In our Western States there is a marked annual loss of stock due
to various causes. Some of these animals die in a condition known
as ‘locoed,’ a term derived from the Spanish word “loco,” meaning
foolish or crazy.
This disorder extends from Montana to Texas and Mexico, and
from Kansas and Nebraska to California.[1]
In 1898 the United States Department of Agriculture sent out,
under the immediate direction of Mr. V. K. Chesnut, a request for
information concerning the ravages of the loco disease. It was
found that in the ten States of California, Colorado, Kansas, Montana,
Nebraska, New Mexico, North Dakota, Oklahoma, Texas, and
Wyoming the loss in 1898 was $144,850. Of this amount, $117,300
was attributed to Colorado alone; in fact, the disorder spread so
that this State expended more than $200,000 in two years and over
$425,000 in a period of nine years in attempts to eradicate the loco
plants, the supposed cause of the trouble.[2]
The loss in one area of 35 by 120 miles in southwestern Kansas
amounted to 25,000 cattle in 1883.[3] This loss in stock has been so
great that the raising of horses has of necessity been abandoned in
certain areas on account of the prevalence of these loco weeds.
It is difficult to obtain accurate data, as the ranchmen believe that
any information as to the prevalence of the disorder would interfere
with the value of their stock.[4]
Dr. James Fletcher, of the Central Experimental Farm, Ottawa,
Canada, testified before the Select Standing Committee on Agriculture
and Colonization that he had never seen a case in the North-west
of a Canadian bred animal being locoed, although the loco
plants were prevalent. He explained this absence of loco disease
by the abundance of grass on the range, because of which the animals
do not acquire the habit of eating loco plants.[5] Cases have been
reported, however, in Manitoba.[6]
The condition known as “locoed” is popularly believed to be due
to eating various plants, especially the members of the Astragalus
and Aragallus genera of the Leguminosæ, or pea family, but
particularly to Astragalus mollissimus and Aragallus lamberti.
These plants have therefore received the name “loco plants,”[7] or
crazy weed. But others, as Astragalus mortoni,[8] A. hornii, A.
lentiginosus, A. pattersoni,[9] A. nuttallianus, A. missouriensis, A.
lotifloras, A. bisulcatus, A. haydenianus,[10] A. tridactylicus,[11] Crotalaria
sagittalis, Lotus americanus,[12] Sophora sericea, Caprioides aureum,
Aragallus deflexa,[13] A. campestris,[14] A. lagopus,[15] Malvastrum coccineum,
Amaranthus graecizans, and Rhamnus lanceolata, are considered
by some as loco plants.[16] In other places Stipa vaseyi, Leucocrinum
montanum, Fritillaria pudica, Zygadenus elegans,[17] and
even species of Delphinium are considered loco plants, so widely has
this name been used.
In Mexico the term “locoed” embraces a condition due to the
action of Cannabis sativa and various members of the nightshade
family. This term has been much abused and has been made to
embrace many groups of symptoms. In fact, if an animal dies while
showing more or less stupor it is said to be locoed.[18] The early
Spanish settlers seemed to be unfamiliar with the disease, or at least
of any causative relation between the plant and the disease. The
Spanish name for Astragalus mollissimus was “Garbanzillo,” from
its resemblance to Garbanzo (Cicer arietinum), which is used in
Spain as a food.[19] The term as applied to this condition seems to
be of comparatively recent origin.[20]
A somewhat similar condition to the loco in stock is sometimes
attributed by the ranchmen of our Western States to eating various
sages.[21] In Texas the loco disease is known as “grass staggers.”[22]
Hayes[23] has described as follows a condition known as grass staggers,
which apparently has little resemblance to loco and is supposed
to be due to eating overripe grass, especially rye.
The symptoms, generally, take two or three days to become developed. The
animal gradually becomes more or less unconscious and paralyzed and staggers
if forced to walk. Although he may have great difficulty in keeping on
his legs, he is extremely averse from going down and leans for support against
any convenient object. He breathes in a snoring manner. The mucous membranes
are tinged with yellow. Convulsions, or spasms, like those of tetanus,
may come on.
Recovery may be expected in cases which are not marked by extreme
symptoms.
If animals are not regularly salted, they visit salt deposits and eat
the alkalis. This some sheepmen believe to be the cause of the locoed
condition, but this is disproved by the occurrence of locoed animals
in ranges without salt. Others modify this view by claiming that
the vitiation in taste from eating these alkalis leads to a desire for
the loco weeds and thus to the locoed condition.[24]
The animals usually affected are sheep, horses, cattle, mules,[25]
donkeys,[26] and goats. It is claimed that practically all herbivorous
animals are liable to the disease, even antelopes being affected.[27]
Hogs are said to be unaffected,[28] but definite information is lacking.
Cows seem to be less sensitive to this form of intoxication.[29] The
condition is usually a chronic one, although acute cases are said to
occur at times. The symptoms consist of digestive disturbances, associated
with emaciation and various symptoms suggesting lesions
in the nervous system, central or peripheral. The animals lose their
appetite from the first, begin to emaciate, and show symptoms of
malnutrition and starvation. The head trembles, the gait becomes
feeble and uncertain, the eyes become sunken and have a “flat, glassy
look.”[30] There is a general sluggishness, muscular incoordination,
and difficulty in motion; finally all control of the limbs is lost and
the animal is unable to stand; the coat becomes rough and loses its
luster, and, in fact, all the typical symptoms of starvation appear.
In some cases diarrhea is also present.
All of Nockolds’s animals, however, were constipated and the
stools were covered with mucus.[31] The dependent portions of the
body may swell, simply as an expression of the anæmia.[32] Sometimes
there are symptoms indicating acute pain,[33] the animals running about
as if affected with colic. They may belch and their abdomens swell.
Some claim that the animals are markedly salivated so that the saliva
trickles from their mouths. In other cases the mouth may be dry.[34]
The eyes may be rolled up so that the whites alone show. In
some cases the pupil has been noted to be dilated, as in atropine
poisoning,[35] but Wilcox states that they are contracted as after the
use of eserine.[36] The temperature of the animal falls from 1/2 degree
to 1-1/2 degrees F. below normal.[37] Tetanic symptoms may occur,[38] or
the muscles of the mouth and tongue becoming paralyzed may interfere
with mastication. When water is offered to the animal, it gazes
stupidly at it and may not drink for days. One of the symptoms
noted is the loss of power to back properly.[39] Cows during the first
two or three months of gestation are almost sure to abort.[40] This is
claimed by Knowles, however, to be due to malnutrition. As a result
of these observations, suggesting some uterine action, the drug has
been proposed as an emmenagogue.[41]
The psychical symptoms are shown by errors of judgment. The
animal becomes dull and spiritless and wanders about half dazed.
The mental dullness passes into stupor. This dull, stupid condition
has been compared to intoxication with opium. If the locoed horse
is led across a stick lying on the ground he often jumps high as if it
were a great obstacle. The animal may now have maniacal attacks,
during which he rears and may fall backward,[42] and makes unreasonable
jumps and other unexpected movements, thus rendering
himself dangerous to man.[43] Other symptoms due to disturbances of
the central nervous system are hallucinations of various sorts.
Though the optic nerve itself is apparently not affected, the animal
will stare at an object for a long time without any apparent comprehension
of its nature. This disturbance in the visual function McCullaugh
claims to be one of the first symptoms of this disease.
The animal seems to lose all idea of distance, as he will butt against
an obstruction as if oblivious of its presence. Any sudden or violent
motion made before him may cause him to fall. According to some,
the animal loses the sense which guides him in finding water. A
cow may fail to recognize her calf.[44] There is more or less loss of
control of the limbs[45] and tremors;[46] the feet are lifted abnormally
high when trotting, and, if crowded, the animal falls headlong and
will jump over little hollows as if they were wide ditches.[47] The
horse may shy without apparent cause and kick at imaginary objects,[48]
and, in fact, the reasoning powers seem to be lost. These attacks
are brought on by sudden excitement or when crossing water.[49] There
may be cutaneous hyperæsthesia.
The animals may remain with the herd, but they often wander
away. Stalker records the following observations:
I have seen a single animal miles away from any other individual of the herd,
carefully searching as if for some lost object, and when a loco plant is found
he would devour every morsel of it with the greatest relish. As soon as one
plant was eaten he would immediately go in search of more, apparently
oblivious to everything but the intoxication afforded by his one favorite article
of food.[50]
All of Nockolds’s animals which were locoed were mares more than
6 years of age.[51]
According to Stalker there is a passive type in which the animal
shows symptoms only on being disturbed; the animal then becomes
unmanageable. This happens even with old, well-broken saddle
horses.[52]
There are few published reports as to the symptoms occurring in
sheep which are locoed. Stalker[53] says sheep “become loco-eaters,
grow stupid, emaciated, and eventually die.” One of the few descriptions
of the symptoms is that of Ruedi,[54] in which he claims that
the symptoms in sheep are those comparable to the symptoms of
cerebro-spinal meningitis except that there is an absence of fever.
Ruedi speaks of sheep “lying flat on the ground, not able to stand,
and not able even to lift their heads to drink the offered water;
the head and the vertebra in opisthotonus position; the four legs
stretched out and stiff; breathing was stertorous, pulse slow, abdomen
much distended, diarrhea present. * * * The heart * * * was
very slow and insufficient.” The teeth (in sheep) may blacken
and fall out.[55]
It is mainly the young animals, such as lambs and colts, that are
affected, probably due to the fact that their attention is more easily
directed to the flower of the loco[56] plants. It is claimed (on slight
evidence) that men have become locoed. The symptoms in them are
nausea and headache.[57]
Schuchardt[58] has called attention to the resemblance of the symptoms
in locoed animals to those which occur in so-called lathyrism,
but most observers in this country have especially marked the resemblance
of the symptoms to those induced by the habitual use of narcotic
drugs.[59]
As a rule the loco plants are refused by animals save when there is
lack of other food, although at times animals have shown the keenest
relish for these plants, rejected all other forage, and devoted their
whole attention to searching for the loco plants.[60]
Stalker says that animals not too long addicted to the use of these
plants, if confined, soon lose their taste for them (after two or three
months),[61] although old loco eaters do not readily lose the habit.
Stalker also says that “it is to be presumed that the plant is possessed
of some toxic property that has a specific effect on the nervous centers,
and that these effects have a marked tendency to remain permanent.”[62]
The fundamental character of the disorder seems to be a progressing
anæmia. The interpretation of psychical symptoms in herbivora,
and especially on the range, must often be fallacious.
According to Maiden[63] a condition similar to loco is met with
among animals in Australia and is there believed to be due to eating
various species of Swainsona.[64] As Maiden says, “Its effect on sheep
is well known; they separate from the flock, wander about listlessly,
and are known to the shepherds as ‘pea-eaters’ or ‘indigo-eaters.’
When once a sheep takes to eating this plant it seldom or never
fattens, and may be said to be lost to its owner.” Horses, after eating
this herb, “were exceptionally difficult to catch, and it was observed
how strange they appeared. Their eyes were staring out of their
heads and they were prancing against trees and stumps. The second
day two out of nine died, and five others had to be left at the camp.”
Martin[65] experimentally studied these cases of intoxication and
sums up his work as follows:
1. That one can by feeding sheep upon Darling pea reproduce all the symptoms
which are attributed by pastoralists to this cause. Briefly stated these
symptoms are: Stupidity, loss of alertness and an agonized expression, followed
by stiffness and slight staggering and frequently trembling of the head or
limbs. Later, clumsiness and unsteadiness ensue, which slowly advance until
the animal often falls down. In this stage, the action of the animal in running
over small obstacles is characteristic. It jumps over a twig as if it were a foot
in height. When first it commences to tumble about, it is able more or less
readily to regain its feet, but in the advanced stage of the disease this is impossible
and, after exhausting itself in efforts to do so, it remains lying down
until it dies. During the whole time the sheep become progressively more
bloodless, and in advanced cases the blood when shed appears to the naked eye
lighter in color. It contains fewer red blood-cells (about two-thirds to one-half
the usual number). (The corpuscles were estimated in several cases by
means of a hæmocytometer.) All these symptoms are much aggravated by
driving. Thus, an animal in which the symptoms are little marked may exhibit
them in a striking degree after being driven. In addition to the above the teeth
(especially in young sheep) frequently become loose, and consequently displaced
or even dislodged.
2. That the time which elapses before the onset of definite symptoms is three
to four weeks in sheep of 2 to 3 years old. (It is probable, however, that with
younger animals the time is shorter.)
3. That under the conditions of the experiment, the animals survived about
three months. They lived, however, an invalid’s life. Everything was brought
to them, and it is improbable that if feeding exclusively upon the pea, and left
to shift for themselves in the paddocks, they would survive more than two
months.
4. That if a sheep be returned to proper fodder after one month to six weeks
feeding upon the pea, and before the symptoms are fully established, it may
recover completely.
5. That when once the paralytic symptoms are established it will not recover;
but if returned to proper food, will remain in much the same condition, becoming
neither better nor worse.
6. That Darling pea contains a very fair amount of nourishing material so
that animals may, provided they eat it readily, retain their condition on it for
some weeks, until the poisonous principle contained has had time to exert its
effects.
These plants, if fed with other herbage, do not seem to be injurious
and apparently lose their harmful action upon being cultivated.[66] As
long as salt is properly fed the animals will not eat this plant[67] and
are said to suffer no effects from it. Physiological study has shown
the presence of a body with marked sudorific power which causes
rapid emaciation in frogs.[68]
It has been claimed that these symptoms are due to the presence
of a narcotic poison in the plant.[69] Post-mortem examinations were
negative save for the presence of a peripheral neuritis.[70]
The pathological features as described by previous writers are a
softening and ulceration of the stomach walls[71] and a degeneration of
the walls of the intestines with or without perforations. The peritoneum
may be found inflamed.[72] The peritoneum and omentum in
one case (cow), reported by Sayre, were covered with small nodules.
These were probably tubercular in origin. The colon in one horse
was found enormously distended, while the cœcum and small intestines
were normal,[73] save that the walls appeared thin.
Ulcers have been found at times in the kidneys, but were probably
secondary in origin, as other cases are reported with normal kidneys.
Faville has found in some cases amyloid degeneration. The pancreas
and spleen are reported normal. The abdominal cavity may contain
a slight effusion.[74] The liver has been found cirrhotic, and at times
shows tubercular lesions of a secondary nature. The inner coat of the
bladder has been found softened, and in sheep the bladder may be
markedly distended at the autopsy. The cerebral membranes are
congested and perhaps adherent,[75] and there may be blood clots over
the longitudinal sinus or at the base of the brain. Effusions have
been especially noted around the medulla. The arachnoid has also
shown slight congestion, and in other cases the membranes showed a
slight thickening. The middle ventricle was found filled with yellow
serum, while the fourth ventricle contained a hemorrhagic effusion,[76]
and the base of the brain was covered by a clot. The hemorrhage
may become organized and the brain be held to the membranes by
tough organized fibers. In many cases serous effusion is present in
the lateral ventricles. The arachnoid space is also in some cases similarly
filled. Microscopic examination of the brain in the case of a
steer showed atrophy of Purkinjie’s cells.[77]
In sheep the post-mortem examination showed paleness, anæmia
of the muscles, and great distention of the abdomen. The intestines
were found filled with gases, and the mesenteric blood vessels filled
with blood. No peritonitis, or ascites, or ecchymoses in the mucous
membranes were noted in the autopsies made on sheep by Ruedi.
The liver has been seen enlarged. In sheep the brain was anæmic.
Microscopically the brain showed atrophy and the Purkinjie’s cells
disappeared or their processes atrophied. In these sheep the brain
was so anæmic that the distinction between the gray and the white
matter was hard to define.[78] The membranes of the cord have been
found inflamed and adherent, but the spinal cord was usually normal.[79]
In some cases, however, the spinal cord has been found softened[80] and
œdematous. The arteries of the limbs were gorged with blood,[81] and
at the same time there was a collection of serum in the abdominal
cavity. Death is thought to be due to starvation.[82] In other words,
the pathological condition, according to published accounts, shows
little that is characteristic save some action on the gastro-intestinal
tract.
During the western immigration of 1849 the Indians along the Missouri
River described to the immigrants a plant (Astragalus mollissimus)
producing death in horses and cattle, which was preceded by
various forms of excitement.[83]
The attention of the United States Department of Agriculture was
first called to the toxic action of the loco plants in 1873, when specimens
of the plants, which were identified as Astragalus hornii and A.
lentiginosus,[84] were sent from California by Mr. O. B. Ormsby, with
the statement that they were poisonous to stock, especially to horses.
