"y. The corpuscle may be surrounded by projections of another kind. The main body shrinks gradually into an irregular lump, while minute, translucent spherules of various sizes present themselves round its edge. These spherules do not appear to consist of the same substance as the main bulk of the corpuscle; they may even become detached from it, and float away. The appearances are those which might be presented by a coagulum slowly shrinking and expelling a clear fluid from its interstices; the fluid not being miscible with that in which the corpuscle is suspended. Whether a leucocyte in this state may, as in the two foregoing conditions, resume its migratory powers, I am unable to state.

"3. Permanent repose or death. The corpuscle is spherical or spheroidal, with a distinct outline. It does not exhibit any sort of movement; its protoplasm is very granular, and its nuclei are well marked. This condition is irremediable, and is the immediate precursor of disintegration.

"The first of these conditions is that of the highest vital activity; the second may pass either into the first or into the third. It is possible so to graduate the dose of a poisonous agent as to obtain the second or the third condition at will. In the following experiments, the exact state of the colorless corpuscles is usually indicated; the discordant results of previous observers in the case of quinia being probably due to a neglect of this exactitude. The condition of the red discs is often noted, inasmuch as they furnish the most delicate test of the neutrality of the liquid in which they float - the faintest trace of acid causing the delimitation, a larger proportion the granulation, of their nuclei."

Quinine very rapidly enters the circulation of men and of animals, whether put into the stomach, the subcutaneous tissue, or the cavities.

It is also very rapidly eliminated again, as was proved by Thau;1 nearly the whole dose taken being discharged as quinine in the course of about twelve hours. Yet it has been proved by the researches of Bence Jones and Dupre that quinine itself (or a body in every respect resembling it) is, in minute proportions, a natural constituent of the body. Under these circumstances it is interesting to inquire whether more quinine is retained in the body when the drug has been given to a fevered, than when it has been given to a healthy subject; but the only difference shown by Thau's researches is, that in the former case the second period of six hours, and in the latter the first period of six hours, is the time during which the greatest elimination occurs.

The power of quinine to reduce bodily temperature, which is mainly a therapeutic and not a physiological effect, must be mentioned in this place, because it stands, or stood until lately, on debatable ground: it was doubtful, that is to say, whether the influence is one exerted through the nervous system by the medium of a supposed heat-regulating centre in the brain, or whether it is a part of a more generalized action on the tissues and fluids of the body. At the present time it is evident that scientific opinion is coming to agree with that expressed by Binz, namely, that the lowering of bodily temperature is produced by means of a general interference of quinine with the oxidation processes of the body in almost every part of it.

The special action of quinine upon the nervous system is most clearly seen in the symptoms which are associated with "cinchonism." When a patient is saturated with excessive doses of quinine, he gets loud ringing noises in the ears, splitting headache, vertigo, amaurosis, sometimes even delirium. In animals, a fatal dose of quinine has often produced convulsions and paralysis of the hinder extremities. It would appear that the lowered sensibility of parts, and the diminished muscular action, are due not to direct paralysis of nerves or to any interference with muscular irritability, but to a diminution of reflex action. For man it is not easy to say what would be a fatal dose of quinine, since enormous doses have been lately given with only temporary bad effects. Still it is certain that, if the stomach could be got to retain a sufficient quantity, we should have a fatal result, preceded, in all probability, by convulsions.

There are other local poisonous actions of quinine which are less constant, and which we can but little explain. One of the most singular of these is its very powerful and disagreeable action on the skin of many patients. Most medical men have met with one or two individuals in whom any dose of quinine, but especially a large one, produced irritation of the skin, followed by free desquamation; cases have not unfrequently been seen in which the whole skin of a hand or even of a limb has come off like a glove or a stocking.

Another occasional effect, more common than the last named, is the influence of large doses of quinine in accelerating the heart's action and the respiration. Many persons seem quite insusceptible to this influence even when very large doses are given to them; but in others the palpitation and hurried breathing are so pronounced as to cause much distress.

Physiological Action of Cinchonine. - This alkaloid, formerly supposed to be next in activity to quinine among the cinchona alkaloids, is now known to be the feeblest of them all. The experiments of Ber-natzik, in 1867, showed that upon dogs the fatal dose of cinchonine was one-fourth larger than the quantity of quinine which would kill other animals of the same weight.

1 Practitioner, 1869, vol. ii.

Still more recent observations1 confirm this estimate, by showing that the influence of cinchonine as a protoplasm-poison, though resembling that of quinine, is weaker not only than the quinine action, but than the action of either of the other alkaloids. It will be seen presently that this physiological position of cinchonine corresponds to its place in the therapeutic scale.