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Hugh McGuigan.

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AMINO ACIDS 309

histidine are alkaline, and in solution absorb CO2. The mono-
amino dicarboxylic acids are acid to litmus.

II. Solubility. — As a rule they are soluble in water. Tyrosine
is but slightly soluble in cold but is soluble in hot water. They are
soluble in dilute acids and alkalies. They are insoluble in ether.

III. Combinations. — Since amino-acids contain both NH2
and COOH group they will unite with both acids and bases. The
NH2 group unites with acids as does ammonia. The COOH
group unites with NaOH etc. to form salts of the amino acid.
Through the amino group they unite with salts of the heavy
metals, such as Cu, Pt, Ag, Hg etc. to form such combinations as
— CH8.CH2.CH.NH2CuCl2.COOH. These salts are insoluble in
water.

IV. Condensation. — Amino acids may condense or unite with
each other to form polypeptides. The amino group of one uniting
with the carboxyl group of another. Such combinations are two
molecules of glycocoll or glycyl-glycine:

NH2CH2CO.NHCH2COOH and
Leucyl — asparagine :

COOH

CHsv

)CH.CH2.CH(NH2)CO.NH.CH
CHa^ I

CH2

' CONH2

A great number of such polypeptides have been prepared and
are named di, tri, penta, etc. according to the number of amino
acids in the combination. The most complex of these so far
synthesized contained 18 amino acids, and contained three
leucine and 15 glycocoll groups. It was 1-leucyl-triglycyl-l-
leucyl - triglycyl - 1 - leucyloctoglycylglycine. NH2CH (C4H9) CO.
(NHCH2CO)8.NHCH(C4H9)CO.(NHCH2C08).NHCH(C4H9)
CO.(NHCH2CO)8NHCH2COOH.

CONDENSATION PRODUCTS

The alpha amino acids readily condense by the elimination of
water from the COOH groups :



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310 CHEMICAL PHARMACOLOGY

CH2 NHIH HOIOC CH2 NH OC



+ 2H,0



CO OH HIHN CH2-> CO— HN— CH2



Beta amino acids condense through loss of ammonia with the
formation of unsaturated acids:



|NH2|CH2_CHlHl COOH = NHs + CH2 : CH.COOH

B. amino propionic acid acryUc acid

Amino acids through the loss of water yield inner anhydrides
which, because of the similarity to lactones, are called lactams:

CH2 CH2 CH2 CO CH2 CH2 CH2 CO



NH( H OH ) HN '

Amino butyric acid — > lactam of aminobutyric acid

Lactones are the inner anhydrides of gamma and delta hy-
droxy acids, i.e., instead of the amino group in amino acids a
hydroxyl group may be substituted. Such condensations as
these may explain the formation of alkaloids in plants. Thus
when solutions of leucine are evaporated diketo condensation
imides are formed:

O

II
(CH3)2=CH— CH2— CH.NH— C

I
0=C— NH— CH— CH2— CH=(CH3)2.
Leucinimide (Diisobutyl-diketopiperazine)

This gives rise to diketo piperazine from which piperazine may
be prepared:

NH CH2— CH2

II HN NH

H2C CO \ /

I I CH2— CH2

CO CH2

\y/ piperazine

NH
Diketo piperazine



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LACrtM URIC ACID



311



From the pharmacological point of view, lactams are interesting
preparations producing strychnine like convulsions in animals.
This is a common characteristic of ring compounds. The amino
acids themselves are devoid of visible action. Such molecular
rearrangements may be the cause of many obscure reactions in
indigestion, uremias, gout, etc.

The precipitation of urates in gout according to some (Gudzent)
is due to uric acid changing from the lactam to the lactim form.
The lactim form of uric acid is:

N = C— OH



HOC C— NH



\



COH



N O



^



-N



C/. formula p. 284.

Piperazine has been advocated in the treatment of gout, but
it is without influence.

Condensation with Formaldehyde

Ammonia condenses with formaldehyde to form hexamethylene
tetramine. The product formed in this case is N4(CHj)6.

The amino acids also condense with formaldehyde according
to the formula.



