Part 4

Carl Ruedi[11] 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:

KEY TO ASH ANALYSIS: A = SiO_{2}. B = Fe_{2}O_{3} and Al_{2}O_{3}. C = CaO. D = MgO. E = K_{2}O. F = Na_{2}O. G = H_{2}SO_{4} H = Cl. I = P_{2}O_{5}. J = CO_{2}

+-----+-----+-----+-----+----+-----+----+----+----+----+-----+ Plant.|Total| | | | | | | | | | | |ash. | A | B | C | D | E | F | G | H | I | J | ------+-----+-----+-----+-----+----+-----+----+----+----+----+-----+ AM |12.15|32.77|16.26| 6.05|3.11|13.30|3.21|3.9 |0.47|6.12|10.55| | | | | | | | | | | | | AL |13.52|17.08|12.21|14.27|2.62|17.26|5.75|3.22|3.87|3.30|17.37| | | | | | | | | | | | | AC |12.36| 7.82| 5.97|12.10|3.55|23.35|3.38|5.56|9.0 |4.67|20.62| | | | | | | | | | | | | ------+-----+-----+-----+-----+----+-----+----+----+----+----+-----+ KEY TO PLANTS: AM = _Astragalus mollissimus_ (whole plant) AL = _Aragallus lamberti_ (whole plant) AS = _Astragalus caryocarpus_

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]

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FOOTNOTES:

[83] Storke, B. F. The Loco Weed. Med. Current, vol. 8, p. 155. 1892.--Kellogg, A. California and Colorado "Loco" Poisons. Cal. Acad. Sci. Proc. for 1875, vol. 6, p. 3. 1876.

NOTE.--The very early reports of these loco plants were purely botanical. See Torrey, J., Botany, in Report on the United States and Mexican Boundary Survey, by W. H. Emory, vol. 2, p. 56, 1859; also Botanical Register, London, vol. 13, pl. 1054, 1827.

[84] Vasey, G. Plants Poisonous to Cattle in California. Rept. of Commissioner of Agriculture for 1874, p. 159. 1875.

[85] Vasey, G. Botanical Notes. Monthly Reports of Dept. Agriculture for 1873, p. 503. 1874.

[86] Vasey, G. Botanical Notes. Monthly Reports of Dept. Agriculture for 1874, p. 513. 1875.

[87] Brewer, W. H., and Watson, S. Geological Survey of California, Botany, vol. 1, p. 155. 1876.

[88] Rothrock, J. T. Notes on Economic Botany, in G. M. Wheeler's Report upon U. S. Geographical Surveys West of the One Hundredth Meridian, vol. 6, p. 43. 1878.

[89] Kellogg, A. California and Colorado Loco Poisons. Cal. Academy of Sciences, Proc., 1875, vol. 6, p. 3. 1876.

[90] Rothrock, J. T. Poisonous Properties of the Leguminosæ. Acad. of Nat. Sci., Phila., Proc., vol. 29, p. 274. 1877.

[91] Prescott, A. B. Laboratory Notes--A Partial Analysis of the Oxytropis Lamberti. Amer. Journ. Pharm., vol. 50, p. 564. 1878.

[92] Rept. of Commissioner of Agriculture for 1878, p. 134. 1879.

[93] Rept. of Commissioner of Agriculture for 1879, pp. 89, 90. 1880.

[94] Rept. of Commissioner of Agriculture for 1886, p. 75. 1887. Rept. of Commissioner of Agriculture for 1884, p. 123. 1884.

[95] Rothrock, J. T. Notes on Economic Botany, in G. M. Wheeler's Report upon U. S. Geographical Surveys West of the One Hundredth Meridian, vol. 6, p. 43. 1878.

[96] Gibbons, H. Poisonous Effects of Crotalaria--Vulgo Rattle Weed, Loco Weed. Pacific Med. and Surg. Journ., vol. 21, p. 496. 1878-79.

[97] Ott, I. Physiological Action of Astragalus Mollissimus. New Remedies, vol. 11, p. 227. 1882.

[98] Hill, J. R. Note on a Species of Astragalus from Cyprus. Pharm. Journ. and Trans., 3 s., vol. 18, p. 712. 1887-88.

[99] Sayre, L. E. Loco-Weed. Proc. Amer. Pharm. Assoc., vol. 36, p. 112. 1888.

[100] Sayre, L. E. Loco Weed. Amer. Vet. Rev., vol. 11, p. 556. 1887.

[101] Kennedy, J. Loco Weed (Crazy Weed). Pharm. Rec., vol. 8, p. 197. 1888.

[102] Day, M. G. Experimental Demonstrations of the Toxicity of the "Loco Weed." N. Y. Med. Journ., vol. 49, p. 237. 1889.

[103] Presumably a 10 per cent decoction, U. S. P.

[104] Storke, R. F. The Loco Weed. Med. Current, vol. 8, p. 157. 1892.

[105] Day, M. G. The Separation of the Poison of the "Loco Weed." N. Y. Med. Journ., vol. 50, p. 604. 1889.

[106] Sayre, L. E. Active Principle of Loco Weed. Notes on New Remedies, vol. 2, No. 12, p. 1.

[107] Day, M. G. Loco Weed, in F. P. Foster's Reference-Book of Practical Therapeutics, vol. 1, p. 588. 1896.

[108] Stalker, M. 1st Ann. Rept. State Vet. Surg. Iowa, p. 16. 1885.

[109] Power, F. B., and Cambier, J. Chemical Examination of Some Loco-Weeds. Pharm. Rundschau, vol. 9, p. 8. 1891.--Power, F. B. Notes on the So-called Loco Weeds. Pharm. Rundschau, vol. 7, p. 134, 1889.--See also Hoffmann, F., Loco-Weeds, in Pharm. Rundschau, vol. 7, p. 168. 1889.