Mrs. J. S. Whipple also corroborated this information. The botanist
of the Department, Dr. George Vasey,[85] published a note and requested
further information concerning the plants. These notes were
enlarged by a similar contribution by Dr. P. Moffat on Aragallus
lamberti.[86] The following year Vasey reported with more fullness,
and his description of the action of the plants is substantially what
we find in most of the books of to-day.
In 1876 Lemmon[87] noted that Astragalus mortoni was “a deadly
sheep poison.” At the same time Rothrock,[88] botanist of the United
States Geographical Survey under Lieutenant Wheeler, described
these plants, and Kellogg,[89] a botanist in California, reported that
Astragalus menziesii was causing great losses in horses, sheep, and
cattle and claimed that the stockmen had been familiar with this
disorder for at least ten or fifteen years. This report of Kellogg
was followed by that of Rothrock[90] in 1877.
In 1876 a specimen of Aragallus lamberti was sent from Colorado
to Professor Prescott, of the University of Michigan, under the name
of “crazy weed,” with the statement that it was poisonous to horses
and cattle and that, while the Mexicans often used it in making beer,
it sometimes caused symptoms in men. His pupil, Miss Watson, undertook
a study of its chemical properties. She failed to isolate any
pure chemical compound, but claimed that in the root there was a
body giving alkaloidal reactions and that there was also a resinous
body present. Another of his pupils, W. R. Birdsall, took the ground-up
root himself in doses of 20 grains at various intervals for several
days and later 40-grain doses in one and a half hours, but without
experiencing any marked symptoms except colicky pains. A kitten
also was given about one and a half ounces of the fluid extract without
effect. Prescott[91] sums up by saying that “it would seem that the
dried ground root possesses no poisonous properties.” The work of
Miss Watson was considered of sufficient importance to be abstracted
in the Annual Report of the Commissioner of Agriculture for 1878
(1879), page 134.
Gradually the Department of Agriculture became more and more
interested in this subject, and Peter Collier, chief chemist, in 1878,
examined the roots and leaves of Aragallus lamberti for alkaloids,
but found none.[92]
In 1880 Peter Collier published a proximate analysis of Astragalus
mollissimus made by Francis A. Wentz, of Kansas. His investigations
showed it to have an ash content of 6.76 per cent, while the
Aragallus lamberti, analyzed by L. F. Dyrenforth, of Chicago,
showed an ash content of 4.32 per cent. Collier[93] sums up by saying:
From the additional work done at this Department it seems probable that the
deleterious effects observed from animals eating this plant may be due principally
to the fact that the sweet taste causes cattle to reject more nutritious
food and strive to subsist upon the Oxytropis only. This plant is mechanically
a very unfit substance for food, being of a tough, fibrous, and indigestible
character. It is possible that, when the animal becomes somewhat enfeebled
by lack of proper nourishment, the small amount of alkaloid may have a direct
poisonous action. Again, it seems probable that the plant may contain much
larger proportions of alkaloid at certain stages in its development than at others,
or the seeds may prove to be the most injurious portion.
The departmental work was continued by further short notices by
Vasey[94] in 1884, 1886, and 1887, and by the report of Stalker in 1887.
This report by Stalker is still the best description on the clinical side
of the question.
Rothrock,[95] meeting the loco plants in his survey work, describes
their effects on animals as follows:
Certain it is, however, that, once commenced, they continue it, passing through
temporary intoxication to a complete nervous and muscular wreck in the later
stages, when it has developed into a fully marked disease which terminates in
death from starvation or inability to digest a more nourishing food. The animal
toward the last becomes stupid or wild, or even vicious, or, again, acting as
though attacked with “blind staggers.”
Under the name of Crotalaria, H. Gibbons,[96] in 1879, refers to a
plant growing in California which it was claimed was producing
characteristic symptoms of poisoning in horses and sheep. This
plant Professor Maisch afterwards identified as Aragallus lamberti.
Dr. Isaac Ott[97] undertook the physiological study of the question
and used an alcoholic extract of Astragalus mollissimus. He found
from its action on frogs, rabbits, and cats that the plant had decided
physiological action, as follows:
(1) It decreases the irritability of the motor nerves.
(2) Greatly affects the sensory ganglia of the central nervous system, preventing
them from readily receiving impressions.
(3) Has a spinal tetanic action.
(4) Kills mainly by arrest of the heart.
(5) Increases the salivary secretion.
(6) Has a stupefying action on the brain.
(7) Reduces the cardiac force and frequency.
(8) Temporarily increases arterial tension, but finally decreases it.
(9) It greatly dilates the pupil.
Doctor Stockman, in England, about this time tried the action of
the aqueous and alcoholic extracts of the dried Astragalus mollissimus
sent from Texas. He experimented with frogs and rabbits in increasing
doses, but without result.[98]
In 1888 Hill reported that a species of Astragalus was acting detrimentally
on cattle, goats, and sheep in Cyprus and that these animals
fell down as if intoxicated, and also that the natives in time of great
drought feed their cattle with this plant mixed with straw, but that
they were always made sick until they became used to it.
In 1885 Professor Sayre, of the University of Kansas, undertook
the investigation of the loco question. His first report was made in
the Transactions of the Kansas Academy of Sciences for 1885, and
his reports have been continued at various periods up to 1904. The
results of his experiments on various animals—dogs, cats, and
frogs[99]—have been entirely negative. He administered alcoholic
preparations to himself and took them until they became too nauseous
to continue, and found they produced absolutely no symptoms besides
the nausea. He suggests, however, that if the plant really is poisonous
it is due to its fine hairs, which might mechanically cause death.
Sayre has stated that he has sent thousands of pounds of the dried
loco plants to various investigators in America and Europe, but all
reports were negative as to pharmacological activity. He has, however,
done some work on the pure chemistry of the plant and found
that the plant contained 10 per cent of moisture and yielded 12.01
per cent of ash. Of this ash, 25 per cent was soluble in water, while
50.6 per cent was soluble in HCl. The insoluble portion consisted
largely of silica. He found CaO, K2O, MgO, Al2O3, and Fe2O3, with
the acid radicals SO3, Cl, P2O5, CO2, and SiO2.[100] Although Sayre
claims that the plant is physiologically inactive, he tried by chemical
means to isolate a physiologically active body and, naturally enough
under the circumstances, failed to find one. He claims that while
the plant might give alkaloid reactions, he was unable to isolate this
body in a pure state, and that alfalfa reacted similarly.
The investigation on animals was continued by Kennedy.[101] He
administered an infusion of 1/2 ounce of green Astragalus mollissimus
to a fasting dog weighing 23 pounds, but there were no symptoms
after 12 hours. A decoction of 1 ounce of the green plant and one
of 4 ounces of the dried plant were likewise without action. Extracts
with hydrochloric acid were also inactive. When 400 grams of the
dried and powdered plant were fed in substance the result was merely
to increase the appetite. The organic acid obtained from 4 ounces of
the plant was also found to be inert.
Kennedy did not state in what season the plant was collected and
from what locality it was obtained, but says simply that the plant
extract was inactive to a dog, a carnivorous animal, and that therefore
the plant is nonpoisonous. He adds that death might be due
to the tough fibers and indigestible character of the plant. He overlooks,
however, the fact that the plant might vary in its toxicity, and
he infers from the experiments on carnivorous animals that these
results would hold good for herbivora, yet he does not claim that
carnivora become locoed in nature.
Kennedy found that the plant lost 80 per cent in weight on drying
and that the water extract which represented 30.6 per cent of the
powdered and dried plant contained magnesium sulphate and sodium
chlorid, tannic acid, gum, coloring matter, an extractive, and a
“peculiar organic acid.” The ashed plant yielded 20 per cent of
ash, consisting of magnesium sulphate, sodium chlorid, alumina,
silica, and a trace of iron. “The abundant precipitate produced by
the alkaline hydrates, potassium, sodium, and ammonium was found
to consist of magnesium hydrate, an abundance of this base being
present in the plant.” Kennedy also obtained alkaloidal reactions,
but failed to isolate the body giving these reactions.
In 1889 the investigations were greatly stimulated by the report of
Doctor Day,[102] then of the University of Michigan. She claimed that
she was able to produce marked physiological symptoms, using both
Astragalus mollissimus and Aragallus lamberti in her work. She
administered daily 60 to 70 c.c. of a decoction[103] of the plants to kittens,
together with abundant milk and other food. She states that
in two days—
The kittens became less active, the coat grew rough, appetite for ordinary
food diminished and fondness for the “loco” increased, diarrhea came on, and
retching and vomiting occasionally occurred. The expression became peculiar
and characteristic. Emaciation and the above symptoms progressively increased
until the eighteenth day, when periods of convulsive excitement supervened.
At times the convulsions were tetanic in character; frothing at the mouth and
throwing the head backward as in opisthotonus were marked. At other times
the kitten would stand on its hind legs and strike the air with its forepaws,
then fall backward and throw itself from side to side. These periods of excitement
were followed by perfect quiet, the only apparent sign of life being the
respiratory movements. After a short interval of quiet the convulsive movements
would recur. These alternate periods of excitement and quiet lasted
thirty-six hours, when the posterior extremities became paralyzed, and the
kitten died about two hours afterward. There was no apparent loss of consciousness
before death.
The post-mortem examination revealed the presence of ulcers in the stomach
and duodenum. Some of the ulcers had nearly perforated the walls of the
stomach and duodenum. The heart was in diastole; brain and myel appeared
normal. As might be expected from the emaciated condition, the entire body
was anæmic.
In a second case 60 to 70 cubic centimeters of a more concentrated
decoction were fed daily, with other food as before, to a vigorous adult cat.
The symptoms of inactivity, loss of appetite, rough coat, diarrhea, and the
peculiar expression of countenance were as in the first case. By the twelfth
day the cat was wasted almost to a skeleton, and was correspondingly weak.
Paralysis of the hind limbs came on, and the cat died on the thirteenth day.
There were no periods of excitement in this case.
These cats developed a craving for the decoction and “would beg
for it as an ordinary kitten does for milk, and when supplied would
lie down contented.”
Doctor Day made controls with healthy animals under the same
conditions, with the exception that they received no loco plant. She
also fed a young wild jack rabbit on milk and grass for a few days
and then substituted fresh loco plants for grass.
At first the “loco” was refused, but after two or three days the “loco” was
eaten with as much relish as the grass had been. After ten days of the milk
and “loco” diet the rabbit was found dead, with the head thrown back and
the stomach ruptured.
Subcutaneous injections of the concentrated decoction caused nervous twitchings
in frogs and kittens, and if large amounts were used death followed in
from one to two hours from paralysis of the heart. The same symptoms were
produced in frogs by the injection of an alcoholic extract of the residue left
after the evaporation to dryness of the decoction.
In other words, Doctor Day was able to produce a chronic form of
loco poisoning with the characteristic symptoms so often described
save in the occurrence of diarrhea. Diarrhea is not usually noted on
the range. Sayre had already reported an ulcerated condition of
the intestines of a locoed cow similar to that described by Doctor Day
as occurring in cats. Doctor Day urged that the reason previous
experimenters failed to produce symptoms was that they had used
too small an amount of the plant and that by systematic feeding to
healthy cats cases of loco disease may be produced.
Storke states that “Dr. V. C. Vaughan, of the University of Michigan,
has since fully corroborated Dr. Day’s views.”[104]
In her experiments Doctor Day used the leaves, roots, and stems
of the plants gathered in September. She believed that the greatest
amount of poison is present in autumn and winter. She later undertook
the isolation of the active principle, and proceeded as follows:[105]
The roots, stems, and leaves were boiled ten hours, strained, and the decoction
concentrated to a sirup, poured, while hot, into a hot flask, corked and
set away. At the end of ten days the sirup had separated into two layers—the
upper a blackish liquid, the lower a brownish sediment. The liquid was
poured into a flask and covered with six times its volume of very dilute alcohol,
30 per cent (the sediment also was washed with dilute alcohol, to insure
a complete removal of the liquid), corked, and let stand three days; agitated
occasionally, then filtered, and the filtrate slowly evaporated in the air, when
crystals were formed. It was found important not to hurry the evaporation,
for when this took place too rapidly the crystals did not form.
These crystals are microscopic in size, blue-white in color, and of a variety
of forms. The most characteristic are slender and pointed, arranged in rosettes
or grouped in various ways. They are soluble in distilled water and very dilute
alcohol, very sparingly soluble in strong alcohol, not soluble in chloroform or
ether.
The evaporated mass containing the crystals, when dissolved in distilled
water, is slightly acid in reaction. A small amount of this fed to a kitten produced
the train of characteristic toxic symptoms—sleepiness, loss of appetite,
retching, and diarrhea—that is produced by quite large amounts of the decoction.
The crystals Sayre[106] claims to have already seen. He says that
they gave no precipitate with Mayer’s reagent, platinum chlorid, or
with ammonia, but that barium chlorid and ammonium oxalate gave
a precipitate, and he believes that they were in reality an inorganic
combination of calcium, so that while Doctor Day may have obtained
an extract which produced characteristic symptoms she certainly has
not isolated any pure active principle. Later she admitted that it was
not possible “to make positive statements as to the chemical character
of the active principle.”[107]
In 1884 there was a fatal outbreak of a disorder in horses in portions
of the Missouri Valley in Iowa, Nebraska, and Dakota. This
was almost uniformly fatal in a few weeks or months. The animals
lost strength and became emaciated, although they were kept in pasture
where there was abundant grass. There was marked stupor, the
animals falling asleep while eating, and they “would remain standing
for a whole week, sleeping much of the time, with the head resting
upon some object.” The post-mortem examination showed that
“in every instance there was marked hemorrhagic effusion into the
fourth ventricle, the liver and spleen were abnormally dense, the walls
of the intestines were almost destitute of blood, and the stomach enormously
distended with undigested food.” The post-mortem find and
clinical symptoms suggested to Stalker[108] that this disorder was due to
some plant analogous to Astragalus mollissimus. He found abundant
in these regions Crotalaria sagittalis, or rattle-box, one of the so-called
loco weeds, and by the administration per os to a young horse
of an infusion of 15 pounds of the plant, given in two days, produced
the clinical symptoms and the post-mortem condition of the
brain which he previously observed on the range.
Power and Cambier[109] undertook the chemical study and the isolation
of the active principle of this plant, together with that of
Astragalus mollissimus. They found that the Astragalus mollissimus
if distilled with water yielded a distillate which possessed a
peculiar odor, which they thought due to a trace of volatile oil. On
distilling with alkali they obtained ammonia and a trace of trimethylamine.
In the case of Crotalaria only ammonia was found.[110] They
argued that because trimethylamine was not obtained in this case
choline was not present. On distilling the Astragalus mollissimus
with acidulated water (H2SO4) the distillate was found to contain
acetic acid—settling the nature of the “peculiar organic acid” described
by Kennedy. From this plant they obtained a resin or mixture
of resinous bodies by extracting the plant with alcohol, and after
concentration precipitating with acid water. These resins in doses
of from 2 to 5 grains failed to produce any symptoms in kittens.
An albuminoid which was obtained by precipitating a concentrated
aqueous extract of Astragalus mollissimus by means of alcohol likewise
was found to be inactive to a kitten in doses corresponding to
50 grams of the crude plant. A globulin which was isolated by
precipitation from a 10 per cent sodium chlorid solution proved
also to be inactive in doses of 0.2 gram. They then extracted 3
kilograms of these plants with 1/2 per cent sulphuric acid, and after
evaporation to a thick gum the mass was extracted with strong
alcohol, the alcoholic solution was evaporated, and the alcoholic
residue taken up in water and precipitated by neutral and basic lead
acetates, and after removing the lead with sulphureted hydrogen the
filtrate gave precipitates with various alkaloidal reagents. The
sirupy residue which they obtained from Astragalus mollissimus by
decomposing the precipitate with Mayer’s solution administered to
kittens in doses of 0.1 gram produced merely frothing at the mouth
with profuse flow of saliva, but the animals soon recovered. The
presence of a large amount of calcium was shown but not estimated
quantitatively.
Power and Cambier summed up their conclusions by stating that
both the Astragalus and the Crotalaria contain very small amounts
of toxic alkaloids, to which they believe the symptoms of poisoning
produced were due. Their work from a chemical standpoint is excellent,
but from a pharmacological point of view seems to be deficient;
in fact, Power does not claim to be a pharmacologist. What would
seem to be the proper course would have been to test for themselves
the action of the plant on various animals and, after deciding which
reacted most characteristically, test, after various precipitations, both
the precipitates and filtrates on various animals to see whether the
original symptoms and pathological lesions could be produced. They
failed, however, to test their mother substance. It is well recognized
that plants grown under varying conditions and on different soils vary
in the amount of the physiologically active principle they contain.
