could supply pure drugs, and experimental physiology had taught us how to set about examining their action on various organs and tissues.

Bichat, when he pointed out, early in the present century, that all organs were composed of several tissues, and that some of these might be diseased and others healthy, seems to have also noted that the action of drugs on different tissues and organs needed study. His early death prevented him from undertaking such investigations. The first real pharmacological research was made by his great pupil, Magendie. Its subject was strychnia, and since his work is an excellent example of the investigation of the physiological action of a drug, and as our reasons for prescribing this remedy in certain diseased states and avoiding it in others are based on Magendie's work, I shall give an account of his investigation in some detail. What Magendie actually used was upas, a poison known to cause convulsions and death, and suspected to act on the spinal cord. It was shortly afterwards proved that the active principle of upas was strychnia. To avoid confusion I shall speak as if Magendie had worked with that alkaloid. Magendie's research was undertaken to discover whether this substance could be proved experimentally to have a special affinity for and a specific action on some one organ.

It is almost incredible to us now, that but sixty years ago this had not been proved for a single medicine. That Epsom salts purged and squills caused diuresis was well known, but there had been made no attempt to ascertain the method of action of either. The knowledge now at the physician's disposal, which enables him to select a purgative or a diuretic according to the pathological state of his patient, was entirely wanting. The reasons which to-day guide us to choose digitalis as a diuretic in some cases of dropsy, and squills or nitrous ether in others, did not exist.

Magendie's plan* was very simple. It was not exactly the method which we would now employ as regards details, but it was the same in principle. The symptoms of upas poisoning indicated that the drug acted primarily on the spinal cord. This he tested by administering it under conditions which allowed it to reach quickly all organs of the body except the spinal cord. The result was that convulsions did not occur until sufficient time had elapsed for the poison to be carried by the blood to the cord, but then they appeared. Next he applied the poison to the spinal cord alone; this caused *Lauder Brunton, Pharmacology and Therapeutics, page 74.

convulsions almost at once, but first of all in the regions of the body supplied by nerves arising from the segment of the spinal cord on which the upas was placed. Next he gave the poison after destroying the spinal cord, and found that no convulsions resulted. Finally, he administered it and, after convulsions had commenced, gradually destroyed the spinal marrow from above down. As this was done the tetanus disappeared, first in the fore limbs and anterior regions of the trunk, then in the belly muscles, finally in those of the hind legs and tail. When the whole cord was destroyed all the convulsions ceased. Magendie concluded that upas was a spinal excitant, a conclusion which subsequent investigation has abundantly confirmed.

His next idea was that practical medicine might be aided by a drug which was a specific stimulant of the spinal cord, for, as he points out, many serious diseases are due to defecti ve activity of that organ. But unfortunately upas was not an article of commerce, and should it be found a valuable therapeutic agent there still remained the problem, How to get it?

This problem Magendie tried to answer by investigating the physiological action of extract of nux vomica, a plant belonging to the same natural order as the upas tree, and readily purchasable.

He found this extract to act exactly like the upas, and it consequently came to be used in certain cases of paralysis, especially in cases of what we would now name defective reflex excitability.

Fonguier, incited by Magendie's discovery, appears to have been the first to use the new medicine in such diseases. Magendie afterwards prescribed it with benefit to his own patients; and it is now recognized as one of our most valuable therapeutic agents.

To-day we order strychnia, the active principle, rather than the crude drug, but our knowledge of its activity and our ability to select the cases in which its administration is advisable, are due to Magendie's research.

From strychnia, the most potent exaltant of reflex excitability, let us pass on to consider briefly chloral, a powerful depressant.

In this valuable, though in the hands of the laity often abused, medicine we have a remedy which we owe entirely to scientific research. It is no "simple," no plant or mineral which any one might gather, and test as to its effects on human diseases. It is an artificial product created by the chemist, and its introduction to the pharmacopoeia was not due to any random attempts to discover whether it

might have some physiological activity, but to knowledge of its chemical reactions.

When Liebig, in 1830, prepared the first chloral, he was engaged on a purely chemical research, and had no thought of producing a useful medicine. The hydrate of chloral was soon after discovered, but like chloral itself remained for years merely a chemical curiosity. The sole interest and importance of chloral depended on the fact that it was an aldehyde in which three atoms of hydrogen were replaced by three atoms of chlorine; and on the light thus thrown on the chemical architecture of ethylic alcohol and its derivatives and allies.

As the chemists continued their work on chloral, seeking to unravel its molecular structure, it was discovered that when treated with alkalies it broke up into formic acid and chloroform. Physiological research having already proved that the circulating blood is feebly alkaline, it occurred to Liebreich thirty years after the discovery of chloral, that this substance might be of therapeutic value that by slowly giving off chloroform in the blood, it might act as a safe anæsthetic; and in cases where thorough anæsthetism was not desired, might be useful in producing sleep. This was first tested on the lower animals and the efficacy and safety of the drug being demonstrated on them, it was next administered to human beings, with what success you know.

