NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
iv
PREFACE.
on the treatment of Surra in equines have been continued and
the results previously obtained, viz., that the administration of
Arsenic by a certain system results in a complete cure in
75% of cases, have been repeatedly confirmed. Part II deals
with the study of Rinderpest. On account of the increasing
demand for Rinderpest anti-Serum and of the increasing difficulty
in obtaining Hill bulls for the manufacture of the prophylactic,
the discovery of some method of preparing the serum from
animals other than Hill bulls became a question of the most
urgent necessity. A large number of experiments have been
carried out, and it is satisfactory to record that methods of pre-
paring a potent serum from Plains bulls and buffaloes have been
evolved. The methods have been adopted in the routine serum-
making at Muktesar, with the result that the output of Rinderpest
anti-Serum has risen from under six lacs of doses in 1909-1910 to
over ten lacs of doses in the succeeding year, and, moreover,
by the publication of these improved methods the output of this
prophylactic has been nearly doubled, while the increase in
expenditure involved is so small as to be almost negligible.
Part III deals with further experiments on Hæmorrhagic
Septicæmia, and Part IV contains a record of the work done
on Anthrax.
J. D. E. HOLMES,
Imperial Bacteriologist.
THE TREATMENT OF SURRA IN HORSES BY MEANS
OF ARSENIC AND ITS DERIVATIVES.
THIRTY-TWO CASES OF SUCCESSFUL TREATMENT.*
BY
MAJOR J. D. E. HOLMES, M.R.C.V.S., M.A., D.SC., I.C.V.D.,
Imperial Bacteriologist to the Government of India.
THE value of arsenic in the treatment of trypanosomiasis
is no new discovery.
Evans, who described the first pathogenic trypanosome,
recommended the administration of arsenic. Lingard for
many years investigated Surra in India and treated twenty-
one horses suffering from that disease with arsenious acid.
One horse survived. His system of treatment was, the ad-
ministration of arsenic in the form of Fowler's solution com-
mencing with 5 grains twice daily and gradually increasing to
10 grains. Treatment extended over several months; the
total amount of arsenic given, in some instances, amounted
to over 2,000 grains. During the period of treatment inter-
missions of 30 to 50 days were recorded, but all the animals,
with one exception, finally succumbed to the disease. Bruce,
treating Nagana in Zululand, gave 6 to 12 grains of arsenic
in the form of arsenite of soda to horses and asses suffering
from that disease. Trypanosomes remained absent during
the period of treatment, but reappeared immediately treat-
ment ceased. Trélut claims to have cured cases of Dourine
by the daily administration of 3 to 6 grammes of arsenious
acid. Archangeliky and Novikoff also record cases of Dourine
cured by them with arsenite of sodium and cacodylic acid.
* Reprint from the Journal of Tropical Vety, Science, Vol. V, No. 1, published
during 1910.
Also the Journal of Parasitology, Vol. III, No. 1, published during 1910.
1
2
SURRA.
Maukal stated that he cured five stallions suffering from Dou¬
line by subcutaneous injections of 1 gramme of cacodylate of
soda. Loeffler and Rueh record a number of successful experi-
ments on animals affected with Nagana which they treated
with a solution of arsenious acid. They consider this solution
to be a specific cure and a prophylactic for Nagana. Laveran
and Thiroux repeated these experiments and came to conclu-
sions different from those of Loeffler and Rueh.
At the present day the consensus of opinion regarding the
value of the arsenic treatment in trypanosomiasis is in favour
of the view that, though the drug exercises a marked influence
on the course of most affections due to trypanosomes, it cannot
be considered either a curative or a prophylactic agent.
In 1905, Thomas brought to notice the value of atoxyl,
a derivative of arsenic, which contains 24 per cent. of that drug
and is said to be forty times less toxic than arsenious acid.
It was supposed to owe its trypanocidal properties to the large
amount of arsenic which could be administered without toxic
effect in the form of atoxyl. The appearance of atoxyl has
been followed by similar derivatives of arsenic, principally
soamin, orsudan, kharsin prepared at the Messrs. Burroughs
and Wellcome Laboratory, and arsacetin and arsenophenyl
glycin, prepared and advocated by Professor Ehrlich. These
arsanilates showed promise of the successful treatment of try-
panosomiasis and gave a fresh stimulus to workers on the che-
mo-therapy of trypanosomiasis.