In the case of Crotalaria, Power and Cambier had before them the
experiment of Stalker, in which he reproduced the disorder by feeding
the plant extract to horses, yet they claimed that the body which
they administered was the active principle, merely because it produced
some frothing at the mouth and salivation in a kitten. The
percentage of active principle they found would be too small to
account for the symptoms, except in the case of a very active
compound.
Certain of these precipitates were also later examined physiologically
by O’Brine.[111] He also found the resin precipitated from an
alcoholic extract of the plant and also the alcoholic extract from 2.2
pounds of the dried Astragalus mollissimus to be physiologically
inactive.
Oatman,[112] using Power and Cambier’s method with alfalfa (Medicago
sativa), obtained a noncrystalline mass which when given in
0.1 gram dose caused frothing at the mouth in a kitten, but no serious
symptoms. This 0.1 gram represented about 5 pounds of powdered
leaves and tops of the plants.
Since the appearance of Power and Cambier’s work Sayre has
published various papers on the loco weeds in the Transactions of the
Kansas Academy of Sciences for 1903-4, vol. 19, p. 194, 1905; 1901-2,
vol. 18, p. 141; Seventh Biennial Report of the State Board of Agriculture
of Kansas, vol. 12, p. 97, 1891; Journal of the Kansas Medical
Society, vol. 4, pp. 222 and 241, 1904, etc. He has contributed nothing
especially new, but says that “the old theory that an alkaloidal
poison is secreted in the plant causing the loco trouble has not been
found tenable,” but wishes to be understood that he does not discredit
the ground for the opinion that in some mysterious way
certain disorders occur in cattle in connection with what is commonly
called loco-weed. He suggests that this connection might be somewhat
similar to the relationship between the disorder caused by over-feeding
half-starved animals on clover or alfalfa[113] and has had the
plant analyzed as to its nutritive value, giving the table in the Transactions
of the Kansas Academy of Sciences, vol. 19, p. 194. He
makes the suggestion that any injurious action the plants may have
might be due to the fine, hair-like projections on the plant which
mechanically set up irritation. This supposition can be thrown out
at once by the experiment of Day and others, who induced symptoms
in animals by extracts of the plant, and by the fact that other coarse
plants do not act similarly. This fine, hair-like material was found
to constitute about 33 per cent of the plant on grinding. But Sayre
himself does not seem to be positive as to any conclusion. He, like
O’Brine and others, has obtained alkaloidal reactions from the plant,
but states he has obtained similar ones from alfalfa.[114] At one time
he said:
I do not consider loco directly or indirectly the cause of the condition, but
am of the opinion that what is called “locoed” is, first, congestion of the
brain and spinal marrow (causing blindness and first symptoms), and, second,
softening to a greater or less extent.[115] These terms describing the alleged
symptoms of “locoism” might occur in well recognized diseases resulting from
brain lesions, which latter occur in so-called forage poisoning and poisoning
from foul drinking water, etc.
We are not prepared to affirm or deny that the loco-weed produces a train
of symptoms characteristic of the plant.[116]
Again Sayre states:
It seems not unreasonable to suppose that the peculiar condition of the animals
of the plains, when they gorge themselves with this highly nitrogenous
weed, has something to do with the disease. A condition of malnutrition may
set in and give rise to the rapid growth of a toxic-producing micro-organism
or an irritating principle. This principle may be capable of cultivation and of
producing disease artificially. Be this as it may, we feel warranted in saying
that the so-called poison is a development within the animal, not a product
preexisting in the weed itself.
Sayre also suggests the possibility of the plants producing hydro-cyanic
acid, which, it is well known, occurs in sorghum.[117] In the
Journal of the Kansas Medical Society (vol. 4, p. 243), he claims to
have isolated a crystalline body, but this he has not tested physiologically.
Sayre especially deserves credit for keeping the loco investigation
alive, and no doubt his change in position is due to his lack of
facilities for pharmacological testing.
Carl Ruedi[118] fed rabbits daily by a stomach tube with 10 c.c. of an
extract (unstated strength) of Astragalus mollissimus and recorded
the following results:
After only five injections one of the rabbits died, and the post-mortem showed
to a nicety the congestion of the whole tract of the vena portæ and the anæmia
of the brain. I put six rabbits under the influence of loco, and the effect was
marked, but not rapid, if not given in very concentrated solutions. The solutions
were prepared differently, and each of the rabbits had its own preparation,
but the effect was nearly the same. In the beginning loco acts as a
stimulant; the animals get lively, hilarious, running about; cleaning themselves,
etc. This lasts about eight hours, then they become very quiet, sit in a corner
of a box, and one can do with them pretty nearly what one likes; they do not
move from the place, or just run into another corner, to fall back into the same
complacent reverie. One can leave the door open and hammer away at the
box, but they do not show any inclination to run away. During the excitement,
however, they become fierce, and I had once the opportunity to watch one of
the drollest things possible: One of the rabbits, two hours after dosing it, got
loose and ran under a porch. A heavy tomcat came near this hole, and commenced
sniffing about; this offended the rabbit highly, and it jumped on the
neck of the cat, bit it through the skin, and the cat ran screaming away. When
the animals are first under the influence of moderate doses of loco, they suffer
greatly from hyperæsthesia of the cutaneous nerves; when one touches them
with a stick while lying in a corner, without hurting them, one sees the platysma
working away very forcibly, and sometimes they utter sounds of pain. According
to my experiments the loco-weed works slowly but surely; as soon as the
anæmia of the brain sets in, the animals act in every respect mad like; one hour
they are excitable, and then again dull and languid as can be. The rabbits eat,
when well, very quickly, and whenever they have opportunity; not so the locoed
rabbit; he eats slowly for a minute or two, then he goes into a corner and
meditates, comes forward to nibble at a carrot or a piece of cabbage, but he
never eats greedily, and does not steal it from the mouth of his neighbor, or
only very exceptionally. I observed these rabbits for ten days; they did not
die, because I gave them weaker solutions; but they all became very ill, and as
I had to leave the park I killed them with the needle inserted into the medulla
oblongata, and made the post-mortem. In all of these cases I found great congestion
in the abdomen, and marked anæmia of the brain. The congestion of
the vena portæ commences certainly very early, but still the first symptoms
are the nervous symptoms, first as excitants, then depressing or sedative, with
a marked hyperæsthesia of the cutaneous nerves.
Ruedi made an attempt to isolate the active principle and separated
a base, which he calls “locoin,” from an ether shaking. This
base, however, he found to be physiologically inactive, but believes
the activity to be due to a body which he calls “loco-acid,” which is
present in the mother liquid after the shaking with ether. He, however,
has not obtained this in any degree of purity and gives no
chemical data to substantiate this statement save that the fluid was
acid.
Experiments made at the University of Pennsylvania with certain
loco plants on cats, dogs, and rabbits proved negative.[119]
Other experiments on rabbits have been made by Doctor Lewis.
These rabbits were fed on the leaves, stem, and whole plant, and also
extracts of one of the loco plants (presumably Astragalus mollissimus)
for one or two months, without producing any noticeable effect.[120]
This uncertainty in the results of the investigation as to the cause of
the loco disease turned the attention of observers into other lines. President
Ingersoll,[121] of the State Agricultural College of Colorado, in his
autopsies on sheep was struck by the presence of tapeworms (Taenia
expansa) in the gall duct and small intestines. He apparently tried
to prove a relationship between the tapeworms and the locoed condition
by feeding the extract of a loco plant to sheep, and thus showing its
harmlessness. He prepared a decoction from 20 pounds of loco plant
(the species was not stated) and boiled this down from 12 gallons
to 1 quart. This concentrated extract was fed in three days to a
bottle-fed lamb; this lamb showed no symptoms, although kept under
observation for two weeks. This theory of the causation of loco
by worms was also considered by Curtice,[122] and later brought forward
by Steele[123] and Marshall.[124] This idea is very suggestive when considered
in relation to the etiology of bothriocephalous anæmia.[125]
Others, again, have claimed that the disease is due to a parasite
found upon the loco plants, but all specimens examined by entomologists
proved to be harmless.[126]
Lloyd, from his study of the subject, says:
From first to last I have failed in obtaining a characteristic proximate principle,
either from the fresh or dried plant. The disease called loco was as
murky as the milk sickness so prevalent in the new settlements of Indiana
and Kentucky in early days, and, like the numberless herbs that have been
presumed to produce that obscure peculiar disease, milk sickness, loco was unresponsive
to my chemistry.[127]
It may be safely said that if a specimen of the plant were to be examined
in the ordinary manner by a chemist who had no idea of its importance he
would report that it did not contain a characteristic proximate constituent.[128]
Can it be that an admixture of loco and some undetermined plant or earth
infected with bacteria taken with the roots, each innocuous under other conditions,
can by digestion together in the stomach and intestines result in the
production of a poison?[129]
To sum up, it seems to the writer that the poison of loco is a product, and
not an educt.[130]
But Lloyd adds, in speaking of the reports of various experts and
ranchmen:
Their description concerning its toxic action on animals agreed, and it was
folly to argue that so many observers from so many sections of the country
could be misled. There must be an undetermined something behind the loco
weed.[131]
In 1893 O’Brine, from Colorado, and Mayo, from Kansas, reported
on their work with the loco plants. O’Brine failed to isolate any
alkaloidal or other poisonous body, and his feeding experiments on
himself and on rabbits having failed, he sums up in despair: “The
more I examine the loco question, the more I am persuaded that we
must look for some other cause besides the loco-weed.”[132] At the end
of his report he gives some ash analyses but fails to interpret them.
He also fails to give details as to the method of obtaining and estimating
his ash. O’Brine’s ash analyses are as follows:
| Plant. | Total ash. | SiO2. | Fe2O3
and
Al2O3. | CaO. | MgO. | K2O. | Na2O | H2SO4 | Cl. | P2O3. | CO2. |
Astragalus mollissimus
(whole plant) | 12.15 | 32.77 | 16.26 | 6.05 | 3.11 | 13.30 | 3.21 | 3.9 | 0.47 | 6.12 | 10.55 |
Aragallus lamberti
(whole plant) | 13.52 | 17.08 | 12.21 | 14.27 | 2.62 | 17.26 | 5.75 | 3.22 | 3.87 | 3.30 | 17.37 |
| Astragalus caryocarpus | 12.36 | 7.82 | 5.97 | 12.10 | 3.55 | 23.35 | 3.38 | 5.56 | 9.0 | 4.67 | 20.62 |
These analyses are evidently incorrect, as O’Brine estimates a
carbon content of 4.13 per cent for the first, and for the second 2.22
per cent, showing incomplete combustion.
Mayo[133] experimented with alcoholic and aqueous extracts of dried
Astragalus mollissimus on guinea pigs, with negative results, and
was first led to deny a relationship between the disease and the plants.
Later, as a result of the post-mortem findings, he was convinced that
his first conclusion was wrong and that “the disease is certainly the
result of animals feeding upon the loco-weed.” Mayo says:
A careful survey of the experiments performed and observations noted leads
me to the opinion that the disease known as “loco” is the result of malnutrition,
or a gradual starvation, caused by the animals eating the plants known
as “loco weeds,” either Astragalus mollissimus or Aragallus lamberti. If
there is a narcotic principle in the plant, chemists have failed to find it and a
fluid extract does not possess it, and a ton of the plant eaten by an animal
ought to contain enough of the poisonous properties to destroy an animal.
Kobert[134] has also tested the activity of Astragalus mollissimus and
says, “Ich fand Astragalus mollissimus ziemlich unwirksam.”
Doctor McEackran[135] fed dried Astragalus mollissimus and Aragallus
lamberti mixed with feed to a stabled animal for two months without
result. (Animal not stated).[136] Similar negative experiments are
reported from the State of Washington, but the amounts used were
too small to form any conclusions.[137]
Mr. V. K. Chesnut[138] has busied himself with the loco problem,
but mainly in an executive capacity, his own efforts being directed to
the study of the relation of the loco plants to the disease on the range.
He has done no laboratory work. Chesnut and Wilcox made numerous
autopsies on sheep and experiments on animals. They claimed
that an extract of Aragallus spicatus produced some slight narcotic
action in rabbits. Their pathological examinations failed to show
any characteristic lesion, but they state that the cerebral membranes
were in all cases slightly congested. They deny any causative relationship
to the presence of worms or with feeding upon alkalis.
They believe that sheep are more likely to become locoed if not salted
regularly. Chesnut describes one case in which a lamb became locoed
by nursing from a locoed mother.
In 1901 Reid Hunt, at that time a special agent of the United
States Department of Agriculture, studied the loco question in Montana,
working mainly with Aragallus spicatus. He moistened the
ground-up plant with 93 per cent ethyl alcohol and then percolated it
until exhausted. This extract was evaporated and taken up with water
so that 1 c.c. of the solution corresponded to 10 grams of the plant.
This was fed to an active young rabbit weighing 490 grams, 6 c.c.
being fed by the mouth and followed in about an hour by 10 c.c.
more, and two hours after this by 15 c.c. This rabbit showed no
symptoms during the following day. The next day it was very dull
and there was marked muscular weakness, as the rabbit’s legs were
spread wide apart and his nose rested on the ground. Later respiration
became very slow and the pupils were dilated. The paralytic
symptoms increased and finally, after a convulsive movement, the
animal died, thirty-six hours after the first feeding. Hunt merely
states of the post-mortem examination that the stomach was well
filled and that the “walls seem normal.”
Hunt tried to isolate an active principle by the Dragendorff
method, but failed to obtain any physiologically active shakings.
He tried hypodermic injections of 80 per cent alcohol extractions of
the fresh green plant, and after the injection of an extract corresponding
to 60 grams of the fresh plant there was no effect produced. He
tried to induce symptoms by feeding the plant itself to rabbits, but
was unsuccessful, as the rabbits refused to eat the plant. He was
not able to induce symptoms with the extracts of the dried plant.[139]
Marshall[140] studied the loco question with regard to sheep and practically
denies the existence of a locoed condition due to eating the
loco plants, but believes the condition due to bad feeding, parasitism,
etc. He lays great stress upon the presence of worms, but fails to
see that they may be merely a secondary infection superimposed
upon an already morbid condition produced by eating the plants.
Others have claimed that the cause is an insect living upon the
loco plants. Others, again, have suggested an analogy with trypanosome
disorders.
Chesnut has held the view that many of the cases of so-called locoed
sheep were really due to parasites, but that there was a true locoed
condition due to eating the loco weeds.
The lack of agreement in the results of the investigators has caused
many to doubt any positive relation between the plant and the disease,
and even as late as 1904 Payne[141] practically says these diseases
are due to lack of nutrition and not to the loco plant. The matter
has been summed up in a recent work as follows:
Though many chemists have sought for the constituents, none have been
able to locate the active properties, the trace of alkaloids, resins, volatile and
fixed oils having each in turn been found destitute of it. Yet the poisonous
properties are fully established by field observations. The destructiveness of
these plants to stock is so great as to have probably caused upward of a million
dollars loss in the aggregate, and large bounties have been offered by State
governments for an effective method of avoiding such losses. It is considered
very probable that the poisonous constituent is albuminoidal.[142]
Astragalus caryocarpus is at times eaten in some of the Western
States, but is claimed by some at certain stages of its growth to contain
a poisonous principle. Frankforter,[143] from experiments on himself,
however, denies this.
Astragalus glycophyllus has been used as a diuretic and Astragalus
exscapus in the treatment of syphilis.[144] “The seed of A. boeticus,
planted in Germany and England, are found to be the very best substitute
for coffee yet tried, and so used—roasted, parched, and mixed
with coffee.”[145] Astragalus nuttallianus, according to Smith,[146] is a
highly nutritious forage plant in spring. Astragalus crassicarpus
has been prophesied by him to be a valuable addition to early spring
soiling crops. Astragalus adsurgens (nitidus) and one or two other
species of Astragalus are still used in Chinese medicine.[147] The Indians
of the Southwest are familiar with certain loco plants.[148] The Tewans
of Hano are said to eat the root of Aragallus lamberti, and Astragalus
mollissimus is applied locally for headaches by some of the Arizona
Indians. One of these species is used as a flavoring material by the
Coahuillas and is mixed with other plants as spices.[149] Astragalus
kentrophyta had a reputation among the Navajos for the treatment
of rabies.[150] The use of certain loco plants—Astragalus mollissimus—has
been advocated on theoretical grounds in the treatment of certain
forms of insanity, but without favorable results.[151] In Peru and Chile
Astragalus garbancillo, A. unifultus, and A. ochroleucus have been
considered injurious to animals.[152] Astragalus glyciphyllus and A.
alpinus have been used in Europe as food for stock.[153]
Details as to the use of other Astragali can be found in Planchon,
G., Sur les Astragales, in Journal de Pharmacie et de Chimie, 5th
series, vol 24, p. 473, 1891; 5th series, vol. 25, pp. 169, 233, 1892.
