UC-NRLF
(vorm: E. Sobering)
BERLIN.
•flfcf
MEDICINAL AGENTS
OF THE
CHEMICAL WORKS
(VORMALS E. SOBERING),
BERLIN.
1893.
CONTENTS.
I'ACE
PREFACE , v.
PlPERAZINE ... ... ... ... ... ... ... I
PHENOCOLL 29
Phenocoll and Piperazine in combination ... 43
CHLORALAMID ... ... ... ... ... ... ... 47
PARALDEHYDE ... ... ... ... ... .. 63
THE CHLORAL GROUP 71
Chloral Hydrate 71
Butyl-Chloral 72
Chloroform from Chloral ... ... ... ... ... 72
SALOL 73
SALICYLIC ACID AND SALTS ... ... ... ... ... 93
Bismuth Salicylate ... ... ... ... ... ... 94
Lithium Salicylate ... ... ... ... ... ... 95
STRONTIUM SALTS ... ... ... ... ... ... 97
POTASSIUM BROMIDE 101
THIOSINAMINE ' "103
DlABETIN ... ... ... ... ... ... ... ... 107
IODOFORM, ELECTROLYTIC 109
CRESIN in
PREFACE.
The discovery of the DAGUERRE method of producing
pictures of natural objects — in other words, the invention of
the art of photography — gave an important stimulus to the
preparation of chemicals in a high state of purity, and
indirectly exerted an influence upon the synthesis of organic
compounds. The importance of the art was recognised by
ERNST SCHERING, founder of the Chemische Fabrik auf
Actien, who set himself the task of preparing the chemicals
used in it in a condition of the utmost purity. In thus sketching
in barest outline the origin of the firm, allusion may be made
to the historic interest that gathers round the design impressed
upon the title-page and cover of the volume. Though by no
means a conspicuous figure, it is associated with the earliest
history of the Fabrik, and has more significance than appears
at first sight. Those readers acquainted with alchemic lore
and symbols will recognise the superimposed forms represent-
ing fire and water as well as the central circle which stood for
the third of the " elements" of the ancients.' The part played
by the sun as a source of energy in chemical processes is
symbolised by the halo of rays streaming from the " star,"
while the particular application of this curious group of signs
to the firm is indicated by the initials (E.S.) of the founder.
vi. Preface.
This may be regarded as the commencement of the
manufacture of fine chemicals by this firm, which has now
attained the dimensions indicated by the number of products
described in the following pages — products which are, with
few exceptions, all of recent introduction.
From the preparation of well-known compounds in
qualities distinguished by their high purity to that of entirely
new bodies of definite chemical nature was a natural transition.
The development of synthetical organic chemistry revealed
new and better methods of procedure, which were promptly
investigated and taken advantage of in the works, and the
inevitable result of the progressive tendency always kept alive
was that the firm of E. SCHEKING occupied the foremost place
among those chemical manufacturers engaged in the produc-
tion and investigation of new remedies.
It is noteworthy that the very first of the synthetical
remedies — Chloral Hydrate — was prepared in the chemical
works of the firm, and the prestige conferred by this achieve-
ment was again enhanced by the introduction of Salicylic
Acid. It may be remarked, in passing, that although since the
debut of these compounds the class of synthetical medicinal
compounds has enormously increased, they still maintain their
high position in materia medica, and, indeed, have become
almost indispensable in modern therapeutics.
It will be seen that the derivative of chloral, Chloralamid,
rivals the mother-substance in general importance, and in
Preface. vii.
certain cases is preferable to it. The steadily-growing litera-
ture of the compound establishes its valuable hypnotic
properties and the freedom of its medicinal action from
unpleasant after-effects. This latter feature has attracted
general attention; to it is largely due the great strides
which Chloralamid has made in the favour of medical men
in all countries.
The monograph on Piperazine, the first remedy in the
gouty diathesis which organic chemistry has yielded, should
prove especially interesting. Although so recently introduced,
the peculiar chemical and chemico-physiological behaviour
of the base, especially in relation to uric acid and its com-
pounds, has procured for it a searching investigation and
extensive trial which enable a sound judgment as to its value
to be already formed. When combined with Phenocoll it
seems to form the most efficient remedy for the various forms
of gout which has hitherto been discovered.
The noteworthy points in the therapeutical uses of
Phenocoll are its comparatively ready solubility in water, and
its freedom from any deleterious action on the blood or
circulatory system generally. The medical practitioner will
not need to be reminded that the possession of both these
properties gives Phenocoll a marked advantage over all other
remedies of the same class.
Finally, the attention of the reader may be directed to the
chapters on Diabetin, Strontium Salts, and Thiosinamine,
viii. Preface.
the latest comers among therapeutical novelties. It is not
possible, of course, to predict with certainty what position
these substances will finally attain in materia mcdica ; but it
may at least be said that they give promise of winning
recognition as real enrichments of the physician's armament
against disease.
Chemische Fatoft auf Actien
Yormals E, Sobering,
BERLIN,
February, 1893.
PIPERAZINE.
An interesting paper was read in Berlin some months ago by
Finzelberg, which illustrates the chain of events by which Piperazine
was discovered and its therapeutical value established. It appears
that the father of the chemist just named died from uraemia caused
by renal stone, and this led his son to resolve to find, if possible, a
substance that by internal administration might either prevent the
formation of deposits of uric acid or effect their solution when
formed.
Consultation with other chemists as to the most likely means of
effecting this end led to a determination to experiment with all the
known organic bases, as regarded their solvent action on uric acid, in
the hope of discovering one that would produce the desired result
without producing any deleterious or toxic effect upon the organism.
Several years passed by during which the investigation was carried
on as opportunity presented, until general attention was directed to
the natural base, spermine, and to the synthetically prepared diethyl-
enediimine of Ladenburg, by the work of Schreiner and Professor
Poehl.
At first spermine and Ladenburg's base were believed to be identical,
but the different appearance of their bismuth iodide compounds under
the microscope convinced Schmidt and Majert that they were different
bodies. A purer preparation of the synthetical compound named
Piperazine — a designation indicating its relationship with piperidine,
piperine, and pyrazine — was subjected to careful investigation, the
upshot of which was the discovery of the remarkable properties detailed
in the following paragraphs.
PHYSICAL AND CHEMICAL PROPERTIES.
Piperazine is represented by the formula C4 HIO N2. Crystallised
from water it assumes the form of glassy lustrous tables. When
B
Piperazine.
exposed to the air it is deliquescent, the crystals rapidly absorbing
carbon dioxide and water, and becoming liquid. When subjected to
the action of heat it melts between 104° and 107° C., and boils at
i45° C.
The compound is very readily soluble in water, forming an almost
tasteless, strongly alkaline but non-caustic solution.
Hydrochloride of Piperazine, a salt of the base which has also been
used therapeutically, forms silky, lustrous, lanceolate crystals, very
easily soluble in water and, with more difficulty, in alcohol.
The most important chemical property of Piperazine is its power of
combining with a large proportion of uric acid, forming urate of
Piperazine, a salt distinguished by its ready solubility in water. Even
in the presence of an excess of the acid only the neutral salt is
formed.
The clearest idea of the action of Piperazine as a solvent of uric
acid is obtained by comparing it with that of lithia, the remedy
chiefly resorted to, prior to the discovery of the synthetical base, in
the treatment of uric acid diathesis where the primary indication was
to effect the solution and elimination of uric acid. Now when brought
together in the cold with aqueous solution of the acid, Piperazine
dissolves twelve times as much as the same weight of carbonate of
lithium under similar circumstances. Further, the salt formed by
the organic base was found to be much more soluble in water than
urate of lithia ; the latter requires 368 parts of water for solution, while
one part of Piperazine urate is taken up by 50 parts of water.
A number of observers have examined the chemical activity of
Piperazine as a solvent for uric acid, especially when in the form
of those concretions which, originating in the renal pelvis and
bladder, give rise to severe pain and other serious symptoms.
Dr. Finzelberg subjected to the action of Piperazine, urinary calculi,
consisting either of pure uric acid, or of that compound together with
ammonium urate, calcium phosphate, etc. He found that all these
forms of concretion dissolved freely and perfectly within a compara-
tively short time in a one per cent. Piperazine solution. In some
cases nothing remained but a light honeycombed skeleton, which
consisted of the hardened cementing mucus. It was particularly
Pipe.
razme.
striking that the edges of the calculi, sometimes very sharp, dissolved
away rapidly in the Piperazine solution.
A similar research was carried out by Drs. Biesenthal and Schmidt.
The " stones " they had for experiment consisted of uric acid (or
urates), or were. of a composite nature, being made up of alternate
layers of uric acid and calcium oxalate or phosphate. The authors
recorded the observation that even large compact pieces belonging to
the first class, dissolved with extraordinary readiness in a solution of
Piperazine.
One series of experiments was especially interesting as showing the
comparative activity of Piperazine, sodium carbonate, lithium carbonate
and borax, in effecting the solution of uric acid stones. A " tophus"
was obtained of great hardness, made up of concentric layers of uric
acid. Cubical pieces, of as near as possible equal weight, were sawn
from this, and each suspended by means of test-tubes with fine
perforations at the end, in one per cent, solutions of Piperazine and
of the salts enumerated above. All the solutions were kept at blood-
heat and under exactly the same conditions. The results of the
experiment are shown in the following paragraphs : —
1. PIPERAZINE SOLUTION. — Two and a-half grns. of the stone,
after only six hours, was all dissolved save a scarcely per-
ceptible residue without stratification. The solution had
become yellow in consequence of the organic matter which
had also passed into solution.
2. LITHIUM CARBONATE SOLUTION. — Three grns. of the stone
was not dissolved after 48 hours, a compact skeleton being
left, in which fine stratification was clearly recognisable.
This residue was removed to the Piperazine solution, where,
with the exception of a few scarcely visible flocks, it had soon
all dissolved.
3. SODIUM CARBONATE SOLUTION. — After 48 hours immersion in
this, a fragment of the stone weighing 2^ grns. was unaltered
in bulk. A white crust of sodium acid urate had formed on the
stone, which, though at the most -6L0-th of an inch thick, pre-
vented any further action of the soda solution. Beneath the
B 2
Piperazine.
white coating, the stone was as hard as ever, but transferred
to the Piperazine solution it dissolved in a few hours.
4. BORAX SOLUTION. — A fragment weighing £ grn. only dis-
solved after a digestion of 20 hours, and then the same
compact skeleton was left behind, as with lithium carbonate.
It rapidly and entirely dissolved in Piperazine, save a few
scarcely perceptible flocks.
The capability shown by the solution of Piperazine of dissolving a
part of the organic substances, which enter into the composition of
these stones, explains the rapidity with which they are broken down
and pass into solution when digested in it.
Experiments with other stones confirmed the observation of Finzelberg
that, long before complete solution takes place, sharp edges are broken
down and the concretion assumes a slippery character. It is shown
later that every feature of the behaviour of tophi with Piperazine
solution has been of significance in determining the therapeutical
application of the compound.
Drs. Biesenthal and Schmidt also carried out in the chemical
laboratory a series of experiments on the comparative diffusibility of
the urates of Piperazine, sodium and lithium through animal membrane.
The results demonstrated that Piperazine urate diffused more rapidly
than either of the other salts. This observation has also therapeutic
significance in view of the important part which osmosis is known to
play in nutritive and other processes in which the tissues are
concerned.
Among the experiments performed by Biesenthal and Schmidt was
the following : —
A solution of Piperazine hydrochloride was placed in a fractionating
flask, provided with a small separating funnel, and the side tubulure
of which dipped into the bulb of a second similar flask containing
barium hydrate solution ; both the flasks were joined up with air-tight
fittings, and exhausted. Soda carbonate solution was allowed to fall
through the funnel, and the apparatus again made completely vacuous.
On warming the mixture to 40° C. (104° F.) and constantly shaking
the barium solution, the latter gradually became turbid, and a thick
layer of barium carbonate formed.
Piperazine.
These phenomena were due to the double decomposition of sodium
carbonate and Piperazine hydrochloride with the formation of sodium
chloride and Piperazine carbonate, which latter, on warming, gave off
carbon dioxide.
The bearing of this experiment upon the behaviour of Piperazine
in the organism is evident ; it becomes largely converted into hydro-
chloride in the stomach, and this salt is brought into contact with
sodium carbonate in the alkaline juices of the tissues.
But it would be equally important to the efficient action of Piperazine
as a solvent of gouty secretions that the urate should not undergo
double decomposition with the sodium carbonate of the alkaline
juices; if this were the case Piperazine carbonate and the relatively
insoluble sodium urate would be formed and the latter re-deposited.
In order to test this question the authors above-named arranged
two fractionating flasks again as in the experiment just described. In
the one was placed 400 cc. of a solution of 24 grns. of Piperazine with
45 grns. of uric acid (from which all possible traces of carbon dioxide
had been removed by long boiling). The other contained barium
hydrate solution as before. The flasks were again exhausted, soda
carbonate solution introduced, and the whole system heated to
40° C. No trace of turbidity appeared, however, in the barium
solution, thus showing that no decomposition occurred and no
Piperazine carbonate was formed in the flask under conditions closely
approximating to those which obtain in the human body.
TESTS.
In order to ascertain the precise manner in which the remedy is
affecting the excretory functions, and to enable the physician to
control its action, it is necessary to be able to trace Piperazine in the
excretions, and particularly in the urine. The method of doing this is
as follows : —
About 10 ccm. of the urine to be examined for Piperazine is
decomposed by few drops of concentrated soda and slightly warmed
Piperazine.
for a short time. After cooling the liquid is filtered from the floccuient
precipitate of phosphates, etc., made decidedly acid by few drops of
hydrochloric acid (avoiding any large excess) and treated with a
solution of potassium-bismuth iodide.
The first effect is the formation of a dirty-coloured amorphous
precipitate which contains no Piperazine, but is produced by nucleo-
albumen, a constituent of normal urine. The mixture is warmed for
a short time to about 40° — 50° C., in order to cause the precipitate
described to aggregate, and then rapidly cooled and filtered. On
energetically rubbing with a glass rod, a pomegranate-red crystalline
compound appears in microscopic needles which assume a distinctive
arrangement.
When the proportion of Piperazine present is too small to be
detected in this way, another more refined modus procendi is
available : —
The urine is made decidedly acid and evaporated ; a tenacious
brown residue is left behind which is rubbed down with caustic soda
in powder. The evolution of ammonia which occurs is due to the
decomposition of the urea. The mass is then mixed with about an
equal weight of sand and rapidly distilled in a retort with an efficient
condenser until no more water- vapour passes over. The Piperazine
present in the urine passes over in the distillate unchanged, but
organic nitrogenous bodies like sarcosin, creatine, and xanthine are
decomposed. The liquid, which collects in the receiver, has a strong
odour of alkylamines, is boiled for a short time in order to get rid of
the greater part of the ammonia, filtered, acidified with hydrochloric
acid, and tested with the double iodide solution referred to already.
A convenient but less striking process depends upon the character-
istic crystalline form of benzoyl-piperazine. Phosphates are separated
as in the first process outlined above, a drop of benzoyl-chloride is
added, and the whole powerfully agitated. After standing half a day
the dirty- white sediment is thrown on to a filter and extracted with
absolute alcohol ; the extract is evaporated on a watch-glass, and a
drop of the concentrated liquid examined under the microscope. The
benzoyl compound of Piperazine separates in characteristic trans-
parent rhombs of great regularity.
Piperazine.
PHYSIOLOGICAL ACTION.
It has been already intimated that Piperazine was at first supposed
to be identical with the "Spermine" of Drs. Brown-Sequard and
Poehl ; hence it was primarily regarded as a nervous stimulant.
The earliest physiological examination of Piperazine was carried out
by Prof. Robert of the Dorpat Pharmacological Institute. The result
was to demonstrate the freedom of the compound from any injurious
or poisonous action. At the same time no evidence was obtained of
the stimulant action upon the nervous system anticipated. Similar
results were obtained by Bock, who concluded that Piperazine did not
possess any marked physiological action.
Light was thrown upon this apparent discrepancy by the discovery
that there was no identity between Piperazine and spermine. Then
attention was directed to the solvent power of the synthetical base
for uric acid, and on this property was based its employment in
medicine.
Dr. Vogt, in conjunction with the chemists Ferdinand Vigier and
Gautrelot, investigated the effects which Piperazine produces upon the
metastasis or tissue change continually going on in the animal body.
They confined their attention to the urine of patients undergoing
treatment with the synthetical compound. The excretion was ex-
amined two days before the administration, then after the substance
had been given three days and again two days after its use had been
discontinued.
The results of this work led the authors to conclude as follows : —
1. That the percentage of urea in the dry residue had fallen about
a sixth during the treatment, but that it was higher two
days after the administration was discontinued than before it
was begun.
2. That the percentage of uric acid had decreased after three days
of the treatment, and still more so two days after suspension.
3. That the ratio of uric acid to urea also fell steadily and
continuously during the period of observation.
Piperazine.
The interesting results are noteworthy, though they have not
received confirmation by other workers. As a matter of fact our
knowledge of the influence of Piperazine on metastasis is still far from
complete. It is appropriate that mention should be made here of the
experiments which Drs. Heubach and Kuh made upon themselves
with Piperazine. Taking as much as 2^ grammes daily they did not
observe any functional disturbances or any ill-effect upon the general
well-being, but in every experiment a slight increase was observed in
the amount of uric acid excreted.
Drs. Biesenthal and Schmidt (Berl. klin. Wochenschr., 1892, January)
turned their attention also to the harmlessness of Piperazine when
given internally. Daily doses of 15 to 45 grns. gave rise to no kind of
disturbance, and in some cases the compound was taken in ounces at
this rate without any unpleasant symptoms appearing. Further, they
convinced themselves that much larger doses even than these of
Piperazine could be given without any undesirable albuminous changes
occurring. This was proved by experiments on a healthy man, under
strict diet, to whom during six days i£ drms. of Piperazine was given,
and whose urine was carefully examined day by day. The urine main-
tained its acidity, but after the use of Piperazine this considerably
diminished ; the base was always present in the urine in large
quantities.
Further, it was of course necessary that such a remedy intended for
the solution of gouty concretions in the human tissues, should be
stable, as if split up during its passage through the organism, it would
be of no use as a solvent for uric acid deposits. It has, however, been
shown that such stability is possessed by Piperazine (tier, d. D. chem.
GeselL, 1891, pp. 243 and 3237). After a single dose of 75 grns. by far
the greater part is excreted with the urine in the course of 24 hours,
but even after six days the presence of Piperazine can be detected in
the urine, which would not of course be the case if it underwent
decomposition in the body.
It was one object of the research of Drs. Biesenthal and Schmidt
to trace Piperazine in its course through the digestive organs and the
circulatory system, until it arrived at the point where gouty deposits
had been formed.
Piperazine.
They stated that when the base enters the stomach it is converted,
largely at least, into a hydrochloride. This salt, with the sodium
carbonate of the alkaline juices, undergoes double decomposition,
sodium chloride and Piperazine carbonate being formed. They
experimentally demonstrated the mutual decomposition of Piperazine
hydrochloride and sodium carbonate when brought into contact
(v. under *' Chemical Properties"). Piperazine carbonate has a solvent
power for uric acid similar to that of the base, and coming in contact
with the gouty deposits forms Piperazine urate, a compound which
is more stable to a marked degree than the hydrochloride, as shown
by the experiments of Biesenthal and Schmidt, detailed in the
previous chapter.
MEDICINAL PROPERTIES AND USES.
From the time of Pliny downwards, attempts have been made to
effect the solution of urinary stones by chemical means — that is to say,
by the administration of agents which were believed to exert a solvent
action upon the concretions. This treatment was, however, first
placed upon a rational basis by the researches of Fourcroy and
Vauquelin, who proved that the stones were dissolved by alkalies if
consisting of urates, and by acids when made up of phosphates.
There has, however, always been the difficulty to contend with, that
substances used in the laboratory with success, proved of little value
when used clinically, because they underwent changes in the organism
and reached the seat of the disease in altered, and, for the purpose in
view, inert forms. Carbonate of lithium, for instance, which formed
the most soluble compound of uric acid known prior to the introduc-
tion of Piperazine, appeared in the urine mostly as insoluble chloride.
Other authors, such as Pfeiffer and Posner, tested the effect of
various remedies upon the solvent power of the urine for uric acid,
both pure and in the form of stones and gravel. With all these
remedies, it was observed that so long as they were used the uric acid
decreased, but as soon as they were discontinued, the proportion of
acid rose again.
TO Piperazine.
A further disadvantage of these earlier remedies was that neither
the stomach nor the '. 'adder was capable of bearing the quantity of
alkali necessary for the . jlution of the concretions, while this class of
substances had other serious disadvantages. For instance, if given in
too large quantities, so that the urine became unmistakably alkaline,
phosphates were thrown out of solution and formed secondary layers,
increasing the size of the stones already formed.
Altogether the internal treatment of phosphate stones has been
associated with great difficulties. Injection of acid solution has
sometimes proved effective, but by that method alone their formation
cannot be prevented. This could only be done by assiduous catheter-
isation, drainage and washing out of the bladder, so as to prevent the
ammoniacal fermention of the urine.
Unfortunately the alkalies do not attack the organic foundation of
the stones, and, although theoretically the solution of a vesical stone is
conceivable enough, experience has not hitherto been able to record
a single well-authenticated case in which such an effect has been
attained in the human body. When sometimes physicians and patients
have believed that the use of such solvent remedies had improved the
disease, this was due either to a beneficial effect upon associated
symptoms (e.g., vesical catarrh) or to a spontaneous effort of nature.
Under these circumstances it should not excite surprise that the
introduction of a compound possessing such remarkable powers of
dissolving uric acid as Piperazine should have at once attracted
attention.
At the same time it must be noted that vesical and renal calculi are
not generally of the same composition chemically; vesical " stones"
consist almost always of calcium phosphate, or, more rarely, oxalate,
with the exception of the small nucleus that is always present, while
renal stones much more frequently are composed nearly entirely of
urates, though sometimes mixed with phosphates and oxalates also.
Any foreign body in the bladder may form the nucleus of a calculus,
especially if the patient's urine be loaded with phosphates or urates.
A small renal calculus may, of course, figure as a vesical stone by
subsequent deposition upon it of phosphates, oxalates, etc., unless it
Piperazine. 1 1
be passed away with the urine immediately after arriving in the
bladder.
Further it is believed that the formation of both vesical and renal
calculi is accelerated by the continuous imbibition of large quantities
of strongly alkaline mineral waters ; these agents, in neutralising the
urine, give rise to eminently favourable conditions for the formation
of concretions.
In considering the extensive literature which has accumulated on
Piperazine, it will be convenient to give attention first to its employ-
ment in troubles of the urinary tract due to the formation of
concretions of the solid constituents of the urine.
IN RENAL AND VESICAL CALCULI, ETC.
(a] Internally.
Although Dr. Vogt made a special study of the physiological
behaviour of Piperazine, he also records its employment clinically in
cases of gravel (gouty) associated with severe renal pain. After the
administration of Piperazine had been continued a few days the pains
entirely ceased, and the urine gave evidence of an increase in the
amount of urea excreted, with a corresponding decrease in the amount
of uric acid.
Though the first diagnosis turned out to be incorrect, yet a case of
presumptive gravel which came under the observation of Drs. W.
Ebstein and C. Sprague (Berl. klin. Wochenschr., 1891, No. 14) should
not pass without mention. The principal symptoms were cystic
spasm, local pain during urination and obscure transient pains in
various parts of the body. Piperazine was given in doses of 30 to 45
grns. daily for a fortnight, during which the patient was strictly
dieted, and the urine daily estimated for total nitrogen and for uric
acid.
