| dc.description.abstract | In the therapeutics of organismal diseases, the
trend of research during recent years has been devoted
almost entirely to the study of vaccine and serum
therapy, but the latest discovery in therapeutic scienc:
comes from another direction. Ehrlich has shown us that
chemistry has its place in the treatment of these affections
and the role that chemico-therapy is likely to
play, opens up a still wider field for research and may
even rival the discoveries in serum therapy. The
results of the researches made by Ehrlich are by no
means chance ones. For twenty five years he endeavored
to put into practice a principle that he alone held,
namely that, to get a threapeutic effect a drug can have
influence only upon the tissues of the body with which
it forms a chemical combination.
As some drugs could act very injuriously upon the
Living cells of the body, he strove to find those which
act similarly upon the organisms which are the causes
of the various diseases. He conceived the theory of
chemico-septors and worked with substances which according
to their chemical characteristics formed combinations
with the tissues upon which he desired, to produce an
effects.
For years he conducted his experiments entirely at
his own expense,and it was not until the "Speyerhaus"
was built by a private donation with ample resources,
that Ehrlich was enabled to obtain, all the means and
opportunities, for his investigations.
Working now hand in hand with some dozen coexperimenters
- biologists and chemists - he endeavoured
to discover the specific chemioo-septors of certain drugs
and put into practice his principles of chemico - therapy.
His first point was to discover those substances which
act upon parasites, that is, which are parásito - tropi
and from these to select those which, though parásito
tropic, were not organo - tropic, having therefore no
action upon the cells of the host.
He divided the drugs which have a parasiticidal
action into three groups.
1. Arsenic and Antimony.
2. The Azo dyes e.g. trypan red, and trypan blue.
3. The basic triphenylmethane dyes e.g. parafuchsin,
methyl violet, and pyrornin.
The action of these drugs was tried upon trypanosomes
and the spirilla of relapsing fever and as these organisms
live and multiply in the blood,investigations were
easily made both in vivo and in vitro, and by these
means specific chemico-septors were established between
any one preparation of the above named groups and the
organism in question.
The products of the two dye groups he found, though,
actively parasito-tropic, were also organo-tropic and
thereby produced severe toxic effects upon the host.
Arsenic, though usually pentavalent and toxic to
the cells of tne host, if used in its trivalent form
was found by Ehrlich to establish arseno-septore with
the trypanosomes and the spirilla of relapsing fever
and to be innocuous to the cells of the host. Consolely
sequently attention was directed^to the arsenic group.
He sought for a preparation that was trivalent and
readily soluable and could produce"by the one fell swoop
and in twenty four hours a therapia magna sterilizans"
with perfect safety to the host.
Beginning with the synthetic arsenical compound,
Atoxyl - which had already been introduced as a treatment
for trypanosomiasis - the ultimate product of his
researches is the substance now known as "Salvarsan or
606" with which he hoped to revolutionise the treatment
in protozoal diseases.
At first his object- was to confine his investigations
to trypanosomes and the spirilla of relapsing fever but
they were extended later on to syphilis as well.
The starting point in the discovery of salvarsan
was the finding of the correct constitution of atoxyl.
This drug was discovered in 1865 by a French Chemist
named Be/champ, who considered the substance to be a very
loose combination of analin and arsenic acid.
Ehrlich working with Bertheim however, discovered atoxyl
to be the sodium salt of para-amidophenÿl arsenic acid,
a stable and active chemical substance capable of forming numerous compounds.
Atoxyl was first brought into clinical importance by
Thomas of Liverpool - in treating trypanosomiasis -
but was soon abandoned on account of its extremely toxic
effects, especially upon the kidneys and the optic nerves.
The reason for this was shown by Ehrlich when he
reconstituted its chemical formula. He proved that
the arsenic was present in the pentavalent form,
and that in the body atoxyl was
split up into two arsenic components, in one of which
the arsenic was trivalent, and in the other probably
pentavalent. The former was capable of fixation with
the parasites, but the latter being incapable of fixati
at all, accumulated in the body as the result of continu
medication and caused toxic effects in persons with a
natural sensitiveness to arsenic.
Starting then with atoxyl,Ehrlich found that the
reduction products he made from it out side the body
were more active in the body, proportionally to the
amount of their reduction. Arsacetin was the next step
along the line but clinically it unfortunately possesses
the same dangerous sequelae to its use • By further
reduction arsenophenylglycin - designated as 418 - was
the next trivalent a.rsenical compound discovered, but
biologically, though acting strongly upon trypanosomiasis,
it was shown to have very little action upon the spirilla
of recurrent fever and therefore not an ideal preparation.
Experimenting further, greater success was obtained wit
arsenophenal which killed the spirilla of relapsing
fever after two injections. Later, greater success at
was obtained with dichlorphenalarsenious acid which
would do the same after one injection.
With this drug the goal had been reached, the
"therapia magna sterilisans" which Ehrlich had been
searching for; but the substance could never be used
clinically on account of the extremely toxic effects
which it produced upon animals, TTith one single injection
mice suffered for two weeks with progressive
nervous symptoms, beginning with shaking of the head
and travelling over the body until the nice became
dancing mice.
Further investigation revealed the drug called
dioxydiamido-arsenobenzol or 592, but as this salt was
insoluble its dihydrochloride was searched for. The
action of both however is identical.
The dihydrochloride of the dioxydianido-arsenobenzol
therefore is the substance "606" or"salvarsan" now upon
the market as Ehrlich’s preparation for the treatment
of spirillary diseases.
"306" then is the 306th derivative of atoxyl,
which is an ami do derivative of phenyl arsenious acid and
though it can be prepared from atoxyl by a complicated
process, it bears no direct relationship to it.
The dioxydiamido-arsenobenzol is a yellow powder,
readily oxidized, insoluble in water, but dissolves
easily on the addition of sodium hydrate. The
dihydrochloride is also a yellow powder, dtasily oxidize
into poisonous compounds end accordingly preserved in
sealed tubes in vacuo or containing inert gases.- It
is soluble in water and readily soluble in warm normal
saline; this solution is strongly acid in reaction.
If the acidity of this solution is neutralised by the
addition gradually of sodium hydrate the free base,
dioxydiamido-arsencbenzol,is liberated and thrown down
is a precipitate.
Then if further sodium hydrate is added to the precipitate,
the hydrogen atoms of the phenol hydroxyls become
replaced by soda to form the soluble sodium salt (the
phenalate of the base) and the compound goes into
solution as the disodium salt of dioxydiamido-arsenobenzol.
Ehrlich emphasises in the constitution of salvarsan
two important facts. Firstly, that it is trivalenjt
- seen by the formula, and secondly, the para-pcsition
of the hydroxyl groups. This position is correlated
with marked spirillicidal properties. ‘Pith this
second compound of arsenic then, we have radicals introduced
which (a) reduce the toxicity of the compound,
(b) increase spirillicidal properties ,(c) render the
compound more stable ’Jerking on the chemical properties
of salvarsan Pucliner and Hilpert estimated the
amount of arsenic in that compound. Taking an ordinary
market specimen they found, after careful weighing,
the tube to be .6510 grm., the extra ’. 'eight of .0510 grm
being due to inert gases or vapour.
Then calculating the arsenic content on the assumption
that the tube contained 0.6grm. of real salvarsan,
35.16% of arsenic was indicated by titration with tenth
- normal iodine. | en |