The first point in our investigations was to determine whether the
plant exerted any poisonous action and to find some animal which
responded regularly to it; then to ascertain if the lack of results of
previous investigators was not due to insufficient doses, and later to
see if by feeding smaller amounts at repeated intervals symptoms
comparable to those described as occurring on the range could not be
produced. The animal finally selected was the rabbit.
Experiment No. 1.—On September 8, 1905, an aqueous extract of
333 grams of fresh Astragalus mollissimus, made in Hugo, Colo.,
and shipped preserved in chloroform,[154] killed a rabbit weighing
1,616 grams in one hour and thirty-five minutes, while an extract
corresponding to 167 grams merely caused drowsiness and loss of
appetite in a rabbit weighing 765 grams.
Experiment No. 2.—On November 29, 1905, a rabbit weighing
1,162.3 grams was fed with a concentrated aqueous extract of 500
grams of fresh Astragalus mollissimus, which had been shipped from
Hugo, Colo., preserved in chloroform in sealed vessels. This animal
died in one hour and ten minutes. The symptoms consisted in dullness,
rapid respiration, and signs of pain. At autopsy the stomach
and upper part of the small intestines showed hemorrhagic ecchymoses,
with dilation of the dural vessels of the brain and cord, with
a clot over a portion of the spinal cord.
Experiment No. 3.—On February 13, 1906, a rabbit weighing 992
grams was fed with a concentrated aqueous extract of 500 grams of
the fresh Astragalus mollissimus, collected in September and preserved
in chloroform water. Before feeding, the rabbit’s ears were
warm and the rabbit struggled when any attempt was made to turn
him on his back. The temperature at 10.50 a.m., the time of feeding,
was 103.5°F.; at 11.15 a.m., 102.5°F. At 11.30 a.m. the rabbit was
breathing very rapidly and would stay on his back for some time if
placed so. The temperature at this time was 102.6°F. Both
pupils, the one exposed to the light and the one protected, were contracted.
At 12.02 p.m. convulsive movements of the legs appeared.
The rabbit made one leap, the temperature rose to 103.6°F., and
after a few convulsive movements of the limbs the anus relaxed and
a small stool appeared, the pupils dilated, and the animal died at
12.06 p.m.
Experiment No. 4.—The feeding of the extract of 464 grams induced
a fall in temperature of 2.4°F. in three hours, and the rabbit
died several hours later (at night).
Experiment No. 5.—March 2, 1906, a rabbit weighing 928 grams
was fed with a concentrated extract of 500 grams of the fresh seeds
and pods of Astragalus mollissimus, made in September, 1905, and
preserved with chloroform water. This animal died in one hour and
seven minutes. The animal showed the usual post-mortem conditions.
It was thus found that the aqueous extract of 500 grams of the
fresh Astragalus mollissimus would cause death in about one hour
in rabbits weighing about 2 pounds (907 grams), these rabbits showing
constant clinical symptoms—urination, paralysis, more or less
convulsive muscular twitchings, often terminating in general convulsions,
drowsiness, and stupor, with more or less anesthesia. The
pupils at the time of death were often unequal. At first there was
usually a slight rise in temperature, but this was soon succeeded by
a fall. Often there were soft stools. The post-mortem lesions in
these cases were marked congestion, with hemorrhages in the stomach
walls and a secretion of thick mucus. The portions of the stomach
walls most affected were the dependent portions near the cardiac
end. The intestines showed dilatation of the blood vessels. The
mesenteric vessels and also the vessels in the cerebral portions of the
dura were markedly dilated; in some cases there were clots, especially
at the posterior portion of the brain, between the cerebrum and the
cerebellum. At times there were clots over the dorsal portion of the
cord. On cutting into the brain the brain substance itself did not
appear to be congested. The cord seemed about normal, but the
vessels of its membranes were well marked. The other organs showed
nothing characteristic macroscopically. These experiments were repeated
many times and found to be constant.
These acute symptoms were likewise produced by an extract of 500
grams of the fresh Aragallus lamberti from Arizona preserved in
chloroform water (rabbit weighing 1,998 grams). An aqueous extract
of 150 grams of the dried Astragalus mollissimus[155] from Imperial,
Nebr. (1906), caused death in one hour and fifty-eight minutes
in a rabbit weighing 1,530 grams, and an extract of 100 grams killed
in one hour and twenty-two minutes a rabbit weighing 736 grams.
An aqueous extract of 100 grams of the dried Astragalus bigelowii
induced death in one hour and thirty-eight minutes, the rabbit
weighing 1,502 grams.
An aqueous extract of 150 grams of Astragalus nitidus collected
at Woodland Park, Colo., in 1906 induced death in three hours and
five minutes, the rabbit weighing 1,672 grams.
An aqueous extract of 200 grams of the dried Astragalus bisulcatus
caused death after several hours (at night), the rabbit weighing
2,423 grams.
In certain cases this production of acute symptoms was not entirely
a question of salt action, as was shown by certain other experiments.
In other cases salt action seems to be the important factor, so that the
production of these acute symptoms can not always be considered
characteristic.
Experiment No. 6.—February 19, 1906, a large gray rabbit weighing
2,055.3 grams was fed with 60 c.c. of fluid representing the concentrated
aqueous extract of 250 grams of the fresh Astragalus mollissimus,
collected September 18, 1905, and preserved in chloroform.
This rabbit was very hard to hold. The ears rested on the body. The
temperature at the time of feeding, 1.30 p.m., was 102.3°F. At 2.57
p.m. the animal looked dull but resisted handling. At 3.30 p.m. it
urinated. At 4.15 p.m. the temperature was 98.5°F., the pupils were
about the same size as before feeding, and the animal became much
duller. The next day at 12.50 p.m. the temperature was 102.4°F.,
and at this time the animal could be handled with greater ease. The
animal ate in the morning. The same amount of extract was again
fed at 1.24 p.m. At 1.35 p.m. the animal was much duller and could
be turned on his back with ease. If disturbed he ran against the wall
as if utterly unconscious of the obstruction. The animal had soft,
liquid, brown stools and tried to lie down as much as possible. If
turned on its back with the feet up it would stay so almost indefinitely.
Temperature, 103.8°F.; respiration very rapid. At 2.40 p.m.
the temperature was 99.8°F., and the animal died a few minutes later.
After death the pupils were much contracted. The vessels of the
dura covering the brain were much dilated, but the vessels inside the
brain were not dilated. The stomach walls were congested and
marked with numerous petechiæ and covered with mucus.
Experiment No. 7.—On February 19, 1906, a white and brown
rabbit whose temperature was 103.2°F. was fed 30 c.c. of aqueous
fluid representing the concentrated extract of 125 grams of the fresh
Astragalus mollissimus, collected September, 1905, and preserved with
chloroform. The rabbit weighed 1,502.5 grams. This extract was
fed at 1.45 p.m., and at 4.15 p.m. the temperature was 102.6°F., but
there were no marked symptoms. The following day at 2.04 p.m. the
temperature registered 102.5°F. The same amount of extract was
given at 2.09 p.m. The temperature at 4 p.m. was 99.8°F., the
animal was dull, and the pupils were perhaps a little smaller. The
animal could not be turned over without resistance. The following
day, February 21, at 1.30 p.m. the temperature was 102.6°F., and at
1.45 the same amount of extract was given. At 1.54 p.m. the animal
was much duller and the breathing was very rapid. At 4.10 p.m.
the temperature was 101.3°F. The animal had been dull ever since
the feeding was begun. It nibbled food shortly before the last feeding.
On February 23 the same amount of extract was given at 2.16
p.m., temperature 99°F. The breathing was very rapid, the ears
shaking, and there was a sleepy, dull look about the animal. At 3.30
p.m. the animal was dull, but would still walk about if disturbed. At
this time the animal weighed 1,445.8 grams. At 4.30 p.m. the temperature
was 102°F. and the pupils were about normal size. There
was a marked sleepy look about the animal, which sat quietly in its
cage.
February 24, at 1 p.m., the animal was very dull and could with
ease be turned on its back with its feet in the air. It would sit in its
cage perfectly quiet. The weight at this time was 1,417.5 grams, the
temperature 96.6°F. On February 26 the animal weighed 1,360.8
grams. It was dull and refused to eat. The abdomen felt very distended
and tympanitic. February 27 the weight was still 1,360.8
grams, and the animal sat in its cage as if asleep, with eyes half
closed. There was no diarrhea and the abdomen was very distended.
At 11.15 a.m. there was a general convulsion and the animal fell
over. At 12 m. the abdomen seemed even more swollen, the animal
was hardly able to walk, and it fell over, uttering a cry. Pupils were
about normal—perhaps a little smaller. The animal died at 12.10
p.m.
The post-mortem, made immediately after death, showed the abdomen
markedly tympanitic, and the large intestines could be outlined
through the abdominal walls with ease. The large intestines were of
a chocolate color, intensely congested, and marked with hemorrhages.
On opening the abdomen there was a decided putrefactive odor, and
about an ounce of bloody fluid was found in the peritoneal cavity,
together with fibrin flakes. The stomach was pale, the first three
inches of the small intestine up to where it turned sharply were pale,
and below this the intestines were injected and full of gas and of a
dark red color. The kidneys were 3-1/2 centimeters long and were pale,
capsules easily peeled off; cortex pale. Liver pale and infected with
some coccideæ. The gall bladder was one-quarter inch wide and one
inch long. Spleen a trifle pale; lungs pale, nothing abnormal; heart
relaxed. On opening the stomach gas and fluid, with some food,
exuded. The walls were pale, but pink in some places. There was
no marked congestion or hemorrhage or perforation. The mesenteric
vessels were dilated. The upper portion of the intestines contained
a little mucus-like fluid, but lower down became bloody, and still
lower contained pus-like fluid. The walls were hemorrhagic. The
large intestine contained a soft, fecal-like fluid, very foul. Its walls
were much congested and full of hemorrhagic points. The cortex of
the suprarenal bodies was sharply defined, the medullæ brownish.
Brain pale, some dural vessels well marked, no clots or hemorrhages.
Base of brain pale. No congestion seen on cutting into the brain.
Spinal cord showed no hemorrhages or lymph effusions.
Experiment No. 8.—On February 18, 1906, at 2 p.m., a rabbit
whose temperature was 102.2°F. was fed with the aqueous extract
of 125 grams of fresh Astragalus mollissimus, collected in September,
1905, and preserved in chloroform, 30 c.c. of the fluid being used.
At 4.25 p.m. the temperature was 102.4°F. No symptoms were
noted. This rabbit weighed 1,644.3 grams. On February 20 at 2.09
p.m. the temperature was 102.2°F. and the rabbit showed no symptoms.
The same dose was repeated at 2.15 p.m. At 4 p.m. the temperature
was 100.3°F. The rabbit was dull but could not be turned
over without a struggle. February 21 at 1.30 p.m. the temperature
was 101.4°F. The same amount of extract was fed at 1.45 p.m.
At this time the animal was dull and breathed more rapidly. At
4.10 p.m. the temperature was 97.3°F. Next day the same amount
of extract was again given at 2 p.m. At 2.16 p.m. the breathing
became rapid and the animal duller. The ears were directed forward.
At 4.15 p.m. the temperature was 101.6°F.; weight 1,757.7
grams; animal slightly dull. February 24, temperature 102°F.,
weight 1,786 grams. March 5, weight 1,729.3 grams. The animal
was fed at 3.20 p.m. with a concentrated extract of 125 grams of
Astragalus mollissimus, collected in September. Temperature at
time of feeding 100.4°F.; 3.40 p.m., no symptoms; 4 p.m., temperature
102°F. March 7, weight 1,644.3 grams; March 8, weight 1,672.6
grams; March 10, weight 1,701 grams; March 12, weight 1,658.4
grams; March 14, weight 1,701 grams.
In this case, where the same dose was given in a period of five
days, very little effect on the rabbit was noted.
Experiment No. 9.—On March 1, 1906, a black rabbit weighing
2,664.8 grams was fed with a concentrated aqueous extract of 250
grams of fresh Astragalus mollissimus, collected in the fall of 1905.
On March 5 the weight was 2,296.3 grams. The animal was then
given the same amount of extract. During the afternoon it passed
mucus and thick pieces of feces and was dull; respiration very rapid.
March 6, weight 2,282 grams; March 7, 3 p.m., animal very dull and
would not eat; sat hunched up, but resisted being disturbed: weight
2,310.5 grams. March 8, weight 2,183 grams; March 9, weight
2,069.5 grams. Pupils dilated; finger could be run almost against
the eye, provided the lashes were not touched, without the animal
winking or paying any attention. Rabbit ate very little and had
not urinated since the preceding day. Left ear had fallen to the side
as if the animal were unable to support it. Weight, 1,912.8 grams.
From March 9 to March 11, 67 c.c. of cloudy urine were voided.
This did not clear with acetic acid. Left eye tearing. March 10,
head held to right side. March 12, weight 1,786 grams. Left pupil
smaller than right, neither responding to light. Rabbit very
weak. March 14, weight 1,729.3 grams. Would not eat. March 16,
weight 1,644.3 grams. Right pupil larger than left, neither responding
to light. Diarrhea present. Breathing noisy. In sitting down
she raised herself on her forelegs, evidently to take the pressure off
her abdomen, which was distended. If disturbed, she would butt
against the side of the cage, apparently oblivious of its presence.
Knee jerks were very active, almost a clonus. Reflex from tendo
Achillis active. March 17, forelegs spread out, head falling to left
side. The temperature had fallen below 94°F. and would not
register on the ordinary clinical thermometer. The ears twitched, the
head was thrown back, the abdomen was distended, and the rabbit
gritted its teeth. Died. Weight, 1,559.2 grams.
Brain and spinal cord pale. Dural vessels plainly seen but not
marked. Intestinal vessels congested. Stomach pale; nothing apparent
macroscopically save a small pin-point ulcer.[156] Heart relaxed.
Post-mortem examination otherwise negative macroscopically.
Experiment No. 10.—A mouse-colored rabbit weighing 1,927.8
grams was fed February 18, 1906, at 2.26 p.m., with a concentrated
aqueous extract of 250 grams of fresh Astragalus mollissimus collected
in September, 1905, and preserved in chloroform water. The
temperature of this rabbit was 102.6°F. The fluid given was 40 c.c.
At 2.45 p.m. the rabbit urinated and at 2.57 p.m. was dull and the
respiration became rapid. The animal then aborted and had three
young, two of which showed some movement after birth, but were
apparently premature.
On February 23 the temperature of this rabbit was 102.9°F. at
1.40 p.m. She was then fed with the same amount of the extract
as before. At 2.16 p.m. she lay down and became much duller; left
ear fallen to side. At 3.30 p.m. the rabbit was unable to stand. The
pupil of the eye exposed to the light was dilated. The animal died
without a struggle. The stomach contained much bloody mucus.
In the dependent portion of the stomach near the cardiac end were
marked petechiæ in the walls, with bright-red blood in the stomach
itself. The heart was relaxed. The intestines showed nothing abnormal.
The dural vessels of the brain were dilated; there was a clot
on the dura over the fourth ventricle. Spinal cord and kidneys normal,
the capsules not adhering. Weight, 1,786 grams at death.
Experiment No. 11.—On March 1, 1906, a rabbit weighing 2,126.2
grams was fed with a concentrated aqueous extract of 250 grams of
the fresh Aragallus lamberti preserved in chloroform water. On
March 5 this dose was repeated, 37.5 c.c. of the fluid being used.
March 6 the rabbit weighed 1,956 grams; March 7, 1,913.6 grams;
March 8, 1,828.5 grams; March 9, 1,701 grams; March 12, 1,672.6
grams; March 14, 1,644.3 grams.
Experiment No. 12. January 19, 1906, a concentrated aqueous extract
of 500 grams of the fresh Aragallus lamberti preserved with
chloroform water was fed to a rabbit weighing 785 grams. The temperature
at 12.10 p.m., the time of feeding, was 101.6°F. The temperature
1 hour and 43 minutes later was 94.6°F., and the animal
died shortly after, showing the same condition as occurred after feeding
extracts of Astragalus mollissimus.
Experiment No. 13.—A large, gray, pregnant rabbit weighing 2,891.6
grams was fed on February 22, 1906, with 42 c.c. of fluid, corresponding
to the aqueous extract of 250 grams of Astragalus mollissimus
collected in September and October, 1905, and preserved with chloroform.
At 4 p.m. the animal was dull, but still resisted efforts to
handle. On February 24 this animal weighed 2,778.2 grams, and on
February 26 it bore a litter of seven young rabbits. One or two of
these showed movements of the limbs, but were apparently immature.