NH2
O



N = CH2
O



R— C— C— OH+HC = = R— C— C— OH+H2O



H H H

Methylene amino acid

This methylene derivative has no basic properties and can be
sharply titrated with alkali. This is the basis for the Sorensen
titration method for the titration of amino acids in a mixture.
This is perhaps one of the mechanisms in the formation of
amino acids in plants and animals. Erlenmeyer and Kunlin^

» Ber. deut. chem. Gesells. 1902-35-2438.



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312 CHEMICAL PHARIIaCOLOGY

were able to synthesize f ormyl derivatives of alanine and glycine
by the interaction of ammonia and glyoxylic acid, and since both
of these occur in plants, the probability of such formation in the
plant is suggested.

CHO • CH2NH CHO

2 I +NH3 = I

COOH COOH+H2O+CO2

Glyoxylic acid Formyl-glycine

CH2NHCHO CH2NH2

I +H2O ~> I +HCOOH

COOH COOH

Formyl-glycine Glycine

THE DEAMINIZATION OF AMINO ACffiS

In the preparation of amino acids from protein, the usual
method is to boil the protein with acid for hours. This fact
shows the stabiUty of the amino groups in acid solution. The
slight amount of nitrogen that is evolved is in the amide condi-
tion, that is, in the form of R.CONH2. Amino acids are also
quite stable in alkaline solution. Arginine decomposes to orni-
thin and urea, and cystine and cysteine lose considerable of their
sulphur, but as a rule Uttle decomposition occurs.

Oxidation may cause deaminization through spUtting oflF
ammonia. Various oxidizing agents like hydrogen peroxide,
and potassium permanganate, cause, in vitrOy the deaminization
as follows:

CHa CH3

I 1

H— C— NH2 + O ±1; C=0 + NH3

I r -

0=C— OH 0=(>-0H

Alanine Pyruvic acid

Where deaminization takes place in the body is not known.
It seems that all tissues, perhaps due to a ferment, have deaminiz-
ing properties. It is thought by some that since no amino acids,
or only a trace, can be demonstrated in the blood, that deaminiza-
tion takes place in the intestine. There is no direct proof that



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CARBAMINO REACTION 313

the intestine possesses this property to a greater extent than any-
other tissue.

URETHANE FORMATION OR THE CARBAMINO REACTION OF

AMINO ACIDS

Chloroformic ester reacts with ammonia to form urethane or
amino ethyl-formate — or the ethyl ester of carbamic acid.

.CI .NH2

C0(; + NH3 = CCk; + HCl

Ammonium carbamate is formed as follows:

O O

II II

HO~C— OH + 2NH3-^NH4— 0-0~NH2

+ H2O
Carbonic acid

Urethane is the ethyl ester of ammonium carbamate, and a
reaction of this kind is known as the carbamino reaction.

Ammonium carbamate is the intermediary compound in the
formation of urea in the body.

.NH2
NH2 - COONH4 = C0<^ + H2O

\NH2

Ammonium carbamate, urea or carbamide.

Carbamate salts, differ from carbonates in their solubilities,
,OCa
2Q>0{ or calcium carbamate being soluble in water.

When boiled however calcium carbonate is formed and NH3 is
driven ofif . This difference in the solubilities is used to advantage
in determining the composition of mixtures of amino acids. If in
a solution containing amino acids the CO2 formed is equivalent

CO

to the N, or -^j^ = 1 the relation is that of mono-amino acids.

If diamino acids or polypeptids are present the ratio is less than 1.



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314 CHEMICAL PHARMACOLOGY

The Taste of Amino Acids

There is nothing distinctive in the taste of amino acids. Glyco-
coll as the name indicates is sweet. Alanine and glycoleucine
are also sweet. Leucine is tasteless and iso-leucine is bitter.
Taste in relation to chemical structure is not well understood.
See p. 205.

OPTICAL PROPERTIES OF AMINO ACIDS

The alpha atom of amino acids is asymmetric, consequently
the acids are optically active. The presence of the asymmetric
C atom does not necessarily confer optical activity, but no opti-
cally active organic substance is known without the asymmetric C
atom. Like most natural products many amino acids are levoro-
tatory; proteins also are levorotatory and on hydrolysis the
rotation increases, so that the rate of digestion can be measured
by increase of optical activity.