Although it has now been ascertained that chloral hydrate does not split up in the blood as Liebreich supposed it might do, but circulates and acts as chloral, yet the fact remains that we owe our knowledge of its therapeutic value to scientific experiment.

What that value is may be stated in the words of Koehler: "Like opium, chloral hydrate is, and will continue, an indispensable agent for therapeutists of all future time."

Interesting as is the history of strychnine and chloral, still more so is that of amyl nitrite, a drug not yet officinal, but now being born, if I may use such a metaphor. The chemist has discovered it; the physiologist and pharmacologist have experimented with it; and now the practising physician is testing it clinically. Whatever his ultimate decision be as to its greater or less value, its story serves well to illustrate how a new remedy is discovered, and how many sciences cooperate to add to the physician's armament.

More than forty years ago certain proprietors of vineyards in the south of France found that the brandy distilled from the "marc,”

the crushed residue of grapes whose juice had been expressed for wine making, had sometimes an unpleasant taste, which greatly diminished its market value. This taste was found to be due to a greasy liquid, named oil of marc. They collected some of this oil and sent it to Balard, then professor of chemistry in the Faculty of Sciences of Paris, asking him to study it, with the hope of learning how it might be separated from the brandy. The substance was already known to chemists but was difficult to obtain. Hence Balard eagerly agreed to the request; to quote his words, "I assented very readily to this proposition because it offered, for myself, an opportunity to obtain materials for a purely scientific research, and for those who asked my advice, some chance to improve the quality of a product which was the principal source of wealth in these districts."

On examining the "oil of marc" Balard found that its chief constituent was a substance already described by Dumas as potato oil. He soon arrived at the conclusion that it was an alcohol; but before his results where published this fact was discovered and announced by Cahours, who named the substance amylic alcohol. Cahours however did not go farther with its study, and so Balard took it up again he examined the compounds which it might form and, to still further elucidate its nature, the action upon it of oxidising agents; among these nitric acid naturally found a place. The combined action of nitric acid and heat gave rise to an ether, entirely analogous to the well known nitrous ether produced in like way from common alcohol, but with amyl instead of ethyl as its radicle. This substance was what we now name nitrite of amyl, and its discovery was announced by Balard in 1844. It remained for years something that merely interested chemists as throwing light on the nature and constitution of alcohols, as no one thought of testing it as a therapeutic agent.

In 1852 Claude Bernard discovered that section of the cervical sympathetic was followed by rise of temparature and dilatation of the blood vessels on the same side of the head, and, following up this discovery, Brown-Sequard demonstrated that irritation of the sympathetic caused vascular constriction. Thus the vascular nerves were discovered; an advance in our knowledge of the physiology of the circulation second only to Harvey's great work.

Bit by bit the functions of the vaso-motor system were ascertained. Its main nerve centre was located in the medulla oblongata, and it

was found that in a variety of ways this centre could be aroused to abnormal activity; that if irritated it might so excite the nerves of the vessels as to cause extreme contraction of the muscular coats of the arterioles, and thus oppose great resistance to the flow of blood through them: in this way enormously raising aortic pressure and putting a great strain on the left ventricle of the heart. It was also demonstrated that destruction of the vaso-motor centre or section of the spinal cord (which put most vascular areas in the body beyond its control) was followed by dilatation of the arteries and a great fall in blood pressure. Thus we came to know that the nervous system and the muscular coats of the arteries played an active part in controlling the blood supply to various regions of the body; and that congestion or anæmia of any organ not only might be, but in most cases is due rather to abnormal activity of nerves or blood vessels, than to changes in the work done by the heart. This fruitful idea was, of course, soon seized by pathologists and applied in many cases with good results, to clearing our conceptions of diseases dependent on local vascular spasm or paralysis.

Years passed by and no one suggested that there might be a disease whose essential symptom was a convulsive activity, an epileptic fit, of the muscles of the arterioles in general.

In 1859, Guthrie* observed that amyl nitrite, when inhaled, caused flushing of the face, throbbing of the carotids, and a quickened heartbeat. Some years later (1865) Richardson called attention to this substance, as an agent which might be useful, from its power of causing dilatation of the smaller arteries and capillaries.

Next Gamgee discovered by experiment on animals, that nitrite of amyl reduced arterial pressure to a remarkable extent, and Lauder Brunton, assisting at some of Gamgee's experiments, had this fact impressed on his mind.

So far we have chemistry, physiology, and pharmacology cooperating; but to give us a therapeutic result pathology was needed. Brunton lived day and night with a victim of angina pectoris: baffled and irritated by his ignorance of the nature of the disease, he strove in every way to get a knowledge of the proximate cause of its frightful symptoms. Marey had invented the sphygmograph for the purely physological end of ascertaining the mode in which the blood flowed through the arteries but it had been learned that this instrument could also afford information regarding intra-arterial pressure.

*Journ. Chem. Society. 1859.