Many remarkable results have been recorded with arsani-
lates used alone or in combination with arsenious acid, mer-
cury and other drugs. In spite of the successes which, from
time to time, have been recorded both in clinical practice and
in laboratory experiments, following the use of these organic
derivatives of arsenic in the treatment of trypanosomiasis,
it is extremely doubtful whether any of these preparations
can be regarded as a curative agent when used alone.
SURRA.
3
The most recent and what appears to be the most hopeful
system of the chemo-therapy of trypanosomiasis is based on
the combination of different trypanocides.
The combined method is said to have the advantage that
the therapeutic value of each drug can be united against the
parasites and a curative effect can be obtained by using doses
much below those which are poisonous.
Among the most striking results of the combined therapy,
Laveran and Thiroux cured guinea-pigs, which they had in-
oculated with Surra, by using atoxyl and the trisulphide of
arsenic. Thiroux and Teppaz treated horses, affected with
Souma and Gambia horse-disease, with atoxyl and orpiment
combined and with orpiment alone. Six months after the ces-
sation of treatment the horses had not relapsed. The same
authors failed to cure horses suffering from Surra by the atoxyl-
orpiment treatment.
Martin, Leboeuf and Ringerbuch conclude from their ex-
perience of the treatment of human trypanosomiasis that the
association of atoxyl and tartar emetic is the most effective
of any which they have tried.
Broden and Rodhain agree that the results of the com-
bined use of atoxyl and tartar emetic are much better than
those obtained with either drug alone.
Moore, Breinl and Nierenstein assert the superiority of
the association of atoxyl and a mercurial salt.
Loeffler and Rueh advise the use of atoxyl with their
arsenious acid solution.
Friedberger used atoxyl and thioglycollic acid with good
results. Mesnil, Nicolle and Aubert have tried atoxyl in asso-
ciation with a benzidine colour. Cures were obtained.
In the experiments which are dealt with in detail in another
part of this paper, we have tested the value of atoxyl, arsenious
acid, soamin, mercury and antimony salts alone, and in various
combinations as curative agents in the treatment of Surra in
horses.
4
SURRA.
In the majority of the cases recorded, treatment was not
commenced till the disease had become well established and
at the period of the second paroxysm. The animals used for
these experiments were worn out or lame pack ponies and a
few aged army cast horses. Many of the ponies obtained for
this purpose were in such poor condition that they succumbed
to the disease in two to three weeks after inoculation and be-
fore treatment was commenced. The cast horses were in good
condition and with them treatment has been most successful.
In all cases, where relapses occurred after treatment, the
trypanosomes appeared in the circulation within a period of
six weeks after the treatment had been discontinued. All
the cases which are recorded in this paper have been under
observation for periods varying from three to fourteen months
after cessation of treatment. None have shewn a relapse.
All have been, therefore, classed as "recoveries.''
The results of these experiments briefly summarised are
as follows:—
ATOXYL.
The administration of atoxyl by the mouth failed to clear
the circulation of the parasites. After a subcutaneous injec-
tion, trypanosomes disappeared from the blood in from six to
eight hours. An intravenous injection acts more slowly than
a subcutaneous one. Continuous treatment with atoxyl for
long periods failed to effect a cure. During the period of
treatment, trypanosomes remained absent from the circulation
but reappeared in every case shortly after treatment was dis-
continued.
Contrary to the experience of other workers, our experi-
ments have indicated that arsacetin is equal in toxicity to
atoxyl, and its administration has much the same effect on the
trypanosomes. In one case, Pony No. C. 30, where arsacetin
was given in a single dose, which produced toxic symptoms,
a cure has been effected.
SURRA.
5
SOAMIN.
From the results of our experiments, I conclude that soa-
min is about equal in value to atoxyl. It is equally toxic when
injected subcutaneously, but, administered by the mouth,
it appears to be much less toxic than atoxyl.
In one case, Pony No. C. 31, where soamin was given in a
single dose, which produced temporary paraplegia, the animal
completely recovered and has shown no return of trypanosomes
for eight and-a-half months.
MERCURY.
Mercury alone has little effect on the course of the disease.
In combination with atoxyl the results were not so good as
when Atoxyl alone was used.
ANTIMONY SALTS.
