th August | 373 | 300,000 |
| 10th September | 3292 | 2,633,600 |
| 24th September | 5323 | 4,258,400 |
| 19th October | 6125 | 4,900,000 |
| 26th October | 17,186 | 13,748,800 |
*Assuming a mean faecal output of 800 grammes.
It is seen that beginning with a low level of infestation in late winter, a heavy infestation was established within 74 days, by which time deaths from haemonchosis were occurring. Weather conditions during this period were not continuously favourable, otherwise there is little doubt that the worm burden would have increased even more rapidly.
The point to he noted is that worm burdens may have to be reduced to extremely low levels before an epidemiologically "safe" level is established.
The affects of small repeated doses of phenothiazine as given in feed or salt lick are worthy of attention. In Australia there has been little success with administration of phenothiazine to sheep in salt. The daily intake has been low and very erratic from time to time, and sheep to sheep, and one could not depend upon this method to prevent outbreaks. There were also disadvantages from the economic aspect. However, this method of attack on parasitic disease, so eagerly awaited alike by the stockowner and the veterinarian, has shown considerable promise elsewhere and cannot be dismissed lightly.
(b) Effect on Sub-clinical Infestations.
The economic significance of sub-clinical parasitism has been recognised fully only since phenothiazine enabled the reduction of worm burdens to less than sub-clinical levels.
Control of the condition presents difficulties, and it appears that phenothiazine is the only drug at present capable of reducing the sub-clinical infestation to harmless levels. Variations in the incidence of sub-clinical helminthiasis are likely to be great in time and place because it is more likely to occur in "marginal" regions, that is, regions in which parasitic infestations are not of regular occurrence, and in which stockownen are not accustomed to recognition and control of parasitic diseases. If anthelmintics are to be used effectively and economically in these regions a much better knowledge of epidemiology is essential.
3. The Erratic Effects of Anthelmintics.
(a) The Oesophageal Groove Reflex.
Studies on the efficiency of anthelmintics for sheep soon brought the realization that ruminants presented many differences from other animals which had simple stomachs. It was shown that fasting did not influence anthelmintic efficiency and the vagaries of the oeosphagral groove reflex were resolved partially. One uses the term "partially" advisedly because the response of the reflex to copper sulphate is indeed erratic.
The significance of the oesophageal groove reflex lies in the fact that many anthelmintics are efficient only if swallowed into the abomasum. Copper sulphate, soluble arsenical compounds, nicotine sulphate, tetrachlorethylene and chlorinated benzenes (para- and ortho-dichlorobenzene) among the more commonly used drugs fall into this category. On the other hand, carbon tetrachloride and phenothiazine are efficient whether swallowed into the rumen or the abomasum. Quite recently it has been found that two "insoluble" compounds, hexachlorethane and lead arsenate, are also highly efficient against H. contortus when administered into the rumen. It has been found that if large doses of copper sulphate (3 g.) or sodium arsenite (0.5 g.), or arsenic pentoxide (0.5 g.), are injected into the rumen, efficiency against H. contortus is marked. However, if these drugs are swallowed into the abomasum in such doses, toxic effects, usually fatal, occur. On the other hand, doses of carbon tetrachloride, phenothiazine, lead arsenate and hexachlorethane which are efficient when injected into the rumen, are nontoxic to the host when injected or swallowed into the abomasum. Thus it appears that the ideal anthelmintic for ruminants must be efficient and nontoxic whether swallowed into rumen or abomasum, and that these anatomical, physiological and toxicological hazards must be kept well in mind when studying anthelmintics for sheep.
When the effect of copper sulphate on the oesophageal groove reflex was discovered there was, naturally enough, a stress on the positive side of the finding, for it did offer great opportunities for testing anthelmintics and applying them in the treatment of parasitic diseases. When field trials were carried out, it was quickly evident that, from the epidemiological point of view, the negative aspect should have been stressed. It was the sheep in which the reflex failed that either succumbed to parasitism or continued to disseminate eggs.
(b) Habits and Habitats of the Parasites.
Variations in efficiency of anthelmintics from species to species in the same host and against closely related species in different hosts, present an interesting field of study.
It was found recently that phenothiazine was not as effective against Chabertia ovina as against Oesophagostomum columbianum. It is thought that the reason may be related to the different feeding habits of the two species. C. ovina usually is attached to the mucous membrane by means of its large mouth capsule, and in consequence may ingest phenothiazine in the bowel contents only when it detaches, from time to time, to move to a new site. Oe. columbianum does not attach to the mucous membrane and is more likely to be exposed continuously to the drug.
Trichuris vulpis, the whipworm of the dog, is found chiefly in the caecum and most anthelmintics, including the latest recommendation, diphenylamine, have rather erratic effects, due probably to the location of the worms. Unless the drug penetrates into the caecum in adequate concentration the worms are not likely to be destroyed.
Parasites in the small intestine of sheep are generally not so readily killed as those in the abomasum or large intestine.
