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.
* * * * *
FOOTNOTES:
[204] According to v. Jaksch, "Sie ist bei der grossen
Toxicität der Substanz immer ernst zu stellen." Vergiftungen,
1897, p. 79.
NOTE.--A thorough pharmacological study of some barium salt
is much needed, and it is hoped that the writer will be able
to complete this work.
[205] Filippi, E. Modificaz. del Ricambio Organice per Azione
del Cloruro di Bario. La Sperimentale, vol. 60, p. 610. 1906;
Sull' Azione Cardiaca del Chloruro di Bario. Archivio di
Farmacol. Speriment., vol. 5, p. 122. 1906.
[206] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d.
unorganisch. Arzneistoffe. Leipzig, 1907, p. 234.--Hare, H.
A. Use of Barium Chloride in Heart Disease. Med. News, vol.
54, p. 183. 1889.
[207] Ferguson, J. C. Symptoms of Poisoning from Muriate of
Barytes. Dublin Quart. Journ. Med. Sci., vol. 1, p. 271.
1846.
[208] Christison, R., l. c., p. 580.
[209] Kennedy, H. Dose of the Muriate of Barytes. Lancet,
vol. 2, p. 28. 1873.
[210] Carpenter, J. S. Barium Choride from a Clinical
Standpoint. Med. News, vol. 59, p. 93. 1891.
[211] Christison, R., l. c., 1845, p. 578.
[212] Schulz, H. Vorles. ü. Wirkung. u. Anwendung d.
unorganisch. Arzneistoffe. Leipzig, 1907, p. 233.--Schwilgué,
C. J. A. Traité de Mat. Méd., 3 ed., vol. 1, p. 441. 1818.
NOTE.--According to the files of the Office of
Poisonous-Plant Investigations, E. D. Smith reported in the
Orange Judd Farmer, 1897, that locoed animals showed a
swelling of various glands. As yet the writer has been unable
to verify this reference.
[213] Scheibler, C. Ueber d. Verwendung giftiger Stoffe,
besonders d. Barytverbindungen bei d. Zuckerfabrication.
Chem. Zeit., vol. 11, p. 1463. 1887.
[214] Schmidt's Jahrbücher, vol. 192, p. 131. 1881.--Walsh,
J. Report of a Case of Poisoning by Chloride of Barium.
Lancet, vol. 1, p. 211. 1859.--Walch. Seltener Fall einer
tödlich. Vergiftung d. Baryta muriatica. Zeits. f.
Staatsarznk., vol. 30, p. 1. 1835.--Carpenter, J. S. Barium
Chloride from a Clinical Standpoint. Med. News, vol. 59, p.
93. 1891.--Eschricht. Dødeligt forløbende Forgiftning med
salpetersurt Baryt. Ugeskrift for Laeger, vol. 4, p. 241.
1881.--Ogler and Socquet. Empoisonnement par le Chlorure de
Baryum. Annal. d'Hyg. Publ., 3 s., vol. 25, p. 447.
1891.--Chevallier, A. Note sur un Cas d'Empoisonnement
Déterminé par l'Acétate de Baryte. Annal. d'Hyg. Publ., 2 s.,
vol. 39, p. 395. 1873.--Courtin, Cas d'Empoisonnement par du
Chlorure de Baryum. Rev. d'Hyg., vol. 4, p. 653.
1882.--Poisoning by a Baryta Compound. Pharm. Journ., 3 s.,
vol. 2, p. 1021. 1872.--Reichardt, E. Vergiftungsfall mit
kohlensäurem Baryt. Arch. d. Pharm., 3 s., vol. 4, p. 426.
1874.--Lagarde, P. Acétate de Baryte livré sous le Nom de
Sulfovinate de Soude. Union Méd., 3 s., vol. 14, p. 537.
1872.--Baum. Zwei Fälle von fahrlässiger Tödtung durch
saltpetersäures Baryt. Zeits. f. Medizinalbeamte, vol. 9, p.