[110] Kennedy, J. Pharm. Rec., vol. 8, p. 197. 1888. Kennedy also obtained ammonia from _Astragalus mollissimus_.

[111] O'Brine, D. Progress Bulletin on the Loco and Larkspur. Colo. State Agric. Coll. Bul. 25, p. 18. 1893.

[112] Oatman, H. C. The Poisonous Principle of Loco Weed. Notes on New Remedies, vol. 4, p. 14. 1891-92.

[113] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol. 18, p. 141. 1903.

[114] Sayre, L. E. Loco Weeds. 7th Bienn. Rept. Kans. State Board Agric. for 1889-90, vol. 12, pt. 2, p. 99. 1891.

[115] Sayre, L. E. Further Report on Loco Weeds. Notes on New Remedies, vol. 4, p. 80. 1891-92.

[116] Sayre, L. E. The Loco Disease. Journ. Kans. Med. Soc., vol. 4, pp. 241-243. 1904.--What is Insanity in Lower Animals? Journ. Kans. Med. Soc., vol. 4, p. 222. 1904.

[117] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol. 18, p. 144. 1903.

[118] Ruedi, C. Loco Weed (Astragalus Mollissimus): A Toxico-Chemical Study. Trans. Colo. State Med. Soc., p. 418. 1895.--Also Treatment of Animals Poisoned by Loco Weed (unpublished article).

[119] The "Loco Disease." Therap. Gaz., vol. 12, p. 30. 1888.

[120] Sayre, L. E. Loco Weed. Kans. Acad. Sci. Trans., vol. 18, p. 142. 1903.

[121] Sayre, L. E. Loco Weeds. 7th Bien. Rept. Kansas State Board Agric. for 1889-1890, pt. 2, p. 98. 1891.

[122] Curtice, C. Tape-Worm Disease of Sheep of the Western Plains. Bur. Animal Industry, 4th and 5th Ann. Rept., p. 167. 1889.

[123] Steele, C. D. New Theory about Loco. Farm and Ranch, vol. 20, No. 35, p. 1. 1901.

[124] Marshall, H. T. Loco Weed Disease of Sheep. Johns Hopkins Hospital Bul., vol. 15, p. 181. 1904.--Data as to these parasites of sheep may be found in Curtice, C., The Animal Parasites of Sheep, Bur. Animal Industry, Rept., 1890.

[125] Faust, E. S., and Tallquist, T. W. Ueber d. Ursachen der Bothriocephalus-anämie. Arch. f. Exp. Path., vol. 57, p. 367. 1907.

[126] Walshia Amorphella and the Loco Weed. Insect Life, vol. 2, p. 50. 1889-90. Snow, F. H. Loco-Weed. Science, vol. 9, p. 92. 1887.

[127] Lloyd, J. U. Loco, or Crazy Weed. Eclectic Med. Journ., vol. 53, p. 482. 1893.

[128] Lloyd, J. U., l. c., p. 483.

[129] Lloyd, J. U., l. c., p. 484.

NOTE.--Eccles had previously announced a somewhat similar idea. Sayre, L. E. Loco Weed. Proc. Amer. Pharm. Assoc., vol. 36, p. 115. 1889.

[130] Lloyd, J. U., l. c., p. 486.

[131] Lloyd, J. U., l. c., p. 483.

[132] O'Brine, D. Progress Bulletin on the Loco and Larkspur. Colo. State Agric. Coll. Bul. 25, p. 17. 1893.

[133] Mayo, N. S. Some Observations on Loco. Kans. State Agric. Coll. Bul. 35, p. 116. 1893.

[134] Kobert, R. Lehrb. d. Intoxikationen, p. 615. 1893.

[135] O'Brine, D. Progress Bulletin on Loco and Larkspur. Colo. State Agric. Coll. Bul. 25, p. 13. 1893.

[136] After the manuscript of this bulletin was sent to the printer it was learned through Professor Carpenter that the animal was a horse.

[137] Nelson, S. B. Feeding Wild Plants to Sheep. Bur. Animal Industry, Bul. 22, p. 12. 1898.

[138] Chesnut, V. K., and Wilcox, E. V. Stock-Poisoning Plants of Montana. U. S. Dept. Agric., Div. Bot., Bul. 26, p. 95. 1901.--Wilcox, E. V. Plant Poisoning of Stock in Montana. Bur. Animal Industry, 17th Ann. Rept., p. 111. 1900.

NOTE.--The writer wishes to acknowledge the great literary help Mr. Chesnut's card catalogue has been to him in the preparation of this paper.

[139] Unpublished report.

[140] Marshall, H. T. Loco Weed Disease of Sheep. Johns Hopkins Hospital Bul., vol. 15, p. 182. 1904.

[141] Payne, J. E. Cattle Raising on the Plains. Colo. Agric. Expt. Sta. Bul. 87, p. 16. 1904.

[142] National Standard Dispensatory, p. 868. 1905.

NOTE.--The field experiments of Harding and Tudor are rather conclusive as to the relation of these plants to this disorder. Sayre, L. E., Loco Weed, Amer. Vet. Rev., vol. 11, pp. 553-554, 1887--Blankinship, J. W., Loco and Some Other Poisonous Plants in Montana, Mont. Agric. Exper. Sta. Bul. 45, pp. 83-84, 1903--Loco Disease, Therap. Gaz., vol. 12, p. 30. 1898.

=NOTES ON VARIOUS MEMBERS OF THE LOCO-WEED FAMILY.=

_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.

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FOOTNOTES: