I have, in this case, searched carefully through many sections, and only found a few bacilli.

It would seem that notwithstanding the difficulty of finding the bacilli uniformly in the tissue, upon their discovery depends our ability to make a positive diagnosis.

In some cases of chronic diffuse orchitis where there is a large cell proliferation, much thickening of the membrana propria, degeneration of the epithelial mass in the centre of the tubules, and even the formation of giant cells, that such an obliterated tubule, a so-called pseudotubercle, may very readily be mistaken for a tubercle granulum; but when in addition to all these we are able to discover the bacillus, the diagnosis is at once cleared up.

FIG. 1.-CHRONIC DIFFUSE ORCHITIS.

a, Seminal tubule, with thickened membrana propria and nucleated granular mass in the centre of the tube.

b, Round cells infiltrating the interstitial tissue and in places aggregated in

masses.

c, Increase in the interstitial tissue, showing the reticulated stroma.

d, Original lumen of seminal tube.

e, Blood-vessels with thickened walls and proliferation of adventitia cells.

FIG. 2.1 -A TUBERCLE GRANULUM.

a, Central degeneration.

b, Giant cells.

c, Obliterated blood-vessel.

d, Blood-vessel containing blood and a few free round cells.

e, Blood-vessel partly empty, partly filled with blood and granular detritus.

HYOSCYAMINE.

BY R. G. ECCLES, M. D.

This alkaloid has lately been ushered into unusual prominence among Brooklyn physicians by a recent death, the alleged error of a drug-clerk, and the coroner's trial that followed. The physician had ordered, as a hypnotic for the deceased, capsules containing, in each, one-eighth of a grain of Merck's amorphous hyoscyamine and the same quantity of sulphate of morphine. The drug-clerk was charged with having substituted Merck's crystalline hyoscyamine, which substitution was supposed to have caused the patient's death. The process of reasoning by which this last conclusion was reached is obvious to all physicians. It is something like this: Since crystals are much

purer than the amorphous mass from which they are obtained, and since the strength and toxic power of the mass depends upon the abstracted crystals plus the same material that refuses to crystallize and not upon the inert extractive that contaminates the amorphous mass, therefore the crystals are by far the most potent and dangerous. In fact, this is the rule in the majority of cases; but unfortunately for such logic, it fails in this case. What is left does not happen to be inert extractive plus uncrystallized hyoscyamine, but the last-named substance with another and totally different alkaloid of as great or greater power.

The last (16th) edition of the "United States Dispensatory" says of it that "various observers have noted that the impure amorphous hyoscyamine is more powerful than is the crystallized alkaloid" (p. 803). Prof. H. C. Wood's experiments showed that its mydriatic effects were much more rapid than those of atropine, and still more so than those of hyoscyamine (Therapeutic Gazette, 9, 1: 594, 760). Emmert and Hirschberg in 1881 obtained mydriatic effects from quantities much smaller than they could of either atropine or hyoscyamine ("Prescott's Organic Analysis," p. 343). Emmert fixes the quantity at one-fifth of that of atropine. The testimony of one of the medical experts before the coroner's jury rather tended to confirm these conclusions. Eight or ten years ago he had given very much larger doses of amorphous hyoscyamine than of late, going almost as high as a grain at a dose. Then the product was the so-called resinoid and contained all of its hyoscyamine. Now it is mainly composed of the alkaloid hyoscine, the hyoscyamine being removed from it by crystallization. Why the doctor, in view of his own reported experience, expressed a fear of the hyoscyamine in its crystalline form in doses greater than one-seventyfifth of a grain was rather strange. It seemed as if he thought that the removal of crystallized hyoscyamine from the resinoid was like the removal of strychnine from brucine, when, in fact, such evidence as we at present possess points in the reverse direction. The weaker alkaloid crystallizes out, leaving that which remains the stronger for its absence. In no alkaloids are there so great discrepancies in the reported doses as these two show. Usually both are fixed at from 1/120 to 1/60 of a grain, and yet the records show that as high as one-fourth of a grain can be given with safety except where contra-indications exist. Indeed, Gnauck, in a paper read at the September, 1882, meeting of German Psychiaters at Eisenach, and reported in their proceedings, fixed the dose for internal use of the pure crystallized hyoscyamine alkaloid at from one-sixth to four-fifths of a grain. The

latter figure is more than twice the quantity taken by the deceased in both of his doses. A report of this can be found in Merck's Bulletin, November, 1889, p. 86.

