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dyspepsia supposedly due to incomplete digestion of starches.
However, for all practical purposes, starches are digested in the
intestine, and it has never been shown that there is any deficiency
of the diastatic intestinal ferments. Diastase preparations as
medicines would therefore seem superfluous. The pepsin of the
stomach is almost always capable of digesting proteins, providing
the reaction is acid, and the deficiency is not in pepsin but a lack
of acid. The treatment therefore, except in rare cases, is acid
medication not the administration of pepsin. However, while
pepsin in the majority of cases is superfluous it is not injurious.

Pancreatic Ferments. — The value of these in medicine is even
more problematical than pepsin. When given they are adminis-



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PATE OP ENZYMES 325

tered in a capsule or in a salol coated pill, to avoid digestion in
the stomach. To get such preparations through the stomach
without digestion, and at the same time, have them in a form
that will be Uberated in the intestine is very difficult. It is
doubtful if any of the preparations that pass through the stomach
undigested are Uberated in the intestine. If they are not liber-
ated they are useless, and if Uberated, superfluous.

THE FATE OF ENZYMES IN THE BODY

Since the chemistry of the enzymes is unknown, the exact fate
cannot be determined. The protein part, or impurity, suffers
the fate of all protein in the body. The enzymes may be used
over again in the body to some extent. They are also excreted
in the urine and faeces.

Under hydrolytic enz3rmes, we find a group of fat-splitting
enzymes caUed lipases or steapsins. This group was found by
Green (1890) and subsequently confirmed by Connstein, Hoyer,
and Wartenberg, who found that castor-oil seeds contain an
enzyme that hydrolyses the fats present. In the tissues of the
body, this fat-splitting r61e of lipase which brings about the
separation of neutral fat in the presence of an excess of water is
reversible and builds up fat, when aUowed to act upon a mixtiu-e
of fatty acids and glycerol in a medium poor in water. Diastase,
which hydrolyses starch to maltose and dextrose, is one of the
commonest of enzymes, and occurs in practically all living matter.

Under fermenting enz3rmes may be mentioned the alcoholic
fermentation of glucose, levulose, mannose, etc., by zymase,
which probably occurs also in animal tissues, this supposition,
however, requires more evidence than has yet been shown. It
is thought that traces of alcohol found in the blood may have
been formed in the intestine by bacterial action.

Coagulating enz3rmes, are represented by rennin, which curdles
milk; thrombin, which coagulates blood; and pectase, which coagu-
lates soluble pectic bodies.

The oxidizing enzymes are divided into (a) those which oxidize
alcohols to acids, and (b) those which set free oxygen from hydro-
gen peroxide or other peroxides. These are the peroxidases or
catalases.

Life processes of all kinds are accompanied by enzyme action.



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326



CHEBIICAL PHARMACOLOGY



Growth, repair, ripening of fruit, decomposition, etc., have been
explained by enzyme activity. Enzymes are not held to originate
an action, but simply to accelerate those already in progress.
Whether the facts justify this opinion remains to be determined.

Enzymes are classified according to the substance acted on as
follows:

Coagulating enzymes (thrombin rennet).

Pepsin, trypsins, erepsins, amidases, catalases, etc.

The most important are arranged in tabular form as follows:



Ferments Acting on Cabbohydrates



Name of Enzyme


Substances on which


Products of the




Enzyme acts.


reaction


Invertin or eucrase


Cane sugar


Dextrose and levulose


Amylase or diastase


Starch and dextrins


Maltose


Glucase or maltase


Dextrins and maltose


Dextrose


Lactase


Lactose mycose or


Dextrose and galactose


IVehalase


Trehalose


Glucose


Cytase


Hemi-cellulose


Mannose and galactose


Pecfcase


Pectin


Pectates and sugars, ara-
binose


Caroubinase


Caroubin


Caroubinose


Invertase which hydro-


RaflBnose to


Levulose and melibiose


lyses






Maltase which hydro-






lyses


Maltose (malt sugar)