It was found out later, thnt the urinary troubles of the patient were
due to a vesical ulcer, but the case is of interest as showing that
Piperazine may be given in considerable quantities for prolonged
periods without producing any disagreeable effects, even when the
epithelial coating of the bladder was the seat of a morbid process.
1 2 Piperazine.
One of the cases described by Dr. Bardet, Paris, was of renal colic.
In the course of six days 75 grns. of Piperazine pur. were given. The
patient had had an attack of colic the day before the medicament was
begun. The treatment was followed by rapid excretion of small renal
stones, and the patient stated that micturition was more rapid and
easy than usual.
Drs. Heubach and Kuh had among their patients a man of 37 who
suffered from renal colic ; there was constipation, difficult urination,
urine with much sediment and some albumen. After a week's
treatment with the usual routine remedies, one tablespoonful of a
£• per cent, solution of Piperazine every two hours was prescribed.
On the third day of the treatment, violent pains in the region of the
left kidney appeared, which increased during defaecation. A little
later a uric acid concretion was passed with great pain and slightly
bloody urine. The " stone " resembled in size and form a medium
incisor tooth and weighed six grns. The surface bore signs of
corrosion. Since the passage of this stone the symptoms did not
reappear.
In a second case, gravel, consisting chiefly of uric acid, had existed
for years with frequent attacks of colic and haematuria. A table-
spoonful of the % per cent. Piperazine solution every two hours was
prescribed, and after the treatment had been continued ten days
there was an abundant discharge of small round uric acid concretions.
This lasted for several days and was followed by a cessation of the
colic and haematuria.
In a lengthy treatise on the treatment of the uric acid dyscrasia by
internal medication in general, and by Piperazine in particular, Dr.
Brik (Wien. med. Blatter, 1891, December) describes a case of an old
man who had suffered for 45 years from uric acid sediments. The
alkaline method of treatment had been chiefly followed, but this was
not successful in preventing for long the precipitation of uric acid.
The patient had been operated on for stone more than once, very
large concretions being removed each time.
Piperazine was prescribed in daily doses of 15 grns. The first
effect was increased diuresis and a manifest diminution of sediment.
The urine was always acid in reaction. As the Piperazine was con-
Piperazine. 1 3
tinued the uric acid sediment disappeared altogether, and did not
again reappear in notable quantities for four weeks. A few days' use
of the remedy was sufficient to again free the urine from excess of
the acid.
The same. author had under treatment a boy of 14 years with
enuresis nocturna, for which a variety of treatment had b^en tried
during two years, but without success. The specific gravity of the
urine was 1*027, its reaction strongly acid, and 0*2 per cent, of albumen
was present. It deposited a sediment of uric acid in different forms
(such as are constantly seen in incipient calculosis renalis urica} and
also containing red and white blood-corpuscles and epithelial scales.
The urinary tract showed nothing abnormal.
Diagnosing the enuresis as due to incipient calculus formation, the
author ordered 15 grns. of Piperazine in six ounces of water, to be
taken in two days. From the second day the incontinence ceased,
and did not appear again during four successive nights, although the
medication was not repeated. Although the patient was not quite
cured, the result was characterised as exceedingly satisfactory, the
enuresis showing itself only once a fortnight or three weeks.
The combination of diabetes and uric acid dyscrasia presented
special difficulties under the ordinary methods of treatment. Such a
case was also recorded by Dr. Brik. The daily quantity of urine was
between five and seven pints, albumen was present in traces, sugar to
the extent of one to three per cent., and uric acid in large quantities.
After other remedies had been tried without success, Piperazine was
prescribed. The proportion of uric acid considerably decreased, and
for some time sank to zero ; subsequently it rose again to a high level,
to drop once more to nil after a few days.
In this case, and another of similar nature, no effect was observed
upon the excretion of urine and sugar, but the subjective well-being
was markedly improved and the accompanying joint pains disappeared.
The second diabetic patient referred to had also acetonuria, but this
abnormality was soon entirely removed. Without entering into further
detail, the author mentions that very similar results were obtained in
six other cases of excessive excretion of uric acid.
14 Piperazine.
Dr. Brik spoke of Piperazine as the best uric acid solvent, and
svarmly recommended it, especially in the treatment of renal calculus
and in the various nervous disturbances which follow on such affec-
tions. When vesical stones were very large he considered it advisable
to operate and then combat the uric acid dyscrasia with Piperazine, in
order to prevent the re-formation of the calculi.
Dr. Schott, Philadelphia, had also under his care a case of renal
colic in which repeated hypodermic injections afforded only partial
relief. The attacks recurred day after day, and were exhausting the
patient's strength. In consequence an operation was proposed when
on the eighth day, unexpectedly, the cause of all the trouble was passed
in the form of a fair-sized stone.
Potash and lithium salts had been used with very little benefit, and
the author ascribed the fortunate issue of the case to the prescribing
of solution of Piperazine. The patient himself was also very enthusi-
astic about the remedy and the relief which it afforded him. Dr. Schott
added (Notes on New Remedies, 1891, Dec.,) that since attaining this
favourable result he had prescribed Piperazine in other similar cases.
An interesting case is reported by Dr. Pfeiffer, Wiesbaden. The
patient, a lady, suffered from violent pains in the region of the kidneys
extending along the course of the right ureter to the tipper part of
the thigh. There was also observed in the right iliocaecal region a
marked swelling, and the urine, passed in very small quantities at a
time, had a bright yellow appearance. When microscopically examined
it revealed the presence of a great quantity of flocculent mucous
matter with a number of epithelial cells. Although the examination
was repeated daily, no crystals of uric acid could be discovered, and
in the first instance the diagnosis was felt to be difficult, but
Dr. Pfeiffer concluded that uric acid and urate concretions were the
cause of the mischief, and acting on this belief he began a course of
treatment with Piperazine.
Before the course was begun, an attack of sickness came on, and
fever also developed ; the local pain increased to a very great extent,
so that the patient was unable to get quiet rest at night, in spite of
large doses of morphine hypodermically. All the usual uric acid
solvents — lithium carbonate, alkaline waters, etc. — had been tried
without success.
Piperazine. 1 5
Piperazine was ordered in daily doses of 15 grns. in aqueous solution.
After the treatment had been continued four days a number of
fragments of uric acid were to be detected in the urine by the
naked eye. The administration of the remedy was also followed by
diminution of pain and fall of the febrile temperature to the normal
level, while the general condition of the patient improved, and rest
and sleep were obtained without difficulty. The hard swelling also
diminished and local pain practically ceased.
These results were taken as evidence of the correctness of the
diagnosis, Piperazine having rapidly effected the solution of concre-
tions impacted in the right ureter which the older remedies had failed
to move. Three daily doses of 15 grns. so far effected solution of the
concretion that the disintegrated fragments could pass into the bladder.
The patient was kept on 8-grn. doses//'*? die of the remedy, with the
result that the amount of uric acid excreted gradually diminished
to zero.
In previous cases of "stone" treated with the ordinary remedies,
Dr. Pfeiffer had always observed, on about the eighth day, a large
increase in the volume of urine, which then became loaded with uric
acid concretions, and assumed a marked red colour.
In the case treated with Piperazine, the peculiar red colour did not
appear. This he explained as due to the fact that the synthetical base
not only dissolved the uric acid, but the mucous and other matter
which held the constituents of the "stone" together.
This property of Piperazine of dissolving the organic cementing
material of urinary concretions, enables it, according to Biesenthal, to
disintegrate stones consisting almost entirely of calcium phosphate.
At the same time, it has the advantage of not rendering the urine
alkaline, and so leading to phosphatic deposits.
Dr. Biesenthal believed that the continued treatment of patients
suffering from the symptoms of uric acid dyscrasia, by large doses of
alkalies, was very risky — an opinion which received confirmation in
the examination of a renal calculus 'taken from a patient who had been
treated for a prolonged period with an alkaline mineral water. The
calculus had only a small nucleus of uric acid, around which a fairly
thick deposit of calcium phosphate had accumulated.
1 6 Piperazine.
The author had met with 47 cases in his own practice, and collected
from colleagues the details of 220 more, in which Piperazine had been
employed with extraordinary success. Cases of renal colic were
included as well as various haemorrhages from the ureters ; some of the
latter, even when they had existed for years, were completely relieved
by the use of Piperazine.
Dr. Volmer obtained specially gratifying results in the case of a
merchant who had suffered for a prolonged period from renal colic.
He had been through a course of alkaline waters, and concretions
were passed which contained uric acid. In spite of this relief and
continued treatment with ordinary remedies, fresh attacks of colic
appeared, followed in every case by haematuria of several days' duration.
Piperazine was given in doses of 15 grns. (combined with an equal
weight of Phenocoll), and after this dose had been maintained for
four weeks, the quantity was reduced one half. From the very first
the local symptoms improved, and the haemorrhage ceased to recur.
Excellent results in renal colic were also obtained by Professor
Schweninger, the diet and excretions of the patient being so regulated
as to hinder the formation and separation of uric acid in the system.
(£) By Local Irrigation.
Attention was called early in the history of Piperazine to its freedom
from caustic or irritating properties ; the special significance of this
fact lay in the possibility it opened up of applying Piperazine in
solution locally, where vesical stones had to be treated. It has been
already pointed out that not only are the alkalies inefficient solvents
when used in this way, but also that the bladder is incapable of bearing
the quantity of alkali necessary for the purpose.
Dr. Brik specially noted the suitability of Piperazine for injection
into the bladder, owing to the fact that it does not display any local
irritant action. Drs. Biesenthal and Schmidt used for irrigation of the
bladder one and two per cent, solutions, these being borne for pro-
longed periods without the slightest difficulty. Other observers found
that even five per cent, solutions could be borne without difficulty ; it
Piperazine. 1 7
was believed that the necessary renewal of the solution surrounding
concretions would be brought about by the movements of the patients.
In this particular direction there is a field for the initiation of a new
method of treating vesical stones, which promises to be of excellent
service. At any rate the injection of solutions of Piperazine is
worthy of trial, both before proceeding to operative measures and
afterwards with the view of preventing the recurrence of the difficulty.
Summing up the unique properties which Piperazine displays in the
treatment of affections of the urinary tract due to uric acid dyscrasia,
it appears that : —
1. Piperazine dissolves concretions not only of uric acid but
also of phosphates, etc., in consequence of its power of dis-
integrating the mucous or albumenoid cementing-material which
binds them together.
2. Piperazine relieves renal colic and other local pain
associated with the formation of concretions in the urinary tract
owing to its power of dissolving the sharp edges of calculi and
giving them a slippery character.
3. As a consequence of the effect indicated above Piperazine
determines the evacuation of " stones " from the kidneys, ureters,
or bladder, very soon after administration and before time has
elapsed for complete solution.
4. Piperazine is not only superior as a solvent of uric acid
and urates to all previous remedies, but also is free from their
disadvantages.
5. Piperazine does not render the urine alkaline and so
favour the deposition of phosphates.
6. Being free from caustic or irritant action, Piperazine has
been used successfully and without any ill-effects for the
irrigation of the bladder in the treatment of vesical stone.
II.— IN THE GOUTY DIATHESIS.
It should be scarcely necessary to premise that medication alone
can scarcely be expected in every case to effect alone the cure of
c
1 8 Piperazine.
gout. The affection is characterised by marked obstinacy to all
forms of treatment, and further there are factors in its etiology or
causation which have to be taken into account in combating its
symptoms.
Among these factors an important part is played by diet and habits
of living, and it is a well-recognised principle in the therapy of gout
that dietetics are almost equal, in the possibilities of improvement
they offer, to more purely medicinal measures.
Further it would seem to be necessary to point out that when a
patient has suffered for years from the gouty diathesis, when the
whole system is more or less saturated with excess of uric acid and
other abnormal constituents, it cannot be expected that a few doses
of any medicament, however powerful in action, will be sufficient to
effect a complete and permanent cure.
The pathological distinction between rheumatism and gout in their
pure forms is tolerably clearly denned, but there is a large
proportion of cases in which it is difficult to diagnose with certainty
whether they are rheumatic or gouty in nature. It is in such forms of
" rheumatic arthritis," as they are termed, that a trial with Piperazine
is specially recommended by the authors who have written upon the
properties and employment of the base. Sufferers from the uric acid
diathesis and its numerous sequelae fill the various watering places of
Europe, and are recommended to bathe in the alkaline waters, and to
take a certain quantity of them internally.
This treatment is, of course, not within the means of all, and it has
been, therefore, emphasised as a marked advantage of Piperazine that
a course can be gone through without leaving home or temporarily
abandoning the usual avocation. At the same time, as will be seen
from the following recorded cases, the newer remedy is superior in
efficacy to those hitherto employed.
The effects of the administration of Piperazine may be watched
and compared from time to time by examining the urine of patients
periodically for urate of the base, by the methods described in a
previous section. In this way the activity of the remedy in determining
the elimination of the excess of uric acid in the fluids of the body may
also be estimated.
Piperazine. 1 9
Dr. Bardet tried i5-grn. doses of Piperazine in the case of a woman
suffering from gout, in whom the urine was heavily loaded with urates.
In the course of two days the urine cleared up, while the author was
able to detect a slight decrease in the amount of uric acid present
within 24 hours of beginning the treatment.
In a second case a gouty patient suffered from an ulcer of the elbow.
The first two days of the treatment i — 1£ grns. of Piperazine were
given daily (by injection) and afterwards 3 — 6 grns. every two days for a
week. The patient observed that the ulcer and redness, which circum-
scribed it, rapidly decreased simultaneously, while, further, pain was
promptly lessened in intensity. The proportion of uric acid in the
urine was 0*65 before the treatment and 0*52 on the last day of it.
Another man had gout of long standing and podarthritis. He had
been subject to intermittent attacks for five months and had rarely
been free from pain for two days together. Injections of 3 — 5 grns.
of Piperazine (hydrochloride) were made every two days in the
nates. Alleviation of pain was experienced after two days of the
treatment.
An exudation of inflammatory secretion from enormous swellings of
the joints produced by urates was a conspicuous symptom in a second
case of podarthritis, where extensive and unusual deformity in the limbs
had been produced by the disease. The treatment adopted was to
inject 3 — 5 grns. of Piperazine or i to i£ grns. of the hydrochloride
every second day. The patient affirmed that the injection facilitated
and accelerated the excretion of urates through the skin.
The following brief histories of four cases are from a lengthy
treatise by Drs. Biesenthal and Schmidt, on their clinical experience
with Piperazine (Berl. klin. Wochenschr.t 1892, No. 2).
The first was of a man 57^ years old, in whom gout was hereditary,
and who had suffered numerous attacks and undergone a number
of different treatments. During February and March of 1891, about
IS° !S-grn. doses of Piperazine were given, and during that time
gravel and stones, often as large as a small bean, were discharged,
almost daily. In July the treatment was suspended for a time, when
new outbreaks occurred, and Piperazine was again resorted to and
kept up for about six months ; the joints, which had been severely
C 2
2O Piperazine.
affected, gradually regained their normal size, the only abnormality
remaining being a slight painful swelling of the right ankle. The
patient was able to walk about, and felt well.
Anoiher man, of 35 years, came from a family which had been
gouty through the two preceding generations. He had about two
attacks each year, varying in duration from one to three weeks ; both
large toes and the adjacent tissues were the seat of gouty deposits.
The preparation known as Gout Water (r. p. 43 etseg.)was prescribed and
continued till about 30 bottles (each containing 15 grns. of Piperazine)
had been taken. Some months after the discontinuance of the treat-
ment a slight attack of gout appeared, but this was entirely cured by a
single day's use of the water.
A striking illustration of the prompt action of Piperazine is afforded
by the following case. The patient, a man of 43 — not hereditarily
predisposed — had attacks of gout usually in spring and autumn, which
obliged him to keep to his bed for a week or fortnight. In December
of 1891, an exceedingly severe attack set in, for which four grns.
of Piperazine were taken, followed by 12 grns. the next morning, and
15 grns. on the third day. Immediately after this last dose the
condition of the patient was so much improved that he could get up
and walk out ; the swollen and reddened joints reassumed their normal
colour and appearance. After 18 daily doses of 15 grns. of Piperazine,
every symptom of the attack had passed off, and the treatment was
stopped.
Hereditary predisposition was similarly lacking in the next case, a
gentleman of 65 years, who had suffered from uric acid dyscrasia for
some years. The same dosage of Piperazine was adopted as in the
preceding case, and with equally satisfactory results.
Dr. von Herget detailed an instructive case in a monograph specially
compiled by Dr. Biesenthal mentioned above. The patient, a woman,
of 38 years, without any hereditary taint, was attacked by gout during
her second pregnancy. The most obvious symptoms were inflammatory
processes in the wrists and forearms, which steadily increased after
delivery, when the lower extremities were also attacked.
The condition of the sufferer was such that the knee joints were
bent almost at right angles, the ankles and wrists much swollen, and
Piperazine. 2 1
the upper limbs considerably deformed. Pain was very severe during
passive movement of the affected parts, and occasionally appeared
spontaneously. This condition became more aggravated as time
went on, so that the patient was quite helpless and bedridden.
Between February 24th and March 6th, 1892, Dr. Herget prescribed
a pint of Gout Water daily, to be taken in four portions. The
beneficial effects were observed in two or three days ; pain — acutely
felt on the slightest movement — sensibly diminished, and in con-
sequence more movement in the joints became possible, and the
patient felt generally better.
The influence of Piperazine also showed itself in increased
excretion of urine, the quantity rising from 24 — 35 ozs. during 24
hours to 42 — 48 ozs., while, at the same time, it had a different
appearance in consequence of the larger deposits of urates. The
increased elimination of uric acid was also established by analysis
which revealed the following results : —
Before treatment . . 0*045 per cent, of uric acid.
On 3rd day of ditto .. 0-054 „ ,, ,, ,,
., 9th „ „ .. 0-067 „ „ „ „
,r I Oth , 0-059 „ ,, „ „
Further, the solvent action of the Piperazine could be detected in
the deposits at the joints, which became less swollen, and the
overlying integument loose and wrinkled.
With two intermissions of about two weeks each, when alkaline
mineral water was taken, the Piperazine treatment was continued for
several months, with steady and continuous improvement both in the
general condition of the patient and the amount of uric acid
excreted.
Corroborative evidence of the value of Piperazine in arthritis was
obtained by Dr. Volmer from a series of unmistakable cases. He
prescribed 8 — 15 grns. daily to be continued for several weeks. The
subjective symptoms were relieved in a much shorter time, and no
injurious bye-effects were ever observed.
2 2 Piperazine.
Over 150 cases of gout were treated successfully with Piperazine by
Professor Schweninger. From an extensive experience of the treat-
ment of such cases he looks upon the newer remedy as an exceedingly
valuable addition to materia medica. Speaking of the local action of
Piperazine upon uric acid and concretions in which it occurs, he
observes that its solvent effect appears to increase with the circulation
in the affected parts, while .not only is the uric acid eliminated but
secondary inflammatory necrotic changes in the tissues are avoided.
Professor Schweninger administered Piperazine both internally and
subcutaneously in doses of 15 to 30 grns. pro die. He always
obtained good results with the remedy, far superior to those yielded
by the ordinary methods of treatment, such as that based on the use
of alkalies, of colchicum, and so on ; at the same time he never
observed any drawbacks in the action of the substance.
After the acute symptoms had subsided, 8 — 15 grns. of Piperazine
were ordered every third day for months afterwards. Subcutaneously
i^ grn. in ten per cent, solution was employed, and in this way large
gouty concretions in the elbows, ears, and even eyelids, which
otherwise must have demanded surgical interference, were removed
by solution.
The injections were made two or three times a day in the neigh-
bourhood of the deposits, while simultaneously 8 — 30 grns. were given
internally per os. The author characterised his results as so markedly
beneficial that he hoped never again to be without the remedy. Most
of the cases which came under his care had been subjected to the
principal so-called cures in vain, and yet in these obstinate cases the
Piperazine treatment proved successful in 90 to 92 per cent, of the
number. Although he had had a wide experience of many acute and
chronic cases of gout during a number of years, and had tried all the
different remedies, none had given such satisfactory results as
Piperazine.
Dr. J. O. Ungerhaunen, writing from South Africa, stated that he
had used the Piperazine gout water in a few cases with unexpected
success; he looked upon it as a remedy worth more than any which
had been previously recommended for the same purpose.
Piperazine. 23
III.— IN SOME OTHER ALLIED DISEASES.
The reader will have noticed from the outlines of cases described
in the preceding sections that one effect of the administration of
Piperazine is an increased secretion of urine. This diuretic action
of the base is specially emphasised by Dr. Umpfenbach, who made
use of it in a variety of diseases where more active uropoesis was
indicated.
In a case of asthma in a paranoic patient, who also suffered from
fatty degeneration of the heart, with occasional exudation, dropsy,
oedema, etc., as well as oliguria and albuminaria, about f- of a grn.
of Piperazine subcutaneously afforded great relief. He breathed
more freely and slept well. The volume of urine increased from
1 6 — 1 8 ounces in the twenty-four hours to 66 — 70 ounces, while
the albuminaria fell off at the same time from 7 — 8£ to % per cent.
As the amount of albumen rose again, and that of the urine
diminished, when the remedy was discontinued, it was held proven
that these effects were due to the Piperazine.
A similar increase in the volume of urine, with consequent
reduction of exudation, was produced in a case of severe oedematous
swelling and infiltration of the leg, following on fracture, in an old
man ; confirmatory evidence of the diuretic activity of the preparation
was also obtained in other cases, including one of chronic nephritis.
OTHER SEQUELAE OF THE URIC ACID DIATHESIS. Besides the
renal and vesical calculi, the gouty deposits and other symptoms of
the uric acid habit already referred to, there are some other affections
associated with the presence of uric acid in the blood, in which
Piperazine either has been used or would appear to be indicated.
Early in the literature of the remedy, Dr. Krakauer reported
(Aerztl. Central. Anz., p. 543), on its use in two cases, which did not
belong to the regular forms of gout, and where he obtained results
characterised as very satisfactory.
Dr. William S. Disbrow, Newark, N.J. (Notes on New Remedies, 1892)
expressed his experience with Piperazine as follows : "I have had
24 Piperazine.
opportunity to employ Piperazine, and have noted successful results.
Not the least satisfactory effect of the remedy is the relief it affords in
pruritus. " Who is there among general practitioners who has not seen
the muddy-complexioned, dry-skinned itcher, — the unfortunate whose
urinary excretion is filled with urates, and whose system is poisoned
with the toxic elements due to imperfect nitrogenous elimination ?
Why do gouty or rheumatic patients complain of this same symptom ?
You ask them where they itch. They show you, and you find no
evidence of local irritation — they simply itch. In these cases I
have used the new synthetic remedy, Piperazine, with very satisfactory
results, in conjunction with diminished nitrogenous food and hydro-
chloric acid. The patient's itch may, of course, be due to various
causes; but I think I have clearly indicated one cause, and one
remedy with which I have achieved good results."
There are, besides those above-mentioned, other forms of disease
which are associated with the uric acid diathesis, or in which uric acid
is regularly present in the blood, or excreted in abnormal proportions.
In these affections a course of the Piperazine treatment is also
considered indicated.
In leucaemia, for instance, in which an absolute increase of uric acid
has been observed by Fleischer and Penzoldt, and a relative increase
compared with the amount of urea eliminated, Professor Hosier
reported that Piperazine exerted a very favourable influence on the
course of the disease.