This rabbit on March 10 weighed 2,537.3 grams; March 12, 2,438
grams; March 14, 2,508.9 grams; March 22, 2,494.7 grams.
Experiment No. 14.—On March 1, 1906, a black rabbit weighing
2,721.6 grams was fed at 12.15 p.m. with a concentrated aqueous extract
of 250 grams of the fresh Astragalus mollissimus collected in
September, 1905. On March 2 it weighed 2,438 grams; at 2.58 p.m.
it still resisted efforts to turn it on its back; at 3.15 p.m. it could be
turned on its back with ease. March 6 the weight was 2,338.8 grams;
March 7 the animal was very dull, would not eat, pupils dilated, hind
legs paralyzed; died during the night; weight, 2,267.9 grams.
The stomach walls were pale save at the dependent portion near
the cardiac end, where there was a hemorrhagic, ulcerated area about
1-1/2 by 1-1/2 inches. The intestines were full of gas, but not hemorrhagic.
The uterus contained eight immature fœti. The uterine walls were
hemorrhagic. The kidneys weighed 9-1/2 grams; their medullæ were
dark and the straight tubules well defined. The cerebral dural vessels
were congested and the spinal dural vessels were well defined.
The bladder was found contracted. The blood gave no bands for
methæmoglobin, but showed merely those of oxyhæmoglobin on spectroscopic
examination.
Experiment No. 15.—Control experiments made by feeding water
were negative, except when a large quantity (150 c.c.) of water was
given to a rabbit weighing 1,020.5 grams. The animal died in 12
hours with marked pallor of the tissues (hydræmia), a pathological
condition quite different from that obtained by feeding extracts of
the loco plants, and no such results were secured with the amount of
water used in our feeding experiments, 50 to 70 c.c.
Experiment No. 16.—On February 28, 1906, a white rabbit weighing
581.2 grams was injected subcutaneously at 10.35 a.m. with a concentrated
aqueous extract of 83 grams of fresh Astragalus mollissimus
collected in September, 1905, and preserved with chloroform. The
temperature before injection was 102.1°F. At 1.40 p.m. the animal
was dull; at 3.12 p.m. the temperature registered 99.8°F. The animal
died during the night. The post-mortem examination was negative.
Stomach pale; heart relaxed save left ventricle, which seemed
contracted; dural vessels of the brain dilated; kidneys perhaps normal.
No microscopical examination.
Experiment No. 17.—February 28, 1906, at 10.25 a.m., a guinea
pig weighing 496 grams was injected subcutaneously with a concentrated
aqueous extract of 83 grams of the fresh Astragalus mollissimus
preserved in chloroform water. At 1.40 p.m. there was muscular
twitching. The animal was dull and could be easily turned
on his back. The hind legs began to show weakness. At 1.50 p.m.
the hind legs were almost completely paralyzed and the animal could
be easily turned on his back. Muscles of the limbs twitched and
semen was expelled. Animal died at 2.15 p.m.
Post-mortem showed dural vessels of cord and brain full of blood.
Stomach pinker than normal: mesenteric vessels dilated. Heart
almost empty of blood. Kidneys congested.
These experiments indicate that an acute form of poisoning may
be induced by feeding concentrated aqueous extracts of Astragalus
mollissimus and Aragallus lamberti from Hugo, Colo., and Imperial,
Nebr., to rabbits, and that if the extract is given in smaller and repeated
doses a more prolonged or chronic condition may follow.
The rabbits showing the chronic effects of these plants exhibit
symptoms which have a marked parallelism with those reported as
occurring in larger herbivora (horses and cattle) on the range when
locoed; that is, the loss of appetite (Experiment No. 9), the emaciation
and loss in weight (Experiment No. 9), the dullness and
stupor, with more or less anesthesia (Experiment No. 7), the disturbance
in the visual function (Experiment No. 9), and the mental
symptoms (Experiment No. 6). The occasional abortion compares
with what has been observed in larger animals. The dried Astragalus
mollissimus and Aragallus lamberti still retained their poisonous
properties, as we were able to kill with aqueous extracts of the dried
plants made in the laboratory under the proper conditions.
Experiment No. 1.—On May 31, 1906, a sheep weighing 32.2 kilos
was fed with a concentrated aqueous extract of 1,000 grams of the
fresh Astragalus mollissimus preserved in chloroform water. The
temperature at 11 o’clock, the time of feeding, was 103.4°F. At 11.45
a.m. this dose was repeated. At 12 o’clock the temperature was
104.1°F. At 12.45 the animal urinated. At 1.10 p.m. a similar
extract of 2,000 grams was fed. The total liquid used was 1,500
c.c. On June 1 no symptoms were noted. On June 5 an extract of
3,000 grams of fresh Aragallus lamberti and 3,000 grams of Astragalus
mollissimus was fed. After feeding this the animal could
be easily turned over on its back and its ear pricked with impunity.
The animal at this time weighed 30.8 kilos. On June 6, at 11 a.m.,
the temperature was 104°F. The sheep had numerous soft stools,
and was very dull, and would not eat. On June 7 the temperature
was 103.7°F. and the sheep still refused to eat. On the 8th the temperature
was 103.2°F. at 10.40 a.m., and the stools were still numerous
and soft.
There were then fed 640 c.c., representing the aqueous extract of
4,000 grams of the fresh Aragallus lamberti. The animal could be
easily turned on its back. It weighed at this time 28.57 kilos. On
June 9, at 10.47 a.m., the temperature was 103.4°F. The sheep
still did not eat, but had no diarrhea. It now weighed 27.9 kilos,
and the temperature was 103°F. at 10.45 a.m.
On June 13 the animal began to eat, and 1,700 c.c. of fluid, representing
5,500 grams of the fresh Aragallus lamberti, were fed. The
temperature at 12.30 p.m. was 103°F. On June 14 the temperature
was 103.4°F., the animal weighed 28.3 kilos, and refused food. On
June 16 the weight was 28.3 kilos; the temperature at 2 p.m. was
103.5°F. There was no diarrhea.
On June 19 the aqueous extract of 1,000 grams of the dried Astragalus
mollissimus was fed with 420 c.c. of water. The temperature
was 102.6°F. On June 20 the temperature was 102.9°F. at 10.45
a.m.
On June 21 500 c.c., representing the aqueous extract of 1,000
grams of the dried Astragalus mollissimus, were again fed. The animal
now weighed 26.9 kilos. On June 26 the animal weighed 26 kilos,
and its gait was very uncertain. The temperature was 104.2°F. It
was fed 300 c.c. of fluid, representing the extract of 400 grams of
the dried Astragalus mollissimus. On June 29 the animal weighed
26.8 kilos and the temperature was 102.8°F. It was fed the extract
of 1,000 grams of dried Astragalus mollissimus in 500 c.c. of water.
On June 30, at 10.45 a.m., the temperature was 104.2°F. The animal
was very dull and died at night.
At autopsy the intestines and stomach merely appeared pale. There
were no worms, and the lungs and other organs appeared normal.
Experiment No. 2.—A lamb weighing 15.4 kilos was fed on July
6, at 1.10 p.m., with 640 c.c. of fluid, representing the extract of
2,000 grams of Astragalus mollissimus. At 1.17 p.m. the animal
could be turned on its back, and it regained its feet with difficulty.
At 1.24 p.m. it urinated and had a stool. The lamb died during the
night.
The autopsy the following morning showed the heart filled with
clots; lungs normal save for hypostatic congestion. The cerebral
and dural vessels were dilated. About 1-1/2 teaspoonfuls of bloody
serum were found at the base of the brain. There was none in the
lateral ventricles, and no clots. The kidneys exhibited no marked
congestion. There was no fluid found in the peritoneal or the pleural
or pericardial cavities. The first stomach, however, contained small
hemorrhagic spots, and the second was black. There were small
hemorrhages in the intestines.
Experiment No. 3.—July 13, 1906, a sheep weighing 19.5 kilos
was fed with 640 c.c. of fluid, representing the extract of 2,000
grams of Aragallus lamberti. The temperature at the time of
feeding, 1.10 p.m., was 105.3°F. At 1.49 p.m. the sheep could be
easily turned on its back. At 2.23 p.m. the temperature was 103.6°F.
At 3.42 p.m. the temperature was 103.5°F. At 4.20 p.m. the
respiration was fairly rapid. On July 14, at 11.15 a.m., the temperature
was 103.6°F. The sheep would run about but could easily
be turned over. It had not eaten, but there was diarrhea present.
July 15, at 3.30 p.m., the temperature was 104°F. The animal
had eaten. On July 17 the temperature was 104°F. and the animal
weighed 18.8 kilos. On the 27th it weighed 17.2 kilos; on August
29, 20.8 kilos.
Experiment No. 4.—A lamb weighing 19 kilos was fed August 21,
1906, with 740 c.c., representing the aqueous extract of 2,500 grams
of the fresh Astragalus mollissimus, shipped to Washington in September,
1905. This animal ate at night, but the following day was
dull. When seen on August 27 there was diarrhea present and the
animal was still dull. On the 28th the animal died, weighing 16.7
kilos. There was no autopsy on account of decomposition.
Experiment No. 5.—A lamb weighing 15.6 kilos was fed on September
4, 1906, with an aqueous extract representing 3,500 grams of
the dried Aragallus lamberti, 1,000 c.c. of water being used. The
temperature at the time of feeding was 104.3°F. At 2.48 p.m. the
animal on rising to its feet developed a slight tremor of the fore legs
and showed marked disinclination to stand on its feet. The temperature
was 104°F. The animal died at 4.25 p.m. The post-mortem
was negative, save for some reddening of the second stomach.[157]
These feeding experiments in sheep can not be considered quantitative,
because, as is shown later, aqueous extracts of dried plants are
often inactive, yet poisonous principles may be obtained from the
plants by treatment with digestive fluids.
Extracts of dried loco plants vary much in their toxicity; with
some the writer was unable to kill rabbits, even when an extract of
300 grams of the dried plant was used. It is interesting to note that
when the field station was established at Hugo, Colo., in 1905, almost
all the aqueous extracts of dried specimens sent to Washington would
produce the acute symptoms of poisoning in rabbits, but during the
third season of its existence many of the samples sent from the same
area were much less active, if not inactive.
The fact that the aqueous extract of 500 grams of the fresh Astragalus
mollissimus, or of 200 grams (in some cases 100 grams) of
the dried plant, when fed by mouth, would regularly kill a rabbit
weighing about 907 grams, with certain definite clinical symptoms
and pathological lesions, was at first arbitrarily selected as our test
to aid in the isolation of the active principle. Later the production
of chronic symptoms by the aqueous extract or digestion of 200 grams
of these dried plants given in doses of 100 grams each on two successive
days was considered essential. Carnivora, such as dogs and
cats, vomit so easily as to render them unsuitable for these investigations.
The aqueous extract was distilled with and without steam,
also after acidifying with sulphuric acid, and likewise after the
addition of magnesium oxid, but in all cases the distillate was
inactive.
The concentrated aqueous extract was shaken by the Dragendorff
method with petroleum ether, benzol, chloroform, ether, and amyl
alcohol, both in alkaline and acid condition, but the shakings yielded
no physiologically active body. Shakings by the Otto-Stas method
also proved inactive. Lead acetate, lead subacetate, silver nitrate,
mercuric chlorid, alcohol, phosphotungstic acid, trichloracetic acid,
ammonium hydrate, sodium carbonate, sodium hydrate, Mayer’s solution,
uranyl acetate, silver oxid, and barium carbonate also failed to
remove the active constituent. They gave heavy precipitates in all
cases, but these proved inactive. Hydrocyanic acid was sought for
with negative results. The pathological lesions in the very acute
cases suggested in some respects oxalic acid, a saponin, a metal, or
perhaps a toxalbumin as the active principle, but none of the precipitants
for saponins, such as lead and copper, or the magnesium oxid
method yielded a body which was active. Proteids were excluded
by the fact that the various proteid precipitants—alcohol, trichloracetic
acid, lead subacetate, mercuric sulphate or chlorid, and salting
out with ammonium sulphate and sodium chlorid (complete saturation
and half saturation)—failed to give an active precipitate. Glucosidal
or alkaloidal bodies were also excluded. On dialysing for
twenty-four hours, some of the active principle went into the dialysate
and some remained in the dialyser. Ether yielded a precipitate from
alcoholic solution which failed to kill. The possibility of the activity
of the plants being due to its normal acidity was excluded by neutralizing
the extract with sodium hydrate and precipitating the salts
with alcohol. The filtrate proved active after removing the alcohol.
The negative results in looking for active alkaloidal, or glucosidal,
or proteid bodies suggested that perhaps the action was due
to some inorganic constituent. The writer then boiled the extract
three minutes and as the filtrate was still found active and the proteid
precipitate inactive became convinced of the inorganic nature of the
active constituents, and finally incinerated the plant. The acid
extract from this was also active, but death was delayed several
hours. This was believed to be due to the insoluble form into which
the compound was converted.[158] In fact, the question of solubility
and the avoidance of an acid reaction, which of itself may kill, are
the main points to keep in mind.
These experiments indicated that the injurious action toward
rabbits of the Astragalus mollissimus and Aragallus lamberti collected
at Hugo, Colo., was due to one or more inorganic constituents,[159]
but it does not follow that all loco plants have the same poisonous
principle nor that the same species occurring on all soils has the
same poisonous action.[160]
Of Astragalus mollissimus from Imperial, Nebr., collected in 1906,
200 grams were ashed in a platinum bowl and extracted with water.
This aqueous extract when neutralized produced no marked symptoms
in a rabbit and the weight of the animal remained about the
same.
The ash undissolved after this extraction was then treated with
acetic acid and water overnight, and after carefully evaporating off
the acetic acid on the bath (tested by litmus paper) the residue was
fed, partly in solution and partly suspended in water, to a rabbit
weighing 1,800.2 grams. Next day the rabbit weighed 1,771.8 grams,
showed paralysis of the limbs, and died during the morning. The
stomach was intensely reddened and contracted.
An extract of a similar ash was made by boiling the same amount
with a large quantity of 94 per cent alcohol. This was evaporated
in vacuo and taken in water and fed to a rabbit weighing 1,459.9
grams. On the sixth day the animal died, having lost 70.9 grams in
weight. The stomach showed reddening but no ulcers.
An acetic acid aqueous extract, made from the ash after the alcoholic
extraction, proved inactive, showing that the alcohol had removed
the active bodies. A 70 per cent alcohol extract of another
ashed lot proved active, killing the rabbit overnight.
Of Astragalus mollissimus from Imperial, Nebr., 200 grams were
ashed in a platinum bowl and the ash treated with acetic acid water.
After freeing from acid, one half of the solution and emulsion was
fed one day and the second half fed the following day. The rabbit
at the time of feeding weighed 1,275.7 grams. Fourteen days later
the animal died, weighing 1,105.6 grams. No autopsy.
A similar extract of the ash from between 100 and 150 grams of the
same dried plant produced death in a rabbit weighing 1,190 grams in
two hours and fifty-eight minutes.
The acetic acid extract of the ash of 125 grams of a mixture of the
dried Astragalus mollissimus and Aragallus lamberti received from
Hugo, Colo., June, 1907, after freeing from acid, was fed to a rabbit
weighing 1,304 grams on July 29. On July 30 it weighed 1,332.4
grams. August 1 it weighed 1,219 grams, and it died the same day.
The stomach was reddened and showed ulcers.
A similar extract from 250 grams of the same dried plants on boiling
gave a heavy precipitate, but this precipitate was inactive, while
the filtrate killed a rabbit in four hours.
Of dry Aragallus lamberti collected in September, 1906, 200 grams
were extracted with water and fed to a rabbit weighing 1,516.7
grams. Two days later the animal weighed 1,360 grams and died the
same day.
The ash from 200 grams of the same dried plant was extracted
with acetic acid, and after evaporating off the acid this was fed to a
rabbit weighing 2,045.3 grams. Seven days later the animal weighed
1,729.3 grams, having lost 316 grams in weight.
The ash from 250 grams of the same species of plant, after similar
treatment with acetic acid, induced death in a rabbit weighing 2,069
grams in 2 hours and 20 minutes. The stomach was inflamed.
The filtrate from the ash from 200 grams of dried Astragalus mollissimus,
from Imperial, Nebr., after similar treatment with acetic
acid water and freed from free acid, killed a rabbit in several hours.
Hydrochloric acid also rendered the toxic agent of the ash soluble
in water, but proved unsuitable for our work, as it was found impossible
to obtain neutral residues by mere evaporation on the bath. At
first one of the heavy metals or members of the H2S group[161] was suspected,
but on passing H2S into the slightly acid extract of the ash no
active precipitate resulted, but the filtrate remained active.[162] A special
Marsh test was, however, made for arsenic and antimony with
negative results. A test for tungsten with zinc and hydrochloric
acid proved negative.