Knowing the formula of a compound it is impossible to tell
what direction the rotation may be, and when one group is sub-
stituted for another prediction of the change can not be made.

It is possible by substituting one group for another to transform
an optically active compound into its optical antipode. This is
known as Walden's inversion. In several cases it has been
possible to start with a substance and by a reaction cycle obtain
the optical antipode and again the original substance Walden
treated 1. Chlorsuccinic acid with moist silver oxide and obtained
1. maUc acid. This on treatment with phosphorus pentachloride
was converted into d. chlorsuccinic acid, which was converted
into d. malic acid which on treatment with phosphorus pentach-
loride yielded 1. chlorsuccinic acid.

These transformations are diagrammed in the following scheme:

AgOH
1-Chlorosuccinic acid > 1-MaUc acid



t IPCU

AgOH



PCU



d-Malic acid<-^ d-Chlorosuccinic acid

With alanine, and nitrosyl bromide — Emil Fisher worked out
the following Reaction cycle:



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OPTICAL PROPERTIES



315



NOBr



d-Alanine-



NH3



d-Bromopropionic acid<^



->l-Bromopropionic acid
NH3



4-Alanine



The significance of optical activity in so far as amino acids
are concerned, and in general, is little understood. A knowledge
of the cause of these facts would do much to advance the under-
standing of drug action.

The facts that certain moulds can, ferment dextrotartaric
acid and not levo; that yeast will ferment such sugars as d-
mannose d-glucose, or d-fructose, but will not ferment 1-fruc-
tose, 1-glucose, 1-mannose, or 1-galactose; and that dextrohyos-
cyamine, dextro-epinephrine, etc. are so much more potent than
the levo forms, are full of suggestions and when understood may
do much to clarify vital activities.

Regarding the formation of optical bodies little is known,
but in plants photo chemical reactions seem to play an important
role. Cotton (Am. Chem. Phys., 1896, VII, 8, 373) found that
the dextro and levo forms of tartaric acid absorb d. circularly
polarized light at different rates, which suggest a method of
their formation.

The Action of Amino Acids in the Body
The amino acids are utiUzed in the body as foods. This use
may be in the building up of protein in the body, and repair of
used protein. Amino acids may also be to some extent converted
into carbohydrate and consequently into fat and will exert the
action of these food stuffs. The following formulas show the
possibility of carbohydrate formation from amino acids:



COOH



COOH



► C6H12O6



CH2



+ H2O-



CHNH2

I
COOH

Aspartic acid



CH2
CH2OH

2CO2
fi. lactic acid



Dextrose



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316



CHEMICAL PHAEMACOLOGY

COOH COOH



CH2 > CH3

I —

CH2 + HOH CH2OH

! I

CHNH2 + HOH-> CHOH



COOH
Glutamic acid



COOH
Glyceric acid



Two molecules of glyceric acid forms glucose on reduction: —
Glyceric acid— ^glyceric aldehyde— ^glucose

When fed to glycosuric dogs, many amino acids, like protein,
increase sugar excretion, and are converted into sugar. It is
probable that, carbohydrates may be used to some extent in
the formation of amino acids, though this is not definitely prov-
en. The only nitrogen containing (carbohydrate of the body
is glucosamine. This is found especially in chitin which forms
the external skeleton of orthopods. It can also be prepared
from cartilage and ovalbumin.

Besides their function in metabolism, amino acids exert a
specific stimulating action on metaboUsm. A similar action
however is exerted by all food stuffs and is known as the specific
dynamic action. When for example, an animal is starving and
the energy metaboUsm is represented by 100 calories and we wish
to keep the animal at this level by feeding protein, it will be
necessary to feed 140 calories, or fat 114 calories or carbohydrate
106 calories. The excess of heat generated above the 100 per
cent, is the specific dynamic action. Lusk (1912) thinks that
in the case of proteins this is due to the mass action of the
amino acids on the cell protoplasm which they stimulate.

