Part 21

----+--------+-------+-----------+-----------+-------+--------------- | |Caffein| | Duration | | No.|Weight. | per | Symptoms. | of life. | Diet. | Remarks. | | kilo.| | | | ----+--------+-------+-----------+-----------+-------+--------------- |Grams.| Mg. | | | | 194| 1,310 | 114 |Present |Survived |Oats |White female. 556| 1,635 | 134 |10 minutes |20 minutes | do. |Gray female. 557| 1,580 | 114 |Present |Survived | do. | Do. 558| 1,590 | 100 | do. | do. | do. | Do. 292| 1,770 | 141 | do. | do. | do. | Do. 194| 1,350 | 126 | do. |10 minutes |Carrots| Do. ----+--------+-------+-----------+-----------+-------+---------------

SERIES B, GROUP I.

----+--------+-------+-----------+-----------+-------+--------------- 562| 1,650 | 200 | |1½ hours |Oats |Gray female. 561| 1,450 | 200 | | do. | do. | Do. 560| 1,620 | 200 |Present |Less than | do. | Do. | | | | 24 hours | | 559| 1,875 | 190 | do. |Survived | do. | Do. ----+--------+-------+-----------+-----------+-------+---------------

SERIES B, GROUP II.

----+--------+-------+-----------+-----------+-------+--------------- 279| 1,320 | 166 | |1 hour | |Gray and white | | | | | | female. 254| 1,285 | 160 | |Survived |Oats |Gray female. 567| | 162 | |About 45 | | Do. | | | | minutes | | 255| | 158 | |Died | | ----+--------+-------+-----------+-----------+-------+---------------

SERIES C.

----+--------+-------+-----------+-----------+-------+--------------- 293| 1,610 | 500 |Present |Survived |Oats |Gray female. 227| 2,320 | 570 |None | do. | |White male. 563| 1,650 | 500 |Present | do. | do. |Gray female. 564| 1,515 | 460 | do. | do. | | Do. 565| 1,545 | 320 |None | do. | do. | Do. 566| 1,900 | 310 | do. | do. | do. | Do. ----+--------+-------+-----------+-----------+-------+---------------

SERIES D.

----+--------+-------+-----------+-----------+-------+--------------- 569| 1,475 | 100 |Present |Survived |Oats |Gray male. 574| 1,555 | 112 | do. | do. | do. | Gray female. 571| 1,530 | 100 | do. |About | do. | Do. | | | | 2 hours | | 568| 1,605 | 100 | |20 minutes | do. |Gray male. 570| 1,225 | 100 | |Less than | do. | Do. | | | | 20 hours | | ----+--------+-------+-----------+-----------+-------+---------------

SERIES E.

----+--------+-------+-----------+-----------+-------+--------------- 572| 1,770 | 200 |Present |About |Oats | | | | | 24 hours | | 573| 1,810 | 200 | | do. | do. | ----+--------+-------+-----------+-----------+-------+---------------

SUMMARY.