Members of the ammonium sulphid group were then suspected,
but while ammonium hydrate alone gave a heavy white precipitate,
this precipitate, as also the black one with ammonium sulphid, proved
inactive save when not thoroughly freed from acid (used for solution).
The action of this ammonium sulphid precipitate on rabbits
was watched for sixteen days, but without result. Nevertheless, the
writer still suspected some of the rare earths.[163]
Sestini[164] had found that if certain plants were nourished with a
solution of a beryllium salt, in the ash of these plants could be shown
the presence of beryllium.
Two grams of beryllium chlorid were fed in aqueous solution to a
rabbit weighing 1,800.2 grams. In four days this animal lost 241
grams and died. The stomach showed the same general pallor seen
in chronic locoed rabbits, but no ulcers. The tests for beryllium by
Sestini’s method, however, failed to show beryllium in the active loco
plants examined.
Thorium chlorid, cerium chlorid, and lanthanum chlorid in 2-gram
doses and zirconium chlorid in 3-gram doses produced no chronic
symptoms in rabbits or, in fact, any disturbance. Titanium chlorid,
2.5 grams, evaporated in the air and then fed in an emulsion to a
rabbit, also proved inactive, but this inactivity may have been due to
its insolubility.
Thallium nitrate c. p., in aqueous solution, in 2-gram doses, killed
a rabbit weighing 2,154.6 grams in two hours and fifteen minutes.
The stomach in this case, while pink, was not hemorrhagic.
Zirconium chlorid has an astringent taste, and if fed repeatedly will
cause the metallic astringent action. On boiling an acetic acid solution
of the ash with sodium acetate a precipitate formed.[165]
The presence of zirconium was thus suspected and Dr. E. C. Sullivan,
of the United States Geological Survey, estimated it to be
present in the ash of a sample of Aragallus lamberti in about 0.01
per cent zirconium oxid, with also 0.1 per cent titanium dioxid.[166]
Zirconium chlorid, 3 grams, was fed in aqueous solution to a rabbit
weighing 850.5 grams. This rabbit lost 96 grams in seven days,
and was then fed 3 grams more of the same solution and the following
day 2 grams more. It died eight days later, weighing 656
grams. The stomach and intestines were contracted, but showed
no ulcers. However, 4 grams killed a rabbit in two hours and thirty-two
minutes.
The filtrate, after treating an active solution of the ash with hydrogen
peroxid, proved active, thus showing that zirconium was not
entirely responsible for the poisonous action.
Yttrium, while not found in the plant, was administered as yttrium
chlorid to a rabbit weighing 1,530 grams in 2-gram doses in solution.
This animal gained 113.4 grams in five days.
Didymium chlorid c. p., in 3-gram doses, was fed to a rabbit
weighing 1,020 grams. This rabbit lost 70 grams in four days.
The administration of manganese acetate[167] in 2-gram doses was
followed by a gain in weight of a rabbit of 42.5 grams, while a dose of
3 grams killed a rabbit weighing 1,077 grams in two hours and thirty
minutes. Wohlwill[168] has emphasized the fact that the members of
the iron group owe their comparative harmlessness to not being absorbed
by the gastro-intestinal tract.
No zinc was found in the plant.[169]
It is well recognized that potassium salts given hypodermically
are decidedly toxic and that ammonium salts given per os will kill,
so that the writer considered the possibility of other members of the
group being responsible for the injurious action. The fact that the
alkaline distillate of the plant proved inactive eliminated the ammonium
salts.
Cæsium chlorid c. p., 2 grams, was fed in aqueous solution to a
rabbit weighing 1,077.2 grams. In six days this animal lost 255
grams in weight, when it died.[170]
A second rabbit, weighing 1,020.5 grams, was fed with 2 grams
of the same solution and lost 368 grams in twenty-one days. The
spectroscopic test, however, failed to show cæsium in the ashed
plant. Rubidium chlorid c. p., in 2-gram doses, proved inactive. The
platinum chlorid precipitate from the extract of the plant proved
inactive.
The fact that the filtrate after precipitation of the phosphates
by tin and nitric acid and H2S was active excluded the phosphoric
acid radical, and the filtrate after treatment with BaCO3 and AgO
being active excluded the H2SO4 and HCl radicals as the toxic
body. Fluorine was proved to be absent.
A radio-active substance was suspected, but Dr. L. J. Briggs,
Physicist of Bureau of Plant Industry, reported that the dried plant
showed no special amount of radio-activity.[171]
Power and Cambier, Sayre, and Kennedy had previously called
attention to the abundance of calcium in the plant, and the writer’s
investigations confirm this. Pharmacologists are averse to believing
calcium given per os poisonous. The writer has, however, fed 5
grams of the acetate of calcium in solution to a rabbit weighing
652 grams. This animal died in two hours, with marked irritation
of the stomach, the result being due to the so-called “salt action.”
Much larger amounts were fed in divided doses, but without injury.
Calcium phosphate and calcium sulphate in 2-gram doses proved
harmless to a rabbit weighing about 1,400 grams. Three grams of
magnesium acetate[172] were fed in solution for five successive days
to a rabbit weighing 1,417 grams, but without apparent effect.
Strontium acetate c. p., in 2-gram doses, likewise caused no disturbance.[173]
No strontium in any amount recognizable by chemical
tests was proved in the plant. So that by a process of exclusion the
writer was forced to think of barium as the main cause of the trouble.
The writer noted that if the ashed plant was extracted with H2SO4
water and this extract freed from sulphuric acid with PbCO3 and
H2S the solution proved inactive to rabbits and also that after this
extraction the acetic acid extract of the ash failed to kill. In other
words, the sulphate of our body was insoluble in water. At times
in passing H2S into active solutions of the ashed plant freed from
the acetic acid by evaporation the filtrate and likewise the precipitate
were inactive. Noyes and Bray[174] have noted that if H2S is passed
into certain solutions in the presence of an oxydizing agent, such
as ferric iron, H2SO4 would be formed, which would throw any
barium out of solution.
In one blood-pressure record made with a dog (vagi nerves cut),
a rise in blood pressure (a characteristic physiological action of
barium) was seen to follow the intravenous injection of the aqueous
extract of the plant, in spite of its normal acid reaction.
Accidentally the writer found that Sprengel[175] had reported the
presence of barium in Astragalus exscapus, a closely allied plant.
Barium has also been found in the vegetable world by Scheele in
1788, and later by Eckard,[176] who found it in beech, while Forchhammer[177]
proved it in birch, and Lutterkorth found it in the soil of
the same area in which Eckard worked. Dworzak[178] noted the occurrence
of traces of this element in wheat grown along the Nile, and
Knop[179] found it in the soil. Doctor Balfour, of Khartum, Egypt,
informed the writer that he knew of no cases in which this barium
in wheat had produced poisoning. Hornberger[180] found barium both
in the red beech grown in Germany and in the soil on which these
trees grew. It has also been claimed that various marine plants
may take up barium from the sea.[181]
Hillebrand[182] has called attention to the fact that the igneous rocks
of the Rocky Mountains showed a higher percentage of barium than
rock from other portions of the United States, so that under these
conditions one might expect the presence of barium in plants growing
in this region. A sample of Aragallus lamberti and one of Astragalus
mollissimus were sent to the Bureau of Chemistry for spectroscopic
examination for various elements and they reported traces
of barium in each.[183]
With these arguments the writer felt sure of the presence of
barium, and the matter was discussed with Dr. E. C. Sullivan, of the
United States Geological Survey, and he kindly corroborated the
conclusions reached as to the presence of barium, controlling its
presence by means of the spectroscope, and estimated it roughly as
0.1 per cent BaO in the ash of a sample of Aragallus lamberti (6.3
milligrams BaSO4 in 4 grams ash). This determination was made
by Hillebrand’s method.
Kobert has anticipated this result, saying that “all plants are in
the position occasionally to take up barium combinations from the
soil,” and “the plants which thus contain barium may act injuriously
to men and animals.”[184]
The reports of the ash analyses of the loco plants show marked
variations in the total amount of the ash. Thus, from Aragallus
lamberti Dyrenforth obtained 4.32 per cent and O’Brine 13.52 per
cent of ash. The Bureau of Chemistry analyzed two different
samples of this dried plant and reported in one case 11.15 per cent
and in the second 11.64 per cent of ash. O’Brine[185] obtained 13.52
per cent of ash from the same species. The writer’s analysis[186] gave
in one sample of Aragallus lamberti, collected at Hugo, Colo., in
1907, 18.8 per cent of ash; a second lot (1907), 12.44 per cent; a
third (1906), 11 per cent, and a fourth (May, 1905) gave 37.3 per
cent of ash.[187] One lot from Woodland Park, Colo. (October, 1906),
gave 6.4 per cent. One lot from Hugo, Colo. (October, 1907),
yielded 9.6 per cent.
In the case of Astragalus mollissimus, Wentz obtained 6.76 per
cent, Sayre 12.01 per cent, Kennedy 20 per cent, O’Brine 12.15 per
cent, while the sample analyzed by the Bureau of Chemistry gave
18.4 per cent of ash. One sample from Kit Carson County, Colo.
(December, 1906), which proved inactive physiologically, gave an
ash content of 6.9 per cent. A sample of Astragalus missouriensis
collected at Hugo, Colo., June, 1907, yielded an ash content of 21.8
per cent, and an Astragalus missouriensis collected at Pierre, S. Dak.,
September, 1907, yielded 27 per cent. An Astragalus nitidus from
Custer, S. Dak. (July, 1907), gave 5.2 per cent ash, while an Astragalus
nitidus collected at Woodland Park, Colo., in October, 1906,
yielded 7.8 per cent, and another specimen of Astragalus nitidus
also collected at Woodland Park, Colo., in October, 1907, gave 12.2
per cent. An Astragalus drummondii from Custer, S. Dak. (July,
1907), gave 5.9 per cent. Astragalus pectinatus (Hugo, June, 1907)
yielded 6.1 per cent. A fresh (undried) specimen of Astragalus
mollissimus (unknown origin, November, 1907) yielded 3.8 per cent
of ash. One sample of Astragalus decumbens (Ephraim, Utah,
August, 1907) gave 21.8 per cent of ash.
These determinations must necessarily be only approximate, as
the plants were collected by different persons who exercised different
degrees of care in freeing them from adherent soil, and possibly
in drying the plants, so that the main value of these figures
is their aid in determining the amount of barium present.
Attention has been called to the fact that in ashing plants containing
barium a part at least of this barium is converted into the
insoluble sulphate and a part into the carbonate, so that the characteristic
pharmacological action of the ash will depend not upon
the total barium present, but upon the form in which it occurs—little
action if much BaSO4, and more complete if more BaCO3
results. A further difficulty in the recognition of barium in plants
is due to the fact that certain inorganic salts interfere with the
precipitation by H2SO4.
A specimen of Aragallus lamberti (Hugo, summer of 1907) with
12.44 per cent of ash was examined for its barium content by Hillebrand’s
method.[188] The method was as follows:
Two grams of the ash were first fused with sodium carbonate and
the fused mass washed with water containing sodium carbonate. The
residue was washed into a beaker and treated with a few drops of
sulphuric acid. The residue now remaining was filtered and after
ignition was treated with hydrofluoric and sulphuric acids. After
evaporating off these acids, the residue was treated with sulphuric
acid water, filtered, and then fused with sodium carbonate. After
extracting with sodium carbonate water, the residue was dissolved in
just enough hydrochloric acid and precipitated with sulphuric acid.
The precipitate was dissolved in concentrated sulphuric acid and
reprecipitated by water and weighed as BaSO4.[189] So far as the
writer can ascertain, there have been no control experiments made for
this method to determine the experimental error.
Of the above ash, 1.998 grams gave 5.2 milligrams of BaSO4, which
would correspond to 75.75 milligrams of barium acetate crystals—Ba(C2H3O2)2+H2O—in
200 grams of the dried plant. The residue
by the Hillebrand method after weighing was tested with the spectroscope
and gave a bright spectrum for barium. The same ash was
analyzed by the Bureau of Chemistry, using a shorter method, and
they reported 2.7 milligrams of barium sulphate in 1.1217 grams of
ash. A second sample collected earlier in the summer, with an ash
content of 18.6 per cent, was shown to yield barium corresponding to
3.4 milligrams of BaSO4 in 2.5 grams of the ash.[190]
One lot of Aragallus lamberti collected at Hugo, Colo., in May,
1905, and which gave an ash content of 37.3 per cent, was found to
yield 3 milligrams of BaSO4 from 1.998 grams of ash, or 173.88
milligrams of Ba(C2H3O2)2+H2O in 200 grams of the dried plant,
but this ash also contained 0.27 per cent of SO3. The Bureau of
Chemistry reported the barium to correspond to 2.9 milligrams of
BaSO4 in 2.45 grams of the ash.
The Astragalus missouriensis (Hugo, June, 1907), with an ash
content of 21.8 per cent, gave 3 milligrams of BaSO4 in 2.01 grams
of ash, or 76.58 milligrams of Ba(C2H3O2)2+H2O in 200 grams of
the dried plant. The residue after weighing was tested spectroscopically
and gave a bright barium spectrum.
The Astragalus drummondii from Custer, S. Dak. (1906), Astragalus
mollissimus from Kit Carson County, Colo. (December, 1906),
and Astragalus nitidus from Woodland Park, Colo. (October, 1907),
were reported by the Bureau of Chemistry to contain no barium.
The ash of the Astragalus pectinatus (Hugo, June, 1907) was reported
by the Bureau of Chemistry to show no barium on spectroscopic
examination.
Two grams of active loco plant ash yielded from 5 to 6 milligrams
of BaSO4, but it can be easily seen that in multiplying this amount to
correspond to 200 grams of the dried plant errors would be likely to
arise, so that the whole amount of barium would not necessarily be
accounted for.
One sample of the soil from near Hugo, Colo., from which the
Aragallus lamberti was collected, was examined by the Bureau of
Soils, and that Bureau reported the absence of barium and zirconium,
at least of any recognizable by the chemical methods used, so that it
can not be said that the barium came from any soil accidentally mixed
with the ash. Traces of titanium were, however, found. Evidently
the plant must collect minimal quantities of these elements from the
soil and store them.
The water from a well of an adjacent area was examined by the
Bureau of Chemistry and reported to contain 37.4 parts of calcium
and 13.7 parts of magnesium in one million, and that the water contained
no barium.[191]
On these figures the writer took 0.2 gram of crystallized barium
acetate c. p., using the acetate because acetic acid has been proved in
certain loco plants by Power and Cambier, and after dissolving it in
water fed it at 9.45 a.m. to a rabbit weighing 1,177 grams. The
head soon fell forward so that the nose rested on the ground. At
10.58 a.m. the rabbit seemed unable to guide itself and would run
into obstructions if forced to move. There was no diarrhea but it
urinated several times. There was a peculiar tremor of the muscles
noted. The animal would not startle by sudden noises and at 11.06
a.m. could be placed on its back with ease. The pupils appeared
about normal. The whites of the eyes showed very prominently. At
11.35 a.m. the fore legs were paralyzed. The following morning the
animal was dead, its weight being 1,120 grams. The heart was dilated;
the stomach was not hemorrhagic, but rather pale.
A second rabbit, which weighed 1,630 grams, was fed with a solution
of 0.5 gram of the same salt at 9.42 a.m. At 10.35 a.m. the
animal passed soft stools and showed a marked disinclination to
move, with evidence of pain. The diarrhea[192] became more marked
and the animal’s hind quarters were soiled with feces. At 10.48 a.m.
there was marked incoordination of the limbs and inability to stand.
Finally, at 10.56 a.m., convulsions began and the animal died at 11.02
a.m. The autopsy was made about two hours later. The animal
was then rigid. The kidneys seemed rather congested. The intestines
were relaxed; mesenteric vessels dilated. The pyloric region
of the stomach appeared hemorrhagic.
A third rabbit, fed like the preceding with 0.5 gram of barium
acetate, showed much the same result. In this case there was some
retching, but the other symptoms were as above, the animal dying
in one hour and five minutes. No hemorrhages were seen in the
stomach walls. It was noted that after the administration of certain
doses, 0.2 gram, there was no diarrhea.
On September 23, 1907, a rabbit weighing 1,757 grams was fed at
10.42 a.m. with 0.1 gram of the same barium acetate. The temperature
at the time of feeding was 102.9°F. At 12.05 a.m. the animal
urinated. Temperature, 101.4°F. On September 24 the animal
weighed the same. Temperature at 10.55 a.m., 102.3°F. The same
amount of barium was fed. At 3.40 p.m. the temperature was
102.5°F. On September 25 the animal weighed 1,800 grams. Temperature,
102.2°F. at 10.39 a.m. The dose of barium was repeated.