The United States Dispensatory," which fixes the highest dose of amorphous hyoscyamine at one-sixtieth of a grain, tells of one-quarter of a grain, being taken at once, with good results. Thus is the reader confused by conflicting statements. In the Formulaire des Nouveaux Remèdes, 1888, p. 176, MM. Bardet and Egasse fix the dose of amorphous hyoscyamine at one-twelfth to one-sixth of a grain. They add, however, that it may be gradually increased up to three-fourths of a grain. As early as 1873 Oulmont, in the American Journal of Medical Science (April, 1873, p. 528), fixed the dose of hyoscyamine at onethirtieth to one-fifth of a grain. This was before its true composition and distinction from hyoscine were known.

Atropine is certainly the most dangerous of the mydriatic alkaloids, and a number of cases are on record of adults taking a grain without fatal results. (Vide "Taylor's Treatise on Poisons," p. 732.) Oneand-a-half and two grain doses have been known to kill. If any smaller amount of atropine, hyoscyamine, or hyoscine has proven fatal, the report has escaped the attention of the writer.

17

These three alkaloids are as closely related chemically as they are therapeutically. Their common formula is C17 H23 NO, they being someric bodies. In decomposition they all give up tropic acid, showing that they are tropates, but, while hyoscine produces pseudo-tropine, hyoscyamine and atropine produce tropine. This last product is one of the most interesting substances known to students of organic chemistry, because of its being an easily traced derivative of pyridine, and forms the first piers of the bridge that is yet destined to lead us to the synthetic production of quinine, morphine, strychnine, cocaine, aconitine, etc.

Ladenburg, who first separated hyoscine from hyoscyamine and showed what amorphous hyoscyamine really was, worked out the rational formula of atropine, the type of this group. The changes can be best shown graphically. Beginning with benzol, the near relative of aniline and other coal-tar products, we have this molecule:

This becomes pyridine, the probable starting-point of all alkaloids, ptomaines, and leucomaines. By replacing in the ring of carbons a nitrogen atom, N, for the C-H, we have:

By successive steps this has four more hydrogen atoms added, thereby forming tetra-hydro-pyridine, thus:

If now we remove two hydrogen atoms and replace one by the ethylene hydroxyl radical

we get, as a product of the changes, tropine, the base of hyoscyamine and atropine, thus:

While this base is the same in hyoscyamine and atropine, it differs in hyoscine merely in the place where the methyl or ethylene hydroxyl radicals are attached. The exact relation of neither has been determined, but it cannot be greater than the removal of the methyl group to the carbon above, thus:

The union of the tropine molecule with tropic acid gives atropine or hyoscyamine, according to the place on the ring it attaches itself. Ladenburg believes atropine to be an optically inactive base, related to hyoscyamine as racemic acid is to lævotartaric acid. When hyoscyamine is heated five or six hours, above the melting-point, it is converted into atropine. Boiling hydrochloric acid splits up both atropine and hyoscyamine into tropine and tropic acid; while the same treatment converts hyoscine into pseudo-tropine and tropic acid (Hyoscyamine in "Watt's Dictionary of Chemistry"). Chloride of gold forms with hyoscyamine a lustrous golden yellow precipitate soluble in excess of liquid and that crystallizes in yellow prisms that melt at 198° C. Hyoscine under the same treatment gives a yellow precipitate almost free from lustre and scarcely soluble even in great excess. This fact enables the chemist to separate hyoscine from hyoscyamine (Ber, der Chem. Ges., xiii., pp. 251, 909, and 1549; and Amer. Jour. Pharm., 1883, p. 463, and 1884, p. 201).

Until Ladenburg began the investigations in 1878 that led to these discoveries, everybody believed that hyoscyamine and hyoscine were but crystallizable and uncrystallizable forms of each other. Amorphous hyoscyamine was supposed to be impure hyoscyamine only. We now know that it is a totally different alkaloid, and should hence forth go by its proper name. To write for "hyoscyamine amorphous (Merck's)" is exactly the same as writing for "soda water (Matthews')." Most druggists would be likely to know what the last article is, but some one might interpret it literally, especially if some man of the name