The relatively faster passage of ingesta through the duodenum was thought to be one of the reasons for the lower degree of efficiency of phenothiazine against Trichostrongylus spp., compared with its efficiency against Oe. columbianum in the large intestine. It seemed likely that in a sheep suffering from trichoatrongylosis, in which diarrhoea was present the rate of passage of ingesta might be so great that anthelmintic efficiency was further reduced. However, when an experiment was earned out there was no difference in efficiency between sheep passing normal pellet-type faeces and those passing very soft to diarrhoeic types of faeces.
(c) Age of Worm.
The relative resistance of immature worms to anthelmintics has been mentioned. It may well account for much of the variation recorded in field trials. Phenothiazine is quite effective against immature H. contortus but is not very effective against immature Trichostrongylus spp. unless the dose is increased considerably.
In outbreaks the necessity for repeated treatments is due largely to the resistance of immature worms, and in part to reinfestation if the outbreak is of sufficiently long duration,
(d) Measurement and Assessment at Efficiency.
Criteria of efficiency vary according to improvements in anthelmintics and changed concepts of their requirements in an over-all control plan. Consideration of the properties of anthelmintics used epidemiologically in a preventive capacity indicated the necessity for very high degrees of efficiency in order to reduce the residual worm burden and the post-treatment egg output to harmless levels.
In field trials improvement in general health and productivity is an important criterion of the efficiency of an anthelmintic.
The effects of phenothiazine on egg laying and on the development of eggs and larvae in faeces introduce new factors to be assessed in the general consideration of anthelmintic efficiency.
THE DRUGS AND THEIR USES.
1. Sheep.
Phenothiazine.
The wide range and high degree of efficiency and low toxicity combine to make this drug a very valuable weapon for the attack on nematode parasites of sheep. Its efficiency even when swallowed into the rumen, and the possession of a very high degree of efficiency, give phenothiazine a "preventive value" beyond that of other anthelmintics.
It is highly efficient against H. contortus and Oe. columbianum and far surpasses other anthelmintics in efficiency against Trichostrongylus spp. Some work still is required in order to establish the effective dose rate for use against the latter parasite. It is clear that the dose should be greater than that which is effective against H. contortus and Oe. columbianum. Larger doses are required if high efficiency against immature Trichostrongylus spp. is to be achieved.
Further studies are needed to determine its efficiency against C. ovina, Nematodirus spp. and Ostertagia spp.
In outbreaks of haemonchosis and trichostrongylosis phenothiazine is the only drug which has a marked effect in reducing worm burdens and egg production to harmless levels.
Phenothiazine has disadvantages in the large volume of the dose, difficulties in administration, staining of the fleece and cost; but these, with the exception of cost, gradually are being overcome.
Excepting ewes in the last month of pregnancy the toxic effects of phenothiazine for sheep are of no practical significance.
Carbon Tetrachloride.
This anthelmintic shares with phenothiazine the advantage of exerting its effects even when swallowed into the rumen. Its chief use is against F. hepatica and it should he recalled that the usually prescribed doses (1-2 ml.) are not very effective against immature flukes wandering in the liver tissue. Larger doses, up to 4-5 ml. have been used with success in terminating mortality in outbreaks of acute fluke disease. Doses of this magnitude do not appear to increase the toxic hazards of this drug.
Carbon tetrachloride is very effective against adult Paramphistomum spp. in the rumen and reticulum of sheep. The bulk of the dose used, 5 ml. of a 2:3 mixture of carbon tetrachloride and liquid paraffin, ensures that it will be swallowed into the rumen of most sheep.
Carbon tetrachloride at a dose rate higher than that used against F. hepatica (2 ml. instead of 1 ml.) is highly effective against adult H. contortus, but less effective against the immature worms.
The unpredictable toxic hazards of the drug are its greatest disadvantage.
Tetrachlorethylene.
Thus drug has fairly wide anthelmintic effects, but is efficient only when swallowed into the abomasum. With this reservation it is effective against H. contortus and ovine hookworms, and is more efficient than the copper sulphate-nicotine sulphate mixture against Trichostrongylus spp. There are toxic hazards which may be serious unless care is taken with the handling of sheep after treatment.
Copper Sulphate.
The essential value of this drug lies in its effect on the oesophageal groove reflex, an effect shared only with other soluble copper salts. It has a fairly high degree of efficiency against H. contortus in young sheep, and also in adult sheep if the dose rate is specially increased. It is not very effective against immature worms and fails badly in outbreaks. It has very little effect on other species. The drug is cheap and its toxic effects are generally slight.
Copper Sulphate-Nicotine Sulphate.
This mixture, provided it is swallowed into the abornamm, is very effective against H. contortus, being more effective against the immature worms and in adult sheep than copper sulphate alone, and has a fair degree of efficiency against Trichostrongylus spp. The precise degree of efficiency against the mature worms has been studied under a variety of conditions and will be discussed fully in a forthcoming paper on anthelmintics. In a series of 42 sheep in which nicotine sulphate or copper sulphate-nicotine sulphate mixture was injected into the abomasum, efficiency varied from 20 per cent to 95 per cent. with a mean of 56 per cent. The combination of the two drugs was not more effective than nicotine sulphate alone under these conditions.