At 3.55 p.m. the temperature was 101.4°F. On September 26 at
9.38 a.m. the temperature was 101.1°F., and again the barium was
given. At 3.57 p.m. the temperature was 101.5°F. On September
27 the rabbit weighed 1,772 grams. The temperature at 9.53 a.m.
was 102.3°F. The barium was fed for the fifth time. At 10.27 a.m.
there were general convulsions. The eyes teared. At 10.32 a.m.
soft stools appeared and the animal urinated. Stools were passed at
various periods. At 11.30 a.m. there were no signs of pain on
pinching the ear. At 11.58 a.m. the animal retched. The animal
was lying with the fore legs wide apart and could not support itself.
At 12.05 p.m. the temperature was 98°F. and the rabbit died
shortly after.
The peritoneal cavity seemed normal. The small intestines were
relaxed, while the mesenteric vessels were dilated. The kidneys seemed
congested. The stomach walls were pink and in places covered with
mucus. The heart was relaxed save the left ventricle, which seemed
firm.
On September 23, 1907, a second rabbit, weighing 1,360 grams, was
fed with a similar solution and the feeding was repeated at the
same time the first rabbit was fed. On September 27 the animal
weighed 1,416 grams. On this day a peculiar movement of the hind
legs on jumping appeared, apparently due to an inability to draw
the legs completely up, and the fore legs were spread wide apart, as
if too weak to support the animal. The temperature had also fallen.
On September 28 the animal had apparently recovered. Weight,
1,516 grams on October 21.
On September 23, 1907, a third rabbit, weighing 1,304 grams, was
fed with 50 milligrams of barium acetate. This dose was repeated
each time the other two rabbits were fed. On September 27 it
weighed 1,304 grams. Marked muscular twitching appeared, with
disinclination to move. Finally there were convulsions and paralysis
of the limbs. No stools were seen. This animal lay quiet all night,
apparently unable to move, and continued on its side until 3.15 p.m.
on September 28, when it gradually recovered, weighing 1,346 grams
on October 24.
On October 24, 1907, a rabbit weighing 1,346.5 grams was fed with
a solution of 25 milligrams of crystallized barium acetate. On the
next day the weight was 1,318 grams, and the dose was repeated. On
October 26 it weighed 1,275.7 grams, and the dose was repeated; on
October 30 it weighed 1,332 grams, and on October 31 its weight was
1,375 grams. The animal died at night on November 6; weight, 1,134
grams. The post-mortem examination, made with Dr. Meade Bolton,
of the Bureau of Animal Industry, was negative save for the presence
of necrotic tissue in one enlarged thyroid.
On October 24, 1907, a rabbit weighing 1,332 grams was fed with a
solution of 25 milligrams of crystallized barium acetate. On the
next day the animal weighed the same, and the dose was repeated.
On October 26 it weighed 1,289 grams, and the same amount of
barium was given. On October 28 the weight was 1,219 grams and
two days later 1,289 grams.
On October 31, 1907, a rabbit weighing 723 grams was fed with a
solution of 25 milligrams of barium acetate. This rabbit was fed in
all nine times during a period of ten days. At the end of this time
it weighed 779 grams and died six days later, weighing 723 grams.
The post-mortem was negative.
A rabbit weighing 779 grams was also fed on October 31, 1907,
with a similar amount of barium. This dose was repeated six times
during an interval of eight days. At the end of that time the animal
still retained its normal weight. On November 14, 1907, it weighed
709 grams, having lost 70 grams. Thus after daily doses of 0.1 gram
of crystallized barium acetate no symptoms appeared until the fifth
day, when death resulted. After the similar administration of 50
milligrams severe symptoms developed on the same day, but the animal
recovered. After the administration of 25 milligrams on three
successive days the animal died. In other cases of feeding 25 milligrams
for several successive days, some lost weight and died; others
merely lost in weight, but recovered.
Bary fed a rabbit weighing 0.9 kilogram a solution of 30 milligrams
of barium chlorid on one day, on the second day 90 milligrams, and
on the third day 30 milligrams. The only symptom noted was diarrhea.
The animal died on the fifth day. In other words, after feeding
small doses of barium salts for several days acute symptoms suddenly
set in, showing a cumulative action. This cumulative action
has been noted on man.[193]
Onsum[194] fed a medium-sized rabbit daily with small doses of barium
carbonate, beginning with 20 milligrams. When the total amount
reached 0.19 grams the rabbit died. The animal before death
showed paralysis, respiratory disturbances, and fall in temperature.
The sensibility of the cornea diminished, but the pupils responded to
light. The stomach walls showed ecchymoses and the blood vessels
of the brain, the spinal cord, and the abdominal vessels were dilated.
Emboli in the pulmonary arteries were also noted.
In a rabbit the application of 0.66 gram of barium chlorid to a
wound was followed in twenty minutes by convulsions, paralysis, and
finally coma and death.[195]
Of barium nitrate 0.66 gram mixed with sugar and fed to a rabbit
caused death in less than one hour, and 0.33 gram induced death in
another rabbit in twenty-seven hours.[196]
Six grains (0.4 gram) of barium iodid fed in solution to a
rabbit caused death the following day. On this day there were
tremors of the neck and shoulders with convulsive movements of the
limbs. There was also grinding of the teeth. “The mucous membrane
of the stomach was rose-red at the cardia, and softened.”
Membranes of the cord and brain also were congested.[197]
For rabbits weighing 1,500 to 2,000 grams the lethal dose of barium
chlorid on subcutaneous use is stated to be 0.05 to 0.06 grams.[198]
A rabbit weighing 1,106 grams was fed with a solution containing
50 milligrams of crystallized barium acetate c. p. and 50 milligrams
of zirconium chlorid (pure). In fifty-seven minutes the animal
showed difficulty in moving the fore legs, developing marked
paralysis of the same about five hours later, and died the following
morning—that is, twenty-two hours after feeding. The heart was
found dilated, kidneys congested, stomach walls pink and covered
in places with mucus and partly digested blood, and cerebral dural
vessels dilated, but no clots were seen; bladder full.
Mixtures of 0.5 gram of calcium acetate and 50 milligrams of
barium acetate failed to kill. Mixtures of titanium and barium were
not tried, as no titanium salt soluble in water and of neutral reaction
was accessible.
Mittelstaedt called attention to the fact that pregnant rabbits were
more easily affected by the barium administration than nonpregnant
ones, and noted abortion in one case.[199]
One gram of the barium carbonate killed a dog in eight hours. A
second dog died in fifteen hours. Both of these animals vomited so
that a portion of this must have been lost.[200] Barium carbonate was
formerly employed as a rat poison.[201]
Of barium chlorid 0.6 gram, fed in aqueous solution, caused death
in a dog in forty-eight minutes if vomiting was prevented.[202]
In Tidy’s hands 2 grams of the barium nitrate caused death in a
small terrier in three and three-fourth hours. This dog had slight
convulsions, was almost unable to stand, and had vomiting and purging.
The reflexes were diminished. A small dog recovered only
completely in five days after being fed 0.66 gram, while a large dog
after being fed 1.3 grams only recovered after two days.
In cats 0.8 gram of barium carbonate when introduced into a
wound caused on the third day languor, slow respiration, feeble
pulse, twitching of hind legs, dilated pupils, and death.[203]
The high toxicity of barium was called attention to by early observers,
but it was attributed by some to admixed arsenic. The
reports of feeding experiments with barium on animals have varied
markedly, but now care is being advised in the use of barium salts.[204]
Barium was introduced into medicine in the treatment of scrofula,
but has fallen into disuse, and only recently attention has been called
to it on account of its action on the circulatory system. Filippi,[205]
however, says, “The effects on the heart and on the pressure are
already the first indication of poisoning.” This metal has also been
used in the treatment of chronic diseases of the spinal cord, as multiple
sclerosis and paralysis agitans.[206]
After the administration to a woman of 1/12 grain (0.005 gram) of
barium chlorid three to five times a day for a few days, a total of 2-1/4
grains (0.135 gram), the patient developed rapid respiration, tenderness
over the epigastrium, nausea, constipation, cramps in the limbs,
loss of appetite, weakness, great emaciation, dysuria, some deafness
with tinnitus, difficulty in speaking and thinking, with vertigo.[207] In
this case the eyes were glassy, the vision indistinct, and the cheeks
flushed. Kohl after the use of small doses of the same noted salivation,
swelling of the gums, and falling out of the teeth, with a
mercurial odor to the breath. Christison[208] states: "I have known
violent vomiting, gripes, and diarrhea produced in like manner by
a quantity not exceeding the usual medicinal doses." According to
Kennedy few persons are able to bear 1/8 grain (0.0075 gram) of barium
chlorid.[209]
In Carpenter’s case after three doses of 1.6 grains (0.070 gram) of
barium chlorid the patient developed almost lethal symptoms.[210] Carpenter
calls attention to the drowsiness which developed in this
patient after the administration of barium, a fact which had already
been noted by Christison.[211]
A cartarrhal affection of various mucous membranes and a swelling
of various glands have been noted, especially of the lymph and
salivary glands, and in the male the testes have at times swollen.[212]
The inflammation of the glands may pass on to suppuration. The
skin becomes dry and shows a tendency to crack. Febrile attacks
are reported after the repeated use of small doses of barium.
Scheibler[213] has called attention to the possibility of producing
chronic barium poisoning in man from the use of barium in the manufacture
of food products.
Acute cases of poisoning in man from four or more grams of barium
carbonate or chlorid or nitrate have been reported more or less frequently.[214]
In the acute case of poisoning in man reported by Tiraboschi
and Taito, no macroscopic changes were noted in the stomach
mucosa.[215] Lopes[216] has reported one case of acute poisoning in man
from less than 1 gram of barium chlorid. In this case paralysis of
the limbs was a marked feature. Stern[217] cites Perondi and Lisfranc
to the effect that “remarkably large doses of barium chlorid can be
borne without injury by gradually increasing the doses (dissolved
in much water).” Lisfranc[218] has suggested that the sensitiveness to
poisoning by barium salts is greater in certain climates than in others.
No data are as yet available as to the influence of altitude and partial
starvation on the toxicity of barium salts. As is well known,
almost all recorded cases of locoed animals have occurred at a high
altitude.
It must also be remembered that the addition of one salt to the
solution of another may greatly increase the toxicity of the first one.
Thus, the addition of a few milligrams of barium chlorid to a solution
of a sulphocyanate renders the latter much more poisonous.[219]
This may be due to the fact that the salts are more completely
ionized.
The post-mortem examinations in cases of acute experimental barium
poisoning, according to Schedel,[220] show punctiform or large
hemorrhagic effusion in the fundus ventriculi[221] and in the large and
small intestines, contraction of the bladder, and hemorrhage into the
walls of the bladder and uterus. The heart is usually found relaxed
or the left ventricle contracted in systole, while the right is relaxed.
Only once were ecchymoses under the endocardium seen. The liver and
kidneys showed nothing special. The urine was free from albumen
and sugar. In a few cases the lungs showed some infiltration with
blood. In chronic cases, according to our own investigations in rabbits,
there are no characteristic macroscopic lesions, a result which
agrees with Mittelstaedt’s report.[222] Nothnagel and Rossbach[223] claim
that in chronic poisoning by barium the peripheral nerves are altered.
The same negative results have also been reported in chronic
poisoning in higher animals. Reynolds[224] noted a layer like a blood
clot under the cerebellum in a horse fed with barium chlorid. Fuchs[225]
has called attention to the fact that the flesh of cattle poisoned with
barium chlorid was harmless, perhaps owing to a conversion into an
insoluble salt, a fact which may be considered in the use of locoed
animals for food.
On October 21, 1907, a rabbit weighing 1,531 grams was fed with
an extract of 95 grams of dried Aragallus lamberti (Hugo, Colo.,
1907), with an ash content of 12.44 per cent, with a barium content
estimated as 2.6 milligrams of BaSO4 in 1 gram of ash. On the following
day it weighed 1,517 grams, and the same dose was again
administered. On October 23 the weight was 1,488 grams, and the
dose was repeated. On the next day the weight was the same and
the dose was repeated. On October 26 the weight was 1,446 grams,
and again the same extract was given. On October 30 the animal
weighed 1,502.5 grams; on October 31, 1,531 grams. The animal
received a total extract of 475 grams of the dried plant without serious
injury. This result was apparently contradictory to the earlier
work.
On October 21, 1907, a rabbit weighing 1,743 grams was fed with
an extract of 47.5 grams of the same dried plant. On the next day
its weight was 1,729 grams, and the same amount of the extract was
fed. On October 23 the weight remained the same, and the dose was
repeated. On October 24 the weight was 1,658 grams, and the same
amount of extract was fed. On October 26 the animal weighed
1,630 grams, when it was again fed with the same amount of extract.
On October 28 the animal weighed 1,573.5 grams, but two days later
the weight had risen to 1,644 grams. An extract of 237.5 grams had
been administered. Here again the results appeared contradictory.
On October 21, 1907, a rabbit weighing 1,517 grams was fed with
an extract of 77.5 grams. On the next day it weighed 1,545 grams,
and the dose was repeated. On October 23 the animal weighed 1,531
grams, and the same amount of extract was given. On the following
day it weighed 1,488 grams, and the dose was repeated. On October
26 it weighed 1,474 grams, and again the dose was repeated. On
October 30 the weight had risen to 1,545 grams, and on October 31
it was 1,559 grams. This animal received in all an extract of 387.5
grams of the dried plant. An aqueous extract of 200 grams of the
same in one dose also failed to produce the acute symptoms.
These feeding experiments show little of the characteristic action
seen in the earlier experiments made with aqueous extracts either
of the dry plant or of the fresh plant preserved with chloroform.
In other words, the aqueous extract of the dried plant was only
slightly poisonous, yet the plant from which the extract was made
contained barium.
Of this same dried loco 200 grams were then extracted with water
and digested with pepsin and finally with pancreatin in the thermostat
(37.5°C.). The extract was concentrated and fed to a rabbit
weighing 1,616 grams. After five hours and ten minutes the animal
appeared weak in the fore legs and unable to support himself, and he
died during the night. The intestines the following morning were
found full of gas, the stomach red, the lungs seemed normal, and the
heart was relaxed.
A rabbit weighing 1,545 grams was fed on November 15, 1907, with
a preparation made in a similar manner, save that the plant was not
extracted with water before digestion. On the next day it weighed
1,517 grams and on November 19, 1,361 grams. The following day
the weight was 1,318 grams; on November 21, 1,233 grams, and on
the next day 1,162 grams. The animal died during the night, and
the autopsy was made the following morning.
The animal was greatly emaciated and the subcutaneous fat had
almost all disappeared. The mesenteric vessels were dilated, but
the intestines were not dilated. The peritoneal cavity was normal.
The kidneys were perhaps a little injected, and measured 3 cm.
in length. The lungs were normal. The left ventricle was contracted
and the rest of the heart relaxed. The liver was normal and
the spleen apparently normal. The stomach walls were dark, owing
to decomposition. No ulcers were seen. The suprarenals were perhaps
a little enlarged. The examination of the brain was negative,
and no clots were found.
A similar digestion from 200 grams of the same dried plant was
then ashed and the ash treated with acetic acid and freed from acid
by evaporation on the bath. The ash which was insoluble in water
was ground up into a fine paste and the whole was fed to a rabbit
weighing 992 grams. This animal died in forty minutes, showing
the characteristic symptoms seen in acute cases already described. In
the autopsy the lungs and other organs seemed perfectly normal
macroscopically. The stomach walls, however, were reddened and
ecchymotic, and the mesenteric vessels were dilated.
On January 8, 1908, a similar digestion of the same batch was
treated with a few drops of sulphuric acid to remove the barium, and
the filtrate was then treated with lead carbonate to remove the sulphuric
acid. After careful filtering, H2S was passed into the solution
and after concentration was fed in one dose on January 9, 1908,
to a rabbit. The following morning the rabbit had gained in weight.
On January 14 this animal weighed 30 grams more than its initial
weight.
The residue of this plant after such a digestion, examined by the
Hillebrand method, showed no weighable amount of barium, so that
it can be seen that barium in relatively large amount was found in
the plant itself, but not after the digestion. It must therefore have
been the aqueous digestion which produced the characteristic symptoms.
The examination of this fluid for barium might, however, be
misleading, as the large amount of proteids would unquestionably interfere
with the determination of this amount of barium, unprotected
by other salts and silica, so that this side of the investigation was not
pursued. Control feedings with an emulsion of one-half gram each
of pepsin and pancreatin proved inactive.