An interesting series of experiments were also carried out by
Bartels with the remedy in chlorosis, and its use has been suggested by
other authors in croupous pneumonia, in which there is a constant
increase of uric acid, in pulmonary emphysema and in advanced cardiac
degeneration with oedema.
A review of the entire literature of Piperazine, of which a resume
necessarily brief has been given in the preceding pages, throws into
Pip
erazne.
prominence the following salient features in the properties and uses
of the base: —
1. Piperazine is non-toxic, however administered.
2. Piperazine passes through the organism without undergoing
decomposition," appearing as a salt (urate of Piperazine) in
the excretions.
3. When administered in the treatment of the uric acid diathesis
Piperazine arrives at the seat of the disease in a form (as
carbonate) which readily combines with uric acid (of gouty
deposits, etc.), the resultant compound being stable, and
excreted, as such, from the organism.
4. Piperazine has a greater power of dissolving uric acid, and
the compound formed is much more stable than is the case
with any substance yet employed for the same purpose.
5. In the treatment of calculi of the urinary tract, Piperazine has
the further advantage over the older agents employed, of
being able to dissolve the albumenoid substances which form
the foundation of the calculi, holding the earthy constituents
together.
6. Being free from caustic or irritant action on the mucous
membrane, Piperazine may be injected in solution (2 — 5 per
cent.) into the bladder for the relief of gravel and stone.
7. Piperazine acts beneficially not only in the more character-
istic and well-marked forms of uric acid dyscrasia, but also in
the remoter, secondary and sympathetic phenomena frequently
observed.
8. By its adaptability for local application, both as an irrigation
and as a subcutaneous injection, Piperazine has effected
excellent results in the treatment of cases of calculi and of
gouty tophi which otherwise would have necessitated
surgical interference.
9. Piperazine is worthy of trial in all affections which are accom-
panied by the presence in the blood or the excretions of an
excess of uric acid.
26 Piperazine.
METHODS OF ADMINISTRATION AND
APPLICATION.
It will have become clear from a consideration of the foregoing that
an essential factor in the usefulness of Piperazine is that it should be
absorbed as promptly and completely as possible into the blood, and
circulate with it through all the tissues, being finally excreted with the
urine, carrying with it in firm combinaiion the uric acid, which is the
abnormal body to be got rid of.
For these reasons it is advisable, and even necessary, to administer
Piperazine in the form of solution, and not as pills and other less-
soluble preparations. Other considerations which would lead to the
selection of the solution as the most suitable, are the hygro scop i city
of the compound and the readiness with which it is taken up by
water.
An agreeable mode of taking Piperazine is in some simple aerated
water either by itself or in combination with an equal dose of Phenocoll
(v. p. 43). This plan has also the advantage of securing the adminis-
tration of the remedy in a sufficiently dilute form. It is a well-
recognised and familiar fact that the proportion of water in which a
soluble compound is taken is often an important factor in determining
the effectiveness of its action.
It may be repeated here, though already stated in the preceding
sections, that the routine dosage of Piperazine per os is 15 grns. pro
die, in divided portions ; this quantity may, of course, not only be
increased in severe and obstinate cases, but also may be reduced with
advantage when the more urgent symptoms of a case have been
successfully removed and the continuance of the remedy is necessary
only to complete the cure or ensure the avoidance of a relapse.
But Piperazine has also been administered with conspicuous success
by subcutaneous injection. It was used in this way — dose i — 5 grns. —
as a diuretic by Dr. Umpfenbach (v. p. 23), by Dr. Bardet against
gout (v. p. 19), and by Dr. Schweninger in the local treatment of gout
Piperazine. 2 7
concretions, which otherwise would have called for surgical operation
(v. p. 23).
The ready solubility of Piperazine in water renders its adminis-
tration in this way very convenient and simple ; solutions varying in
strength from 2 — 10 or even 20 per cent, have been employed, and
although not quite painless yet the local tenderness soon passes off
when the diluter solutions are employed. In the treatment of general
gout the injections were made in the nates, but as a matter of course
when the resolution of well-defined concretions was aimed at, the
injection was made at the seat of the disease.
Finally Piperazine was applied in solution as a compress, a
Priessnitz bandage being saturated with a lotion made as follows : —
R. Piperazine pur grns. xv.— xxx.
Spiritus 5ss.
Aquae giiss.
M. ft. Solutio.
Drs. Biesenthal and Schmidt report that this application had a
beneficial effect on gouty swellings, and formed a useful adjunct to
the internal treatment.
The prescription of Piperazine with Phenocoll — a specially efficient
combination — is separately treated in a chapter following the treatise
on Phenocoll (v. p. 43).
PHENOCOLL
Of the various classes of remedies with which synthetical chemistry
has enriched our materia medica, none perhaps has assumed much
larger dimensions than that of antipyretics. The chief reason for this,
if one at all be sought, would probably be found in the fact that the
modern development of synthesis, as applied to the production of
medicaments, had its origin in attempts to build up in the laboratory a
substitute for the natural antifebrile alkaloid of cinchona.
In spite, however, of this multiplicity of antipyretics, it must be
added that they have not all succeeded in doing as much as they were
expected to, while not a few have proved, when carefully tested, to
possess serious drawbacks, such as a poisonous action upon the blood,
a tendency to bring about cyanosis, collapse, &c.
Further, the greater number of synthetical antipyretics are com-
paratively insoluble in water, or only slightly taken up by that solvent.
This lack of solubility in water is of course accompanied by a
corresponding slowness of absorption, so that the effect is likely to be
diffuse and unreliable. It is of course quite unnecessary to emphasise
the significance of this difficult assimilation in the treatment of severe
febrile temperatures.
The following pages, containing a brief resume of the literature
of Phenocoll, show that it is entitled to take a high rank among the
members of the class Antipyretica, by virtue of a number of well-
marked distinctive properties.
CHEMICAL NATURE AND PROPERTIES.
The researches of a number of physiologists and chemists have shown
that by the introduction of acid groups into the molecules of acetanilide
and phenacetine, compounds are produced which, whatever other pro-
perties they may display, do not possess any antipyretic virtues. A good
30 PhenocolL
deal of work was carried out in the investigation of this question
which started with the observation of Ehrlich that the affinity which
certain substances had for the central nervous system disappeared
when one or more acid sulphone groups was introduced into the
molecule.
This difficulty was solved in the case of Phenocoll by the addition
to the phenetidine group, not of an acid, but of a basic group —
namely, glycocoll. The relation of phenacetine and Phenocoll is
understood at once by a glance at the following formulae : —
XOC2H5 /OCsH*
CeH-iN^ CeH*^
XNHCOCH3 XNH.COCH2NHa
Phenacetine. Phenocoll.
Owing to the presence of the amide group (NH2) in Phenocoll, it
is capable of uniting with acids to form salts, of which the hydro-
chloride has been chiefly used in medicine.
Phenocoll hydrochloride occurs in the form of a white micro-
crystalline powder, soluble at 17° C., in about 16 parts of water,
forming a neutral solution. When crystallised from hot water, it
assumes a cubical form, while from alcohol, in which it is soluble only
at a fairly high temperature, it separates in the form of needles.
The pure base, Phenocoll, is thrown out of combination in the salt
on the addition of ammonia or the fixed alkalies (or their carbonates)
to the solution. It forms white matted needles which melt at 95° C.,
and contain one molecule of water of crystallisation.
The most noteworthy of these physical characters is the ready
solubility of the compound in water. This property distinguishes it
very markedly from phenacetine, which is chemically closely allied to
it, but is only sparingly soluble in water.
PHYSIOLOGICAL PROPERTIES.
Prof. R. Robert, in Dorpat, was the first to examine the physio-
logical properties of Phenocoll hydrochloride, and from the results of
his investigation concluded that it was not poisonous to animals, and
that it had no effect even on the blood. In this respect the new
Phenocoll. 3 1
compound contrasted with the majority of synthetical antipyretics
previously used.
Experiments on rabbits and other animals with Phenocoll hydro-
chloride were also made by Professor v. Mering, who found that i£
grammes (about 24 grns.) could be taken by a large rabbit without
any perceptible effect being produced.
Dr. Isaac Ott, Easton, Pa., also made a series of experiments with
the compound, and recorded that in frogs it manifested an influence
upon the cerebro-spinal axis, evidenced by a general paralysing effect.
In rabbits it produced a cyanotic condition of the ears, while the
force and frequency of the heart's action was reduced. Even when
given in very large doses, the compound does not kill by its effect
upon the blood or the heart, but through the centre of respiration. It
showed a tendency to diminish vascular tension, while upon the
temperature its effect was one of reduction.
These experiments, concluded the author, explained the utility of
the compound in rheumatic pains and in pyrexia. It was evidently a
drug of considerable power and rapid in its action. This drug seemed
to be worthy of a fair trial at the hands of the profession.
An elaborate and exhaustive research into the physiological action
o'f Phenocoll was carried out by David Cerna, M.D., Ph.D., and
William S. Carter, M.D., of the Pennsylvania University. They
worked at the same time with other synthetical antipyretics, but, as
will be seen below, their conclusions were decidedly in favour of
Phenocoll.
They pointed out early in the treatise (Notes on New Remedies, 1892,
September), that unless given in enormous amounts the action of
Phenocoll upon the circulation was not marked. At the same time
they expressed the belief that, in ordinary medicinal quantities, the
substance exerts a slight stimulant effect upon the circulatory system.
In the dogs used for the experiments the blood-pressure fell slightly
after the injections, but soon rose again to the normal level. Respira-
tion became somewhat shallow and diminished in frequency, and
respiratory failure was the cause of death when the administration was
pushed to that extent. These results, it will be noted, agree with
those obtained by Dr. Ott.
32 Phenocoll.
The authors corroborate the finding of Professor Kobert that no
change could be detected in the character of the blood.
Long series of experiments were made upon the action of Phenocoll
in reducing the body-heat, both upon normal animals and those in
which fever had been artificially produced by repeated small injections
(five drops) of putrid blood. In this way a steady fever was brought
about, while single large doses of the decomposed liquid were followed
by intense febrile reaction, which soon reached its maximum and
again fell.
In order to throw light upon the precise manner in which Phenocoll
acted as an antipyretic, the normal heat production and dissipation
were carefully ascertained first. Then the compound was given and
these factors observed again.
Neglecting slight variations as being possibly due to accidental
causes or to the conditions of the experiment, the authors noted that
fever was brought about the first day by an increase of heat production ;
dissipation was scarcely disturbed. After the fever was established,
the former factor fell, but, being still in excess of the dissipation, the
temperature continued to rise.
In common with most synthetical antipyretics, Phenocoll did not
exhibit any effect upon the normal temperature. In the case of those
animals in which fever had been artificially produced, a decided
antipyretic effect was noted. Summing up the results of the two
series of experiments carried out upon the circulatory, and the heat
phenomena observed with Phenocoll, the authors expressed the
following opinions : —
1. Phenocoll, in ordinary amounts, has practically no effect upon
the circulation.
2. Large doses diminish the blood-pressure by influencing the
heart.
3. Phenocoll reduces the pulse-rate by stimulating the cardio-
inhibitory centres. It then increases the rapidity of the
pulse by paralysing said centres. The final diminution is of
cardiac origin.
4. Upon the blood itself Phenocoll has no action.
Phenocoll. 33
5. Phenocoll causes in fever a very decided fall in temperature,
which occurs the first hour after the administration of the
drug by the stomach. This reduction is the result of an
enormous diminution of heat production, without any
alteration of heat dissipation.
Drs. Cerna and Carter believe, judging from the results of their
work, that of the compounds they examined, the safest for practical
purposes, especially as regarded an action upon abnormal temperatures,
would be Phenocoll. In their opinion, its advantages are that it is
readily soluble, rapidly absorbed and undoubtedly promptly eliminated.
They found that it had a very decided power of reducing abnormally
high temperatures, and this in therapeutic doses without depressing
the circulatory system.
Phenocoll was therefore concluded to be superior as an antipyretic
to the other members of the same class investigated.
MEDICINAL PROPERTIES AND USES.
Phenocoll has been successfully employed in at least three principal
roles which may be advantageously considered separately. Its
primary use of course was as an agent for combating the high
temperature of fevers, and its activity in this field will therefore
naturally be dealt with first.
L— AS AN ANTIPYRETIC.
The physiologist von Mering, who examined the effect of Phenocoll
in the animal organism under normal conditions, also tried the
substance in cases of pneumonia and typhus with the most satisfactory
results. He recorded that in doses of one gramme it lowered the
febrile temperature about 2° C. ; no cyanosis nor collapse was
observed.
Dr. Hertel was one of the earliest to publish detailed results
obtained with Phenocoll. He employed it as an antifebrile in
advanced pulmonary tuberculosis and stated (Deutsche med. Wochenschr.\
1891, No. 15) that during the whole time of the application there
D
34 PhenocolL
were no disturbances of any kind in the functions of the heart, lungs
or digestive organs. It was possible by judicious dosage to produce
in some cases almost complete apyrexia ; he thought, however, that
the effect upon the high evening temperature was more marked and
reliable than that upon the high diurnal temperature.
Reascension of the supernormal body-temperature occurred without
any unpleasant subjective symptoms, such as, for instance, shivering
or perspiration.
The author added some comments on changes which occurred in
the urine during administration of Phenocoll. It always had a
marked dark brownish-red colour, which deepened on long exposure
to air. The presence of indican and hydrobilirubin could be always
detected. The colour also became more intense with solution ef
sesquichloride of iron; it was partly cleared away by concentrated
sulphuric acid, but never entirely vanished. Viewed by transmitted
light, it revealed a peculiar green shade.
Experiments made on various types of fever by Dr. O. Jacobi,
showed that Phenocoll was specially effective in the treatment of that
characterised as hectic. In doses of 15 grns., it reduced the tempera-
ture in 2^- hours to the extent of 1*4° C. This effect was not attended
by any unpleasant subjective symptoms.
A lengthy communication by Dr. Benno Hcrzog to the Giessen
Medical Society, contained the record of 1 1 cases in which Phenocoll
was administered as an antifebrile. These included four cases of
phthisis, two of erysipelas, and one each of apical pulmonary infil-
tration, pleuritic exudation, pneumonia crouposa, abscess and febrile
cholelithiasis.
The remedy was given in doses of eight grns. at 9, 10, 1 1 a.m., and 12
noon, then 15 grns. at noon. On a subsequent occasion, the dosage
was altered to 4 — 8 grns. subcutaneously, while TOO--^O- grn. of
atropine was given internally ; by this method the temperature could
be kept sufficiently reduced without any outbreak of perspiration.
The pulse improved in frequency and general character, and the
patients felt well. There was no shivering when the temperature rose
again to a febrile level.
PhenocolL 35
In the case of apical pulmonary infiltration, 32 grns. of Phenocoll
in four portions were given at first, but subsequently it was found that
15 grns. brought about a state of freedom from fever with little or no
sweating or rigors. In the other cases the same dosage — sometimes
varied by the subcutaneous administration of eight grns. — was followed
by equally beneficial results. In one of the cases of erysipelas, fever
permanently disappeared on the third day after three i5-grn. doses.
The conclusions of the author as to the value of Phenocoll in
combating fever were expressed as under : —
1 . Phenocoll has no unpleasant effect upon the digestive tract.
The saline taste may be covered by administration in wafer.
2. In one emaciated consumptive, symptoms of dyspnoea,
cyanosis and heart-weakness were observed after 32 grns.,
but otherwise even much larger doses never produced
similar symptoms. On the contrary, the patients were
gratified with the general feeling of well-being induced,
while the respiration and pulse improved both in frequency
and character.
3. The antifebrile action, though lacking after small doses, was
almost always evident after larger. Phenocoll appeared to
work best if given when the fever was at its height. Its
action was manifested as a rule in an hour, the minimum
temperature was reached in three to five hours, and the febrile
level again attained only after seven hours or (rarely) more.
4. Reduction of temperature was almost always accompanied by
perspiration, which, however, only reached a high degree in
patients with whom this symptom was present otherwise.
Further it could be controlled by the simultaneous adminis-
tration of T^Q- - eV gm. of atropine.
A most copious combination of reports upon the use of Phenocoll
in malaria was presented by Professor P. Albertoni to the Medical
D 2
36 PhenocolL
Society of Bologna. Dr. Prati, who carried out a portion of the
work, gave details of twenty-two cases, and concluded that Phenocoll
was equal if not superior to quinine in therapeutical activity against
malaria, and said he had arrested by its means febrile attacks against
which quinine proved ineffective. In those isolated cases where no
effect was observed, the author believed that either the dosage was too
small, or the absence of effect was a matter of idiosyncracy.
He found that Phenocoll was well borne, doses of 30 grns., at
intervals of two hours, not being once followed by disturbance. The
taste was easily covered by sugar, and hence Phenocoll was superior
to quinine in the treatment of children.
Drs. Alfred Novie and Victor Venturini also reported upon eleven
cases, and expressed very favourable opinions as to the value of
Phenocoll in malarial fever. Out of the entire number of cases which
were treated by the Italian medical men, a cure was effected in 70 per
cent., while the result was negative in 1 5 per cent., and doubtful in as
many more. Like quinine, Phenocoll must be given a few days after
the attacks have ceased, in order to avoid relapse.
Five cases which illustrated the antipyretic virtue of Phenocoll,
were recorded by Dr. Paul Cohnheim (Therap. Monatsh.^ 1892, No. i),
who used the substance in the in-patient ward of the Jewish Hospital,
Berlin. The cases included two of ileo-typhus and three of phthisis.
In the former, eight-grn. doses were given, with the result of
bringing about a fall of temperature amounting, in some instances,
to 2-3°— 2-8° C.
In the cases of phthisis, the same doses were given, and the bodily
temperature kept within the limits of 37° and 39*7° C. In the second
case the patient often had spontaneous falls in the temperature, after
the use of the remedy had been discontinued. The pulse, which had
been dicrotic for weeks, was hardly at all affected by the medication.
In no case were unpleasant bye-effects, such as collapse, prostration,
sickness, tinnitus, etc., observed. The small doses adopted had no
appreciable influence on the urine. Pointing out that the results
corroborated those of Hertel and Herzog, Dr. Cohnheim urged that
Phenocoll is indicated as an antifebrile in fevers, especially of the
hectic type.
Phenocoll. 37
Dr. Balzer studied the antipyretic action of Phenocoll in 15 cases of
various nature, namely, seven of abdominal typhus, four of advanced
phthisis, three of pneumonia, and one of erysipelas.
In all the cases of typhus, Phenocoll exerted a very favourable
influence upon the course of the fever, and after a few doses there was
a decided tendency for the temperature to remain low. A dose of 15
grns. sufficed to reduce and maintain the temperature at a normal level
for four to six hours even in the height of the fever.
Similar favourable results followed the administration of Phenocoll
in the cases of phthisis accompanied by intermittent hectic fever ;
when given in the morning the evening rise of temperature was delayed
for several hours. Corresponding to the antifebrile action, a slowing
of the pulse was generally observed, though this did not occur in the
same ratio. The remedy was always administered in capsules as
powder, and nausea was never produced.
In a case of erysipelas, Phenocoll was administered in the form of
a suppository, and although maintained in position only half-an-hour,
an antipyretic effect was produced, indicating that the absorption of
the compound from the intestines takes place very rapidly.
Phenocoll proved, in the hands of Dr. Rudolph Bum, a strong and
very reliable antipyretic in cases of phthisis, whilst in low fevers it
also exerted a beneficial influence. The maximum dosage adopted
was 75 grns.
II.— AS AN ANTIRHEUMATIC.
Four cases of rheumatism figured among those described by
Dr. Hertel early in the history of the use of Phenocoll. In the first of
these, the joints of the right knee, the hip, elbow, hand and fingers,
were attacked, as well as the lower portion of the spinal column. All
the joints were highly swollen so that active movement was scarcely
possible. Antipyrine with morphine, sodium salicylate and acetanilide
having been given in vain, Phenocoll was prescribed in daily doses of
75
38 Phenocoll.
On the second day of the treatment considerable improvement was
noted, with less swelling of the joints. Painfulness persisted in the
cervical vertebrae, but on the whole was so far reduced that active
movement of the body could be effected without particular difficulty.
By the evening of the fourth day every joint was painless and swelling
had passed off.
For about a fortnight after this, the stock of Phenocoll being
exhausted, ether remedies were resorted to, but pains reappeared in
various joints. Finally Phenocoll was again returned to, and the
symptoms permanently removed.
In the remaining cases, described by Dr. Hertel, the older remedies
were first administered without satisfactory results. Phenocoll in daily
doses of 45 — 75 grns. in separate portions of 15 grns. brought about
the cessation of joint-pain in two or three days.
Drawing general conclusions from his cases, the author stated that
in severe acute febrile articular rheumatism, partly with complications,
the remedy, in daily doses of 75 grns. had a good effect upon the
painful joint affections, but none immediately upon the temperature ;
the latter receded to the normal level only when the other symptoms
improved. These beneficial results were obtained after the ordinary
remedies had failed.
In a single case of chronic rheumatism of the left hip-joint, Dr.
Herzog made two subcutaneous injection of four grns. of Phenocoll
into the gluteal region. The diminution of pain was sufficiently
marked to enable the patient, who had previously gone on crutches,
to walk unaided, though, of course, with considerable difficulty.
Opportunity of observing the antirheumatic action of Phenocoll was
afforded Dr. Cohnheim by three cases, in two of which very striking
results were obtained. In both the disease was in the acute stage ;
one patient suffered with marked swelling and pains in the right
wrist and hand, while in the other the left knee was the seat of
the affection.
In the first case, after a single day of the treatment, free movement
of the affected joint was possible, and on the fourth day the patient
was entirely free from pain. In the second, pain was entirely got rid
of after n days of the treatment, but two days later there was a
Phenocoll. 39
recurrence ; is-grn. doses were again resorted to and followed by an
almost immediate disappearance of pain, and the joints could be
freely moved without discomfort. Beyond copious perspiration and
consequent thirst, no unpleasant effects were noted, even when \\
drms. were being taken daily.
The value of Phenocoll in rheumatic affections was most marked,
according to Dr. Balzer, in acute polyarthritis, and was particularly
useful in cases where salicylates were contra-indicated or did not
produce the desired effect. The action of the remedy was examined
in six cases of acute and two of chronic polyarthritis, and although
(like all antirheumatics) less active in the chronic forms, it produced
prompt relief in acute cases where the routine methods of treatment
had failed. Like most observers, Dr. Balzer noted that in rheumatic
affections larger doses were necessary than when employed as an
antifebrile.
III.— AS AN ANTINEURALGIC.
Two instructive cases illustrative of the value of Phenocoll in the
treatment of neuralgic pains were recorded by Dr. Herzog. One
patient (a woman) suffered from otitis media with very violent head-
ache of the left side, which had only been relieved for a short time
by acetanilide. Phenocoll was prescribed in doses of four grns. with
the result that an hour later pain was annulled for an hour. On the
next day four grns. was given again and the headache disappeared
for two hours.
The second case was also of otitis media with very violent pains on
the left side of the head ; four grns. of Phenocoll dispersed the pain in
about two hours. On the three succeeding days the same dose was
repeated, being given once in the morning, once in the evening, and
the third day, an hour past noon. Then eight grns. was ordered, with
the result of effecting in each instance cessation of pain, followed after
varying periods by recurrence.