There are toxic hazards, but they are not very serious.
Copper-Sulphate—Soluble Arsenicals.
Sodium arsenite and arsenic pentoxide are equally effective against H. contortus if swallowed into the abomasum. Their combination with copper sulphate has been used as a drench for many years and as very effective against adult H. contortus in both young and adult sheep, and is more effective than copper sulphate alone against the immature worms.
Arsenicals are fairly effective against Moniezia spp. but have little effect on other helminths. Enemas of sodium arsenite are highly effective against Oe. columbianum.
Lead Arsenate.
Studies in U.S.A. by a number of workers have shown that this drug is highly effective against Moniezia spp., and it appeared to be non-toxic for the sheep in anthelmintic doses. Lead arsenate was tested against nematode parasites of sheep at the McMaster Laboratory, where doses of 0.5 to 2.0 grammes infected into the rumen showed very promising results against H. contortus. The toxicity of similar doses injected into the abomasum has yet to be tested fully.
Hexachlorethane.
This "old and new" drug has become prominent for use against F. hepatica in cattle and sheep largely through the work of Olsen in Texas, who found anthelmintic effects against H. contortus. and Trichostrongylosis axei but not against Ostertagia ostertagi and Bunostomum phlebotomum in cattle.
This drug has been given some attention and its high degree of efficiency against F. hepatica by rumenal injection confirmed. It also proved very effective against adult Paramphistomum spp. in sheep when injected into the rumen. Whether it is effective if it by-passes the rumen and is swallowed into the abomasum remains to be determined. A determination of its efficiency against immature Paramphistomum spp. in the duodenum of cattle is a pressing need because this stage of the parasite ts probably of much greater pathogenic significance than the adults.
Injection of hexachlorethane into the rumen of sheep has proved highly efficient against H. contortus.
3. Cattle.
Hexachlorethane now is being used widely in other countries. It is effective against liver fluke and adult paramphistomes and is apparently "safer" than carbon tetrachloride.
Lead arsenate has been used against Moniezia spp. in calves in doses of 0.1 to 1.0 gramme followed by castor oil.
3. Horses
Some doubts have been raised in England about the efficiency of phenothiazine against the large strongyles (Strongylus spp.). It is highly efficient against the small strongyle, (Triodontophorus spp. and Trichonema spp.).
Observations by workers with the Veterinary Research Trust in England have indicated the best times for use of anthelmintics for horses. Treatment against Ascaris equorum should be carried out when foals are 3½ to 4 months old. Against strongyles treatment should begin at 5 to 6 months, and the bulk of the infestation with there parasites may not be vulnerable to treatment until the animal is about 12 months old.
4. Pigs.
Sodium fluoride has proved a highly effective treatment against Ascaris lumbricoides, and if used with reasonable care it is "safe". It can be given in dry feed and it has useful effects against Stomach Worms (Ascarops and Physocephalus) and Nodule Worm (Oesophagostomum spp.)
5. Poultry.
It is now clear that while phenothiazine is very effective against the Caecal Worm (Heterakus gallina) its effects are rather erratic against the Large Roundworm (Ascaridia galli).
In U.S.A. a mixture of phenothiazine and nicotine bentonite (nicotine sulphate absorbed into bentonite clay) is a useful dual purpose anthelmintic for use against both of the common roundworms of poultry.
The tapeworms of poultry have long defied successful anthelmintic attack, but work in U.S.A has indicated a number of drugs of considerable promise. They are as follows:—
(1) A mixture of stannous tartrate and pellitierine tartrate (the alkaloid of pomegranate bark).
(2) Hexachlorophene (dihydroxy hexachlorodiphenyl methane). This drug may be mixed with nicotine bentonite and phenothiazine to form a triple purpose anthelmintic for fowls.
(3) Phenyl mercuric compounds, particularly the phthalate, borate or benzoate. These can be mixed with phenothiazine to produce a dual purpose anthelmintic.
None of these preparations has been tested in Australia.
6. Dogs.
For treatment against Ascarids and hookworms, carbon tetrachloride, tetrachlorethylene and Oil of Chenopodium are still in common use. N-butyl chloride is a very effective and safe drug for the same purpose and is possibly more effective against the Whipworm.
"Butylphen" (p-tertiary butyl phenol) is a crystalline drug which is effective against arcarids and hookworms.
Diphenylamine, the parent drug of phenothiazine (thio-diphenylamine) has some value against Whipworm. It is probably best to give the drug on three or four successive days in order to increase the chances of its entering the caecum. It should be in a very finely ground form for anthelmintic use.
A newer ascaricide is "Caracide" (1-diethyl carbamyl 4-methyl piperazine).
For treatment against tapeworms, Arecoline and its derivatives are still the must useful drugs. "Acetarsol" has given good results. "Nemural" is also useful. A new drug, perthiocyanic acid, has been stated to have useful taenicidal effects.
There are some promising new compounds for use against the Heartworm (Dirofilaria immitis), derived from wartime studies on anthelmintics for treatment of human filariasis.