Part 5

[143] Frankforter, G. B. A Chemical Study of Astragalus Caryocarpus. Amer. Journ. Pharm., vol. 72, p. 320. 1900.

[144] Maisch, J. M. Poisonous Species of Astragalus. Amer. Journ. Pharm., vol. 51, p. 240. 1879.--Fleurot. Chimiques et Pharmaceutiques sur la Racines d'Astragale sans Tiges. Journ. de Chim. Med., vol. 10, p. 656. 1834.

[145] Porcher, F. P. Resources of the Southern Fields and Forests, p. 204. 1869.

[146] Smith, J. G. Fodder and Forage Plants. U. S. Dept. Agric., Div. Agrost., Bul. 2 (rev. ed.), p. 12. 1900.

[147] Holmes, E. M. Notes on Chinese Drugs. Pharm. Journ. and Trans., vol. 21, 3 s., p. 1149. 1891.

[148] Hough, W. Environmental Interrelations in Arizona. Amer. Anthropologist, vol. 11, pp. 143, 147. 1898.

[149] Barrows, D. P. Ethno-Botany of the Coahuilla Indians of Southern California, p. 67. 1900.

[150] Matthews, W. Navajo Names for Plants. Amer. Nat., vol. 20, p. 772. 1886.

[151] Givens, A. J. Loco or Crazy Weed. Med. Century, vol. 1. p. 21. 1893.--Compare Hurd, H. M. Amer. Journ. Insanity, vol. 42, p. 178. 1885-86.

[152] Rosenthal, D. A. Synopsis Plantarum Diaphoricarum, Erlangen, 1861, p. 1004. Greshoff, M. Beschrijving d. Giftige en Bedwelmeude Planten bij de Vischvangst in Gebrulk, p. 51. 1900.

[153] Pott, E. Handb. d. tierisch. Ernährung, vol. 2, p. 113. 1907.

=LABORATORY EXPERIMENTS--PHYSIOLOGICAL.=

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.

=EXPERIMENTS ON RABBITS.=

=ACUTE CASES.=

_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.

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FOOTNOTES:

[154] In all cases in which the plants were preserved with chloroform sealed vessels were used for shipping. The chloroform was carefully evaporated off in vacuo before feeding the extract, the evaporation requiring several hours. The plants were collected by Dr. C. Dwight Marsh, in charge of the field investigations at Hugo, Colo.

[155] All extracts from dried material were made at Washington.

=CHRONIC CASES.=

_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_.

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FOOTNOTES:

[156] Compare Plönius, W., Beziehungen d. Geschwürs u. d. Erosionen d. Magens z. d. funktionell. Störungen u. Krankh. d. Darmes, Arch. f. Verdauungsk., vol. 13, pp. 180, 270, 1907, and Tixier, L., Anémies Exper. Conséc. aux Ulcér. du Pylore, Comp. Rend. Hebd. Soc. de Biol., vol. 62, p. 1041, 1907.

=PREGNANT ANIMALS.=

_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 foeti. 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.

=SUBCUTANEOUS INJECTIONS.=

_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.

=SUMMARY OF FEEDING EXPERIMENTS ON RABBITS.=

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.