Dextrose


Inulase which hydro-






lyses


InuHn to


Levulose



Ferments Acting on Fatty Substances

Steapsin or lipase | Fatty substances | Glycerin and fatty acids

Ferments Acting on Glucosides



Emulsin



Myrosin



Betulase



Phytase



Amygdalin
glucosides



and other



Potassium myronate



Gaultherin



Phytin



Glucose, oil of bitter al-
monds, and hydrocy-
anic acid

Glucose and allyl iso-
sulphocyanate

Oil of wintergreen

Glucose

Inosite and phosphoric
acid



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FERMENTS
Ferments Acting on Proteins. — Continued



327



Name of Enzyme



Substance on which
Enzyme acts



Products of the
reaction



Ferments Acting on Proteins



Rennet



Plasmase
Pepsin
Trypsin
Trypsin

Papain



Caseinogen

(Casein, Etammarsten)
Fibrinogen

Albuminoid substances
Albuminoid substances
Albuminoid substances

Albuminoid substances



Casein

(Para casein)
Fibrin

Proteoses, peptones
Proteoses, peptones
Polypeptides and amido
acids

Polypeptides and amido
acids
Erepsin contained in the intestine which hydrolyses

Proteins to Polypeptides and amino

acids
Bromelin contained in the pineapple juice which hydrolyses





Proteins to


Polypeptides and amino
acids


Ferments (


;^AUsiNG — Molecular D


ECOMPOSITION


Zymase or alcoholic di-




Starches. Alcohol and


astase




carbonic acid. Vari-
ous sugars CO2 lactic


Lactic acid bacteria


Lactose


acid etc.


Butyric bacteria, etc.


Lactose


Butyric acid


Ferments Ac


TING ON Proteins to C


A.USE Clotting


Rennin (Chymosin)


which curdles milk




Thrombin


which coagulates blood




Pectase


which coagulates soluble
pectic bodies




Laccase


Uruschic acid


Oxyuruschic acid


Cbddin


Tannin, anilin, etc.


Unknown products of




Coloring matters of


oxidation




cereals




Malase


Coloring matters of


Unknown products of




fruits


oxidation


Tyrosinase


Tyrosine


CO2 parahydroxy ethyl-
amine, NHa etc.


Oenoxidase


Coloring matter of wine


CO2 parahydroxy ethyl-
amine NHs etc.


Oxidases which oxidize


alcohols to


acids e.g.y action of My-
coderma aceti, etc.



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328 . CHEMICAL PHARMACOLOGY

Ferments Acting on Proteins. — Continued



Name of Enzyme



Substance on which
Enzyme acts



Products of the
reaction



Urease

Nuclease
Guanase
Adenase

Oxidases
Catalase



Ferments Acting on Urea



Urea

Deamidizing Enztbies

Splits nucleic acid
Converts guanine
Converts adenine ,

Oxidizing Ferments
Causes oxidation of or-
ganic substances
Decomposes hydrogen
peroxide



I Ammonia and COs

Purin bases, etc.

Xanthine

Hypoxanthine



Water, oxygen



XXK. CHLOROPHYLL

Chlorophyll (Gr. chloros, green — phyllon, leaf). Plant colors
have no physiological action and if used in medicine, it is for
their esthetic or psychic eflfect. But the relation between chlor-
ophyll and hemoglobin is of great biological significance.

The name chlorophyll was first applied by Pelletier and Caven-
tou to the green coloring matter of plants. By the use of the
spectroscope it has been found that chlorophyll of the green leaf
instead of being one simple color, contains at least seven different
pigments.

The reactions in the formation of chlorophyll are not well
understood. Light is essential. The presence of iron and mag-
nesium is necessary. Starch and sugar may or may not be
essential. This point is still under investigation; as is also
the chemistry of the substances which immediately precede
chlorophyll and from which it is formed. Lecithins and proteins
seem to take part in its formation. The chemistry, is complex
and not definitely known, but is sufficiently understood to
show a definite chemical relationship between chlorophyll and
hemoglobin.



