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 dec.u.mbens_ (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 const.i.tuents 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 ca.n.a.l._

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 pota.s.sium, but it was free from a.r.s.enic.

=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 pota.s.sium.[231] However, extracts of ashed plants, treated with acetic acid, which contained calcium and pota.s.sium, 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 Ludeking[232] pointed out, large quant.i.ties 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.

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 Inst.i.tute, vol. 2, p. 274. 1884.

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

[232] Ludeking, C. a.n.a.lyse d. Barytgruppe. Zeits. f. a.n.a.l.

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. a.n.a.l. 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.

Frohner[239] has carefully summarized the literature on the use of barium chlorid in veterinary work, and reports that its use in the Zurich 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 Frohner.[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 succ.u.mb,[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]