Giglio found salicylate in the synovial fluid of many joints; and Fillippi and Nesti obtained it from the synovial fluid from the hip-joint of dogs one hour after its administration by mouth. It was present for from twenty-eight to fifty-four hours. They found it also in the joints of acute articular rheumatism, but only in the merest traces in a gonorrheal joint. Hanzlik and his co-workers find the percentage in joint fluids and blood practically the same, that after 200 grains (13 gm.) in both rheumatics and non-rheumatics being about 0.025 per cent. They found only the sodium salt and not any free salicylic acid. Dixon states that the joint pain and stiffness are removed by the injection into the joint of a salicylate. According to Falk and Tedesco (1909), it appears in all inflammatory exudates; and they recommend this as a diagnostic point in sputum examinations. They claim that the sputum of tuberculosis and pneumonia, being an exudate, gives the salicylic test, while the sputum of bronchitis and bronchiectasis, being a secretion, does not give the test. Bastedo and Johnson were unable to distinguish by this test, and found no salicylate in tuberculous sputum.

Except for the dilatation of the skin arterioles, which is pronounced, the effect upon the circulation is usually negligible in therapeutics. The tendency of moderate doses is to stimulate slightly the heart muscle and the vasoconstrictor center; that of large doses is to depress them. In the blood the leukocytes tend to be increased in number.

Metabolism

As shown by the rise of nitrogen, phosphorus, and sulphur in the urine, there is increased protein destruction. The excretion of urea and uric acid are increased, the rise in the latter being sometimes as much as 50 per cent. Fine and Chace and Denis have shown a marked reduction of the uric acid in the blood, Denis attributing this to a lowered threshold of the kidney for circulating urates. It does not produce an acidosis (Hanzlik).

Excretion is by the kidneys, chiefly as salicyluric acid, a glycocoll compound which gives a violet-red color with ferric chloride. Traces are also found in the bile, milk, and sweat. The appearance in rheumatic and other exudates has been referred to above. In rheumatism there seems to be an increased destruction.

The kidneys may be irritated by large quantities, and Hanzlik and associates have shown that, both in rheumatics and non-rheumatics, albumin, leucocytes, and casts appear in the urine after full doses, the albuminuria ceasing when the salicyl is excreted. They found no effect on the phthalein excretion or on the blood nitrogen. But among drugs of this class salicylic acid is a comparatively safe one, for quite frequently 100 or 200 grains a day of sodium salicylate have been given without signs of kidney inflammation.

Toxicology

The early signs of overdosage are: nausea, vomiting, and sometimes diarrhea; or headache, ringing in the ears, and deafness; or mental excitement. As judged by these signs, Hanzlik (1913) found that for human adults the toxic amount of sodium salicylate is about 200 grains (13 gm.), of methyl salicylate and aspirin about 120 grains (8 gm.), and of displosal, 100 grains (6.7 gm.).

Salicylism resembles cinchonism and is characterized by fulness in the head, headache, mental excitement with loquacity or a talkative delirium, or mental dulness and apathy, with ringing in the ears, deafness, disordered vision, and muscular weakness. The ear symptoms are not so common as from quinine, and are due either to congestion or anemia or to degeneration of the nerve-elements of the cochlea. Scheyer reports a case of labyrinthitis with permanent impairment of the hearing. The eye symptoms are also associated with circulatory changes in the retina or degenerative changes in retina or optic nerve.

In the salicylic intoxication the cerebral symptoms may resemble those from atropine, producing the so-called "salicylic jag." The patient is talkative and very cheerful, and may pass on to delirium with hallucinations, motor activity, and attempts to get out of bed. The cerebral excitement may be prevented, at least in part, by bromides.