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CHLOROPHYLL 329

RELATIONSHIP OF CHLOROPHYLLS AND HEMOGLOBINS *

There are several different chlorophylls, just as there are dif-
ferent hemoglobins. The hemoglobin of different animals varies
slightly in composition but all are closely related chemically.

By the action of glacial phosphoric acid containing HI on
hematin or hemochromogen, haemopyrrol, CgHisN, a colorless
oil which in air gradually changes to urobilin is formed. Uro-
bilin is also produced by the action of the same reducing agents
on the chlorophyll derivative, phyllocyanin. This shows a close
relationship between chlorophyll and haemoglobin.

There are two well known chlorophylls:

,C00CH3

Chlorophyll (a) C32H29N3Mg^-COOC2oH39

.COOCHa
and chlorophyll (6) C32H2802N4Mg(^

OOOO20H39
(Willstatter and Isler)

When these are treated with alkalies, two groups of products are
formed:

1. Phyllins, which contains magnesium and

2. Porphyrins, which are free from magnesium.

On oxidation with chromic and sulphuric acid, Marchlewski, also

c — a

Willstatter and Asahina, think the pyrrol group | y N

C C^

exists in the chlorophyll molecule since the pyridine derivatives

CH3.C CO.

II yNH Haematinic acid imide, and

COOH.CH2.CH2C CO^

CH3.C CO.

II yNH Methylethylamaleinimide are formed.

CH3.CH2C CO^

CH3.C.COOH
Haematinic acid - || has been obtained

COOH.CH2.CH2.C COOH



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330



CHEMICAL PHABMACOLOGY



from hemoglobin and the imide of this obtained from chlor-
ophyll again establishes a relationship between chlorophyll and
hemoglobin. Hematin and hsematoporphyrin also yield h»-
matinic acid imide.

Pyrrol is an important nucleus in many biological compounds,
being found in alkaloids, nicotine, cocaine, and others, and
in proteins. In fact, proteins may be looked upon as containing
an alkaloidal nucleus.

The structure of the pyrrol derivatives is indicated as follows:

fi) ' HC C H (p

II II
a) HC C H (a

\/
NH

Besides these mentioned, the following derivatives of hsematin
are of biological importance.

(I) (11)

CHa. C C C/2XI6 CHg — Cr— — C — C2M5



CH,. C CH

\/
NH
Isohemopyrrol
|3-ethyl a' j8' dimethyl pyrrol

(III)
CHs. C C C2H5



CHs



C CCH,

\y

NH

Kryptopyrrol or a
methyl /3 ethyl /3-
methyl pyrrol

(IV)
C C CHj.Cfl2.COOH



CH3 C C CHs

\/
NH

Phyllo pyrrol or a methyl
i3-ethyl a' /S' dimethyl
pyrrol



C C

\/
NH

Isophonopyrrol carboxyUc acid
or i3-propionic acid a' P'
dimethyl pyrrol.



The bile acids are derivatives of hemoglobin and also contain
pyrrol nuclei which are derived from the hematin of blood. When
blood is dropped into acetic acid containing some NaCl and the
solution heated to 95°C. the hydrochloride of hsematin, hsemin



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COLORING MATTERS



331



C3lH84N4^



C3iHi204N4FeCl, crystallizes out. When haemin is treated
with HBr, a dibrom compound is formed and iron is lost. When
the dibrom compound is hydrolysed hsemato porphyrin is formed
which is a dibasic acid of the formula:

OH
COOH
^COOH
Hemat opor phyri n
The intermediate reaction is not known. When hematophyrin
is reduced by heating with methyl alcoholic potassium hydroxide
in pyridine solution, hemoporphyrin C83H36O4N4 is formed, which
on heating with soda lime forms aetioporphyrin C81H36N4.
Willstatter thinks this is the mother substance from which both
chlorophyll and hematin are derived.

HC=CH



CH3 — C-CH,



C2H6-C-C



\
/

_>

C2H5 — C — Cv



c— c



;n



N:



-C:



:C— CH



CH,— C=C<^



NH



HN:



//

>

Xj — \j — G2H5

< I

\C— C— CH3



CH,



Aetioporphyrin.



