Original communication| Volume 17, ISSUE 5, P650-666, May 1945

Influence of caffeine on ulcer genesis

Experimental production of gastric ulcer in guinea pigs and cats with caffeine, together with a study of its effect upon gastric secretions in dog and man
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      When 200 mg. of crude caffeine alkaloid in beeswax were injected daily intramuscularly in a series of five guinea pigs, the toxic manifestations were so severe that death ensued too rapidly for any satisfactory data to be obtained. However, in a series of ten guinea pigs in which the dosage was reduced to 100 mg. of caffeine alkaloid in beeswax injected in a similar fashion, eight (80 per cent) guinea pigs developed some degree of upper gastroduodenal pathology. Four (40 per cent) exhibited “peptic” erosions or ulcers. Microscopically, these are typical ulcers similar to those found in man superimposed on a moderate to severe gastritis.
      Cats receiving intramuscularly 300 mg. of caffeine alkaloid in beeswax daily exhibited upper gastrointestinal pathology in fourteen of twentysix animals. Eleven of these cats (40 per cent) developed “peptic” erosions and/or definite ulcers.
      In standardized pouch dogs, the subcutaneous injection of aqueous caffeine citrate and aqueous caffeine alkaloid in dosages up to 600 mg. produced no significant change in pouch acidity and volume. However, when the dosage of caffeine alkaloid was increased to 1,200 mg. a definite stimulation effect of pouch acidity and volume was observed.
      This dosage in dogs was computed to be approximately one-half of the dosage used to produce ulcers in cats on the basis of milligram per kilograms of body weight. Consequently, four pouch dogs were injected with 2,500 mg. of caffeine alkaloid in beeswax intramuscularly for four consecutive days. A marked increase of pouch acidity and volume occurred.
      These latter results suggest that the ulcers produced in cats by the injection of caffeine alkaloid in beeswax may well be explained on the basis of the stimulation of free acid.
      Nineteen experiments were conducted on human beings. To evaluate the effect of coffee on gastric acidity and volume, these tests were devised to control the possible thermal and psychic effects of the coffee. The ingestion of cold coffee produced the most striking results. It is possible that the increased temperature of the hot beverage inhibited to some degree the gastric secretory response. Psychic stimulation appeared to be of no real significance. In eleven instances (73 per cent) a definite stimulatory effect on gastric acidity was observed. The variation in the volume of gastric juice was not striking.
      In nine of ten experiments (90 per cent) in man, a striking stimulatory response of gastric acidity was observed when caffeine-containing drugs were administered parenterally (aqueous caffeine alkaloid, 300 mg. and caffeine sodium benzoate, 488 to 976 mg.).
      Computed on the basis of milligram per kilogram of body weight, the dosage of aqueous caffeine alkaloid or caffeine sodium benzoate necessary to produce a stimulation of gastric acidity in man is approximately 4.3 mg. per kilogram of body weight. In guinea pigs plus-minus 200 mg. of crude caffeine alkaloid (in beeswax) per kilogram produced ulcers; in cats approximately 104.8 mg. of the same material per kilogram were necessary for ulcer formation. In pouch dogs (average weight 20 kilograms) a total dose of 1,200 mg. of aqueous caffeine alkaloid was needed to evoke a stimulation of gastric secretions in the majority of experiments. This is approximately 60 mg. of drug per kilogram. This dosage is twelve times the amount which regularly produces a moderately severe stimulation of gastric acidity in man. It is apparent that man's gastric secretory mechanism is exceedingly sensitive to caffeine stimulation. It is undoubtedly much more sensitive to the caffeine effect than is that of the dog. Further comparisons of dosage on the basis of body weight suggest also that man's gastric secretory apparatus is probably more sensitive to caffeine than both the guinea pig and the cat.
      No important differential response in pouch secretion was observed in any experiments between the Heidenhain (vagus destroyed) and Pavlov (vagus intact) pouch dogs. The fact that a stimulatory effect was noted in the Heidenhain pouch dogs suggests that the vagus nerve is not necessary for the production of this effect. However, in Pavlov pouch dogs and in human beings, atropine sulfate seems to produce a minimal temporary depression in pouch and gastric secretions in certain instances. Therefore, the stimulatory effect of caffeine must occur mainly by direct action on the parietal cells of the stomach.
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