Very large doses produce weakness of the heart and depression of the respiratory and vasoconstrictor centers, with collapse. But the writer has frequently seen 20 grains of the sodium salicylate given every two hours, and occasionally 30 grains, without any noticeable effect on the heart's action or the blood-pressure. Occasionally, through idiosyncrasy, even small doses induce cardiac weakness. Seiler reports the death of a seven-year-old child after 75 grains (5 gm.), Gubler the death of an adult after 2 1/2 drams (10 gm.), and Goodhart a death after 55 grains (3.6 gm.) given in proper therapeutic doses. Hanzlik found no especial tolerance for the salicylates in acute rheumatism. (Although phenol and salicylic acid are closely related chemically, nevertheless they cannot be considered together pharmacologically or therapeutically.)

Therapeutics

Locally, salicylic acid itself is employed:

1. As a surgical antiseptic, in the form of Thiersch's solution or boro-sal (acid salicylic, 2; acid boric, 8; in water, 1000).

2. In sweating of feet and hands, in alcoholic solution; and in bromidrosis (smelly feet), mixed with boric acid, and placed dry in the shoes.

3. In fungous skin diseases (ringworm, etc.) and chronic eczema, in ointment form. Lassar's paste (Pasta Zinci, N. F.) is composed of salicylic acid, 2 parts, zinc oxide and starch, of each, 24 parts, and petrolatum, a sufficient quantity to make 100 parts.

4. To remove corns and warts, in solution in flexible collodion, 15 grains (1 gm.) to 2 drams (8 c.c.). It should not be applied beyond the corn, or it may cause the adjacent skin to peel.

Internally, the sodium salicylate is employed:

1. In acute articular rheumatism and its complications - 10 to 20 grains (0.7-1.3 gm.) every two or three hours. That the salicylates give prompt relief is a very frequent experience, but there is some evidence that they do not diminish the length of the disease, the occurrence of endocarditis or the frequency of relapse. Denis suggests that their value may be due to the promotion of the excretion of toxins. The writer believes in their specificity.

2. In acute tonsillitis, pharyngitis, growing pains, sciatica, lumbago, muscular rheumatism, pleurisy, etc., all of which may have a true rheumatic origin. Seibert recommends it in chorea, but most men find it useless in this disease. Cockayne treated 355 cases with 60 to 300 grains (2-20 gm.) daily without influence on the course of the chorea.

3. In the indefinite muscular, joint, or neuritic pains, which are loosely spoken of as rheumatic.

4. In gouty attacks it is as valuable as atophan (Fine and Chace). In chronic gout and chronic rheumatism it is analgesic, but not curative.

5. In diabetes, von Noorden (1912) considers it the most valuable of the drugs used, except the nerve sedatives (codeine, etc.), but Hall could distinguish no desirable effect. (See also Acetyl-salicylic Acid and Salol.)

Administration

Sodium salicylate is given in capsules or cachets with plenty of water, or in solution in wintergreen water or other flavored liquid. Its sweetish taste is unpleasant and nauseating to many. An alkaline bromide lessens the tendency to salicylism, and sodium bicarbonate lessens the irritation of the stomach, though it does not diminish the toxicity or the irritant action on the kidneys. There is nothing gained by enormous doses of sodium bicarbonate, as recommended by Lees. To avoid too great toxic effects the doses should be divided up and given at frequent intervals, and constipation assiduously avoided.

Seibert (1911) has suggested the hypodermatic use, recommending the injection of 10 c.c. of a 20 per cent. solution for each 100 pounds of body weight. He repeats the dose every twelve hours, preceding it by an injection of a weak cocaine solution because of the pain. Heyn advocates rectal administration, the beginning dose being about 2 drams (8 gm.) with 4 to 6 ounces (120-180 c.c.) of water or starch-water. It appears in the urine in fifteen to thirty minutes, and is mostly absorbed in twelve hours.

It has also been used intravenously in 20 per cent. solution in doses of 20 grains (1.3 gm.), but this solution causes inflammation or a slough if it leaks into the tissues, and may cause thrombosis in the veins, so the author prefers a 5 per cent. solution. In several instances it has been more effective than large doses by mouth.