CHf-C-Cl



.1 7N

C2H6 C — C^

)c-

CHr-CHj— C=C/



CH3

HC=CH

I I

c— c



N'



C



HOOC CHs— C=C^

I
CH3



NH



HN



\
\
\



C— CH



C=C— CHr-CH,



C==C— CH, COOH



CH3
Hsemoporphyrin.



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332 CHEMICAL PHARMACOLOGY

The following skeleton formulse has been suggested by Werner
to show the relationship between chlorophyll and hsematin.

C G-

'Mg
C / C

Chlorophyll Haematin

In addition to chlorophyll plants contain many other related
pigments such as carotin, the yellowish red pigment of carrots,
which is found with chlorophyll in many plants. It has the
molecular formula C40H56. Xanthophyll C40H56O2 and carotin,
both neutral substances, are closely i elated and on reduction
xanthophyll can be converted into carotin. Tucoxanthin
C40H54O6 isolated from brown algae has basic properties and forms
blue salts with HCl and H2SO4.

Besides the colors mentioned, there are yellow colors known
as flavones and xanthones as well as anthocyanin, which give
blue, red, and violet tints; and many others, which have as yet
only a remote interest in the chemistry of drugs. Chlorophyll is
the only one that has been investigated in detail.

While chlorophyll and hemoglobin are related chemically,
their functions are quite dissimilar. The chief function of hemo-
globin is as a carrier of oxygen, while chlorophyll participates in
both metabolism and assimilation. Chlorophyll contains no
iron, while the main function of hemoglobin depends on this
element.

The following diagram shows the relationship of chlorophyll,
hemoglobin and bile pigment (after Mathews, p. 423) :

The great difference between plants and animals is that in the
plant, reduction and synthesis are the predominant chemical
processes, while in the animal, oxidation and hydrolysis predomi-
nate.



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HEMOQLOBIN



333



I.

Hemoglobin

/\
Globin Hematin

CssflssNiOsFeC?)
i



II.



III.
Chlorophyll

i
Phyllocyanin



Hematoporphyrin Bilirubin Phylloporphyrin

C32H36N406(?) C32H36N406(?) C32H86N4O2

I



Biliverdin

082X136^408



Urobilin

C32H40N4O7(?)



i i i

Hemopyrrols Hemopyrrols Hemopyrrols

CgHisN (etc.) CsHxaN (etc.) CgHuN (etc.)

\ . ^ y

Hematic acids

C8H8O6C7H9NO2 C8H9NO4
The Fate of Chlorophyll in the Body

• We known nothing definitely about the transformations of
chlorophyll in the alimentary tract. Neither chlorophyll nor
hsematin are absolutely essential in the diet, since the animal
body is apparently able to construct respiratory pigments from
the split products of protein.' Those containing the pyrrol ring
are probably used in this synthesis.



Other Plant Colors

Litmus results from the fermentation of the
lichens Rocella and Lecanora. These lichens con-
tain orcinol, partly free and partly as orsellic
acid and combinations. By special treatment
with ammonia and potassium carbonate, litmus
is formed. The concentrated salt mixed with



CH3



OH



V

Orcinol



OH



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334 CHEMICAL PHARMACOLOGY

chalk or gypsum, constitutes commercial litmus. Little is known
of the chemistry of this substance, which contains several colors,
azoUtmin, erythrolitmin, and erythrolein. The first named is the
most important and is soluble in water, but insoluble in alcohol.
The others are insoluble in water and soluble in alcohoL When
orcinol is exposed to the air and ammonia it changes to orcein,
C28H24N2O7, which is a reddish brown amorphous powder, the
chief constituent of archil, which is also known as cudbear or
persio. It is sometimes used to color medicines.

Curciunin, curcuma, C14H14O4 or tumeric is the coloring prin-
ciple in the root of curcuma longa. It dissolves in alkahes to*
form brownish red salts.