The Fate of Amino Acids in the Body

The amino acids derived from protein hydrolysis are readily
oxidized in the body and ultimately excreted as urea, CO2 and
H2O. Stolte found that when injected intravenously into rab-
bits, the nitrogeA of glycine and leucine is almost totally excreted
as urea, while that of alanine, cystine, aspartic acid and glutamic



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FATE OF AMINO ACIDS



317



acid ^re less readily catabolized, and phenyalanine and tjrrosine
led to no immediate urea excretion.

Traces of unchanged amino acids may be found in the normal
urine. The presence of glycine has been definitely established, and
it may reach as high as 1 per cent, of the total nitrogen output.

Tyrosine, leucine, and glycocoU are regularily found in the lu'ine
in cases of acute yellow atrophy of phosphorus poisoning and in
other conditions. Cystine is found in cases of cystiniu-ia, a
disease of metabolism not well understood. In these cases, the
diamines, putrescine and cadaverine, formed by putrefaction in
the intestine may also be found.

In the normal catabolism of the amino acids, the first step in the
formation of urea is thought to begin with the alpha position:
. R.CH2CHNH2COOH + 02 = RCH2COOH + CO2 + NHs

Many examples of this kind of reaction are known, e.g., leucin
on oxidation gives iso- valeric acid

CHsN



CH



>



CH-CHjCHNHjCOOH + O* =



CHi



CH



'\



;CH.CHsCOOH+ CO* + HjO



Iso-valeric acid
In cases of alkaptonuria tyrosin undergoes a similar change to
form homogentisic acid

OH HO



OH



CH2


CH» +CO,+NH,


— >

CH.NHs


COOH


COOH




Tyrosin


homogentisic acid



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318 CHEBilCAL PHARMACOLOGY

Homogentisic acid in turn is oxidized by the normal organism,
and this may be the usual mechanism of tjrrosin cataboUsm. In
alkaptonuric cases homogentisic acid is either not oxidized or at
a much slower rate than in the normal.

Alanine is oxidized in the body as follows,

CH3CH.NH2.COOH + O ~> CHaCHO + CO2 + NH3

When oxidized in vitro by hydrogen peroxide or potassium
permanaganate the amino group is replaced by oxygen and a
ketonic acid is formed:

CH3 CH3

I I

H— C— NH2 0±=^ C = 0+NH3

I + I

COOH COOH

This reaction may be reversed by reducing agents. By reduc-
tion of the alpha ketonic acids hydroxy acids may be formed, in
this case lactic acid

CHa

I
CH.OH

I
COOH

is fjormed, and this indirect method may explain the production
of lactic acid in the body. Lactic acid is found chiefly in cases
of tissue asphjrxia due to excessive exercise, or deficient supply of
oxygen.

The reversibiUty of the alanine — ^lactic acid reaction, and the
relation of lactic acid to carbohydrates, suggests the possibiUty
of a synthesis of amino acids from carbohydrates and ammonia
in the body. Embden obtained evidence of this synthesis by
perfusing a liver with glycogen and found that alanine was
formed. Many other examples of alpha ketonic acids being
formed from alpha amino acids. It is assumed that alpha
ketonic acids are essential products in the oxidation of alpha
amino acids, and hydroxy acids are formed from these by reduc-



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FATE OF AMINO ACIDS



319



tion and are not directly derived from the amino acids (see Dakin,
Oxidations and reductions in the animal body).

The ultimate fate of alpha amino acids and alpha ketonic acids
in the body is the same but, in the process of catabolism the
ketonic acid may imdergo three types of change:

1. It may be oxidized to a lower fatty acid:

R.CH2CO.COOH + O = R.CH2COOH + CO2

2. It may be reduced with formation of an hydroxy acid:

R.CH2.CO.COOH+H2 = R.CH2CHOH.COOH

3. Its ammonium salt may be reduced to the corresponding
amino acid:

R.CH2CO.COONH4+H2 = R.CH2.CH.NH2COOH+H20
These three types have been imitated in vitro.