Tartar emetic in 1% solution, injected intravenously,
has a rapid but temporary effect on the trypanosomes in the
circulation. Administered by the mouth, it has no influence
on the course of the disease. Injected subcutaneously in very
dilute solutions it causes local irritation, frequently followed by
necrosis of the skin, at the seat of inoculation.
The sodium antimonyl tartrate and lithium antimonyl
tartrate gave no better results than the potassium salt, and
were equally irritant when injected subcutaneously in horses
and rats. The combination of tartar emetic and mercury
kept the circulation free from trypanosomes during the period
of treatment only. A similar result followed the employment
of tartar emetic and atoxyl, also of tartar emetic and arsenious
acid solution. One pony, No. C. 32, was cured by the treat-
ment with tartar emetic, atoxyl and arsenious acid. The cura-
tive effect was probably due to the arsenious acid.
ARSENIOUS ACID.
Ten cases, treated with arsenious acid alone, are record-
ed. In eight cases (C. 1 to C. 8) treatment has been success-
6
SURRA.
ful. Five of these received ten doses, one eight, one five and
one was cured by a single dose, of arsenious acid. Two re-
ceived four doses only and had a relapse. The arsenious acid
was given in full sub-toxic doses at an interval of one day
between each dose. The amount of arsenic was gradually
increased as the animals showed a tolerance to the drug.
In addition to these cases here mentioned, a few animals,
which were put under this treatment, showed an intolerance
to the arsenic and each dose was followed by toxic symptoms.
In these cases treatment was abandoned.
The administration of arsenious acid had no prophylac-
tic effect even when the Surra inoculation was made 24 hours
after the dose of arsenic.
ARSENIOUS ACID AND ATOXYL.
Two systems of combining these drugs were tried.
In the first, the atoxyl and arsenic were given alternately,
five doses of each, with an interval of one day between each
dose. In a former paper, some of these cases described here
were stated to have been treated with atoxyl and orpiment.
In this same paper I drew attention to the fact that the sample
of orpiment used was a commercial one, obtained from a dis-
pensing chemist. On analysis, this was found to contain 95 to
97% of free arsenious acid. Consequently, I have here includ-
ed these cases as being treated with arsenious acid and atoxyl.
In a number of experiments, some of which are not yet
finished, we have tried treatment on the lines advised by Laver¬
an and Thiroux with atoxyl and "orpiment precipite." but
the results up to the present have been negative. In the
second system of treatment, the arsemous acid and atoxyl were
given as follows. Arsenious acid solution (drench) (Loeffler
and Rueh), atoxyl (subcutaneously) and arsenious acid (bolus)
were administered on consecutive days. These three doses
were repeated once or twice after an interval of four days, and
finally after an interval of eight days. The object sought in
SURRA.
7
adopting this method of dosage was to bring the action of the
arsenious acid solution and the atoxyl at the same time into the
circulation, and also it was thought probable that, by adminis-
tering arsenic at one time in the form of drench and at another
time in the form of bolus, the gastric symptoms of arsenical
poisoning would be less likely to occur and the drug would be
better tolerated.
In a number of experiments, we found that arsenious acid
given in drench or bolus at a period of paroxysm freed the blood
from trypanosomes in about 24 hours.
Atoxyl, subcutaneously, cleared the circulation in six to
eight hours. Consequently, in these experiments, the atoxyl
was injected sixteen hours after the dose of arsenious
acid.
Out of sixteen cases treated on the first system, seven had
a relapse, nine were cured.
Sixteen ponies were treated on the second system, four
had a relapse, twelve were cured.
CONCLUSION AND REMARKS.
(1) Exception may be taken to the practice of regarding
as cured cases which have been under observation without
relapse for a period of three to six months only. The fact that,
among the animals treated, there has not been one case of re-
lapse occurring after a period of six weeks from the cessation
of treatment, and that the majority of cases quoted as cured
have been under observation for three to fourteen months,
establishes reasonable grounds for including all these animals
under the head of "recoveries.''
(2) Arsenious acid is, undoubtedly, a specific for Surra
in horses. It must be administered in full sub-toxic doses
and at intervals; and not in continuous daily dosage.
In the light of these results it is clear that, in the early
experiments conducted by Lingard, Bruce, and others, arsenic
was given in too small an amount, and in continuous treatment.