Hemotoxylin Ci6H]406 + 3 H2O is the coloring matter of
logwood, sometimes used in medicine for its astringent effects.
It reduces FehUng's solution, dissolves in alkalies with a violet
color (and therefore may be used as an indicator). When fused
with KOH it yields pyrogallic acid and resorcinol.

Red Saunders is the heart, wood of pterocarpus santalinus.
When extracted with alcohol, it gives a red solution and is used to
color the compound tincture of lavender.

Coccus (cochineal) is the coloring matter of the cochineal bug.
Besides its use in pharmacy, it is particiilarly valuable in chemis-
try as an indicator and is employed especially in the titration of
ammonia and the carbonates.

Carmine is prepared by extracting the cochineal with water
and precipitating with alum and Ume or cream of tartar.

Crocus or saflfron is made of the stigmas of crocus sativa.

Caramel is partly burnt sugar.

Annate is the pulp surrounding the seeds of Bixa Orallana, a
South American Plant. Annate and saffron are also used to
color butter and oleomargarin.

Alkanet is the root of alkanna tinctoria. This is red with acids
and blue with alkaUes.

Indicane CTHeNCOCeHuOs is a glucoside found in a number of
plants, as indigo fera anil
I. arrecta
I. tinctoria

I. summatrana and many other plants. When boiled
with a mineral acid, indicane breaks up into glucose and indoxyl.



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INDICAN 335

.COH^
CtH^COCHuO, = C,Hi20e + C,H/ /)CH

^ NH ^
Indican Indoxyl

When indoxyl is exposed to the air it is oxidized and gives a
deep blue coloring matter indigo

CeHiv yC : Cv yC6H4

Indigo blue

It was formerly supposed that plant indican was identical with
urine indican the latter being so named, because of this supposed
identity. The two are not identical, however, although both
may give rise to indoxyl; plant indican through hydrolysis, and
urinary indican by oxidation of indol.

Indol C«H/ /CH is also formed in the intestine as the

result of putrefaction. It is oxidized most probably in the liver
to indoxyl and this is eliminated as the potassium sulphuric ester.
CCOSOjOK)
/ \ . -

CeHi^^ y CH. This ester is known as urine indican

^v y and on oxidation gives indigo blue and

^NH acid potassium sulphate.



XXX. COLLOIDS

In all reactions of chemical pharmacology, one of the reacting
bodies is a colloid. The word colloid was first applied to
bodies that had the properties of glue (Gr. kolla, glue; eidos,
appearance). More recent study has widened the original
scope of this word. Graham, in 1861, divided substances into
crystalloids and colloids, classifying them on the following
basis; those substances that would diffuse through an animal
membrane or parchment paper he called crystalloids, and those
that would not do so, colloids. Sodium chloride, sugar, alka-



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336 CHEMICAL PHARMACOLOGY

loidal salts and the like are crystalloids, while gums, starches,
resins and proteins are colloids.

Besides the property of non-dififusion through membranes,
colloids are amorphous, viscous, and when sufficiently concen-
trated, form gels. The pseudo solution of the colloid to distin-
guish it from a true solution is called a sol. According to the
Uquid in which the colloid is suspended (water, alcohol, etc.) the
sol is called hydrosol, alcosol, and the gel, hydrogel, alcogel.

Graham also found that under some conditions, non-colloidal
matter might become colloidal. He discovered that by adding
au excess of dilute hydrochloric acid to a dilute solution of sodium
silicate he obtained a clear solution instead of a precipitate of
siUcic acid. When such a solution was dialyzed, the sodium chlor-
ide was washed out and the ordinarily insoluble silicic acid
remained in a colloidal condition. A similar method is used at
present to prepare colloidal iron. .

Colloidal matter under some conditions can also be crystallized;
hemoglobin and egg albumen have been obtained in crystalline
form. At the present time, therefore, the opinion is that the
colloidal condition is not entirely due to the kind of matter, but
also to the condition under which the matter is found, and the
size of the particles. In proper solvents, perhaps any form of
matter may be amorphous or crystalline. Even such a typical
crystalloid as sodium chloride in benzene may be colloidal, while
under other conditions the typical colloid, albumen, may be
crystalUne. These extreme cases, however, should not minimize
the difference between crystalloids and colloids as they are found
in nature.