In two cases of sciatica of the right side, subcutaneous injections
were made once or twice daily (dose 4—8 grns.) at the seat of the
disease. Pain was removed in both instances, though sometimes it
set in again in the night.
4O Phenocoll.
Dr. H. Aronson, who made a chemico-pharmacological study of
Phenocoll and allied compounds, said at the conclusion of the article
in which his work was recorded, "As an antineuralgic it displayed,
in a few cases observed by me, a safe and prompt action."
Phenocoll was prescribed by Dr. Paul Cohnheim in neuralgias of
various parts associated with phthisis, neurasthenia, chorea, enteritis
acuta, hysteria and myelitis transversa. The remedy produced the
desired effect in all the cases save in the first and last two forms,
where also other usual remedies were without beneficial influence.
The author observed that after these trials Phenocoll was justly entitled
to a place among the recognised antineuralgic remedies. There were
no unpleasant bye-effects. Whilst small single doses were ineffectual,
the results of eight grns. three times a day were unmistakable.
The influenza epidemics offered a good field for testing the power
of Phenocoll over pain of nervous origin, and the literature relating to
its employment in these cases showed that it came well out of the
trial. Seven cases classed by Dr. Cohnheim under neuralgias were due
to influenza, and in these Phenocoll was given with success ; pain was
alleviated and sound sleep induced. In a few instances variations
were observed in the manner in which the pains of Influenza were
affected ; generally those in the back were relieved at once, while the
headache was only little or not at all affected. In all the cases, it
should be noted, the febrile stage had been passed before Phenocoll
was given against the pain.
The fact that influenza was liable to influence the heart and the
digestive organs, contra-indicated the use of a number of the ordinary
antipyretic and aritirheumatic remedies. For the same reason
Phenocoll was expected, upon a priori grounds, to prove a harmless
and efficient remedy in influenza, and the results of the practical
trials made with it showed this expectation to be perfectly well
founded.
Dr. Lazarus reported on the employment of Phenocoll against
influenza, to the Berlin Society, for internal medicine. He prescribed
it not purely as an analgesic, but also as an antipyretic and anti-
rheumatic. In doses of eight grns., very satisfactory results were
obtained, without any unpleasant bye- or after-effects.
PhenocolL 4 1
Dr. C. W. Brandenburg, Brooklyn, New York, also treated a
number of cases of "la grippe" with Phenocoll, and recorded one
(Notes on New Remedies, 1891, Dec.) in which, by its means, an attack
which threatened to be of a severe type was successfully aborted.
The patient, when first seen, was suffering severely with frontal
headache and pains in the cervical and lumbar regions of the spine.
Other symptoms were considerable muscular soreness, a general
feeling of weakness and malaise, coryza and pain in the left ear.
The temperature was 103° F., and the pulse 120.
The author prescribed eight grns. of Phenocoll in water every two
hours, until four had been taken, and then one to be taken the
following morning. At the latter period, Dr. Brandenburg called on
the patient, expecting to find him in bed, but instead of this he was
away at business as usual. Shortly after the third powder perspiration
became marked, aches and pains disappeared, and sound sleep
followed until the morning, when the patient felt well enough to
attend to business.
Observations of a similar nature were made by Dr. J. O.
Ungerhausen, district surgeon of the Lion's River Division, South
Africa. It gave very satisfactory results in the treatment of influenza,
and also in the first stage of a common cold, when the mucous
membrane of the upper part of the respiratory tract was swollen and
inflamed. All stages were remarkably shortened, headache disappear-
ing, and catarrh setting in more rapidly, but not developing into so
severe a form.
In the Drasche Clinic, Vienna, Dr. Bum found that as an anti-
neuralgic, Phenocoll had a very marked beneficial influence upon
migraine, and unpleasant symptoms were seldom observed.
Similar observations were made by Dr. Balzer in three cases of
sciatica, in one of lumbar neuralgia, and two of uraemic cephalalgia.
In those of sciatica the favourable effect of the remedy was quite
manifest ; improvement took place gradually, and was not followed
by any relapse if the administration of Phenocoll was continued for
a few days. The results were not so satisfactory in the cases of
lumbar neuralgia and chronic nephritis, accompanied by uraemic
headache. The maximum dose pro di°, was 60 grns., and the largest
42 Phenocoll.
quantity taken by any single patient was i£ ounces. The author
expressed the opinion that Phenocoll was specially indicated in the
forms of neuralgia arising from chills.
DOSAGE AND METHODS OF USE.
It will not be necessary to deal with the dosage of Phenocoll at great
length here, since the subject has been included in the preceding
sections where the quantities appropriate in each form of disease were
indicated. It will be sufficient to say that the average dose as an anti-
pyretic was 75 grns. pro die divided into powders of 15 grns. each ;
sometimes 45 grns. during the day was found sufficient. The general
rule that advanced consumptives require smaller doses of antipyretic
remedies than the usual must of course be also adhered to in the
case of Phenocoll. Outbreaks of perspiration, when occurring to an
uncomfortable extent, may be prevented by the simultaneous adminis-
tration of atropine in doses of i£-0- - eV grn.
In malaria 30 grns. was given with intervals of two hours between
the doses.
Against rheumatism and neuralgia, full doses — 75 grns. daily in
divided portions — must be given in order to ensure satisfactory results.
The compound may be prescribed as powders to be taken in wafers
or in simple aqueous solution with some ordinary flavouring agents ;
the latter form is perhaps the best under usual circumstances, as the
absorption of the compound is more certainly ensured.
Hypodermically doses of 4 — 8 grns. were chiefly employed. Dr.
Herzog prepared a glycerine solution made by dissolving 15 grns. of
Phenocoll hydrochloride in 30 grns. of glycerine warming to 50° — 6o°C.
This solution was determined chemically to contain exactly four grns.
in 1 6 minims ; it had to be warmed before use, as in about an hour it
became a compact white mass, similar to paraffin in appearance. By
using glycerine as the solvent it is possible to administer an appropriate
dose without having to inject too large a volume of liquid.
Phenocoll with Piper azine. 43
PHENOCOLL AND PIPERAZINE
IN COMBINATION.
The pronounced analgesic properties of Phenocoll, particularly in
rheumatic conditions, in conjunction with its perfect harmlessness,
suggested the idea of giving it in combination with Piperazine for the
treatment of gout. While Piperazine would act as solvent for and
facilitate the elimination of uric acid, the Phenocoll would relieve the
symptoms of topical inflammation due to localisation of uric acid
deposits.
Owing to the established custom of taking aerated mineral waters
for the relief of the gouty diathesis, Piperazine was also largely
administered in carbonated water, when its value in the treatment of
gout became recognised. Hence the next step was naturally to
prepare a Phenocoll-Piperazine water, each pint of which should
contain a certain definite amount of each remedy. The amount
selected was eight grns., so that if two bottles were used daily the
quantities of the compounds taken would be considerably less than
had been administered for prolonged periods without any kind of
disturbance.
The employment t>f such a preparation was of course so simple and
safe that it was felt to be worthy of extended trial. Treatment with
such an aerated water could be carried on with but little of the
constant claim upon the physician's attention, which is necessary in
the case of many remedies, owing to the freedom of both the active
ingredients from any corrosive or poisonous action. Again, the
rapidity with which the compounds are secreted from the body
removed any apprehensions as to the production of unpleasant
cumulative effects.
The earliest report upon the action of this combination recorded
its value in the treatment of the uric acid diathesis.
(a) IN GOUTY AND RHEUMATIC DISEASES.
Dr. Ritter, of Dresden, described a number of cases characterised
by chronic gouty enlargements of the joints and various morbid local
44 Phenocoll loith Piperazine.
changes. The Piperazine and Phenocoll were given in daily doses of
15 grns. in the form of solution in aerated water.
In the first case pain decreased after the treatment had been con-
tinued nine days and the swelling of the joints was reduced ; the urine
was clear and abundant, the colour of the skin improved. After four
weeks' treatment the patient could walk again and remained free from
pain.
In the second the swelling of the joints decreased after a week ;
there was evident improvement of the general well-being, the appetite
and the colour. The amount of uric acid excreted increased.
Pronounced excretion of urates through the skin was a conspicuous
symptom in the third case. After a fortnight, symptoms of swelling and
inflammation subsided. The total duration of the treatment was three
weeks, the same dosage being adopted as in the former cases.
In a case of hereditary gout, four weeks' treatment produced
excellent results. The great toe joint was rapidly reduced in size and
pain was markedly alleviated. The urine was clear and abundant,
vesical catarrh disappeared and urates increased. There was abundant
sticky perspiration, but the general feeling was excellent, and the
appetite good.
The Phenocoll and Piperazine combination was also tried by
Dr. Herget in gout, with the result that beneficial results were observed
in two or three days. The pains occasioned by the slightest move-
ment sensibly diminished, and, in consequence, movements of all the
joints became more free and easy, and the patient felt generally better.
The appetite did not suffer. During an interval of some days the
remedy was discontinued, and an ordinary mineral water given. The
pains, however, grew in intensity, and the combined treatment was
again resorted to, and followed by lessening pain, freer movements
and undisturbed sleep.
It was noticed that the medication had a further favourable influence
both on the quantity and character of the urine. The secretion
increased in activity, the volume passed during the 24 hours prac-
tically doubling ; at the same time, owing to the larger amount of
urates deposited, the fluid has a different appearance. The effect
Phenocoll with Piperazine. 4.5
upon elimination of uric acid, as determined by chemical experiment,
was found to be as follows: —
Before commencement of treatment, 0*045 per cent, uric acid.
On the third day of ,, 0-054 »» >, ,»
„ ,, ninth ,, ,, ,, 0*067 » " »
„ „ tenth „ „ „ 0-059 >. „ „
Locally the solvent action of the combination was evidenced in the
reduction of the enlargements due to gouty deposits. So rapidly were
these deposits carried away that the skin covering them had not time
to adapt itself to the altered form of the parts, but became loose and
wrinkled.
(3) IN VESICAL AND RENAL STONE.
Among Dr. Ritter's cases was one of a man aged 64, who had
been operated on 14 years before for vesical stone. At the time of
observation there was evidence of the presence of gravel in the renal
pelvis and small stones. The principal symptoms were severe renal
colic and vesical catarrh.
The combination was prescribed in daily doses of 30 grns. and the
treatment continued for 20 days. The vesical catarrh was first to
yield, and the urine became clear and abundant. There was a slight
excretion of gravel. The patient felt much better in himself at the
end of the course.
(0 IN GASTRIC TROUBLES.
It would appear that certain forms of digestive disorder are sequelae
of the rheumatic or gouty habit. Such cases are by no means easy to
treat, since they are resistant to the ordinary remedies. Consideration
of the etiology of these gastric troubles indicates the administration
of specific remedies, and in this way excellent results may be obtained
in cases which other methods fail to improve.
An illustration of the truth of this view is afforded by the following
case recorded by Dr. Schott, Philadelphia (Notes on New Remedies,
1890, July). The patient, a lady of about 60 years, who had previously
46 Phenocoll with Piperazine.
suffered much from rheumatism, sought relief from annoying pains,
due to irritability of the stomach, which always recurred after meals,
no matter how carefully the food was selected. Every kind of food
was rejected, and nourishment could be administered only in the form
of enemata of peptonised beef.
Dr. Schott ordered Phenocoll and Piperazine in is-grn. doses
of each, pro die, dissolved in carbonated water. Pain was relieved in
a very short time, and then the vomiting stopped. After taking the
combination for about six weeks, the patient seemed to have completely
recovered, and felt as well as she had ever done in her life.
Dosage and Prescription,
The minimum dose of the Phenocoll and Piperazine combination
is 30 grns. daily, that is, 15 grns. of each. This quantity may be
increased up to one drm. of each, pro die, if the smaller doses are not
efficient, or if the case be exceptionally severe. It has been already
shown that neither Phenocoll nor Piperazine has any disturbing
influence upon the heart or blood, and that they may be taken for
prolonged periods without affecting the vital functions of the body.
The best way to prescribe the combination is to order the dose to
be taken in a tumblerful of plain or aerated water. It is necessary to
point out that if plain water be selected as the vehicle, a certain
amount of turbidity may be produced. This, however, is at once
cleared up on the addition of aerated water. The medicament may
be taken with meals if desired, but seems to be more effective when
taken at frequent intervals between them.
C LORALAMID
In earlier times the physician was chiefly dependent upon the
opium alkaloids, or upon chloral hydrate, in cases where a narcotic or
hypnotic was indicated. But these medicaments could not be safely
employed in every instance. The continued administration of opium,
for example, is soon followed by habituation on the part .of the
patients, so that the doses have to be constantly increased ; at the
same time there is the risk of producing the opium habit. Chloral
hydrate, again, is not always free from risk, as regards its action upon
the heart, nor from unpleasant after-effects, such as giddiness,
depression, an unpleasant taste in the mouth, etc.
It followed therefore that in the development of synthetical
chemistry, as regards the production of medicinal agents, which has
taken place of late years, the preparation of hypnotic remedies has
excited general interest, and each compound which displayed an action
of this kind was exhaustively and searchingly examined.
The advantages of Chloralamid among this class of remedies were,
in consequence, early recognised, and all the minute investigations of
its properties only served to establish it more firmly in the high
position it obtained among pure hypnotics capable of bringing about
a sleep indistinguishable in character from physiological slumber.
PHYSICAL AND CHEMICAL CHARACTERS.
Regarded as a chemical compound, Chloralamid is chloral
formamide, being an additive product of chloral anhydride
CC13CHO and formamide CHO NH2. One of the hydrogen atoms
of the amide group (NH2) forms hydroxyl (HO) with the oxygen
48 Chloralamid.
atom of the chlorar, and the resulting compound has the constitution
represented by the formula —
CCl CH/°H
XIMHCHO
It forms colourless lustrous crystals soluble in about 20 parts of
cold water and in i£ parts of 96 per cent, alcohol. It is partially
decomposed into chloral hydrate and ammonium formate by water
heated above 60° C. (140° F.), but under ordinary conditions, the
aqueous solution is quite stable. Alkalies bring about the same
dissociation as warm water, but dilute acids have no effect. It melts
at ii5°C.
Chloralamid has a mild, feebly bitter taste, in no way pungent like
chloral.
PHYSIOLOGICAL ACTION.
The first contribution to our knowledge of the effect of Chloralamid
upon the healthy animal functions and tissues, was due to Dr. Eugen
Kny, of the Strassburg Psychiatric Institute. His work was too
lengthy to admit of detailed reference ; but generalising, it may be
stated that he found Chloralamid a somewhat less powerful hypnotic
than chloral, but with the marked advantage of being free from action
on the heart, or on the digestive tract ; and, further, on account of
its comparative tastelessness, much more readily taken. In addition,
Chloralamid was not attended by the symptoms of congestion and
unpleasant after-effects sometimes observed with chloral hydrate.
The author's experiments, carried out with the view of ascertaining
the fate of Chloralamid in the animal organism, showed that chloral
hydrate was set free from it ; he detected a large proportion of uro-
chloralic acid in the urine of a dog which had been given three drms.
of the hypnotic.
The problem had therefore to be solved why Chloralamid, even
when exerting its full effect, was without any prejudicial action on
the circulatory system, if, as seemed proved, it yielded chloral in the
Chloralamid. 49
organism, which had been repeatedly shown, powerfully affected the
heart.
Dr. Kny suggested that the difference could be explained from two
points of view. In the first place, it might be that the compound was
only slowly split up by the free alkali of the circulating blood, so that
only small quantities of chloral were set free at any one time. In the
second place the depressant tendency of the chloral might be counter-
acted by the stimulant effect of the formamid, which,* like all amide
derivatives, had a stimulating action upon the vascular centre in the
medulla, and thereby raised the blood-pressure.
Professor A. Langgaard believed that he observed some effect upon
the vascular tension, though the heart's action remained vigorous, but
the reliability of his experiments was called in question by Professor
J. von Mering and N. Zuntz (Therap. Monatsh., 1889) who called
attention to the fact that even physiological sleep reduced blood-
pressure. Their own elaborate experiments satisfied them that
Chloralamid could be safely given, even in cases of disease in which
chloral hydrate, on account of its action on the heart and blood-
pressure, was contra-indicated.
Concordantly with Kny the authors observed that the effect of
chloral hydrate set in more rapidly than that of Chloralamid, but at
the same time the hypnotic effect passed off sooner.
Dr. John Gordon, Aberdeen University, having studied the
physiological action of Chloralamid, concluded (Brit. Med. Journ.y
1891, May 1 6th,) that, in small doses, it tended to increase the
elimination of urea, but that this factor fell off when the doses were
large enough to produce a hypnotic effect. The excretion of
phosphates was diminished in all doses. No irritation of the gastro-
intestinal tract was observed, and no thirst was complained of during
its administration.
Dr. H. C. Wood, Professor of Materia Medica and Therapeutics
and of diseases of the nervous system in the Pennsylvania University,
and Dr. D. Cerna, Assistant in Physiology of the same Institution,
carried out a research upon the physiological action of Chloralamid
quite recently (Notes on New Remedies, 1891, August isth). Dogs were
chiefly used for the experiments, of which some dozen were. performed.
E
50 Chloralamid.
in order to ascertain the effect of the compound upon the nervous
system, the respiration and circulation. The conclusions arrived at
were expressed as follows : —
1. Chloralamid has a slight local action, and in large doses tends
to produce mucous diarrhoea.
2. It acts more powerfully upon the cerebral cortex than upon
any other portion of the nervous system of voluntary life,
thereby causing sleep and muscular relaxation ; it is also a
feeble spinal depressant.
3. It has a powerful influence in moderate dose upon the
respiration, stimulating the respiratory rate by a centric
action and probably also increasing the actual amount of air
breathed ; in toxic doses it causes death by paralysis.
4. Its influence upon the circulation is very feeble, the changes
produced by small doses being probably secondary to other
effects of the drug ; toxic doses, however, depress the arterial
pressure by a direct action either upon the heart or upon the
muscular coats of the arterials.
The authors inferred from these physiological data that Chloral-
amid might be safely given in cases of feeble heart ; its stimulating
influence upon the respiration seemed to render it peculiarly suitable
in cases of nervous exhaustion. The observations of Drs. Wood and
Cerna throw light also upon the finding of Drs. Hagen and Hiifler,
referred to later, that Chloralamid is especially valuable in cardiac
asthma.
THERAPEUTICAL EMPLOYMENT.
(a) In Insomnia.
As already indicated in the preceding section, Chloralamid may be
considered a pure hypnotic without any secondary influence upon the
functional activity of the animal organism. Particulars of its action
in special cases will be given incidentally in considering the experience
of the authors who have employed it clinically, but it will be
interesting to present here, at the outset, some general features of its
therapeutical effects.
Chloralamid. 5 1
Of course it is impossible to lay down any hard and fast rule as to
the time which intervenes between the administration of a dose of
Chloralamid and the appearance of its characteristic effects. Many
factors, including the mode of administration, personal idiosyncrasy,
etc., determine differences in this respect. The average limits may be
given, however, as a half to three hours. Out of 55 cases which
Lettow observed, with special attention to this point, the action set in
after one hour in 29 instances, after two hours in 23, and after three
hours three times.
Another interesting feature of the action of the remedy is the
duration of the sleep it induces. Broadly considered, the time may
vary between two and nine hours. In Lettow's experience — this
author made a special study of these details — the sleep lasted from
4 — 6 hours in 17 cases (out of 21), between 2—4 hours twice, and
twice it lasted only two hours.
Dr. Kny, who made the first physiological investigation of
Chloralamid referred to above, also tried the compound clinically in
31 cases, prescribing it in doses of 24 — 60 grns. He found that
excellent results were given in psychoses, not accompanied by too
active excitement. Regular sleep was also induced in chronic
alcoholics and in patients suffering from tabes dorsalis, even when
they had been taking large doses of morphine. In four cases of
sleeplessness in neurasthenics, satisfactory results were obtained, as
also in instances where the morbid condition was due to bodily pain
of not too great intensity.
Allusion has been already made to the work of Drs. Hagen and
Hiifler on Chloralamid. They believed that it produced a hypnotic
effect immediately, that is, by a direct action upon the centres regu-
lating the function. In this respect, however, they differed from
Professor Alt, who reached the conclusion that the effect of the
remedy was indirectly brought about.
Striking observations were recorded by the two co-workers above-
named in cardiac asthma. During the administration of Chloralamid,
the pulse rose and the attacks entirely ceased. These effects must be
ascribed in all probability to the stimulant effect of the compound
upon the respiratory centres.
E 2
5 2 Chloralamid.
No less noteworthy were the results obtained by Alt in chorea with
Chloralamid. He prescribed 1 5 grns. three times a day, and in from
5 — 8 days the affection was almost entirely cured.
Speaking from a considerable experience with Chloralamid, Dr. K.
Schaffer pronounced it superior to the other synthetical hypnotics such
as chloral hydrate, sulphonal, amylene hydrate, paraldehyde. In 15
cases of progressive dementia paralytica, 30 grns. proved sufficient to
relieve the sleeplessness. Where there was slight excitement he gave
i — \\ drms. or up to i£ drms. in more pronounced cases. In one
instance a morphine injection was simultaneously given. The author
specifically mentioned a number of varieties of dementia and delirium
in which Chloralamid was successfully given. In general he was
satisfied with the action of the compound as an hypnotic, and no
unpleasant bye-effects were observed ; even after doses of i — \\ drms.
the patients did not complain of headache, nausea, or other unpleasant
symptom. The cases in which good sleep was obtained by means of
Chloralamid included one of hysteria and three of hystero-epilepsy.
At a meeting of the Practitioners' Society, New York, Dr. George
L. Peabody gave the results of his experience with Chloralamid (The
Medical Record, 1889, November i6th). Although the effect was
characterised as less energetic and prompt than that of chloral
hydrate, it proved useful in the most varied forms of sleeplessness, even
in alcoholics, and in a case of cerebral haemorrhage accompanied by
great restlessness. It effected great alleviation in two cases of neuralgia
with sleeplessness. No disquieting symptoms were ever observed.
Chloralamid had the advantages over chloral hydrate of being less
irritant to mucous membrane and of having a less unpleasant taste.
Dr. E. Schmidt employed the hypnotic subcutaneously in a case of
carcinoma of the rectum. Each ccm. of the solution used contained
o'O4 grm. of Chloralamid, and one or two syringefuls were sufficient to
induce quiet and refreshing sleep lasting eight hours, in spite of the
violent pains suffered by the patients. A similar result was obtained
in a case of violent hepatic colic.
Further evidence of the value of Chloralamid was furnished by Dr.
Umpfenbach, of the Andernach Lunatic Asylum, who prescribed it in
55 cases (23 men and 32 women). To begin with, 30 grns. of the
Chloralamid. 53
remedy were prescribed, increasing up to i£ drms., pro dost and
pro die.
In 30 of the cases the desired effect was attained, while in 13 it was
only transient, and in 12 absent. The remedy proved most active in
hallucinations, paralysis, and the quickly passing excitement-stage of
epilepsy, while the less satisfactory results were obtained in the rest-
lessness of imbecility, recent psychoses and melancholia. The sleep
lasted a long time, and was unaccompanied by any remarkable
symptoms. On the whole, the remedy had no effect upon the gastric
functions, but was well borne even when administered for months
consecutively. No appreciable influence was observed upon the heart,
the vascular or the urogenital system, and collapse-like phenomena
were never observed. In a case of tremor essentialis, and another of
chorea hereditaria, the motor unrest was considerably reduced under
small doses of Chloralamid (8—30 grns. pro die].