The Fate of Alpha Amino Acids in Abnormal Conditions

In cases of diabetes, in which there is a reduction of the ability
of the tissues to oxidize carbohydrates, and perhaps some other
bodies, amino acids may give rise to sugar and aceto acetic
acid.

The following table from Dakin (oxidations and reductions in
the animal body) shows this:



Increased glucose
excretion when
Substance given to diabetic

animal

Glycine +

Alanine +

Valine ?

Leucine —

Aspartic acid +

Glutamic acid +

Phenylalanine ?

Tyrosine —

Histidine +

Lactic acid +



Acetoacetic acid
formation when
perfused through

surviving Uver



+



+
+
+ (?)



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320 CHEMICAL PHARMACOLOGY

Since carbohydrates can be formed from amino acids, it follows
that alcohols may also be formed. Their actions in the forma-
tions of alcohols appears to be as follows:

oxidation
R.CH2.CH.NH,.C00H ~> R.CH2.CO.COOH ->

a, Ketonic acid

reduction
CO2 + R.CH2CHO ~> R.CH2.CH2 OH

Aldehyde Alcohol.

The fate of cystine, the only sulphm* containing amino acid
is of interest since sulphur is important in pharmacology.
In normal conditions this acid is completely oxidized and the
sulphur eliminated in the form of sulphate. In certain individ-
uals the abiUty to oxidize cystine is lacking and it appears in the
urine. Such persons appear normal, and do not suffer from the
condition. It is an inherited condition and is more frequent in
males than females. The cause of this anomaly of metabolism
is not known.

Taurine, CH2.NH2.CH2SO3H, which is found in the bile
combined with cholic acid, as taurocholic acid, appears to be a
derivative of cystine or cysteine:

COOH COOH CH2.NH2



CHNH» ->

1


CH.NHs ->


CH,(SO,H)
Taurine.


CH,(SH)


CHj(SO,H)




Cysteine


Cysteic acid





Because of the relation to the active principles of ergot, ad-
renalin etc. the fate of tjrrosine, phenylalanine and tryptophane
are of especial interest. These are normally completely oxidized
in the organism. This is contrary to the fact that most aromatic
bodies are not readily oxidized. In cases of alkaptoniuia
tyrosin and phenylalanine may be converted into homogentisic
acid:



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FATE OP AMINO ACIDS

COOH COOH COOH

I I.I

CHNHa CHj CH.NH2



321



CH,



CH,



OH



OH

Tyrosine



OH



Homogentisic acid Phenyl-alanine



The normal organism oxidizes homogentisic acid readily, but
but alkaptonurics have not this power.

Tryptophane. — ^Little is known of the mechanism of the fate
of this body in the human organism. It apparently undergoes
complete oxidation. When fed to dogs, it causes an increase in
the excretion of kynurenic acid.

CH

/\

/ \

HC C-



-C.CHj.CHNH2.COOH



HC CH

\ /\/
\/ NH
CH
Tryptophane



HC



CH COH

,/- \C/ \C.

I COOH

\ /G\ /CH

\/ \/-

CH N

Kynurenic acid



21



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322 CHEMICAL PHARMACOLOGY

In this reaction an additional C atom has entered the indole
ring.

The fate of histidin in the body is of especial interest because
of its relation to the active principles of ergot. When COi is
split oflf from histidin, histamine or fi imido azole ethyl amine,
or ergamine is formed.

C— NHv C— NHv

II >H II >CH

C — ^N^ C — ^N ^

I I +00,

CH2 — ► CH2

I I

CH.NHj CH2NH2

I • •

COOH
Histidin jS-imino azole ethyl amine

(histamine or ergamine)

The effects of ergamine differ in different animals. In dogs
and cats it causes a condition resembling anaphylactic shock
due to dilation of the peripheral vessels. While in the rabbit
it tends to constrict the vessels. It acts directly on the vessel
wall and may have some action on the neuro-muscular jimction.
According to some authors, histamine is the same as vasodilatin.
Such substances as histamine, epinephrine, and perhaps many un-
known hormones may be intermediate products in the catabolism
of amino acids.