CHARACTER, OR NATURE, OF COLLOIDS

Enzymes are colloids, and the study of artificial enzymes has
done much to explain the nature of colloids. Bredig found that
if an electric spark produced by a current of 8-12 amperes at 30
to 40 volts is passed through pure water between two platinum
wire electrodes, the metal disintegrates and. the water becomes
first, yellow, and then a brown or black color. The liquid filters
easily, no particles are visible under the microscope, and ap-
parently the platinum has gone into solution. The physical
constants, however, do not show a true solution. The freezing



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COLLOIDS 337

point, boiling point, or osmotic pressure is but little changed,
whereas if an equivalent quantity of a salt is added, these constants
are definitely changed. Instead of being in true solution, the
platinum is in a pseudo solution or a state of extreme division
(dispersion) that may be seen by the aid of the ultra microscope.
The size of these particles has been estimated at 0.00001 milli-
metre. These particles in colloidal solutions* are known as the
disperse phase of the colloidal solution. The water is the con-
tinuous phase. Gold, silver, copper, and other metals have been
prepared in pseudo solution. These solutions, when allowed to
stand, do not respond to the laws of gravitation; the solution is
rather permahent, due to the fact that the particles carry an
electric charge. The evidence to support the theory that the
particles are changed electrically is:

1. The method of preparation. The current that causes the
disintegration of the metal, and carries it into solution, would
probably remain on it.

2. The particles will wander in the stream if a current of electri-
city is led through the solution.

3. Electrolytes will precipitate colloids. This is well shown by
the action of Na2S04 or MgS04 on the colloidal iron, or by the
action of HCl on colloidal arsenic sulphide and by the fact that
colloidal platinum can not be kept for any length of time if
electrolytes are present in the water.

4. Colloids of opposite electrical sign precipitate each other.
Practical appUcation is made of this in the use of aluminum
cream A1(0H)3 and colloidal iron, Fe(0H)3 to precipitate the
proteins of blood, in blood sugar determinations.

5. Non-electrolytes such as sugar will not precipitate colloids
in water solution. Alcohol, however, which is also a non-electro-
lyte will cause precipitation but this is due to a changed solvent.

The chief electro-negative colloids are arsenious sulphide,
antimony sulphide, gold, copper, and nearly all metals, as well as
most proteins, in neutral or slightly alkaUne solution, lecithin
and phosphatides, the carbohydrates, gum, starch and glycogen,
and nucleic acid and soaps.

The electro-positive colloids are ferric hydrate, aluminum
hydrate, basic proteins, histones and protamines, proteins in acid
solution, alid oxyhemoglobin.



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338 CHEMICAL PHABMACOLOGY

Classification. — The colloidal solution of a metal like platinum
is vastly different in viscosity from a solution of gum or protein.
The classification of colloids, which is based mainly on this dif-
ference of viscosity of their solutions, is as follows:

1. Suspensoids, or inorganic.

2. Emulsoids, or organic.

As the names indicate, suspensoid colloids resemble a suspen-
sion of solid matter in a liquid,* while emulsoids resemble emul-
sions. Colloids differ from simple suspensions or emulsions in
being charged electrically. The particles of colloid all bear the
same kind of electricity, hence repel each other. This keeps them
in solution. The electrical charge also acts against the force of
gravity, and there is but little tendency to form a deposit or
precipitate imtil the charge is neutralized. Only inorganic col-
loids belong to the suspensoid class. They may be prepared first,
by the use of an appropriate electric ciirrent under water, or,
second, by the reduction of dilute solution of metals by reducing
agents such as formaldehyde, third, when hydrogen sulphide is
passed through a solution of arsenious acid, arsenic trisulphide
may remain in colloidal solution. Some other metals act in the
same way. Some of the suspensoid colloids are used in medicine.

Colloidal preparations of silver are used in medicine especially
in the treatment or prevention of gonococcus infections of the
eye and mucous membranes. Colloidal gold is employed as a



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