Of the same Aragallus lamberti 200 grams were similarly digested
and the barium was removed with a few drops of H2SO4, the sulphuric
acid by PbCO3 and a little lead acetate, and the lead by H2S.
Such an extract it was shown in the previous experiment would not
kill. However, to this extract was added 100 milligrams of crystallized
barium acetate in a solution and a precipitate formed. Nevertheless,
the liquid and the precipitate were fed on February 1, 1908,
to a rabbit weighing 1,304 grams. On February 3 the animal weighed
1,233 grams; on February 4, 1,176 grams; February 5, 1,120 grams;
February 6, 1,006 grams; February 7, 1,219 grams; February 8, 1,219
grams; February 10, 1,304 grams.
As a control for this animal, to make sure that the loss in weight
was not due to the acetic acid set free by the treatment with H2S, a
similar aqueous extract of the same lot of Aragallus lamberti was precipitated
with very much more lead acetate than in the preceding
cases and also with lead subacetate and then H2S. After evaporating
to dryness this was fed on February 8, 1908, to a rabbit weighing
1,035 grams. On February 11 it weighed 1,021 grams; on February
13, 1,091 grams, and on February 15, 1,120 grams, showing a gain in
weight.
Of the dried Astragalus missouriensis (Hugo, Colo., June, 1907)
400 grams with an ash content of 21.8 per cent and which was known
to contain barium (3 mg. BaSO4 in each 2 grams of the ash) were
extracted with water and fed in four doses corresponding to 100
grams each in a period of four days. On November 18, 1907, the
first day of feeding, this rabbit weighed 1,856.7 grams. Fifteen days
later it weighed 1,984.3 grams.
One hundred grams of this dried plant after extraction with water
were found to leave about 51.1 grams[226] of the plant undissolved. This
when ashed yielded 8.2 grams of ash. Two grams of this ash yielded
5 milligrams of BaSO4. In other words, the aqueous extract of the
plant was inactive and the barium was found practically unextracted
in the residue of the plant.
Evidently the barium in these dried plants had been converted into
an insoluble form by drying or by some peculiarity of its metabolism,
and was not extracted by water, but could be extracted by digesting
the plants with the combined digestive ferments, pepsin and pancreatin.
Of the same dried Astragalus missouriensis 200 grams were extracted
with water and the extract treated with lead carbonate to
remove any possible free sulphates and after filtering this was treated
with H2S to remove the lead. As the preceding experiment showed
that the aqueous extract of this dried plant was harmless without
barium, the writer decided to add barium artificially, and 100 milligrams
of barium phosphate,[227] crystallized, was added to the liquid and
the whole fed to a rabbit weighing 2,423.9 grams. The following
morning the rabbit was found dead. The autopsy was made by Dr.
H. J. Washburn, of the Bureau of Animal Industry. He found that
the suprarenals were enlarged and congested, and there were small
areas of hepatization at the apex of each lung. There were also acute
corrosion areas on the greater curvature of the stomach and over the
upper portion of the duodenum.
Of the Astragalus missouriensis used in the preceding experiments,
200 grams were extracted thoroughly with water, and the extract corresponding
to 100 grams, together with 80 milligrams of barium
phosphate pure, was fed on March 12, 1908, to a rabbit weighing
1,261.5 grams. During this day the animal walked at times with an
uncertain gait and the following morning it weighed 1,233 grams. It
was then fed the rest of the solution, that is, the extract of the remaining
100 grams of the plant, but without any barium. The animal soon
developed convulsions and died in a little over twenty-four hours
after the original feeding. The autopsy, which was made by Dr. J. R.
Mohler, of the Bureau of Animal Industry, showed that the mucous
membrane of the stomach was markedly hemorrhagic and in areas
gelatinous infiltration was very marked. In one portion of this hemorrhagic
area there was distinct erosion. The large intestines were
full of gas, the lungs were normal, the heart was relaxed, and the
lungs collapsed. The blood vessels of the kidneys were markedly
engorged.
Of the dried Astragalus nitidus (Woodland Park, Colo., October,
1907) which was reported by the Bureau of Chemistry as containing
no barium, 200 grams were extracted with water and fed in 100-gram
doses for two successive days. The animal increased steadily in
weight and fifteen days after the first feeding had gained 99.2 grams.
This amount of the plant was also extracted with water and the residue
was then digested with pepsin and pancreatin in the thermostat,
as in the previous case, and fed in two doses corresponding to 100
grams each. This animal increased in weight, gaining 60 grams in
six days and 165 grams in addition after a further fifteen days.
An Astragalus mollissimus (Kit Carson County, Colo., December,
1906), which was also reported by the Bureau of Chemistry as containing
no barium, was extracted with water, and a dose corresponding
to an extract of 200 grams of the dried plant was fed in one dose
without any serious result. The same amount of the dried plant
was also similarly digested with pepsin and pancreatin and fed in
two doses, but without the production of any symptoms, the rabbit
gaining 60 grams in four days.
Of the Aragallus lamberti (Hugo, Colo., June, 1907), with an ash
content of 12.44 per cent, 250 grams were ashed and the ash treated
with acetic acid and, after evaporating off the acetic acid, was extracted
with water and the ash digested with pepsin and pancreatin.
The aqueous extract and the digestion products of the ash were then
fed after concentration, but without any serious effects to the animal,
indicating that in this plant the barium is in a form insoluble in
water and in the ashing is further changed so that it can not now
be made soluble by digestion—an opposite result to the experiment
in which the barium was first rendered soluble by digestion and the
digestion products ashed, suggesting a possibility that plants might
be found in which the barium is not extracted by digestion, at present
a hypothesis.
Of dried Astragalus decumbens (Ephraim, Utah, 1907), which
was reported by the Bureau of Chemistry to contain no barium, 200
grams also failed to produce symptoms in rabbits by our test.
A solution containing 50 milligrams of barium acetate (crystallized)
was mixed with an aqueous extract of 200 grams of the dried
Aragallus lamberti which had proved inactive pharmacologically,
but a precipitate formed (BaSO4?) and the extract still remained
inactive, suggesting that the question of toxicity depended not only
upon the presence of barium, but also whether other agents, such as
sulphates, etc., might not be present in sufficient amount to render the
barium insoluble; that is, pharmacologically inactive.
This Aragallus lamberti yielded an ash content of 37.3 per cent,
and the SO3 group was estimated at 0.27 per cent of the ash, while
a corresponding lot which was obtained two years later from the
same area yielded an ash content of 12.44 per cent and a SO3 content
of 0.24 per cent of the ash.
It may be urged that the full lethal dose of the barium was not
always found in the plant, yet it must be remembered that the toxic
action was the resultant of the action of the total constituents and
that if the barium was removed the extract was practically harmless.
In looking back over the work the most suitable preparation for
producing the characteristic symptoms in rabbits seems to be the
freshly ground-up plant mixed with water and preserved in chloroform,
for while the dried plant might contain barium, yet the aqueous
extract was often inactive, suggesting, perhaps, the presence of
something in the fresh plant which aided the solution of the barium,
thus accounting for the variations in toxicity of aqueous extracts
made from plants dried under varying conditions. The nature of
the compound in which barium exists in the plant is as yet unknown
and has not been investigated. It is important to remember that not
only must barium be found in the plant to prove poisonous, but it
must be in such a form that it can be extracted in the gastro-intestinal
canal.
The amount of barium found in various species of loco plants will
no doubt vary, and perhaps the pharmacological test on rabbits as
the writer has used it may have to be modified for such plants, so
that at present the wisest plan to test these plants is to determine
their barium content and also make the physiological test, as has been
proposed, and if the barium content runs low, say below 0.11 per
cent of the ash, in plants yielding from 12 to 18 per cent of ash, then
to increase the number of feedings on the rabbit. No doubt on ranges
where a large number of loco plants are eaten, with little other food,
plants with a very low barium content may be poisonous, but if
large amounts of other food are fed the writer would expect few, if
any, serious results.
As the writer’s work has been confined to the laboratory side of the
loco-weed investigations no feeding experiments with barium salts
have been made by him on large animals. Such experiments should,
of course, be made under range conditions; that is, where the water
and food supply is deficient.
The fact that treatment of the loco-weed extract with a few drops
of sulphuric acid, which will remove the barium, renders these extracts
harmless, and even apparently nutritious, would suggest the
theoretical antidotal treatment to be with sulphates, in the form,
perhaps, of epsom salts, but perhaps alkaline bicarbonates may be
present in the stomach, either due to lessened acidity of the stomach
or from drinking alkaline waters, in which case the precipitation
of the barium by sulphates would presumably be interfered with,
and thus the treatment be rendered ineffectual.[228] It is interesting to
note that most of the remedies proposed for the successful treatment
of locoed animals contain sulphates.[229]
In Storer’s experiments on feeding rats with barium carbonate it
was found that the barium carbonate would kill them, but if calcium
carbonate was mixed with the barium the rats survived, suggesting
an antidotal action. This apparent antagonism deserves
further study and may lead to practical results.[230] A somewhat similar
antagonism for at least a part of the action of barium has been
claimed to exist between barium and potassium.[231] However, extracts
of ashed plants, treated with acetic acid, which contained calcium
and potassium, caused death in the experiments of the writer,
but no work has yet been done by him as to the antidotal action of
calcium carbonate on barium. Then, too, as Lüdeking[232] pointed out,
large quantities of calcium chlorid may interfere with the precipitation
of barium as a sulphate. It is well known that the presence of
various salts influences the solubility of barium sulphate in water,[233]
and the fact that barium has been found in solution in the urine in
the presence of sulphates shows that the precipitation of barium as
a sulphate in the body is not so simple as in test-tube experiments.[234]
Again, in very dilute solutions, such as must necessarily occur at any
one time in the stomach, the precipitate with sulphates only slowly
forms and the barium may be absorbed before the insoluble compound
can be formed.[235] Evidently an important point to be considered
in the antidotal treatment of locoed animals with sulphates is the
possibility of inducing a gastritis, with its attendant loss of weight.
It therefore seems apparent that the proper treatment at present
is preventive—that is, removal from the plants.
Lewin[236] has suggested the possibility of acquiring some immunity
to barium, but our experiments point against the production of any
practical immunity.
Barium in the form of barium chlorid has been recently introduced
into veterinary therapeutics by Dieckerhoff[237] in the treatment of
constipation, but Winslow[238] says that "the doses required to produce
catharsis in the horse are almost toxic," and he advises against the
intravenous use of this remedy.
Fröhner[239] has carefully summarized the literature on the use of
barium chlorid in veterinary work, and reports that its use in the
Zürich clinic has recently been so unsatisfactory that it is now seldom
employed and that in the last ten years the preponderance of reports
in the literature are unfavorable to the use of this agent in colic.
After the administration per os, much of the barium must be
carried off in the diarrheal stools. A number of deaths in horses
have been attributed to the use of this agent. No doubt the presence
of sulphates, etc., derived from the food would render the barium
insoluble in the gastro-intestinal tract, and this would explain the
lack of poisonous action in certain of the cases in which large doses
of barium proved harmless.
Husard and Biron administered daily doses of 8 grams of barium
chlorid to one horse, and the same amount of barium carbonate to a
second horse, for several days. A fortnight later the first horse unexpectedly
died, and the second a few days later. The post-mortem
examination was negative.[240] A third horse fed with barium carbonate
also died suddenly. Recently barium occurring in brine has
given rise to acute poisoning in stock.[241]
In a case reported by Stietenroth[242] the horse died after the injection
of 0.5 gram of barium chlorid into the jugular vein. A number
of sudden deaths in horses after the intravenous injection of 0.7 gram
and over of barium chlorid have been collected by Fröhner.[243] The
lethal dose by mouth for acute poisoning with barium chlorid in
horses lies between 8 to 12 grams, while cattle require much larger
doses (40 grams)[244] to induce death.
Dieckerhoff advises against the use of barium chlorid in the treatment
of constipation in sheep.
After a dose of 6 grams of barium chlorid a 2-year-old healthy
ram appeared perfectly well, but the following day he was depressed,
refused to eat, staggered, and became so weak that he was unable to
stand. The muscles of the extremities were paralyzed and the animal
died. “The post-mortem examination revealed œdema of the lungs,
slight cloudiness of the heart muscles, numerous small hemorrhagic
spots on the mucous membrane of the small intestine, and stagnation
of the blood in the vessels of the small and large intestines. Similar
symptoms and lesions were found in a lamb 4 months old which was
given per os 6.0 grams of barium chlorid dissolved in 200 grams of
distilled water.”[245]
Poisonings with barium carbonate have also been reported in
pigs.[246] Domestic animals pastured in the neighborhood of barite
deposits soon succumb,[247] and accidental cases of poisoning are reported
in cows. Poisoning in dogs has also been reported after the subcutaneous
use of this agent.[248] Linossier says that if the barium salts
are used for any time the salts are deposited in various organs, largely
in the kidneys, brain, and medulla, but especially in the bones.[249]
It has been calculated that a medium estimate of food for cattle
on green fodder is about 60 pounds (30 kilos) a day.[250] Calculating
this entirely in terms of Aragallus lamberti and allowing 10 per cent
of moisture for these plants (Sayre) would make 27 kilos of dry loco
eaten by each animal per diem. In the analysis of the writer of one
Aragallus lamberti from Hugo, Colo., it was found to yield 12.44 per
cent of ash, and the barium content corresponded to 2.6 milligrams
BaSO4 in each gram of the ash. This would correspond to 10.24
grams of barium acetate (Ba(C2H3O2)2 + H2O) or 9.15 grams of
barium chlorid (BaCl2 + 2H2O) per diem. This amount daily
administered would, theoretically, readily produce chronic poisoning
owing to the accumulation in the system, as was shown in the case of
rabbits.
There is, however, some question as to whether this full theoretical
amount of loco plants is eaten on the range, and the estimate has been
made that one-sixth of this amount only would be actually taken.
It must be remembered, as Stalker pointed out, that locoed animals
develop an especial taste for these plants and after a time reject other
food, so that while the number of loco plants at first taken may be
small, yet later, perhaps, it is greater. A part of this barium, however,
may not be taken up by the system, but may pass out undissolved.
No actual experiments have yet been made with cattle by
feeding small doses of the pure salt.
No doubt more of the pure barium salts will be required to produce
symptoms of poisoning in animals than would be necessary in the case
of the form of barium found in the plant, as in the loco-weed the
barium is probably better protected from precipitation than are the
barium salts when dissolved in water alone.
(1) Conditions analogous to those met with in locoed animals
occur in other portions of the world, especially Australia.
(2) The main symptoms described in stock on the range can be
reproduced on rabbits by feeding extracts of certain loco plants.
Those especially referred to here under the term “loco plants” are
Astragalus mollissimus and Aragallus lamberti.
(3) The production of chronic symptoms in rabbits is a crucial
test of the pharmacological activity of these plants.
(4) The inorganic constituents, especially barium, are responsible
for this action, at least in the plants collected at Hugo, Colo. Perhaps
in other portions of the country other poisonous principles may
be found.
(5) A close analogy exists between the clinical symptoms and
pathological findings in barium poisoning and those resulting from
feeding extracts of certain loco plants. Small doses of barium salts
may be administered to rabbits without apparent effect, but suddenly
acute symptoms set in analogous to what is reported on the
range.
(6) The administration of sulphates, especially epsom salts, to
form insoluble barium sulphate would be the chemical antidote
which would logically be inferred from the laboratory work, but
of necessity this would have to be frequently administered and its
value after histological changes in the organs have occurred remains
to be settled. But even the treatment of acute cases of barium poisoning
in man is not always successful, even when sulphates combined
with symptomatic treatment are employed. The conditions
under which the sulphates fail to precipitate barium must be considered.
At present it seems best to rely on preventive measures
rather than on antidotal treatment.
(7) Loco plants grown on certain soils are inactive pharmacologically
and contain no barium. In drying certain loco plants the
barium apparently is rendered insoluble so that it is not extracted
by water, but can usually be extracted by digestion with the digestive
ferments.
(8) The barium to be harmful must be in such a form as to be
dissolved out by digestion.
(9) In deciding whether plants are poisonous it is desirable not
merely to test the aqueous or alcoholic extract, but also the extracts
obtained by digesting these plants with the ferments which occur
in the gastro-intestinal tract.
(10) It is important that the ash of plants, especially those grown
on uncultivated soil, as on our unirrigated plains, be examined for
various metals, using methods similar to those by which rocks are
now analyzed in the laboratory of the United States Geological
Survey.
(11) It is desirable to study various obscure chronic conditions,
such as lathyrism, with a view to determine the inorganic constituents
of lathyrus and other families of plants.