POISONOUS PROTEINS

These are protein substances, and have been termed vegetable
agglutinins; they coagulate milk and blood. They resemble
bacterial toxins and ha^e been found in a munber of higher plants,
and are therefore called phytotoxins. The most important are
Ricin — ^from the castor bean (Ricinus communis). Abrin, from
the seeds of abrus precatorius — Crotin, from the seeds of croton
tiglium. Robin from the leaves and bark of the locust, Robinia
pseudoacacia, and Ciu-cin from the seeds of Jastropha curcus.
The general properties and actions of these substances are
similar. Ricin is found in ricinus communis along with castor



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EKZTMSd 323

oil, but the oil itself does not contain ricin. It is the most power-
ful of the phytotoxins. One thousandth of a milligram
per kilo is fatal to a rabbit when given hypodermically. The
ricin agglutinates the corpuscles and also^ precipitates serum.
Death occurs several days after a subcutaneous injection, with
but few symptoms other than loss of appetite, and towards the
end diarrhoea and vomiting. Post mortem examination shows
congestion and inflammation of the gastro-intestinal tract with
ecchymoses; blood in the serous cavities; punctiform hemorrhages
beneath the serous surfaces and extravasations in various organs.
Microscopical examination shows foci of necrosed tissue in the
spleen, liver, intestine stomach and other organs. The whole
pictiu-e is much the same as that caused by diphtheria toxin.
The poisons are eliminated through the intestinal mucosoa, which
accounts for the great amount of gastro-intestinal injury. An
immunity can be developed against these toxins, and antitoxins
can be prepared.

Abrin contains two poisons, a globulin and an albumose, of
whidh the former is more powerful. Crotin is less powerful than
ricin or abrin, but the action is similar. Robin and curcin are less
known than the others. Ciu'cin differs from all the others in
having no hemagglutinative action.

XXVIU. ENZYMES OR ORGANIC FERMENTS

Nothing definite is known of the chemistry of enzymes. The
word means Uterally "in yeast'' (from the Greek "en", in; and
"zyme'', leaven. They are complex organic substances, capable
of rendering food available for the cell. Because of their colloidal
nature and the difficulty of obtaining enzymes in a pure condition,
their chemical nature is unknown. They are formed within the
living cells, although in certain cases, the cells do not secrete the
complete enzyme, pro-ferments or zymogens, which are tr£|,ns-
formed into active enzymes outside of the cell, being first formed.

Enzymes differ from catalysts in their sensitivity to heat and
Ught. All enzymes are destroyed at lOO^C. and most of them ajb
60°C. Each enzyme acts best at a definite temperature which is
the optimmn temperature. For the digestive enzymes this is
about 40°C. The destructive action of heat is perhaps due to a
coagulation of the proteins of the enzyme.



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324 CHEMICAL PHARMACOLOGY

Regarding light, there seems to be two kinds of action:

(a) Those produced by ordinary light in presence of oxygen.
This is greatly accelerated by the presence of fluorescent sub-
stances such as eosin^ quinoUne red etc., which though not under-
stood yet offers hope of therapeutic value in many diseases.

(6) Ultra-violet light independent of oxygen destroys diastase
and other enzymes. In this connection we might add that
various rays of light and emanations are now used with consider-
able effect in cancer and other diseases the causes of which are
unknown.

The colloidal nature of enzymes is shown by lack of diffusibiUty
and by their precipitation by other colloids. Enzymes are
adsorped readily by many finely divided inert particles such as
charcoal, infusorial earth, etc. This adsorption is a phase of
precipitation, and in this case is electrical.

The addition of salts, drugs, etc. influence enzyme action;
those substances hastening it being called accelerators, those
depressing it being called depressants or paralysers.

If enzymes are injected subcutaneously into an animal, an
antienzyme may be formed, which neutralizes the activity of an
enzyme in a manner similar to toxin and antitoxin.

ENZYMES USED AS MEDICINES

The digestive ferments diastase, pepsin, and trypsin have been
used to some extent in medicine. The value of these in most
cases is questionable, for the reason that it is doubtful if defici-
ency of the natural digestive enzymes ever occurs. The term
"Amylaceous dyspepsia'* has been used to indicate cases of



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