The results of the experiments on rabbits show considerable variation in the toxicity of the single dose. Individuals differed so widely in their resistance to this drug that the same experiments had to be repeated many times with each method of administration before satisfactory conclusions could be drawn. This is strikingly illustrated in the experiments by intravenous injection in which a dose of nearly 0.2 gram per kilo was not fatal. Similar instances of exceptional resistance or of sensitiveness to caffein were observed when it was given in other ways. A comparison of the toxicity of caffein administered by different methods in this investigation shows well-marked differences in its activity, although they are not quite so striking as similar experiments with other alkaloids reported by several observers. The toxicity of caffein in these experiments on the rabbit indicates that it is greatest when given by vein and least when given by mouth. The ratio of the minimum toxic doses by these two methods of introduction of caffein was about 7.1; the relation of the minimum fatal dose was about 3.1. The toxicity when given subcutaneously is about 15 to 20 per cent greater than when given by mouth. The difference between the intramuscular and subcutaneous injection is even more marked. The toxicity of caffein when injected into the muscles is about midway between that administered by the subcutaneous and intraperitoneal routes, and is about half that injected intravenously. Meltzer and Auer,(58) who experimented with a number of drugs found that the intramuscular method of administration is as effective as the intravenous, fluorescin forming the only exception according to their observations. In the experiments of Sollman and Brown(81) with ergot, the effect was quite different from those obtained by Meltzer and Auer(58) with the drugs they used. It is quite possible that the result obtained with ergot is merely illustrative of a difference in the behavior of various substances in this regard. This appears probable on account of the difference in the rate of absorption for various substances. Thus, according to Achard, Gaillard, and Ribot (Compt. rend. Soc. biol., 1907, 62: 90), absorption from the peritoneal cavity varies with the concentration of the solution and the size of the molecule. The smaller the molecule and the greater the concentration the more rapid the absorption. That the rate of absorption from the intramuscular tissues is unequal and varies for different substances appears from the experiments of Meltzer and Auer.(58) The difference was very striking between intramuscular and subcutaneous administration of curara or adrenalin; the results were somewhat different with morphin and with fluorescin. As shown in their protocols, the onset of the symptoms after the intramuscular injection of morphin was sooner than after subcutaneous injection, but in time the difference diminishes and disappears altogether. The absorption of fluorescin is much faster when the intramuscular path is used than when given subcutaneously, but the writers state that the rate falls far behind that of the intravenous administration. The difference in toxicity we observed between feeding by mouth and subcutaneous injection, although distinct, was not very great. It was much less than Maurel(55) obtained with the hydrobromid of caffein in the rabbit. Whether this difference between his results and ours is due to the use of the pure alkaloid in our experiments and the hydrobromid employed by Maurel can not be stated at present with any degree of accuracy. It is hoped that the work in progress in the laboratory will throw some light on the subject in the near future. But Maurel's(56) experiments show that various substances behave differently in this regard. Thus the toxicity of strychnin, he states, is three times as great when given subcutaneously as when given by mouth and six times that of the minimum fatal dose by vein. It may be remarked, however, that examination of his data shows that his doses are much too large for the rabbit. In experiments with other drugs little or no difference between the two modes of administration was noticed. Thus, digitalin was but slightly more active when given subcutaneously than by mouth, while the toxicity of emetin hydrochlorid was just the same, whichever one of these methods of introducing the substance was used. Differences in the toxicity of substances have also been observed between subcutaneous and intravenous modes of administration, but here, too, the differences for various substances were unequal.

EXPERIMENTS ON GUINEA PIGS.

The toxicity of caffein was studied in a large number of individuals. The experiments were conducted on full-grown animals and were carried out at different seasons of the year in a variety of ways. Special attention was given to diet as a possible factor influencing resistance to caffein, and the effect of different modes of administration on toxicity. Some animals were therefore fed oats, some carrots, others received both hay and oats. Caffein was introduced subcutaneously, intraperitoneally, and by mouth.

SUBCUTANEOUS INJECTION.

SERIES A.

Preliminary experiments carried out on three guinea pigs, which received 360, 300, and 290 mg of caffein per kilo subcutaneously have shown that such doses were rapidly fatal. Two of the animals were seized with convulsions half an hour after the introduction of caffein and died during the attack. The other had tetanus two minutes after the injection of caffein. Repeated attacks followed, which terminated in the death of the animal two and a half hours later. The fatal and toxic doses must therefore be considerably under 0.3 gram of caffein per kilo when introduced by this path and smaller doses were therefore injected. The results are shown in the experiments of the next series.

SERIES B.

Experiments with 2 decigrams per kilo constituted this series.

Guinea pig 20. Female. Weight, 497 grams. Diet, oats.

April 2: 5 cc 2 per cent caffein injected subcutaneously at 11.30 a. m.; 1.50 p. m., spasm of short duration. Died at 3 p. m., three and one-half hours after injection.

Guinea pig 38. Brown male. Weight, 570 grams. Diet, carrots and oats week previous to injection.

February 11: 3.50 p. m., 6 cc 2 per cent caffein injected subcutaneously in back (210 mg per kilo); 4.15, reflexes increased, had convulsion of short duration when disturbed; 4.45 p. m., on handling, repeated convulsion and paralysis; 5 p. m., guinea pig lying on his side, respiration difficult and labored.

February 11: 5.05 p. m., guinea pig found dead, 2 hours and 15 minutes after injection.

Guinea pig 37. Male. Weight, 820 grams. Diet, carrots and oats during week preceding the injection of caffein.

February 11: 3.35 p. m., 8.5 cc 2 per cent caffein injected subcutaneously in the back; 5 p. m., pig very sensitive, anterior extremities paralyzed when handled, frequent spasms of posterior extremities, no symptoms noticed before 5 p. m., although watched all the time; 5.05 p. m., guinea pig on his legs and looked normal. No attack on handling.

February 12: 9 a. m., found dead; died within 18 hours.