8
SURRA.
Animals cannot tolerate the requisite amount of arsenic
if the dose be too frequently repeated. There is also the ob-
jection that by continuous small doses, not only does the animal
body, but also the trypanosomes acquire a certain amount of
tolerance to arsenic.
(3) It is doubtful whether any advantage is gained by com-
bining atoxyl with arsenious acid in the treatment of Surra.
The results of treatment with arsenious acid alone, given in ten
doses at an interval of one day, were superior to those where
the arsenious acid was alternated with atoxyl. A single dose
of arsenious acid alone keeps the blood free from trypanosomes
for a period of 10 to 30 days and in some cases longer. When
the same dose of arsenious acid is followed, 24 hours after, by
an injection of a full amount of atoxyl, this period is not
increased.
(4) Much has been written on the therapeutic action of
atoxyl. It was at first supposed that atoxyl owed its trypano-
cidal properties to the fact that it contains a large proportion
of arsenic and that it was simply a means of administering a
large amount of that drug without producing toxic effect.
Levaditi and Yamanouski consider that the curative power
of atoxyl is due to its reduction and the formation of trypano-
toxyl. Ehrlich assumes that "the arsanilate as such exercises
no action at all in the organism, but that only the very small
portion which undergoes a reduction in the living organism is
the actual lethal agent."
Some authors still believe that arsenic is split off in the
body and that the action of atoxyl is due to this free arsenic.
Breinl and Nierenstein repeated the experiments of Levaditi
and Yamanouski, but only occasionally got positive results,
and in these cases free arsenic was demonstrated in the solu-
tion of atoxyl. They conclude that "the assumption that
a complicated reduction product of atoxyl is formed, is super-
fluous." According to their view, the atoxyl action may be
regarded as the result of a simple oxidation, by means of which
SURRA.
9
arsenic is set free from the benzene ring. The finding of free
arsenic in the urine, they say, also supports this view.
Tendron, Wedemann, Nierenstein and others found arsenic
in the urine after the administration of atoxyl.
Uhlenhuth and Woithe are of opinion that the action of
atoxyl is clearly not direct, but they repeated Levaditi and
Yamanouski's trypanotoxyl experiments with negative results.
They do not agree with Ehrlich on his reduction theory. They
think that the atoxyl stimulates the cells to a heightened pro-
duction of substances which injure the parasites and that there
is no direct action of reduced atoxyl.
All our observations on the action of atoxyl are in support
of the view that a small amount of cleavage occurs and that
the therapeutic effect is entirely due to the presence of free arse-
nic. We were unable to get any positive trypanotoxyl results
in repeated experiments. Atoxyl is a very convenient form
with which to administer arsenic hypodermically or intrave-
nously, but, even in this form, it is impossible to give arsenic,
without toxic effect, in quantities sufficient to permanently
sterilise the tissues.
Both the toxic and therapeutic effect of arsenic and atoxyl
administered intravenously and subcutaneously are much alike.
Arsenic given hypodermically, from 0.25 to 0.5 grammes, while
it produces sloughing, frees the blood from trypanosomes at
the same time and keeps the circulation free from the parasites
for about the same period as 2 grammes of atoxyl injected
subcutaneously.
When lethal doses are given subcutaneously or intraven-
ously, the symptoms of poisoning are produced about the third
day. With atoxyl the kidneys are the seat of the chief macros-
copical lesions, death, as a rule, being due to acute nephritis.
The same condition is observed when arsenic, in large
doses, is administered subcutaneously or intravenously.
Both atoxyl and arsenic, when given in bolus, produce
death more rapidly than when administered hypodermically.
10
SURRA.
The lesions, in this case, are found in the stomach and intes-
tines.
In several experiments, where atoxyl and arsenious acid
were given at the same time, their toxic effects were undoubt-
edly combined. Ponies, about 250lbs. weight, which could
tolerate 1 gramme of arsenious acid and 50 c. c. of 4% atoxyl,
when administered on separate days, showed symptoms of
colic, dullness and loss of appetite, when 0.5 grammes of arse-
nious acid was combined with the full dose of atoxyl.