759. 1896.--Funaro, A. Sul Veneficio per Sali di Bario.
L'Orosi, vol. 12, p. 397. 1894.
[215] Tiraboschi, A., and Taito, F. Avvelenamento da Bario.
Il Risveglio Medico d'Abruzzo e Molise, vol. 1, p. 171. 1906.
NOTE.--A criticism of this case is to be found in Bellisari,
G., Su Di un Presunto Avvelenamento da Bario. Il Risveglio
Medico d'Abbruzzo e Molise, vol. 2, p. 15. 1907.
[216] Lopes, A. Caso Curioso de Envenenamento Pelo Chloret de
Bario. Medicina Contempt., Lisbon, vol. 4, p. 109. 1886.
[217] Stern, E. Vergiftung mit Chlorbarium. Zeits. f.
Medizinalbeamte, vol. 9, p. 383. 1896.
NOTE.--The writer has always theoretically questioned the
danger of poisoning by loco weeds in well-fed and
well-watered animals. Compare Stalker, M., The "Loco" Plant
and Its Effect on Animals. Bur. Animal Industry, 3d Ann.
Report (1886), p. 271. 1887.
[218] Lisfranc. Leçon sur l'Emploi du Muriate de Baryte
contre les Tumeurs Blanches. Gaz. Méd. de Paris, 2 s., vol.
4, p. 215. 1836.
[219] Pauli, W., and Fröhlich, A. Pharmakodynam. Studien.
Sitz. Kaiserl. Acad. d. Wissens. z. Wien, vol. 115, III, pt.
6, p. 445. 1906.
=PATHOLOGICAL LESIONS IN EXPERIMENTAL BARIUM POISONING.=
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.
* * * * *
FOOTNOTES:
[220] Schedel, H. Beitr. z. Kennt. d. Wirkung des
Chlorbariums. 1903, p. 13.
[221] After subcutaneous injection of barium chlorid, Lewin,
by means of the spectroscope, has found barium in the stomach
walls. Lewin, L. Schicksal körperfremder chem. Stoffe im
Menschen u. besonders ihre Ausscheidung. Deutsch. Med. Woch.,
vol. 32, p. 173. 1906.
[222] Mittelstaedt, F. Ueber chronische Bariumvergiftung.
Dissert., Greifswald, 1895, p. 29.
[223] Nothnagel, H., and Rossbach, M. J. Handb. d.
Arzneimittel, p. 81. 1904.
[224] Reynolds, M. H. A Study of Certain Cathartics. Minn.
Agric. Exper. Sta., 15th Ann. Rept. 1907.
[225] Fuchs, C. J. Vergiftungsfälle durch salzsäuren Baryt
beim Rindvieh. Thierärztl. Mittheil., vol. 5, p. 159. 1870.
Fuchs suggests that further investigations on this point are
desirable. The literature of this class of experiments is
very scanty. See Fröhner and Knudsen, Einige Versuche über d.
Geniessbarkeit d. Fleisches vergift. Thiere. Monats. f.
Prakt. Thierheilk., vol. 1, p. 529. 1890.
=TOXICITY OF VARIOUS AQUEOUS EXTRACTS OF LOCO PLANTS.=
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 BaSO_{4} 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, H_{2}S 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 H_{2}SO_{4}, the sulphuric
acid by PbCO_{3} and a little lead acetate, and the lead by H_{2}S. 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 H_{2}S, 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 H_{2}S. 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. BaSO_{4} 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 BaSO_{4}. 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 H_{2}S
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 (BaSO_{4}?) 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 SO_{3} 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 SO_{3} 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.
* * * * *
FOOTNOTES:
[226] Some was lost, being attached to the cloth used in
squeezing the extract.
[227] This barium phosphate was determined by the Bureau of
Chemistry to be BaHPO_{4} and to contain traces of iron,
sodium, and potassium, but it was free from arsenic.
=THEORETICAL ANTIDOTE FOR LOCO-WEED POISONING.=
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]