Dr. G. Genersich, Klausenberg, considered that Chloralamid had
established its right to be classed among useful hypnotics, and added
that in doses of 45 to 60 grns. the action was reliable and lasting,
sleep supervening in from a quarter to one hour after the dose.
Secondary symptoms were only unimportant, and the digestive and
urinary functions were unaffected. Although the pulse increased in
rapidity and became softer, no serious subjective symptoms were
experienced by the patients.
Dr. Chas. H. Steele, Professor of Materia Medica and Therapeutics,
of the Cooper Medical College, stated (Pacific Medical Journal] that
Chloralamid was successfully employed in combating insomnia,
particularly the simple or idiopathic form not due to excitement or
severe pain. It was, furthermore, possible for the wakeful patient to
enjoy several nights of natural sleep after a single dose. The best
results occurred when the drug was used in insomnia due to nervous-
ness, neurasthenia, hysteria, spinal disease, or old age. When
administered in phthisis it was found that the troublesome night
sweats disappeared.
Dr. W. Hale White, Guy's Hospital, London, gave Chloralamid in
twenty cases of various illnesses in which insomnia was a troublesome
symptom. He found (British Medical Journal, 1889, p. 1,326) that
5 4 Chloralam id.
the compound produced comfortable sleep in all the patients except
two; one of these was suffering from delirium connected with cerebral
haemorrhage, and the other with rheumatic fever complicated by
delirium tremens and salicylic poisoning. Some of the other patients
were suffering from extremely painful diseases, and yet Chloralamid
produced sleep. A woman who had a thoracic aneurysm preferred it
to morphine, and another patient who had carcinoma of the stomach
also slept better with Chloralamid than with morphine.
Other striking cases were of carcinoma of the liver with intense
pain and of cerebral softening; both dozed comfortably after Chloral-
amid. The sisters and nurses, who saw the patients frequently during
the night, told the author that those who took Chloralamid not only
slept well and comfortably but better than after any of the hypnotics
which had been introduced during the past few years.
In none of the patients did any effects follow that could be looked
upon as contra-indications to its use. No depressing results nor
headache were observed to be caused by it. Dr. White concluded
that in Chloralamid we had a safe hypnotic which did not produce
indigestion, and very rarely gave rise to any unpleasant results ; the
author illustrated his conclusions with brief details of the twenty
cases he treated with the hypnotic.
Great care was taken to avoid the disturbing influence of suggestion
by Dr. Ed. Reichmann (Deutsch Med. Wochenschr.^ 1889, No. 31) either
by keeping .the patients entirely in the dark as to the effects of the
medication, or where the patient had become acquainted with the
same, by makmg control experiments with inert substances.
Among the cases detailed by the author were patients suffering from
bronchitis and cephalalgia, from chlorosis with mitral insufficiency,
from endocarditis aortae et mitralis, ecstasia ventriculi, renal colic and
neuralgia. When 30 grns. of Chloralamid were administered during
the day, even if actual sleep did not follow, a feeling of fatigue and
sleepiness was induced. More satisfactory results were obtained by
doses of 45 grns. ; in illustration of this, Reichmann mentions two
cases of obstinate insomnia of alcoholism where morphine had hardly
any effect, but Chloralamid produced sound sleep.
The question whether Chloralamid could be employed as a hypnotic
Chloralamid. 55
with success had therefore, according to Dr. Reichmann, to be
answered in the affirmative ; and further, he experimentally demon-
strated the still more important fact that the remedy had no influence
in \ — i-drm. doses upon the circulation. He ventured to say that
Chloralamid fulfilled all the requirements of a hypnotic, had a safe,
prompt action, and was free from disturbing bye-effects.
Similar conclusions were formed by Professor S. Rabow (Centralbl.
f. Nervenheilkunde^ 1889, No. 15) from experience of the employment
of Chloralamid in cases of mental disease. It proved reliable in the
large majority of cases of sleeplessness following indulgence in
alcohol, as well as in the so-called nervous form of neurasthenia,
hysteria, etc.
An exhaustive paper on the value of Chloralamid as a hypnotic was
written by Dr. D. R. Paterson (Lancet, 1889, Oct. 26th). Observations
made on the various vital functions during the use of Chloralamid
gave negative results. One patient with simple insomnia was an old
woman of 64 who used to spend the night sitting up in bed ; 30 grns.
of the remedy on consecutive nights, induced, after an interval of 30
to 40 minutes, a tranquil sleep lasting eight and nine hours respec-
tively. When the dose was reduced to 15 grns. the onset of sleep
was somewhat more delayed, but it lasted an equal length of time,
and was not followed by the slight unpleasant effects which were
experienced after the larger dose. An old man of 60, convalescent
from an attack of jaundice, and complaining much of resting badly at
night, was given 30 grns. on several occasions. Sleep ensued in from
40 to 75 minutes after administration, and lasted eight hours. The
slumber was unbroken, very sound, and removed a dull headache from
which the patient had been suffering.
Dr. Paterson described other cases — paroxysmal cough, insomnia of
phthisis, heart disease, aneurysm of the aorta — in which good results
were obtained by administration of Chloralamid. He confirms the
opinion of other authors that the hypnotic had no action on the
digestive organs ; the appetite remained unimpaired.
Dr. George P. Cope made a valuable addition to the literature of
Chloralamid in the Dublin Journal of Med. Science, 1890, Feb. After
describing the cases in which he prescribed the compound, he
56 Chloralamid.
expressed the opinion that they demonstrated the hypnotic value of
Chloralamid, the sleep brought about lasting five to eight hours, and
appearing sound and refreshing. A dose of 25 to 35 grns. was
sufficient to cause sleep in patients suffering from melancholia and
chronic mania. No recognised evil effects followed the continued use
of the remedy for eight days, and only one out of twenty-five persons
suffered from gastric disturbance.
According to the observations of Dr. Cope, Chloralamid appeared
to be free from the dangers which accompanied the action of chloral
hydrate, and in explanation of the distinction, he quoted the words
of Dr. D. Leech (Brit. Med. Journ., 1889, Nov. 2nd): "It seems
probable that the formamide element, containing as it does a substitute
NH2 group, will stimulate the circulatory and respiratory centres in
the medulla, thus tending to counteract the depressing influence of
chloral on them."
Dr. Cope corroborated the opinion of Dr. C. Norman, that the chief
disadvantages of sulphonal were its bulkiness, insolubility, slowness of
action, and high price, and pointed out the Chloralamid formed a
contrast in every particular.
Speaking of the indications for the exhibition of Chloralamid,
Dr. John Aulde, Philadelphia College, directed attention to the fact
that ordinarily large doses did not affect the heart and circulation ; in
diseased conditions of the system the remedy appeared to be borne
with a remarkable degree of tolerance, and after-effects were not
objectionable.
Dr. J. M. Thompson, Boston, prescribed about 30 grns. of
Chloralamid for a dose, to be taken dry in powder and followed by
milk. One patient was a neurotic, subject to sleeplessness, in whom
sulphonal produced unpleasant after-effects ; 30 grns. of Chloralamid
at bedtime brought on sleep in about half-an-hour, which was not
followed by any unpleasant after-effects. An habitue* of morphine,
who had almost entirely discarded the drug, could not get sound sleep ;
even the use of chloral, bromides and sulphonal was ineffectual.
Comfortable sleep was brought on by 30-grn. doses of Chloralamid,
lasting four to five hours, and without disagreeable after-symptoms.
Chloralamid. 57
Similar satisfactory results were obtained in cases of influenza,
followed by delirium tremens, in sleeplessness due to overwork, in
angina pectoris, varicose ulcer and alcoholic neuritis. Dr. Thompson
said : " I can safely recommend Chloralamid in any case where a
hypnotic is indicated, and feel sure that it is the best, safest, and most
reliable in use up to date."
Dr. P. Naecke made a number of comparative experiments with
Chloralamid, hyoscine and amylene hydrate as hypnotics, which
showed that the first-named gave the best results. In his hands it
proved free from risk for women suffering from chronic mental
diseases, and for epileptics, and did good service not only in nervous
agrypnia, but also in cases of excitement. It was best given shortly
before the patient's time for sleeping. Though slower in action than
chloral, the author thought it might also be more sure, and was
confident that it was less dangerous, and that the sleep produced
was more refreshing than in the case of chloral.
In three cases put on record by Dr. J. S. Ridge (Notes on New
Remedies, 1891, No. 8), Chloralamid did even more than was expected
of it. The first patient was a consumptive, 60 years of age, to whom,
in consequence of insomnia, morphine, bromidia and sulphonal, had
been given with only partial success. Chloralamid, in a dose of
30 grns., gave the patient eight hours' sound sleep, without any ill
after-effects. This dose always ensured good rest.
In a case of painful vaginal fistula, seven or eight hours' good
sound sleep was always induced by 15 grns. of Chloralamid; the
patient awoke refreshed.
The third of these cases was one of acute gastritis in an opium
habitue". Morphia was prescribed without success ; but 45 grns. of
Chloralamid was followed by seven hours' sound sleep. Refreshing
slumber, free from bad after-effects, was always induced by the same
dose of the hypnotic.
Professor M. Charteris, Glasgow University, having administered
Chloralamid in many cases of insomnia, where pain was not a chief
factor, pronounced it an excellent and safe hypnotic, superior in every
way to sulphonal. If it were dispensed in a complete state of
solution, it would be found to answer well in cases of sleeplessness.
58 Chloralamid.
Comparing Chloralamid with sulphonal, Dr. John Gordon, Aberdeen
University, said (Brit. Med.Journ., 1891, May i6th) : "It was frequently
noticed that, following a dose of sulphonal, the hypnotic action did not
take place for a number of hours, so that sleep was projected into the
following day, whereas with Chloralamid, sleep, if it supervened at all,
came quickly and passed off within six or eight hours. Another claim
for Chloralamid over sulphonal is the fact that sleep is more speedy in
its onset after administration. The comparatively easy solubility of
the substance may so far explain its more rapid action. It was given
in doses of 25, 30, 40 and 45 grns."
Nine cases are described in more or less detail by Dr. Gordon, the
insomnia against which the hypnotic was given originating in senile
changes, heart disease, neurasthenia, phthisis and alcoholism, chronic
bronchitis, hysteria and locomotor ataxy, with characteristic "lightning
pains." In an old man (84 years) suffering from dilated heart and
general anasarca, zo-grn. doses of sulphonal produced what the
patient described as " feelings of intoxication," followed by one or
two hours of sleep. Thirty grns. of ammonium bromide were without
effect, and twenty-five minims of nepenthe gave short uneasy sleep,
with dry tongue and headache in the morning. Chloralamid was then
resorted to, and a dose of 25 grns. prescribed, with the result that in
half-an-hour sleep set in that lasted five hours. On awakening, there
was no confusion or headache, but marked refreshment. The same
medication was given repeatedly, and continued to act .well.
In the case of neurasthenia, the patient stated that on the right
succeeding the taking of the powder he slept well, without a fur her
dose. This experience does not stand alone; other observers have
recorded cases in which the like phenomenon has been observed.
On the basis of his investigations, both physiological and therapeu-
tical, Dr. Gordon concluded that the results were highly reliable in
painless insomnia, and fairly so in insomnia accompanied only by
moderate pain. The hypnotic effect followed, as a rule, within half-
an-hour of the dose — the sleep induced was tranquil, pleasant and
natural — and the awakening free from mental confusion or depression.
He further concluded that there was no deferred action, nor was any
craving for the remedy excited.
Chloral amia. 59
The Therapeutic Committee of the British Medical Association
undertook, among other work, the investigation of the value of
Chloralamid, and in the report (Brit. Med. Journ., 1890, Aug.), gave
details of some half-dozen cases in which the diseases associated
with insomnia were cardiac affections, phthisis, neuralgia and acute
melancholia. The members of the Committee who recorded the
cases were Drs. Charles Angus, William Bullock, and John Gordon,
under the direction of Professor T. Cash, F.R.S., Aberdeen.
Save in the case of acute melancholia, doses of 25 — 40 grns. of
Chloralamid produced a refreshing slumber of five to twelve hours
duration, and not followed by any bad after-effects. Some of the
patients had been previously dosed with opium and other hypnotic
remedies without satisfactory results.
Dr. C. R. Hexamer, Stamford, Conn., had among his patients two
suffering from alcoholic tremor and insomnia. Doses of 30 to 45
grns. were prescribed with unmistakably beneficial results.
A noteworthy contribution to the literature of Chloralamid was
made by Dr. E. Lanphear, Kansas University Medical College, who
called attention to its usefulness in quieting the nervous system, and
producing sleep after an operation of magnitude. He had convinced
himself that it was not always pain which caused restlessness and
insomnia in these cases, but the impression made upon the nervous
system and on the mind. The usual practice of ordering a morphine
injection he considered unjustifiable, and chloral had a dangerous
depressing action upon the heart ; bromides with hyoscyamus some-
times answered, but most stomachs rebelled against it.
Dr. Lanphear believed that in these cases Chloralamid fulfilled
every requirement. It was "the ideal sedative, giving prompt and
satisfactory action, reliable results, and absolute freedom from evil-
side- or after-effect" (Notes New Remedies, 1891, May).
Dr. J. B. Mattison, Brooklyn, had a case of a lady, aged 37, who,
when first seen by him, was suffering from weakness, anorexia,
depression, and sleeplessness. She had been taking chloral regularly,
but this was withdrawn at once and 40 grns. of Chloralamid given.
A full night's sleep was obtained without any ill after-effects. Com-
parative trials with a number of hypnotics showed that Chloralamid
60 Chloralamid.
was by far the best — always procuring refreshing slumber lasting
several hours.
In the treatment of the insomnia of delirium tremens, Chloralamid
proved the remedy, par excellence, in the hands of Dr. T. A. Helm. It
brought about the quiet and refreshing sleep so desirable, and even
essential, to the successful treatment of the malady named.
k Among the medical men in various parts of the United States who
also emphasised the superiority of Chloralamid to other hypnotics,
in the insomnia of nervous and mental diseases, were Drs. J. C. Reeve,
J. O. Jenkins, C. R. Phillips, R. M. Brady.
Dr. S. H. Dupon called attention to the value of the hypnotic as a
sedative in uterine troubles, especially in aggravated cases with
hysterical convulsions. The first dose of 10 grns. frequently gave
immediate relief with no return of pain. One of the cases where
Chloralamid yielded good results had previously resisted all kinds
of remedies.
In the case of an old lady who had suffered from heart disease eight
years, and who sought relief from dyspnrea, cough and consequent
insomnia, Dr. J. A. Patterson (Therap. Gazette, 1891, Aug.) used
Chloralamid with great success. He first tried morphine, but this had
to be given in such large doses that the author was afraid to continue
with it. The synthetical hypnotic in lo-grn. doses, gradually increasing
to 40 grns., good rest and sleep in a recumbent posture was obtained.
The pulse improved at the same time.
It will be unnecessary to cite all the authors who have found
Chloralamid advantageous in insomnia from the most diverse causes.
They agreed in praising the readiness with which it lent itself to
administration in mixture form and the freedom of its action from
unpleasant bye- or after-effects.
(£) In Sea -sickness.
Chloralamid, especially in combination with potassium bromide
(forming the solution termed "Chlorobrom"), has taken a foremost
position among the really serviceable prophylactics against, and cures
for, the much dreaded sea-sickness.
Chloralamid: 61
One of the chief points in the effect of this compound which has
been an important factor in its usefulness in the affection referred to,
is, that it is readily retained by the stomach, allaying irritation and
arresting nausea. Professor M. Charteris recommended that the
remedy should be given after the stage of active vomiting had passed,
and stated that at that time it had invariably proved successful,
removing all distress, depression, etc., and securing by sleep the
gastric and mental repose so urgently required.
Without referring in detail to the reports of the various practitioners
who have successfully prescribed the Chloralamid and potassium
bromide solution, it may be said that their testimony confirms the
experience of Professor Charteris, and shows further that in many
cases the complaint may be altogether warded off by taking ordinary
precautions to avoid upsetting the digestive organs and resorting
to the Chloralamid solution on the appearance of any disturbing
symptoms.
A case recently recorded by Dr. Geo. Macdonald, Glasgow (Brit.
Med. Journ., 1892, Sept. lyth), is noteworthy, because the patient (a
young lady) was suffering from gastric ulcer, which made it the more
imperative to check the retching of sea-sickness, owing to the danger
of rupturing the stomach. Half an ounce of the solution of Chlor-
alamid (equivalent to 15 grns. of the remedy) was given immediately,
and in twenty minutes sound sleep was induced, which lasted for eight
hours. With careful subsequent dieting the patient improved steadily
during the voyage. The case is a striking illustration both of the
safety of Chloralamid and of its reliability in allaying sickness.
METHODS OF ADMINISTRATION.
Among the earliest formulae given for Chloralamid mixtures were
the following : —
"Sf. Chloralamidi .. grns. 45.
Acid hydrochl. dil gtt. v.
Syr. Rub. idaci £ss.
Aq. destill. ad gij.
M. ft. mist. To be taken as a draught.
62 Chloralamid.
!£. Chloralamidi 3iiss.
Syr. Rub. idaei 3J.
Aq. destill. 3iv.
M. ft. mist. Two, three or four tablespoonfuls to be taken before going to rest.
IJ. Chloralamidi grns. 45.
Ac.hydrochl.dil. gtt. ii.
Spirit vini rect m. 15.
Aq. destill. ad giij.
M. ft. mist. For an enema.
It is important to remember that although Chloralamid is somewhat
slowly soluble in water, heat should never be employed to facilitate
solution. Either time. must be given for the compound to be taken
up in the cold or it must be prescribed with some spirituous preparation
in which it can be readily dissolved, and then diluted with water ; 20
grns. of Chloralamid dissolves in a drm. of rectified spirit in 15
minutes and then water may be added without throwing the compound
out of solution.
Dr. Hale White said a good way of giving the hypnotic was to 'tell
the patient to dissolve it in a little brandy, add water to liking, and
drink it shortly before going to bed.
Dr. John Aukle cited the formula given under as convenient and
agreeable : —
Ifc. Chloralamidi 3iv.
Spts. frumenti giij.
Elix. aurantii ad Jiv.
M. Sig. Take one tablespoonful in water every four to six hours, as directed.
Beer and wine have also been used as menstrua for Chloralamid,
and spiced wine proved in Dr. Rabow's experience especially agreeable.
Chloralamid should not be given in powder, as, under these
circumstances, its absorption may be delayed, and the result con-
sequently less satisfactory. The method adopted by some authors of
prescribing the remedy to be taken dry on the tongue, or with milk, is
is not therefore to be commended. The desired result may be
attained in this way, but it is not so certain and reliable, nor so
agreeable as when the mixture form is selected.
PARALDEHYDE.
Nearly all the members of the aldehyde group of synthetical
remedies possess hypnotic properties, though they exhibit differences
in the degree of this effect produced, and also in the character and the
prominence of the secondary effects which accompany the primary
action.
There is another property which may be characterised as common
to the members of the aldehyde group of compounds — namely, a
tendency to form condensation products, by virtue of which the
molecule becomes more complex, without undergoing any change in
the relative proportions of the constituent atoms. That is, the
analysis of one of these substances, yields the same figures for the
percentage composition as that of the mother substance, possessing a
much simpler molecule.
This brings us to the consideration of the
PHYSICAL AND CHEMICAL NATURE
of Paraldehyde. Ordinary ethyl or acetic aldehyde has the formula
CH3CHO, that is, it is alcohol CH3CH2OH, from which two atoms
of hydrogen have been removed. Graphically, the formulae of these
compounds might be displayed as follows : —
H-C-C-O-H H-C-C?
H H H H
Alcohol. Aldehyde.
Now, if aldehyde, which is a volatile liquid with a peculiar, some-
what suffocating odour, a sp. gr. of 0-807 at o° C., and boiling point
64 Paraldehyde
at2i°C., be acted upon at ordinary temperatures by polymerising
agents, such as acids (HC1, SO2) and certain salts (especially ZnCl2),
it undergoes condensation contracting in volume and evolving heat.
The product, Paraldehyde, has a vapour density which corresponds to
the formula C6H12O3, from which it appears that it is formed by the
condensation into one molecule of three molecules of aldehyde, the
union taking place through the medium of the oxygen atoms in
the latter. Its constitution is represented thus : —
H H
The physical and chemical properties of Paraldehyde compared
with those of the mother substance — briefly given above — correspond
closely with the nature of the change by which it is formed — that is,
they are those of a more condensed body.
Paraldehyde, when pure, is a colourless liquid with a sp. gr. of
0-998 at 15° C. and boiling at i24°C. Subjected to a low tempera-
ture it solidifies to a crystalline form and melts again at io'5°C. At
1 3° C. it dissolves in eight parts of water ; unlike most substances, its
solubility is not increased by raising the temperature of the water, on
the contrary an aqueous solution saturated at the ordinary temperature
becomes turbid when heated, and a large proportion of the dissolved
Paraldehyde separates out.
Though fairly stable under normal conditions, Paraldehyde — as the
chemist would expect from the mere consideration of its structure —
is somewhat easily split up. It is very sensitive to oxidising agents,
and is partly reconverted into ordinary aldehyde by mere ebullition ;
in the presence of a small quantity of sulphuric acid the change is
complete on boiling.
In common with aldehydes generally, Paraldehyde is a powerful
reducing agent, forms an aldehyde resin with warm potassium hydrate,
and so on.
Paraldehyde. 65
The Importance of Purity
is generally recognised in the domain of medicine, and it is owing
to the spread of this principle that the use of medicinal agents of
definite chemical composition has attained such large dimensions of
late years. Bodies which have an unvarying chemical composition
and well-defined physical characters are more likely to produce
reliable and exact effects than preparations of which no two batches are
ever exactly similar in composition and therapeutical activity.
But in the case of Paraldehyde it is especially important that the
substance used in medicine should be absolutely pure. It has been
repeatedly found that specimens described as " Paraldehyd. purum "
contained not only ordinary aldehyde, but also amylaldehyde.
Now even only small quantities of these impurities are sufficient
to render the Paraldehyde unfit for medicinal use. Ordinary acetal-
dehyde, as stated above, has a pungent, almost suffocating odour,
and amylaldehyde is poisonous to an unmistakable degree.
No doubt it was the consequence of the introduction of specimens
containing these impurities into medicine, which prevented the com-
pound in the earlier days from attaining that prominent position
among hypnotics which it deserved. Hence the necessity of empha-
sising the importance of seeing that patients get only such a brand of
Paraldehyde as is really absolutely pure, not only in name but in fact.
The physical factors — sp. gr., boiling point, congealing point— men-
tioned above, are valuable tests of the purity of the compound. The
odour, however, is frequently sufficient in itself to indicate the presence
of impurities. Pure Paraldehyde has a spicy aromatic odour, and when
3j. or 3 ij- are evaporated gently on a water-bath, no unpleasant
smelling residue (higher aldehydes from fousel oil occurring in the
spirit from which the preparation was made) should be left.
PHYSIOLOGICAL ACTION.
It seems to have been assumed at first that Paraldehyde would have
the same effect upon the animal organism as aldehyde. The careful
F
66 Par aldehyde.
work of Dr. Vincenz Cervello, Strassburg Pharmacological Laboratory,
showed the unsoundness of this view.
Doses of about £- f- drm. produced in rabbits of average size
narcosis, lasting six or seven hours, not preceded by any stage of
excitement. On awakening, the animals were at first a little unsteady
on their legs, but soon regained their normal certainty. No further
disturbances were noted ; the animals seemed perfectly well, and took
food eagerly.
