Part 9

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.

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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]

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.

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FOOTNOTES:

[228] Mendel, L. B., and Sicher, D. F., l. c., p. 148.

[229] Mayo, N. S. Some Observations upon Loco. Kans. State Agric. Coll. Bul. 35, p. 119. 1893.

[230] Storer, F. H. Experiments on Feeding Mice with Painter's Putty and with Other Mixtures of Pigments and Oils. Bul. of Bussey Institute, vol. 2, p. 274. 1884.

[231] Brunton, T. L., and Cash, J. T. Contribution to Our Knowledge of the Connection between Chemical Constitution, Physiological Action, and Antagonism. Philos. Trans. Royal Soc. London, I, vol. 175, p. 229. 1884.

[232] Lüdeking, C. Analyse d. Barytgruppe. Zeits. f. Anal. Chem., vol. 29, p. 556. 1890.

[233] Fraps, G. S. Solubility of Barium Sulphate in Ferric Chloride, Aluminum Chloride, and Magnesium Chloride. Amer. Chem. Journ., vol. 27, p. 288. 1902.

[234] Santi has paid special attention to the solubility of barium in the body.

[235] Fresenius, C. G. Man. of Qualitat. Chem. Anal. Tr. by H. L. Wells, 1904, p. 148.

[236] Lewin, L. Nebenwirkungen d. Arzneimittel, 2 ed., p. 439. 1893.

=ACTION OF BARIUM ON DOMESTIC AND FARM ANIMALS.=

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 oedema 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]

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FOOTNOTES:

[237] Dieckerhoff. Ueber d. Wirkung d. Chlorbaryum bei Pferden, Rindern und Schafen. Berliner Thierärztl. Woch., p. 265; see also pp. 313 and 337, 1895; Abstract In Vet. Mag., vol. 2, p. 360. 1895.

[238] Winslow, K. Vet. Materia Medica and Therapeutics, p. 152. 1901.

[239] Fröhner, E. Lehrb. d. Arzneimittellehre, p. 399. 1906. Fröhner gives a detailed account of these cases.

Original note in Ehrhardt, J. Erfahrungen ü. ältere u. neue Arzneimittel. Schweizer Archiv. f. Thierheilk., vol. 41, p. 44. 1899.

[240] Pelletier. Observations on Strontian. Journ. Nat. Philos., vol. 1, p. 529. 1797; original in Annales de Chimie, vol. 21, p. 127. 1797.

[241] Howard, C. D. Occurrence of Barium in the Ohio Valley Brines and Its Relation to Stock Poisoning. W. Va. Univ. Agric. Exper. Sta. Bul. 103. 1906.

[242] Stietenroth. Ueber Chlorbarium bei der Kolik der Pferde. Berliner Thierärztl. Woch., p. 16. 1899.

[243] Fröhner, E. Lehrb. d. Toxikol., 2 ed., p. 116. 1901.

[244] Fröhner, E., l. c., p. 116.

See similar reports in Veterinarian, vol. 68, p. 572, 1895, and vol. 69, p. 228, 1896; Zeits. f. Veterinärk., vol. 8, pp. 99 and 211, 1896; Nagler, F., Berliner Thierärztl. Woch., p. 65. 1896.

[245] Dieckerhoff, W. Vet. Mag., vol. 2, p. 362. 1895.

[246] Kabitz, H. Ueber d. Wirkung einiger Baryumsalze beim Schwein. Deutsch. Thierärztl. Woch., vol. 13, p. 317. 1905.

[247] Parkes. Chem. Essays, vol. 2, p. 213. Quoted by Christison, R., in Treatise on Poisons, Edinburgh, 4 ed., p. 581, 1845.--Fuchs, C. J. Vergiftungsfälle durch salzsäuren Baryt beim Rindvieh. Thierärztl. Mittheil., vol. 5, pp. 133, 154. 1870.

[248] Falk. Zur Vergift. von Hunden mit Chlorbarium. Berliner Thierärztl. Woch., p. 40. 1897.--Schirmer, Chlorbariumvergift. beim Hunde. Berliner Thierärztl. Woch., vol. 23, p. 268. 1897.

[249] Linossier, G. De la Localisation du Baryum dans l'Organisme à la Suite de l'Intoxication Chronique par un Sel de Baryum. Comp. Rend. Hebd. Soc. de Biol., 8 s., vol. 4, p. 123. 1887.

NOTE.--Other cases of poisoning in animals may be found in Marder, Beitrag z. Giftwirkung des Baryum chloratum. Berliner Thierärtzl. Woch., vol. 37, p. 436. 1897; Absichtliche Vergift. mit Chlorbarium. Zeits. f. Veterinärk., vol. 9. p. 72. 1897.

=APPLICATION OF THE RESULTS OF THESE INVESTIGATIONS TO THE RANGE.=

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 BaSO_{4} in each gram of the ash. This would correspond to 10.24 grams of barium acetate (Ba(C_{2}H_{3}O_{2})_{2} + H_{2}O) or 9.15 grams of barium chlorid (BaCl_{2} + 2H_{2}O) 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.

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FOOTNOTES:

[250] Lane, C. B. Soiling Crop Experiments. N. J. Agric. Exper. Sta. Bul. 158, p. 18. 1902.--Woll, F. W. One Hundred American Rations for Dairy Cows. Univ. Wis. Agric. Exper. Sta. Bul. 38, p. 12. 1894.--N. J. State Agric. Exper. Sta., 20th Ann. Rept. (1899), p. 193. 1900.

CONCLUSIONS.[251]

(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.

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FOOTNOTES:

[251] Résumé of the results of the loco-weed investigations carried on by the Bureau of Plant Industry was issued as Bulletin 121, part 3, Bureau of Plant Industry, on January 28, 1908, in the form of papers by C. Dwight Marsh and Albert C. Crawford, respectively, under the titles "Results of Loco-Weed Investigations in the Field" and "Laboratory Work on Loco-Weed Investigations."

INDEX.

Page. Abortion, cows, caused by loco poisoning, 13 rabbits, caused by loco and barium poisoning, 41, 42, 62

Acid, acetic, found in loco-weed, 26

Acqua, C., reference to work, 52

Africa, South, goat disease, 17

Alfalfa, extract, experiments, 28

Alkali deposits, supposed to cause loco disease, 11

Alkaloidal reactions, loco plants, 20, 23, 27, 28

Amaranthus graecizans, supposed cause of loco disease, 10

American Pharmaceutical Association, proceedings, reference, 10

Ammonia obtained from loco plants, 26

Ammonium sulphid precipitate, effect on rabbits, 50

Anæmia, progressing, fundamental characteristic of loco disease, 16, 19

Analyses of loco plants, 21, 22, 23, 32

Anderson, F. W., references to work, 10, 12, 14, 18, 19