(5) Our imperfect knowledge of the life cycle of the try-
panosomes in the body is one of the difficulties in the problem
of the treatment of the disease. The periodic appearance and
disappearance of the trypanosomes in the circulation and the
existence and location of the parasite during the intermission
period is, as yet, insufficiently explained. The more generally
accepted theory, regarding the evolution of the trypanosomes
in the body, appears to be that they multiply principally by
longitudinal divisions, that a toxin, produced during the periods
of paroxysm, is destructive to the majority of the mature para-
sites and that during the period of intermission, the survivors
multiply by division in the glands and organs.
In a paper, dealing with the evolution of the Surra para-
site (1904 Journal of Comparative Pathology and Therapeutics),
I suggested that, after the breaking up of the parasites in the
blood stream, the nucleus was capable of reforming into a new
individual and depicted forms which appeared to be undergoing
this process. Breinl and Salvin Moore described somewhat
similar latent bodies which they found became encysted in
the liver cells.
This theory appears to be more in accordance with clinical
observations and supplies a better explanation of the periods
of paroxysm and intermission. At a paroxysm the parasites
continue to increase in the blood for one, two or three days.
If this increase was due to rapid division of the trypanosomes,
one would expect this process to be most marked in the blood
SURRA.
11
during the early part of this period. This is not the case.
The time when multiplication forms are most noticeable in the
blood is when the paroxysm is at its height, and just preceding
the downward curve. This, probably, indicates that the divi-
sion process is an emergency method of multiplication called
forth by products in the blood adverse to the life of the para-
site. These new individuals, as well as the parent stock, be-
come disintegrated to a certain extent and lose their flagellated
form, but those destined to continue the species reform into a
latent or cystic body which comes to rest in some internal
organs, probably the liver or bone marrow, during the period of
intermission, finally developing into flagellate forms, which
again make their way into the blood streams.
The mature trypanosome is easily destroyed by arsenic,
antimony and other drugs. The action of arsenic is direct
and takes place when it is being carried through the tissues
in the circulation. The action of arsenic is of short duration
as it is rapidly eliminated from the circulation. The rapidity
of the destructive action of arsenic on the trypanosomes is in
direct proportion to the dose. Consequently, it is possible,
if the dose is sufficiently large, to sterilise the tissues before
the arsenic is removed. With smaller doses numbers of the
parasites are not destroyed and, entering into a latent state,
remain to cause a relapse. This theory of the life stages of
the trypanosomes would also explain the successful results of
the treatment with arsenic given in full doses at intervals and
the non-success of the continuous dosage with smaller amount.
The toxic effect of arsenic on the system is cumulative, but
the action on the trypanosomes is apparently not so. Arsenic
in the circulation has, probably, little or no effect on the latent
bodies, and the accumulated amount of the drug is stored up
in the liver and other organs where it is not brought in contact
with the mature parasites.
I have to acknowledge the co-operation of Mr. Cross,
Assistant Bacteriologist, in these experiments and the assistance
12
SURRA.
of Dr. Hartley, Physiological Chemist, in questions connected
with Chemistry.
The Bulletin of the Bureau of Sleeping Sickness has been
extensively used for purposes of reference to other works on
trypanosomiasis.
TOXIC DOSE OF ARSENIOUS ACID, SOAMIN AND
ATOXYL.
ARSENIOUS ACID.
The toxic dose for the horse is said to be (Law) 140 grains
in solution or 14 grammes in solid form; (Kaufmann) 3.4
grammes in solution or 45 grammes in solid form; Trélut
administered 3 to 6 grammes daily in treatment for Dourine.
In our experiments it was found that ponies of about
300 lbs. could tolerate repeated doses of 1 gramme without
ill-effect; that a dose of 2 to 3 grammes was fatal for ponies
of this weight; that horses weighing from 900 to 1,000 lbs.
could not tolerate more than 3 grammes. The arsenious acid
was administered after feeding.
Toxic dose is 2 to 3 grammes for ponies, and 4 to 5 grammes
for horses.
Arsenious acid administered in solution (Loeffler and Rueh)
has a more toxic effect than when given in bolus. One gramme
in solution is fatal for ponies weighing 250 lbs.
This is shewn in the following table:—
Pony
No.
1
2
3
4
Weight.
lbs.
225
215
350
250
Dose of
Arsenious
Acid Sol.
c.c.
600
800
1,000
1,000
Results.
No symptoms.
Colic, off feed for 2 days.
„ „ 3 „
Died in 24 hours.