During the stage of profound narcosis the breathing became slower,
but the pulsation of the heart, so far as could be estimated by the
hand, remained strong. No change was perceptible in the pupils.
The effect upon dogs was similar, quiet sleep being induced without
previous excitement. The diminution in the frequency of the respira-
tion was not so considerable as in rabbits. That the compound was
absorbed very rapidly was shown by the fact that five minutes after
injection the gait of the dogs became unsteady and sleep soon
supervened.
Dr. Cervello's conclusions may be summarised as follows : —
1. Paraldehyde acts principally upon the cerebrum and partially
upon the medulla oblongata and spinal cord.
2. In large doses it arrests the respiration, but the heart's action
continues. The animals could be restored by means of
artificial respiration.
3. There is no stage of excitement previous to the narcosis as in
the case of ordinary aldehyde, nor any subsequent functional
disturbance.
Cervello's researches left unanswered, however, the question whether
the preparation had any effect upon the digestive function or not.
Our knowledge of this side of the action of Paraldehyde we owe to
Dr. John Gordon, Aberdeen University, who carried out a series of
experiments, with the view of determining the action of hypnotics on
digestion.
Test-tubes were used of equal size and form, containing £ gramme
of stained fibrin, two decigrammes of pepsina porci, two ccs. of two
percent, hydrochloric acid, 15 ccs. of water, with varying quantities
of the drugs under examination. One tube without any medicament
Paraldehyde. 67
was used for control purposes. The set of tubes was placed in an
incubator, and kept as near as possible at the normal body heat.
In the case of Paraldehyde, the test-tubes were capped with india-
rubber to prevent evaporation. The quantities of the hypnotic added
to the tubes were 0*3, 0*75 and 1*25 cc. respectively. The remarkable
result obtained was that in nine hours the digestion of the fibrin was
complete in the tubes containing the large quantities of Paraldehyde,
and well advanced in the third, while, in the control tube, very little
progress had been made towards digestion.
From a number of experiments, Dr. Gordon drew the conclusion
that the presence of Paraldehyde, even in minute quantities, ac-
celerated the digestion of fibrin, and that the greater the proportion of
the hypnotic present, the more rapid the peptonising process.
It was also observed that putrefaction was prevented by the larger
proportion of Paraldehyde, and delayed by the smaller.
MEDICINAL PROPERTIES AND USES.
The physiological examination of Paraldehyde outlined above in-
dicated its value as a harmless but efficient hypnotic. Dr. Cervello
described a case of sciatica, in which two drms. of Paraldehyde was
given as a three per cent, solution in three doses, with half-hourly
intervals. Two hours after the last portion was taken, the patient was
asleep, and did not awake till ten and a half hours later. No headache,
nausea, or other inconvenience was experienced.
Dr. Gugl used Paraldehyde 336 times, and found that in from half-
an-hour to three hours it produced calm, deep, and refreshing sleep,
closely resembling natural slumber. The duration of the sleep
varied from three to seven hours, or even ten hours, according to
dosage and individual idiosyncrasy. He obtained evidence that it
could be administered without hesitation in cases of heart disease,
even when of very pronounced gravity. The conviction forced itself
upon Dr. Gugl, that the best results were obtained in constitutional or
acquired neuropathic conditions in hysterical and neurasthenic, rather
than hypochondriacal cases. The author cites a number of illustrative
F 2
68 Paraldehyde.
cases which also indicate the freedom with which Paraldehyde may be
given for prolonged periods without causing disturbances.
Good, and even, in some instances, brilliant results were obtained
in cases of alcoholism, and in the simple nocturnal restlessness of
dementia paralytica and senilis. When the hypnotic effect was not
marked, as was sometimes the case, an evident sedative action was
perceptible.
In a case of hystero-neurasthenia, with unusually painful spinal
affection, the patient declared that immediately after taking Paralde-
hyde, she always became sensible of an essential decrease in the
pains.
On the whole, the author concluded that Paraldehyde was a
powerful hypnotic, preferable in many cases to chloral, on account
of its freedom from danger, even when its use was long continued.
In mental diseases and neuro-pathology, the physician had gained,
in Paraldehyde, a powerful aid in combating sleeplessness.
Similar evidence was afforded by the cases under treatment by Dr.
J. Peretti (BerL klin. Wochenschr., 1883, Oct. ist); even decrepit and
paralytic persons could take the remedy without danger, and heart
disease was not a contra-indication to its use. In one case a patient
took over six ozs. in forty-two days ; and in another, nearly 5^ ozs.
was taken in forty-one days, without any injurious effect.
A very trifling fall of temperature was produced, and there was no
congestion or alteration of the pupils. The results of Dr. Gordon's
investigation of the effects of Paraldehyde on digestion outlined above
were clinically antedated by Peretti's observation that not only was
the hypnotic free from prejudicial action on the digestion, but some
persons were able to record an appreciable beneficial influence upon
the digestive function and the appetite. The after taste was not
sufficiently marked to give occasion for complaint, or to affect the
appetite. Further, even prolonged use did not interfere with the
digestive or intestinal functions.
The author expressed the advantages of Paraldehyde over chloral
hydrate, as follows : —
i. Even in large doses Paraldehyde is free from dangerous action
on the heart.
Paraldehyde. 69
2. The action of Paraldehyde is not cumulative.
3. Paraldehyde rapidly induces sleep without previous symptoms
of excitement or congestion.
4. Patients awakening from the sleep induced by Paraldehyde
do not experience any disagreeable sensations.
Prolonged experience convinced Prof. v. Krafft-Ebing that Paral-
dehyde was an efficient and safe hypnotic if given in suitable doses.
He warned medical men, however, against prescribing the compound
in doses exceeding the limit of safety. This warning is now less
necessary, since it has been found by various authors, and is specially
noted by Dr. E. M. Sympson, that Paraldehyde is effective in com-
paratively small doses. Dr. Sympson obtained good results in delirium
and various kinds of insomnia with the remedy.
By Dr. H. Dehio, Paraldehyde was characterised as " the sovereign
remedy " among hypnotics. In his experience it produced a sleep
frequently lasting seven or eight hours, and extraordinarily like natural
slumber ; no headache, giddiness, or other symptoms usual after
narcotics, were observed. Like the physiological sleep, that produced
by Paraldehyde was most profound during the first two hours.
Reference has been already made to the work of Dr. Gordon on
some points in the chemico-physiology of Paraldehyde. The author,
who is Assistant-Physician of the Aberdeen Sick Children's Hospital,
mentions incidentally that he used the compound clinically in a
number of cases, but does not give any details.
DOSE AND METHOD OF ADMINISTRATION.
The average dose of Paraldehyde is about a drm., but the limits are
given as 45 ms. to 2^ drms. ; not more than i^ drms. should be given
as a single dose, nor should the maximum quantity mentioned above
be exceeded during the twenty-four hours.
Owing to the occasional employment of inferior and impure
specimens of Paraldehyde, somewhat exaggerated statements were
made as to its flavour, and the odour it communicated to the breath
of the patients. It appears according to Dr. Dehio and others, that
7O Paraldehyde.
the pure preparation is generally taken without any complaint or any
effect upon the appetite.
Paraldehyde may be conveniently taken with rum, milk or flavouring
essences, while aromatic bitters, like the tincture of orange, have been
favourite correctives. The tincture has the futher advantage of readily
dissolving the remedy. The following formulae yield agreeable
mixtures : —
$. Paraldebyd 5iij.
Tinct. Aurantii 3vj.
Syrupi. simplic. Siij.
M. Sig. One Teaspoonful (15 ms. of Paraldehyde) for a dose.
$. Paraldehyd
Mucilag. Acac. aa 5iv.
Syrup. Amygd 53.
Aquae ad §vi.
M. ft. Emulsio. Two Tablespocnfuls (40 ms. of Paraldehyde) for a dose.
Paraldehyde is very readily absorbed from the digestive tract, but in
some instances it has been administered subcutaneously. Mr. Keraval
employed a solution of 10 ms. each of Paraldehyde and cherry laurel
water made up to 40 ms. with distilled water. Before use he immersed
the bottle in warm water in order to ensure perfect admixture.
Ifc. Paraldehyd m. Ivi.
Spir. Menth. Pip. m.j.
Olei oliv. q.s. ad . m. cxij.
M. ft. solutio.
The solution prepared according to this formula was preferred bj
Drs. Langreuter and Strubisch. In any case the method seems to be
somewhat painful and, save in. very exceptional instances, would not
have any advantages over the usual mode of prescribing.
4wgi^
CHLORALS AND
CHLOROFORM.
CHLORAL HYDRATE was first recommended as a hypnotic and sub-
stitute for opium by Dr. O. Liebreich ; the mother substance chloral
was discovered by Liebig in 1832, having been prepared by him from
dry chlorine gas and alcohol.
One of the most important chemical properties of Chloral hydrate,
CC13COH, H2O, is its hydrolysis in the presence of alkalies into
chloroform and formic acid, thus: —
CC13COH (H80)=CHC18 + HCOOH.
This reaction is practically applied for the preparation of the purest
Chloroform (v. infra].
In the use of Chloral hydrate as of each member of this group of
bodies the greatest care must be taken to ensure perfect purity, as
the organic compounds of chlorine are characterised by a powerful
physiological action, and aldehydes or oxidation products, as well as
free chlorine, either reduce the activity of the preparation or have a
marked local irritant effect.
It is quite unnecessary to describe the physiological or thera-
peutical action of Chloral hydrate in any detail, or to refer to the
enormous literature of its employment in medicine. Its chief
importance depends upon its hypnotic properties ; while it has some
disadvantages compared with opium preparations, it has also many
advantages and is not rarely efficacious where they fail. The best
results are yielded in delirium potatorum, in puerperal mania,
enuresis nocturna, convulsive affections (eclampsia, uraemic cramps,
epileptiform convulsions in children, tetanus, chorea, etc.).
72 Chlorals and Chloroform
The unquestionable success of the remedy in gastro-intestinal
affections of children depends evidently upon its simultaneously
antiseptic and irritant action. The same is also true of most of its
external applications.
BUTYL-CHLORAL HYDRATE, which was at first regarded as the
chlorine substitution product of croton aldehyde, and therefore termed
croton-chloral, must be given in much larger doses than Chloral
hydrate, in order to attain the same degree of hypnosis. Comparative
experiments with Butyl-chloral and Chloral hydrate showed that the
narcosis of the former lasted only a third as long as that of the latter.
A peculiarity of the remedy is that it principally produces anaesthesia
of the cerebral nerves while it affects those of the body much less.
It is therefore especially serviceable in the treatment of trigeminal
neuralgia. It has, however, been successfully given in convulsive and
irritant cough and the neuralgic pains of tabetic patients.
As a sedative, Butyl-chloral hydrate is given in doses of ^ — i drm.,
preferably in solution.
CHLORAL-CHLOROFORM. Reference has been already made to
Chloral hydrate as a source of Chloroform (v. supra) and the equation
given illustrative of the process by which it is formed. The product
is characterised by its high standard of purity and absence of foreign
compounds. It answers satisfactorily to all tests and is appreciably
less prone to spontaneous decomposition than the ordinary chloro-
form of commerce.
Though the presence of oxidation products or foreign chlorinated
compounds is prejudicial to the value of all the members of this
group of compounds, it is especially so in the case of Chloroform,
which is principally used by inhalation. Hence the superiority of a
product which is made from a compound of definite chemical
character which can be readily obtained in a condition of great purity.
SALOL
The important role which phenol played in antiseptic surgery and
medicine was only restricted by its poisonousness. When used inter-
nally, apart from its local caustic action, it was exceedingly liable to
produce symptoms of toxic action, which not only necessitated the
observance of great caution in its employment, but further absolutely
contra-indicated its use in a considerable number of cases.
At the same time, there is a fairly large group of diseases known to
be due to, or at least associated with, the presence of pathogenic
micro-organisms in different parts of the intestinal tract. These
called for the administration of compounds which, while free from
a general poisonous effect upon the organism, would yet be capable
of directly attacking in situ the bacteria which were keeping up the
disease.
The problem was, therefore, to find some combination of phenol
which should be free from its poisonous action but possessed of an
equal, or, at least, of a marked antiseptic power. Such a compound
was discovered in Salol, one of a group of aromatic esters first pre-
pared by Nencki in 1883.
CHEMICAL NATURE AND PROPERTIES.
Salol is systematically termed phenyl salicylate, being represented
by the constitutional formula —
COOCsHs
It occurs in the form of white powder, seen under the microscope to
consist of tabular crystals ; or these crystals may be large enough to
make it necessary to describe the compound as being in crystalline
74 Salol.
tables, which are well defined and transparent. Salol has a feeble
aromatic odour, but being practically insoluble in water, has little or
no taste.
In alcohol the compound is soluble in the proportion of i in 10,
while ether takes up rather more than three times its weight. When
an alcoholic solution of Salol is poured into water a liquid having the
appearance of an emulsion is produced, which really contains the
substance suspended in a fine state of division. It is also soluble to
a considerable extent in fatty and mineral oils, in turpentine, copaiba
balsnm and sandal-wood oil. It will be seen below that this solubility
of the compound in essential oils and oleo-resins has a practical value
in its administration. When subjected to the action of heat, Salol
melts at 42° — 43° C., and if the temperature be raised (the substance
being supported on platinum foil) burns away with a very smoky flame,
leaving no residue.
If an alcoholic solution of Salol be added to solution of ferric
chloride (perchloride of iron) the only result is the appearance of
turbidity; if, however, the process be reversed and the solution of
ferric chloride poured into that of the Salol, the characteristic bluish
or violet colour of phenol is produced. Bromine water precipitates a
monobromo compound that crystallises from alcohol in long needles.
PHYSIOLOGICAL PROPERTIES.
The discoverer of Salol, Professor Nencki, compared it in its
physiological relations to the fats; like these it was split up by the
pancreatic juice into free acid and an alcoholic group, that is into
salicylic acid and phenol. He also believed that the compound
passed through the stomach unchanged, because the feeling of
malaise which almost invariably follows the administration of sodium
salicylate was entirely absent when Salol was given.
A careful research into the destiny of Salol when administered by
the mouth was made by Dr. R. Sievers and Professor C. A. Ewald
(Therap. Monatsh., 1887, Aug.). In 25 experiments in which the
SaloL 75
extracted gastric juice after a dose of the substance was tested every
half hour for free salicylic acid, negative results were uniformly
obtained.
On the other hand, it was observed that in contact with alkalies,
even at the normal temperature, and especially at that of the blood,
the compound was split up into its components. Since the pancreatic
juice and intestinal fluids are alkaline, it followed that when Salol,
having passed through the stomach unchanged, entered the intestines
it would be there split up into phenol compounds and salicylic acid.
It was experimentally proved by the authors that every part of the
intestinal tract was capable of effecting the dissociation of Salol.
They further found that wh'en Salol was brought into direct contact
with the intestinal mucous membrane, 20 — 30 minutes were required
before its constituents appeared in the urine. In healthy individuals
an hour proved to be the extreme limit of time between the adminis-
tration of the compound and its appearance in the urine.
About the same time Professor Sahli studied the dissociation of
Salol in the organism, and obtained results which corroborated those
of Drs. Sievers and Ewald.
In the well-known Pharmacological Institute of Dorpat, under the
direction of Professor Robert, G. Willenz carried out a searching
investigation of the conditions under which the substance split up
into its components. He found, like the preceding workers, that the
members of this class of compounds did not split up in the stomach,
but were resolved into their components only by the alkaline juices
of the intestines. Owing to their dilatory effects upon the vascular
system, the substances exerted an antifebrile effect.
In a research of later date than that mentioned above, Professor
Sahli adduced proofs that large doses of Salol could be taken— doses
which corresponded to an amount of phenol far exceeding what
could be safely given as such — without any symptoms of poisoning.
The author expressed the opinion that when given in large doses
Salol was possibly absorbed undecomposed, while further it might
be that the phenol was very gradually separated from combination
and excreted as fast as it was set free, or converted into harmless
compounds with sulphuric or glycuronic acid.
76 Salol.
Experiments with Salol upon animals were carried out by Dr.
Hesselbach, which demonstrated, beyond doubt, that the dosage of
the substance should not be based upon that of phenol. It was
proved by the fact that the lethal dose of Salol for animals amounted
to 7-6 grms. per kilo (about 53 grns. per lb.), corresponding to a
dosage of 532 grins, for a man of 70 kilo (i54lbs.) weight.
BACTERIOLOGICAL EXPERIMENTS.
The most elaborate research on the antiseptic action of Salol was
conducted by Professor Sahli. The first series of experiments was
made on finely-minced pancreas, diluted with water to a pasty con-
sistence, and containing various proportions of Salol. It was found
that 2^ per cent, of the compound was sufficient to prevent the
process of putrefaction.
It was stated by Koch that the antiseptics were of no value when
used in oleaginous solution; under these circumstances they were,
according to his investigation, practically inert. Professor Sahli made
a special series of experiments, with a view of testing the truth of this
general statement in the case of Salol ; from these it appeared that
even in oleaginous solution, the compound exerted a powerful koly-
septic (or development hindering) action upon bacteria. Apparently
even it was more active when dissolved in almond oil than when
used in powder — a result ascribed by the author to the more uniform
admixture of the antiseptic with the substance containing the
bacteria.
It is unnecessary to refer to all the work which has been done in
the investigation of the antiseptic activity of Salol. In the following
section, dealing with its use in medicine, a good deal of evidence of
its power in this direction will be met with.
THERAPEUTICAL USES.
Salol was recommended in the first instance as a substitute for
salicylic acid, presumably of more rapid effect, and free from irritant
Salol. 77
action upon the stomach, as it was not separated into its components
until it had arrived in the duodenum. This view of the medicinal
function of the compound determined of course the mode of its
employment, and it will be perhaps advantageous to follow, to some
extent, in dealing with its various uses in medicine, the chronological
order of their development.
(a) INTERNALLY.
1. Against Rheumatism.
Salol was employed in 27 cases of typical articular rheumatism by
Dr. Bielschowsky, being given in capsules in doses of i£ drm. pro die
within five hours, and in one case, two drms. within eight hours.
Smaller doses of 30 — 45 grns. were given only for the after treatment
of some cases where slight pains persisted. Of the 27 cases, 19 were
rapidly and completely cured ; in two, the effect was only slight, and
the remaining six passed into the chronic form.
Relapse was observed only eight times, and in each case was cured
by returning to the use of Salol ; smaller quantities of the medicament
sufficed than in the first attack.
The smallest quantity which sufficed to remove the symptoms
amounted to 3^- drms., and, on the average, the treatment had to be
continued for from four to eight days before a cure was attained. Once,
the disease resisted for ten days, but in several cases every trace of the
affection disappeared after three days. In four of the patients, slight
disturbances of the cardiac activity appeared, but were no longer in
evidence when they were discharged. Three suffered from mitral
failure, in consequence of earlier attacks of rheumatism ; they were
not aggravated by the fresh onset of the disease.
The author concluded, from his cases, that Salol must be regarded
as a specific in acute rheumatism, having the advantage over salicylic
acid and the other usual remedies of being free from any bye-effects.
The most careful observation of the patients satisfied the author
that this was so ; neither exanthema, perspiration, nor digestive
disturbances were seen.
78 Salol.
Almost simultaneously, clinical experiments with Salol in rheuma-
tism were carried out by Dr. Siegfried Rosenberg in the Jewish
Hospital, Berlin; He reported (Therap. Monatsh., 1887, No. 2) that
on the whole, the effect was promptly exhibited ; as a rule fever
disappeared and the painfulness of the joints was alleviated after
twenty-four to forty-eight hours. The longest time which elapsed
before symptoms were removed was five days, and in a single case
only, and that of very severe nature, was the remedy entirely without
effect.
So long as fever and pain persisted in the joints, 1^—2 drms. of
Salol were given daily in single doses of 15 grns. at intervals of one
or two hours. As soon as the patients were free from fever and pain,
the dose was reduced to i£, i drm., 45 and 30 grns. pro die (always
in portions of 15 grns. each) in the hope of preventing relapse.
The colour of the urine assumed an olive-green shade, deepening
to blackish green. In a few patients it cleared up later in spite of
continued use of Salol, and exhibited a greenish coloration only on
the upper surface where it came in contact with the air. Unlike
the preceding observer, Rosenberg recorded tinnitus as sometimes
following the use of Salol, but agreed with him that malaise, eructation
and nausea were very rare, and that the persistent digestive dis-
turbances of salicylic acid were never produced. Salol was also
superior to salicylic acid in its freedom from any irritant effect upon
the mucous membrane of the stomach.
Dr. Herrlich gave Salol in 25 cases of acute rheumatism with
satisfactory results. He employed doses of 15 grns. frequently
repeated, and recommended this modus procendi as preferable to large
doses less often.
Concordant results were recorded (Berl. klin. Wochenschr., 1887,
No. 9-11) by Dr. F. E. Georgi, who also tried Salol in acute
rheumatism. Unpleasant secondary effects were not at all manifested.
The average dose adopted was ^\ — 3 drms., and the writer believed
that thorough and lasting effects were attained by continuing the
administration of Salol in decreasing doses.
The crucial test of the safety of a remedy is its effect when adminis-
tered to children, who are most susceptible to the action of medicinal
SaloL 79
agents. This test, as regards Salol, was carried out by Professor
Demme, of the Jenner Children's Hospital, Berne.
From 45 to 60 grns. of Salol daily, in doses of 15 grns., with intervals
of two to three hours, were given to two boys (of 8 and 13 years
respectively) so long as fever, swelling and pain persisted. In one
case the administration was continued in this way five days and in the
other seven days. As the symptoms were alleviated the dose was
reduced to 30 grns. and during convalescence to 15 grns. The dura-
tion of the attack did not exceed 14 and 16 days in these two cases.
In another instance the patient was a girl of seven years, with fever
and severely attacked joints ; the afebrile state and reduction of the
local swelling were attained in 48 hours, during which \\ drm. of
Salol was given. Here, as in the cases of the two boys above
mentioned, there was no relapse.
Salol had also a favourable influence upon two cases of endocarditis
and pericarditis which were of rheumatic origin. Before the specific
remedy was given, the abnormal frequency of the heart's action was
reduced, and the blood-pressure regulated by the administration of
digitalis.
The very markedly unpleasant after-effects of salicylic acid and
salicylate of soda induced Dr. Aufrecht to give Salol a trial, with note-
worthy results (Deutsche med. Wochenschr., 1888, No. 2). The remedy
was given in 30 cases, i^ — 2 drms. daily in i5-grn. doses. One
patient (a woman) took half a pound of the substance in daily
quantities of i^ drm., and bore the treatment well. Dr. Aufrecht
formed the opinion that, in chronic rheumatism, Salol was undoubtedly
superior to salicylic acid. In acute cases he gave salicylic acid until
the fever was reduced (which required two or three days), and then
replaced it by Salol.
Dr. Lepine (Lyon Medical, 1886, July) found that Salol was more
effective than salicylic acid in relieving the pains of rheumatism.
Daily doses of one to two drms. were well tolerated.
Among American observers who have used Salol, Drs. C. J. Sauer,
Brooklyn, New York ; F. G. Dawnitz, St. Louis, Missouri ; and Wile,
of Danbury, Connecticut, may be mentioned. They all spoke very
highly of Salol as much superior to any of the salicylates, and as a
8o Salol.
reliable remedy for gout and rheumatism. Dr. Wile used the
compound in rheumatism complicated with Bright's disease ; 15 grns.
of Salol was prescribed three times a day with a milk diet. The
improvement w£s at once apparent and steadily progressed.
An interesting case of rheumatism, in which Salol was used, was
described in a medical journal of Japan, by Dr. J. Kimura. The
patient was attacked in both knee-joints, and had been long under
various treatments without good effect. At first 10, and later 2o-grn.
doses of Salol were prescribed. In about three months the pain had
entirely disappeared, and the patient, who had been quite unable to
walk, could move about very well with the aid of a stick. Previously
there had been habitual constipation ; but after the use of Salol, the
bowels became quite regular.
Thirty cases of articular rheumatism were treated in the Magdeburg
Town Hospital, by daily doses of i^ — 2 drms. of Salol, under the
direction of Dr. Behm. The results were characterised as very
satisfactory, and there was a noticeable absence of unpleasant bye-
effects. Appetite nearly always remained good, and the amount of
perspiration produced was always less than that which accompanied
the use of salicylic acid.
2. In Diseases of the Genito- Urinary Tract.
While Dr. Rosenberg was examining the anti-rheumatic virtues of
Salol, Dr. L. Feilchenfeld, in the same institution (Jewish Hospital.
Berlin), tried it in vesical catarrh and pyelitis. Single doses oJ
1 5 grns. two or three times a day, produced good effects in all cases ;
the urine, when previously alkaline, became acid, its volume increased
while the amount of pus excreted decreased.
These favourable effects were especially marked in acute cases, and
in cystitis gonorrhoica.
In two cases of pyelitis the pus was unmistakably diminished in
amount to an extent not attainable by other means. Even when the
case was one of prostatic hypertrophy, the quality of the urine was
improved by the use of 45 grns. of Salol.
Salol. 8 1
The dosage employed was not, as a rule, followed by any unpleasant
effects. The so-called carboluria was frequent, but soon passed off
again, although the remedy was uninterruptedly continued. Gastric
troubles were never observed.
Professor Demme (Ber. d. Jennerschen Kinderspital in Bern No. 20)
recorded beneficial results in two cases of vesical catarrh. In one
case the affection was the result of cantharidin-poisoning in a boy of
five years. From 20 — 40 grns. of Salol was prescribed, and on the
second day the previously alkaline urine became acid, and the diuresis
more abundant and painless ; after a fortnight's use of Salol, the boy
could be looked upon as cured. The second case was one of cystitis
following on measles, which passed into the chronic form ; here also
Salol did good service.
In writing on "The present position of the treatment of Cystitis"
(Therap. Monatsh., 1887, No. 2) Dr. Leopold Casper, Berlin, alludes
at length to the effect of internal medication with antiseptics, and
characterises Salol as one of the best. It was ordered in powder
form with sugar i£ — 2^ drms. pro die.
A decidedly favourable issue was attained by Dr. B. Arnold (Ibid,
1888, No. 7) in the case of an old man of 80 years suffering from
paralysis of the expulsory muscles. The constant use of the catheter
was followed by cystitis, the urine being alkaline, turbid and containing
blood and fatty substances. These abnormalities of the urine persisted
in spite of all measures, until finally 15 grns. of Salol was prescribed
twice, and later — as the compound was well borne by the stomach-
three times a day.
During the daily dosage of 30 grns. the urine gradually cleared up,
and when the quantity was increased by another 15 grns. it exhibited
at first a blackish green tinge, and then rapidly became clear ; the
sediment also steadily decreased in amount.
By continuing the use of the remedy, the diseased symptoms were
kept in abeyance, but any suspension of its administration was followed
by a return of the turbidity, etc.
The author observed that the small dose of 45, and then 30 grns.
daily, had the desired effect of preventing the ammoniacal fermentation
of the urine in the bladder, and so keeping it clear and acid. At the
G
82 -Salol.
same time the remedy was very well borne ; the tongue, previously
thickly covered, cleared perceptibly, and the appetite decidedly
improved.
The fact (i) that Salol was split up in the organism into its
constituents, and (2) that it was excreted as salicyluric and phenyl-
sulphuric acids in the urine, led to its employment for attaining
antisepsis of the urinary tract by a number of French physicians also,
whose results corroborated those of the authors above mentioned.
Salol has also been used with excellent results in the treatment of
inflammatory processes of the urethra, both acute and sub-acute in
character, due to micro-organic activity.
Dr. Ch. Talamon, of the Paris Hospital, tried Salol in blen-
norrhagia. In two cases scalding had lasted a week, with abundant
green pus and nocturnal erections. By the second day of the Salol
treatment the excretion was thinner, and the scalding removed ; on the
fourth the discharge was milky, and by the seventh only a drop of
serous liquid could be obtained at the meatus by pressure.
In two other cases the discharge assumed a milky character three
days after the administration of Salol. In all these instances the cases
were recent, and had not been aggravated by the injections which
always tend to perpetuate the discharge.
Dr. Hirtz, of the same Institute, recorded similar results. In 20
cases the remedy checked the discharge at the end of a period varying
from eight to twelve days. The analgesic action was manifested early
in the history of the cases. By this author the combination of Salol
and copaiba balsam or sandal-wood oil was largely prescribed (v. p. 91).
Dr. Dreyfous treated seven cases of gonorrhcea with Salol in doses
of i£ — 2 drms. (Brit. Med. Journal, 1889, Dec. 7th). The discharge
became less abundant, and in some cases a cure was effected in a few
days. The remedy was sometimes given alone and sometimes com-
bined with copaiba and cubebs in order to hasten the cure. Dr.
Dreyfous recommends Salol to surgeons about to operate on the
urinary organs ; it rendered the urine aseptic and innocuous when it
came in contact with wounded surfaces.
Mr. J. Ernest Lane, F.R.C.S., Out-Patient Surgeon of the London
Lock Hospital, gave the results of the administration of Salol in fifty
Salol. 83
cases of gonorrhoea {Lancet, 1890, March 22nd); six were cured,
24 showed considerable improvement, 15 showed no change either
one way or the other, and in five the symptoms were aggravated.
The doses used were from 5 — 30 grns. taken three times a day, and
the beneficial effects manifested themselves in a very short time.
When improvement took place, the symptoms abated in from two
to seven days ; painful micturition was early alleviated, and, in cases
of more chronic nature, the discharge was materially lessened.
At first the author used injections at the same time as the Salol was
given in five-grn. doses, but, subsequently, he raised the dosage to 10,
20, and in a few cases, 30 grns., and relied upon it exclusively. Out
of 40 cases so treated, improvement was noticed in 20 within a week,
while, as already stated, six were completely cured. The author
believed that, in chronic cases, the cure would be materially hastened
by an astringent injection, and that more favourable results would have
been obtained had larger doses been used from the beginning.
Dr. William White described before the American Syphilographical
Society his experience with Salol in over 50 cases of inflammation of
the urethra. In 35 of these the discharge was completely arrested at
the end of a week.
Interesting cases, which may be classed under this heading, were
described by Dr. Vernon Jones in the British Medical Journal, 1892,
Feb. 1 3th. In the first, the patient, who had suffered from gonorrhoea
for some time, strained his knee slightly, in consequence of which
there was great pain and effusion into the joint ; the limb was put on
a splint, and all the usual remedies tried, without avail. The urethral
discharge continued, and the other knee also became involved. He
was then put on 1 5 grns. of Salol three times a day, and from that
time improvement set in ; the discharge diminished, pain ceased, and
eventually, by the aid of local measures, the effusion also subsided.
The second case was less instructive, as the author did not rely
upon Salol alone, but changed about with other agents. The case
recovered in the end. In the third instance recorded by Dr. Jones,
the patient was a woman, and, as might be expected on theoretical
grounds (from the shortness of the urethra), the action was very much
less marked in the female sex.
G 2
84 Salol.
3. In Diseases of the Intestinal Tract.
In the account of the employment of Salol given by Dr. Georgi in
the Bcrl. klin. Wochenschr., 1887, Nos. 9-11, already referred to, there
is a section devoted to the consideration of the value of the remedy
in diseases where intestinal antisepsis is indicated. He found that
beneficial results were produced.
Dr. E. L. Vansant, Demonstrator of Pathological Histology, and
Chief of the Medical Clinic, Philadelphia, gave an account (Medical
Times, 1888, Oct. 15) of some dozen cases of diarrhoea and dysentery
treated by him with Salol, sometimes alone and sometimes with
bismuth subnitrate. The patients were of very varied ages, from 10
months up to 57 years, but in every case the remedy was well borne
and successful in bringing about the desired results. It was found
that much better results were obtained by prescribing the Salol every
three hours than by restricting it to three times a day.
Dr. R. B. McCall (St. Louis Medical Brief, 1888, Nov.) detailed a
case of dysentery in a delicate boy of five years. At first the fluid
extract of ergot did good, but delirium ensued, and so it was sub-
stituted by subnitrate of bismuth combined with paregoric. This
seemed to be having a good effect for a day or two, when the disease
suddenly resumed its first serious character. Then small doses of
calomel (£ grn.) with i grn. of Dover's powder every five or six
hours, was prescribed, but obliged to be given up because of the
nausea produced. Under routine methods it was plain the boy could
not be saved, and Dr. McCall resolved to essay Salol. He ordered it
in 2-grn. powders every three hours, and by the end of the first day
there was evident improvement in the character of the evacuations,
diminution in their number, fall of temperature, and slowing of the
pulse; at the same time restlessness and fretfulness vanished as if by
magic. After the second day the dose was increased and improvement
continued, fever entirely disappearing, the tongue cleaning and
appetite returning.
In about 10 days nearly 200 grns. of Salol were taken by this child
without the least sign of oppression, disturbance of any kind, of
Salol. 85
stomach, heart, kidneys or brain. The author expressed the convic-
tion that Salol was perfectly safe in suitable doses at any age.
Theoretical considerations induced Dr. A. H. Goelet, New York
(Medical Journal, 1887, Aug. 6th) to prescribe Salol in a bad case of
diarrhoea where bismuth, extract pancreatis and sodii bicarbonas, with
a milk diet, had proved ineffectual. Ten grns. of the remedy were
ordered to be taken every two hours. By the next morning the
patient reported himself all right. The motions ceased after the
second dose, as well as the pains and colic. A dose an hour before
each meal for two days was ordered with a practically unrestricted
diet. The motions continued natural in character and number, thus
. proving that the remedy had no constipating effect.
In a second case a fifteen months' child suffering from diarrhoea and
vomiting, one grn. was ordered every two hours dry on the tongue
with a teaspoonful of water after it. The vomiting ceased immediately,
and in six hours the diarrhoea had ceased as well ; on the next day the
•stools were natural, and the Salol was discontinued.
The author expressed the opinion that Salol was the only purely
satisfactory remedy he had ever used in such cases. In typhoid fever,
every three hours, there was nothing better, while he could not say
that it shortened the attack, it annulled the excessively disagreeable
odour of the faeces, and relieved the tenesmus and flatulence due to
accumulated gases in the colon. He did not know of anything which
so satisfactorily relieved flatulence of any origin.
Other cases in which Dr. Goelet successfully prescribed Salol were
summer diarrhoea and dysentery of children ; under such treatment,
if seen early, and properly dieted, there was no need for appre-
hension.
Corroborative evidence was furnished by Dr. O. T. Osborne, New
Haven (New York Medical Journal, 1888, April yth). As indications
for Salol in bowel troubles, he cited vomiting, purging, cramps, and
all the symptoms of the so-called "summer diarrhoea" of children.
He used it in twenty- two cases of all kinds, including one of acute
dysentery, without a single failure. The dysenteric patient had as
many as sixty bloody and mucous stools daily. The treatment was
four grains of Salol internally every two hours with morphine, whiskey
86 Salol.
and ice-water injections into the rectum. These latter failed,
however, to relieve the tenesmus or sanguinolent nature of the stools,
and were therefore substituted by a four per cent, solution of Salol in
alcohol, two teaspoonsful in water being injected as soon as the
tenesmus was felt to be coming on. Immediate relief followed the
first injection, and the next day no blood was passed, but faecal
matter appeared in the stools.
Except in a single case where an eruption occurred after the use of
Salol — which could not be certainly traced to the remedy — there were
no unpleasant symptoms due to its use. All the patients, save the
dysenteric, were cured without opium, and indeed without any other
medications at all, except the Salol. Although it is insoluble in the
gastric juice, the compound allayed vomiting ; this effect, conjectured
Dr. Osborne, might be due to an antiseptic action of Salol per se.
Dr. Kimura, whose paper on the use of Salol has been already
referred to, used the remedy against dysentery with good effect.
About five grns. were emulsified with water and injected into the
rectum; the most satisfactory results followed when the injection was
preceded with two or three quantities of lukewarm water.
Dr. Hirtz prescribed Salol in combination with salicylate of bismuth
in 35 cases of typhoid fever with great benefit. Combined with bicar-
bonate of soda, it arrested eructations, pyrosis, flatulence and diarrhrea,
so often witnessed in dyspepsia, due to dilation of the stomach. The
remedy was always well borne and had the advantage in typhoid of
effecting antisepsis simultaneously of the intestinal and urinary tract.
Similar results were obtained by Hesselmann.
In a lengthy treatise on "Intestinal Antisepsis" (Therap. Gazette,
1891, Aug.) Prof. Dujardin-Beaumetz recommended Salol particularly
as the best of intestinal antiseptics. He prescribed it for rectal cancer
with bismuth salicylate and sodium bicarbonate in five-grn. doses
before breakfast and dinner. He added, however, that the dose of
Salol might be increased to a drachm daily.
Dr. M. H. Fussell devoted an entire paper to the recording of his
experience with Salol in diarrhoea (Therap. Gaz., 1892, p. 508) and
Salol. 87
generalised his results as follows : —
1. Diarrhrea due to dietetic error, and that which is common
in adults and infants in summer, is well controlled by the
administration of Salol and bismuth or chalk.
2. Opium is rarely necessary where Salol is used.
3. Salol controls the abdominal pains equally as well as opium.
4. It is perfectly safe, having no bad after-effects.
5. It is especially useful in the diarrhoea of children.
6. It constantly corrects the foetor of the stools.
Dr. Mensi also adds his testimony to the value of Salol in the
diarrhoea of children (Therapist, 1892, Oct. ijth). Complete recovery
was obtained, with a single exception, by the use of Salol in 27
children suffering from the chronic form of the affection. The daily
dose to young children was 4 — 8 grns ; to elder children, 16 — 30 grns,
4. Salol in Cholera,
It was shown by Dr. W. Lowenthal (Le Progrcs Mid., 1889, No. 2)
(i) that the comma bacillus formed toxic ptomaines with the pan-
creatic juice, and (2) that the process of their formation could be
prevented by addition of a small quantity of Salol. Since this latter
was harmless to man, the author recommended it for the treatment of
cholera, and the suggestion was followed by Dr. Ferd. Hueppe, who
prescribed it in combination with bismuth salicylate, and reported
encouraging results from India.
Dr. James Couldrey (Brit. Med. Journ., 1892, Aug. 6th) also recom-
mended Salol against cholera, suggesting its prescription with tincture
of chloroform and morphine internally, with hypodermic injections of
ether in the relapse stage. ,
Dr. Salvator, of Zambeles, Phillipine Islands, sent Prof. Lowenthal
the record of 53 cases of cholera treated with Salol. Only three-
received in very advanced stages of the disease— terminated fatally.
Doses of 30 grns. were first given, followed by further doses of 8 — 15
grns. every hour or half-hour.
88 Salol.
5. In Yellow Fever.
During an epidemic of yellow fever in Rio de Janeiro, Dr. Ferreira
tried Salol, being led to do so by the theoretical considerations based
on the symptoms of the disease, and on post-mortem revelations. He
reached the conclusion that the fever was intestinal in origin, and his
experience with Salol appeared to confirm the theory in the most
positive manner. He prescribed it in doses of five grns. every twc
hours in water, and regarded its value as beyond doubt, though the
number of cases in which it was tried was not large. Further trials
with Salol in this disease could not fail to be interesting, though it
seems that it must be given in considerable doses if success is to be
attained.
6. In Leprosy.
In the Biennial Report of the Board of Health to the Hawaiian
Government, Dr. Lutz, of Honolulu, stated that he had obtained a
very favourable impression as to the value of Salol in leprosy. In half
a dozen cases the leprous fever was almost immediately interrupted by
the daily use of i| — 2 drms. divided into three or four equal doses.
In some cases the acute eruptions immediately and quickly disappeared
under the use of Salol, leaving the patient in complete health during
the next six months' observation. In another case a few tubercles
appeared, and even persisted during the use of the remedy, but the
author believed these would probably have been prevented by the
use of larger doses.
7. For Diagnostic Purposes.
Salol has done good 'service in the diagnosis of morbid conditions
of the upper digestive tract. This employment of the compound
depends upon the fact that it passes unchanged through the stomach,
and is resolved into its constituents and absorbed only in and from the
intestines. Drs. Sievers and Ewald established that in healthy indi-
viduals an hour is the extreme limit between the taking of the close
Salol. 89
and the appearance of salicylic acid in the urine. Variations from
this standard would be due to pathological causes. On this basis the
diagnosis of changes in the motor efficiency of the stomach could be
readily and reliably made with the help of Salol.
Thus occlusion of the pyloris was successfully diagnosed in a case
where, after administration of Salol, no salicylic acid appeared in the
urine {Brit. Med. Journ., 1890, June i4th), and Drs. Sievers and
Ewald were able, in a number of instances, to diagnose in this way
dilatation and functional disorder of the stomach.
-
EXTERNALLY.
1. In Surgery and Skin Affections.
It will be unnecessary to reproduce extracts from all the literature
which has appeared upon the external application of Salol. As a
substitute for iodoform, the chief advantages which it has manifested
are —
1. Freedom from odour.
2. Almost absolute non-toxicity.
3. Valuable drying properties.
Dr. Eugen Griitzer, Menchi (Therap. Monatsh., 1884, No. 9),
Corner (Journ. Amer. Med. Assoc., 1889, June 8th), Saalfeld, etc.,
observed that when applied to raw or excoriated surfaces, it exerted a
powerful antiseptic and anodyne action. It was used in surgery in
the form of powder, either alone or mixed with starch or French
chalk, as liniment. Professor Demme obtained very good results in
burns ; Dr. Gratzer and others in abscesses of the leg and sycosis
parasitaria ; Saalfeld in impetigo, eczema ; and Professor Barduzzi in
various skin affections, especially those of syphilitic origin.
Very careful researches into the action of Salol externally as an
antiseptic were carried out by Dr. M. G. Patein (Surgical Review, 1887,
p. 519), who recorded its successful use in localised tuberculosis, in
the treatment of variolous pustules of the face (20 per cent, solution
in ether), and other diseases of a similar nature. In cases of epi-
thelioma of the nose, fistula of the breast, mammary and maxillary
go Salol.
abscess, removal of diseased growths, caries of the sternum and rectal
abscess, the results were superior to those obtained with iodoform.
In an operation for a laryngeal cyst, requiring tracheotomy, the action
of Salol was remarkable.
Dr. M. Perrier observed very good results in local tuberculosis ;
where the bones were the seat of disease, this surgeon discarded
iodoform and used Salol alone. In several cases he filled the cavities
with gauze sachets containing varying amounts of Salol powder
without producing any symptoms of poisoning, while all septic action
was arrested.
2. In Rhino -larynology.
The successful treatment of 22 cases of inflammation of the soft
palate, of tonsillitis and pharyngitis by Salol was reported by
Dr. Gougenheim. Dr. Caport (Brussels) first called attention to the
remarkable value of Salol in the treatment of suppurative tonsillitis,
and the publication of his results led Dr. Gougenheim to test its value
in various forms of angina. On account of its insolubility, the remedy
was conveniently dispensed in mucilage 15 — 20 grns. three times a
day, and the diet almost exclusively restricted to milk. In all the
author's cases the dysphagia was cured with the most remarkable
rapidity, no matter what its cause.
Dr. Otto Seifert (Centralbl.f. klin. Med., 1887, No. 14) tried -Salol in
the local treatment of diseases of the mouth, nose, and larynx. He
praised it highly as a mouth wash and gargle — one teaspoonful of a
six per cent, alcoholic solution in a glass of warm water — in stomatitis,
ulceration of the mouth and pharynx, angina; in chronic diphtheria
the remedy did better service than potassium chlorate and salicylic
acid.
Dr. Thorner, Cincinnati (Lancet Clinic, 1887, Dec. loth), charac-
terised Salol as far superior to sodium salicylate, not only in certainty
and rapidity of effect, but also as regarded the relative smallness of
the dose. In those exceedingly painful cases of acute catarrhal
pharyngitis, involving the entire muscular system of the neck, the
pains rapidly disappeared under the use of 9 — 12 grns. of Salol three
Salol. 9 1
times a day. The effects were nearly equal in phlegmonous and
follicular angina, pain disappeared after a few doses, the restless
patients fell into a refreshing sleep and were enabled to swallow
almost without pain.
Good results followed the internal use of Salol in nervous otalgia,
as well as in one case of otitis med. chronica purulenta.
In ozaena, Cozzolina recommends insufflation of a Salol powder
(30 per cent.) in combination with boric acid (15 per cent.), salicylic
acid (3 per cent.) and French chalk, with a minute quantity of
thymol.
In the treatment of diseased condition of the mouth with foetor,
Georgi recommended a mouth wash made by mixing 2 — ^\ drms. of
a four to five per cent, alcoholic solution with six ounces of water.
FORMUL/E AND METHODS OF USE.
When prescribed as powders the slight taste of Salol may be masked
by oil of peppermint. As already repeatedly stated above, it has also
been given in wafers and emulsion.
When given in diseases of the genital tract tho solubility of Salol
in essential oils and oleo-resins enables it to be readily combined
with sandal-wood oil or balsam of copaiba. The employment and
efficiency of these combinations has been already described.
Externally in ulcers, skin affections, etc., the oleaginous solution is
effective, or an ointment (i — 10 per cent, with lanolin). When
employed as a dusting powder it is best mixed with starch or French
chalk.
As a topical application against rheumatism it has been recom-
mended to dissolve four parts of Salol in an equal weight of ether
and add 30 parts of collodion. Painted on the affected areas this
application is a useful adjunct to the internal treatment.
SALICYLIC ACID
AND ITS SALTS.
The value of Salicylic acid in the various forms of the rheumatic
diathesis needs no emphasis; it has obtained a well-recognised
position as possessed of what may be termed specific virtues in the
treatment of the class of affections above-named.
The reputation of the substance and its preparations was largely
built up upon results obtained with the product derived from the
vegetable kingdom, and especially from the oil of wintergreen, and
when Kolbe's method of synthesising Salicylic acid was first used for
the preparation of a medicinal article, doubts were entertained as to
its exact correspondence with the natural product.
Chemical investigation did show, as a matter of fact, that commercial
Salicylic acid contained foreign acids, and physiological work carried
out by Prof. M. Charteris and Dr. W. Maclennan indicated that a
dangerous and even fatal action on animals was produced by these
foreign constituents of the synthetical acid. Professor Charteris
extracted a substance from the acid which in doses of one grn. proved
fatal to a rabbit of 2 Ibs. weight. At the same time it was proved that
it was possible to purify the acid, and the physiological action of the
substance, thus freed from impurities, was not characterised by any of
the symptoms of paralysis or even of depression observed to follow
the administration of the impure article.
In consequence of this work Messrs. Schering turned their attention
to the subject, and adopted additional means of purification. Some of
the product of the modified process of manufacture was placed in the
hands of Prof. Charteris, who examined it physiologically, and stated
that he satisfied himself it was precisely similar to the acid obtained
from natural salicylates, and therefore of such purity as to be equally
eligible for medical use.
94 Salicylic Acid and its Salts.
Subsequent researches, chemical and physiological, proved beyond
doubt that the Salicylic acid and salicylate of sodium, prepared by the
improved process referred to above were absolutely free from foreign
acids or other impurities, and consequently that they were indis-
tinguishable in their action upon the animal organism, whether in
health or disease, from the compounds obtained from natural sources.
Since the salicylates provided by nature are far from abundant and
difficultly isolated, so that high prices follow as a matter of course,
the importance of a means of artificially preparing them which is
comparatively simple and unlimited in productive capacity is self-
evident. But also it is essential that the synthetical body should be
absolutely pure, not only to chemical but to physiological tests as well.
The researches of Professor Charteris and the other workers have had
a very practical and valuable outcome in leading to the manufacture
of a Salicylic acid and compounds which can be used in every way as
freely and harmlessly as the preparations obtained from the vegetable
kingdom.
BISMUTH SALICYLATE.
Basic salicylate of bismuth is a definite compound with the formula
Bi (C7H5O3)3 Bi2O3 containing 76 per cent, of bismuth oxide and
23 per cent, of Salicylic acid. It occurs as an amorphous yellowish
white powder, entirely insoluble in water.
Under the name salicylate of bismuth, however, preparations have
been introduced into medicine which were little else than mixtures of
Salicylic acid and oxide of bismuth ; as the free acid has a well-
marked irritant action when externally employed, it is necessary to
avoid the use of these articles.
It should be noted that neither water, alcohol, ether, nor chloro-
form, should extract anything from the true salicylate of bismuth.
Preparations which contain free Salicylic acid yield it to these solvents
and are thus detected.
The compound has been employed in medicine as a substitute for
iodoform in the treatment of wounds, ulcers, etc. Its value in these
Salicylic Acid and its Salts. 95
cases depends upon the following properties : —
1. It is antiseptic, rapidly removing foetor and arresting morbid
process due to micro-organic activity.
2. It is drying, diminishing secretion, and thus indirectly check-
ing bacterial development.
3. It is soothing and healing, healthy granulations quickly forming
during its use.
In internal antisepsis salicylate of bismuth has also played an
important part, both alone and in combination with other remedies
of the same class. Vulpian recommended it highly in morbid con-
ditions of the intestinal tract, especially of the rectum, and Dr. Solger
used it in affections of this kind with great success.
The best results were obtained in irritated and sub-inflammatory
conditions of the intestines, in which its mild antiseptic action gave
it great advantages over the nitrate of bismuth previously employed.
The pure bismuth salicylate, free from uncombined acid, is well
borne by the stomach, and can be continuously given for months
without ill-effect. It is, therefore, specially suitable in chronic
diarrhoeas, even when of most obstinate nature. Surgeons have also
found it useful to prescribe after operations upon the intestines, in
order to prevent faecal accumulation and development of gases which
endanger the results of the operations*.
Dr. Dujardin-Beaumetz recommended bismuth salicylate (Therap.
Gazette, 1891, Aug.) combined with equal doses of Salol in the
treatment of rectal cancer. He prescribed five-grn. doses of each of
the remedies to be taken before breakfast and dinner; the adjuncts to
this treatment were antiseptic rectal irrigations and a vegetarian diet.
Where the disease did not cause much local constriction he believed
quite satisfactory results could be obtained from the means indicated.
LITHIUM SALICYLATE.
This compound is a white crystalline powder, soluble in little more
than its own weight of water; it is also abundantly taken up by
alcohol.
96 Salicylic Acid and its Salts.
The lithium salts have, as known, been used for years in the treat-
ment of gout and of diseases of the urinary tract. Salicylic acid also
won a high reputation in the treatment of many similar affections,
and, therefore, its combination with lithium promised to display
therapeutical properties most valuable against the uric acid diathesis.
Clinical trials with lithium salicylate showed that the expectations
formed as to its value were well founded. It manifested very valuable
properties in the treatment of acute rheumatism and the various affec-
tions due to, or associated with, an excess of uric acid in the blood.
Unlike the salicylates of the commoner alkali metals, lithium
salicylate does not produce any disagreeable effects upon the digestive
organs. The tendency of the ordinary salicylates to do this is a
contra-indication to their use in some cases, and in these especially
lithium salicylate appears to be very suitable. Over the carbonate of
lithium the newer salt has the advantage of being readily soluble,
and, therefore, its absorption and therapeutical effect are the more
reliable and prompt. The property of dissolving readily and entirely
in water is characteristic of the pure salt, and will serve as a rough test.
Dr. Vulpian found lithium salicylate equal in every case to
salicylate of sodium as regarded therapeutical effect, while, in some
instances, it was distinctly rriore efficient. This was especially
noticeable in some cases of acute rheumatism of the joints ; oc-
casionally, in this affection, the fever, though at a very low level, is
difficult to entirely remove, and sodium salicylate is by no means
always successful, even when its administration is long continued, in
bringing about complete apyrexia. In these cases the lithium salt
proved especially valuable.
In the chronic form of rheumatism, and particularly in rheumatic
affections of the tendons, lithium salicylate proved superior to the
sodium salt.
The medium daily dose for adults is one drm., though it may be
increased to about i| drms. pro die without any disagreeable results.
The compound appears to be worthy of more extended trial than it
has hitherto received, as it possesses a valuable combination ot
therapeutical virtues with a noteworthy absence of drawbacks.
STRONTIUM
SALTS.
Hitherto the so-called alkali earth metals have not yielded salts of
very marked therapeutical value, or, at any rate, where such have been
prepared and employed in medicine, their usefulness has depended
more upon the acidulous group in the salt than upon the metal itself.
This is easily verified in the case of such compounds as calcium
iodide, hypophosphite, etc. The barium compounds are well-known
to be characterised by a powerful poisonous effect, specially manifested
upon the circulatory system, and therefore they have been little or not
at all used.
The close chemical relationship existing between Strontium salts
and those of barium, as well as the difficulty of obtaining the former
perfectly free from traces of the poisonous barium compounds, led to
the impression that the Strontium salts were possessed of similar
dangerous properties.
Original investigations recently carried out in the hospitals of Paris,
and communicated to the French Academy of Medicine and to other
learned Societies, have conclusively proved that the
Strontium Salts are innocuous,
and not only so, but that they have a beneficial influence upon the
nutritive processes.
The first evidence of this kind was contained in a treatise by
Ismael Nassan, the effect of which was to lead to the preparation of
absolutely pure salts for use in medicine. These were employed
therapeutically by a number of experimenters, and with so much
success as to be considered worthy of special notice and emphasis.
H
98 Strontium Sails.
THERAPEUTICAL USES.
BROMIDE OF STRONTIUM.— This compound was found to have all
the useful properties of the alkaline bromides without their tendency
to produce digestive and nutritive disturbances. Dr. Constantine Paul
prescribed it in daily doses of i£ drms. to a young girl suffering
from hystero-epilepsy. Although the attacks had resisted potassium
bromide given perseveringly in drachm doses, they were entirely
arrested by the Strontium salt and did not recur.
Bromide of Strontium was prescribed by Deny for seven epileptics,
and under this treatment the patients had among them 246 attacks
in seven months. During the corresponding period of the preceding
year bromide of potassium had been administered, and the number of
attacks was 331, consequently the Strontium salt reduced the fits by
more than a quarter. Both compounds were given in exactly the
same doses. One of the patients who was most benefited by the
Strontium treatment, ceased to suffer from the maniacal excitement
after each epileptic seizure to which he had previously been
subject.
From the experience of F£r£ and Prof. Germain S6e, it appears that
pure Strontium bromide has no disastrous effect upon the stomach,
even when given in large doses. The latter authority employed the salt
with success in various gastric affections, and it also proved useful in
diabetes, causing a diminution in the amount of sugar excreted.
LACTATE OF STRONTIUM. — Dr. Laborde first recorded the bene-
ficial action of this salt in obstinate painful dyspepsia, and his
observations were subsequently confirmed by other experimenters.
Dr. C. Paul found that it was well borne in daily doses of 2 — 3 drms.,
and employed it with advantage in visceral congestion, and in Bright's
disease ; better results were obtained than with lithia. Though not
a diuretic, Strontium lactate brings about at once a diminution in the
amount of albumen excreted, and correspondently improves the
collateral symptoms. When the administration of the remedy was
suspended, the albumen reappeared in the urine, to again fall to zero
when the treatment was resumed.
Strontium Salts. 99
Other affections of the urinary system associated with excretion of
albumen were similarly benefited. Dr. Dujardin-Beaumetz reduced
the proportion 50 per cent, within one to four days. He characterised
the salt as a valuable agent, both reliable and harmless. Laborde
prescribed the lactate as a taenifuge with success in drachm doses
repeated daily for about a week.
OTHER STRONTIUM SALTS which have been successfully used
therapeutically are the iodide, a one or two per cent, solution being
employed in scrofulous diseases ; the nitrate, given in doses of
% — 4 drms. in articular rheumatism ; the phosphate, regarded by
Laborde as one of the most valuable nutritive and tonic medicaments
known ; and the acetate, which has also a reputation as an active
taenifuge. Altogether there is sufficient evidence that, if perfectly
pure Strontium salts are employed, they will prove a valuable enrich-
ment of materia medica, and increase the power of the physician to
control certain obstinate and obscure diseases.
H 2
POTASSIUM
BROMIDE.
Although of late years materia medica has been enriched by a
considerable number of synthetical hypnotics and sedatives, which
may be described as products of organic chemistry, yet Bromide of
Potassium maintains its position as a most valuable remedy in nervous
diseases, whether due to abnormalities of the nerve centres them-
selves, or to excessive reflex sensibility.
It is necessary, however, to call attention to the desirability of care
in the selection of Potassium Bromide for use in medicine. The
standard to be aimed at is, of course, absolute purity, not only on
economic grounds, but because scientific medicine can only be based
upon the presumption that the substances administered or applied are
of definite composition and perfect purity.
Chemical analysis has shown, however, that there are brands of
Bromide of Potassium which are far from satisfying the requirements
of the high standard alluded to. The examination of commercial
specimens of the salt, carried out by Messrs. Helbing & Passmore,
showed that there are American brands which contain notable
amounts of impurities in the form of combined chlorine.
It is therefore necessary for prescribers and dispensers to exercise
care in the selection of Potassium Bromide for therapeutical use, in
order that the physician may be able to rely upon the constancy of
effect of the remedy he prescribes. Physiological research has shown
that apparently quite insignificant doses of compounds may have an
appreciable effect upon the organism, and there is sufficient difference
between the action of chlorides or bromates (another possible
contamination of commercial bromide) and bromides to render it
undesirable to administer a preparation which contains a relatively
large proportion of these compounds as impurities.
THIOSINAMINE.
This substance is one of a group of bodies which may be regarded
as derivatives of urea. Systematically it is termed allylthiocarbamide —
a name which indicates that in the urea nucleus the oxygen atom is
replaced by sulphur. The place of the allyl group in the body might
be occupied by almost any compound radical such as phenyl, ethyl,
etc., and most of the possible combinations thus brought about have
been experimentally examined physiologically and bacteriologically.
On the whole, Thiosinamine proved the most valuable member of
the group.
A lengthy treatise on the employment and action of the compound
has been written by Dr. H. v. Hebra. In this paper the formula of
Thiosinamine appears as—
/NHC3l-b
CS<
XNHa
and it is described as prepared by acting on volatile oil of mustard
with ammonia in the presence of alcohol. As in the case of most
derivatives of mustard oil, water decomposes the compound, and
consequently alcohol or ether must be resorted to for the purpose of
preparing solutions of Thiosinamine. Such solutions administered
subcutaneously produce a smarting sensation, but this appears to be
of very short duration, and not sufficiently unpleasant to make patients
unwilling to persevere with their use.
THERAPEUTICAL USE.
Some three years ago Dr. v. Froschauer stated that animals could
be rendered immune to bacillary infection by subcutaneous injection
IO4 Thiosinamim.
of allylsulphocarbamide. Careful repetition of the experiments
showed that this was not well-founded, but at the same time led to
the employment of the compound in some chronic cutaneous
diseases.
The medicinal value of Thiosinamine was made the subject of
careful study by Dr. Hebra. He found that a prominent feature of
its action was a well-marked local reaction, not accompanied by any
general constitutional disturbances.
About two hours after the injection the affected site reddened and
began to swell, the intensity of these symptoms depending upon the
extent of the disease and the dose injected. After some four or six
hours these phenomena subsided, and the normal colour was regained
about 1 8 to 20 hours later. No vesicles or serous exudation was ever
observed.
The majority of cases treated were lupus of various severity and
site. On the day following the reaction considerable desquamation
occurred, and all the diseased patches were covered with scales ; the
adjacent healthy skin remained smooth and unaltered.
As regarded the beneficial effects of the treatment a few injections
were sufficient to render this unmistakable. Lupus tumidus became
much less prominent, the whole area sinking considerably, while in
the ulcerated form the thickened margins decreased, and in a few
weeks' time the healing process was established, after vain endeavours
to effect it by external remedies.
The lupoid nodules offered the greatest resistance, owing, doubtless,
to the paucity of the blood supply.
The results, as regarded the cicatricial tissue following the spon-
taneous ulceration of lupus, or the application of caustics, were much
more striking. Whenever such tissue disturbed nutrition or impeded
movement, a complete softening and loosening was brought about
by the medication. Very striking cases, illustrative of this fact, are
described by the author.
Other cases in which favourable results were attained by the use of
Thiosinamine were those of chronic glandular swellings. Syphilitic
affections of the glands were not affected, and it was suggested that
this fact might be made use of for diagnostic purposes.
Thiosinamine. 1 05
On the day of injection an excess of 7-3—18 ounces of urine was
passed, but no untoward effect upon the kidneys was ever observed ;
neither albuminaria nor any other morbid changes were detected,
though carefully watched for. The process of absorption generally
was promoted.
All the patients felt well during the treatment. Appetite increased
remarkably in every case, and coincidently with the administration of
the remedy ; as a natural consequence, nutrition and general body-
weight also improved. Experiments made on animals showed that
doses ten to twenty times as large proportionately as those given
to the human subject, caused only a slight lowering of the blood-
pressure, which was probably due to the solvent.
Dr. Hebra recommended that only old processes should be treated
with Thiosinamine, save in lupus and allied conditions. Carefully
employed, it seems to have a valuable action in clearing nebulae of
the cornea.
DOSAGE.
A 15 per cent, alcoholic solution was employed, two or three
divisions of a Pravaz syringe being injected twice weekly, so that
5 — 7 grns. of Thiosinamine were administered at each injection. In
cases of lupus the dose was increased in the third week to half a
syringeful, and in the fourth or fifth week to a whole syringeful of
15 percent, solution. In a few cases even more was given without
bad effect.
DIABETIN.
The fact that the sugar excreted by diabetics is identical with
ordinary dextrose or grape sugar has always been held a sufficient
reason for cutting off from the dietary of such patients not only all
preparations containing dextrose, but also all farinaceous or starchy
foods which are known to be converted into that sugar by the action
of the digestive ferments.
To a large proportion of diabetics this restriction is a considerable
hardship, and numerous attempts have been made to substitute
ordinary sugar by some preparation which, while satisfying the craving
of the patients for sweetness, should at the same time be free from
any tendency to aggravate the disease.
The most successful of these substitutes, the benzene derivative
termed " saccharin," though meeting the latter requirement, since it
passes through the system unchanged, does not satisfy the craving
for the natural saccharine substance, sugar, because its taste is
altogether different to this. The sweetness of " saccharin " has a
cloying, nauseating character, that generally leads to its speedy
abandonment.
Although the chemical laboratory has failed then to satisfactorily
solve the difficulty alluded to, yet such an enormous variety of sweet
compounds is elaborated by Nature that it was recognised as extremely
probable that some of them would be suitable for the purpose in view.
The true sugars have, as known, a very close relation to one
another in chemical composition, but the progress of the study of
the alliance of chemical structure and physiological action has
revealed the fact that apparently insignificant constitutional differences
are accompanied by the widest variations of medicinal action.
Now dextrose, the sugar which appears in the urine of diabetic
patients, is one member of a group of compounds very closely allied
io8 Diabetin.
among themselves, but also exhibiting certain important differences.
Laevulose is another member of the same class which, in constitution
and general reactions, is very similar to dextrose. Yet experiment has
shown that, as regards physiological destiny, when introduced into
the animal organism, the similarity does not hold, and for this reason
it is probable that laevulose will be available for use by diabetic
patients without aggravating the disease from which they surfer.
But although laevulose or "fruit sugar" is moderately abundant in
the vegetable kingdom, either free or combined, yet its preparation in
the pure state has presented very great difficulties. The only form in
which it was known, even to the chemist, was that of a sticky syrup
that could not be induced to crystallise, and was rarely colourless.
It may therefore be regarded as a triumph of technology, that a
method has now been elaborated, by which this sugar is obtained as a
pure white crystalline powder, as convenient for general use, as a food-
stuff, as any other of the sugars. This pure substance is distinguished
from the older product known as laevulose, by the name Diabetin.
The exact value of Diabetin, as a sweet food for diabetics, can of
course only be arrived at by an examination of its effects in a con-
siderable number of cases under experienced guidance. For this
purpose the attention of physicians is called to the preparation, so
that trials with it may be at once instituted, and the results recorded
in medical literature. *
At present, as a matter of course, Diabetin cannot be produced at
anything approximating to the price of ordinary cane sugar; but,
nevertheless, it can be produced at a figure which places it within the
reach of the majority of patients.
IODOFORM
It is well known that lodoform, as ordinarily prepared, is obtained
from raw materials which inevitably vary in quality, and by the assist-
ance of different solvents for the purpose of recrystallisation.
The effect of these varying factors upon the appearance and even
quality of the product scarcely needs pointing out. That differences
in the purity of the materials from which a substance is prepared,
result in corresponding variations in the purity of the product, is
generally self-evident, and a very little consideration shows that where
processes are not precisely similar, exact resemblance is not to be
expected in the compound produced.
Thus, in the case of lodoform, the size, manner of aggregation, or
even form of the crystals, may depend upon the solvent employed,
while further, this factor has often an appreciable effect in modifying
the odour of the product, owing to the difficulty of removing the last,
traces of the mother liquor.
Modern progress in technical chemistry has been largely along the
lines of increasing the purity of the compounds manufactured, by
means of more refined methods of preparation or of purification, or
both. At the same time the practical applications of the various
forms of electricity have enormously increased, and it has been found
possible, by means of this force, to achieve results in numerous fields
which previously were unattainable.
The dynamo-electric current was pressed into the service of the
chemical manufacturer some time ago, experiments being made to
ascertain the practicability of its employment for the preparation of
fine chemicals, and to compare the quality and appearance of the
products with those of the ordinary chemical processes.
Among the compounds experimentally manufactured in this way
was lodoform, and the results in this case were regarded as being of
1 o lodoform.
special interest, owing to the peculiar nature and importance of the
substance.
The new process started with absolutely pure materials instead of
the ordinary crude substances. Perfectly pure iodide of potassium
was the one reagent and the purest absolute alcohol (unmethylated, of
course,) the other. The interaction of these compounds, which, as
known, have not, under normal conditions, any noteworthy tendency
to react, was brought about by the dynamo-electric current.
In this way lodoform separated immediately in a state of absolute
purity, and so perfect in every respect that recrystallisation proved
unnecessary. Further, the product was found to be always absolutely
uniform in character, as indeed was to be a priori anticipated from
the premises that it constantly separated under precisely similar
conditions.
" Electrolytic lodoform," as it may be termed, has the form of
lemon yellow, soft and delicate scales, characterised by the absence of
sharp or hard edges. The odour is absolutely free from all pungency,
and can be described as mild compared with that of ordinary
commercial iodoform.
As regards its chemical nature, the product corresponds to a body
represented exactly by the formula CHI3. It stands the most
searching tests of those Pharmacopoeias which demand the highest
standard of purity. In its original form it can be applied in medicine
and surgery without producing the irritant effects of the ordinary
product (owing to its softness and delicacy), and if desired in a
powdered form can be readily reduced to an impalpable condition of
fineness.
CRESIN
In the course of the exhaustive bacteriological researches which
have been made upon the compounds of the aromatic series of hydro-
carbons, it was found that the higher homologues of phenol, termed
"cresols," were more powerful disinfectants and antiseptics than
phenol itself. At the same time the noteworthy observation was made
that these compounds were free from the pronounced poisonous
properties of carbolic acid.
The natural conclusion was, therefore, that the cresols were much
more suitable for use as disinfectants than phenol and its derivatives.
But though this was undoubtedly the case, a serious practical hindrance
to their employment was found in the fact that they were very slightly
taken up by water.
This difficulty did not seem at first likely to be easily overcome, and
consequently, for some time after the powerful antiseptic virtues of
the cresols were discovered, the substances were not actually made
use of in therapy.
Accepting as almost insuperable the difficulty of getting the cresols
into solution in a form suitable for medicinal application, efforts were
made to render them available for use by emulsification. The
products thus obtained were, however, not free from objections, apart
from the fact that they did not really solve the problem of rendering
the cresols capable of employment in solution — the only form in which
their pronounced germicidal properties could be taken advantage of
by the physician in their peculiar and unabated energy.
Subsequently attention was again directed to the desirability of
getting the cresols into true solution, and by following the principle
that the phenomenon of solution has often a close relationship with
similarity of chemical nature, the problem was at length satisfactorily
solved.
112 Cresin.
It was found on experiment that the cresols, so insoluble in water,
were taken up by solutions of salicylates, of salts of oxybenzenecar-
boxylic acids generally, of oxybenzenesulphonic acids and other
allied compounds.
These solutions had the great advantage of being neutral, and
therefore specially suitable for use in surgery, etc., where of course
liquids varying in any marked degree from neutrality are very
objectionable.
Cresin is a solution of cresol in an aqueous solution of cresoxy-
lacetate of sodium ; it forms a clear brown liquid which contains 25
per cent, of the active ingredient. The cresol dissolved in this
preparation is, as already stated, markedly less poisonous than carbolic
acid, and yet at the same time its antiseptic power is four times as
great as that of phenol.
On these grounds Cresin is an excellent disinfectant and antiseptic,
which even in highly dilute solutions has a powerful deodorant action.
In one per cent, solutions it has done good service for the disinfection
of surgical instruments, of night-commodes, etc.
In the treatment of wounds and surgery generally, \ — r per cent,
solutions further healthy granulation, and promote healing by first
intention without suppuration. Equally good results are obtained in
the treatment of torpid ulcers of the feet of long standing. In these
cases also \ — r per cent, solutions may be advantageously used.
The preparation is also suitable for use in the local treatment ot
affections of the mucous membrane of the upper part of the respiratory
tract. For such purposes its freedom from irritating and poisonous
properties render Cresin especially useful. Solutions in water of the
strength of \-\ per cent, form gargles which are efficient without
being too unpleasant; the same liquids may also be employed as
sprays or for inhalation with advantage.
Although the liquid is not recommended for internal use at present,
it seems possible that it might be found suitable for employment in
this way in certain cases. Apart from the general fact that the cresols
are free from marked poisonousness, actual experiment has shown that
half a drachm given to a rabbit did not produce any functional
disturbances whatever.
M. S. RiCKEf.BV, Printer, 4, Walbrook, E.G.
UNIVERSITY OF CALIFORNIA LIBRARY
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