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ethylene dibromide is formed:

CH2 CH2Br

I +Br»= I
CH2 CH2Br

This when treated with an alcoholic solution of KCN forms
CH2CN
CH2CN
which is hydrolyzed to -^ CH2COOH.CH2COOH.

TARTARIC ACID

Tartaric acid may occur in levo, dextro, meso, and racemic

forms. It is dihydroxy succinic acid :

CH2COOH CHOH.COOH

I I

CH2COOH CHOH.COOH

succinic tartaric •

acid acid

It was on these acids that Pasteur made his important dis-



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72 CHEHnCAL PHARMACOLOGY

coveries on the polarization of light by organic substance. He
found that certain crystals dissolved in water turned the polarized
ray to the left. Others turned it to the right; and a mixture of
the two was racemic or inactive (external compensation). On
studying the composition of the organic substances, he found that
the active crystals are mirror images of each other. It has been
found that only those with an asymmetric carbon are optically
active. No single base of an organic substance is known that is
optically active without the presence of an asymmetric carbon
atom. However a substance may contain two asymmetric
C-atoms and be inactive. This occurs in the meso form of
tartaric acid, cf. formula III. This is internal compensation.
The importance of this physico-chemical property to living mat-
ter can hardly be estimated. The mould, penicilUum glaucum,
ferments dextro, but not levo tartaric acid. Yeast will ferment 1.
fructose, 1. glucose, 1. mannose, or 1. galactose. Dextro epine-
phrine is only about 3dL2 as toxic as 1. epinephrine; d. hyoscyamine
is but feebly active in comparison with 1. hyoscyamine. It is
probable that time will greatly emphasize the relationship of
optical properties and life processes.

The levorotatory form is represented in formula (I), the dextro
in (II), and meso tartaric in (III).

(I) (II) (III)

COOH COOH COOH

I I !

HO— C— H H— C— OH HO— C— H.

I I I

H— C— OH HO— C— H HO— C— H

I I !

COOH COOH COOH

The central C atoms in (I) and (II) are asymmetric (each
valence has a different element or radical in combination), so
that when both forms are in the same solution, the influence of
one on polarized light neutralizes the other.

Tartaric acid is used in medicine as an expectorant and emetic
in tartar emetic, which is antimonyl potassium tartrate.

• .CHOH COOHK .
1. 2C )H20



^CHOH COO(SbO)^



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CITRIC ACID 73

2. Rochelle Salt, or sodium potassium tartrate, C4H4O6K Na
+ 4H2O, is used as a cathartic and antacid.

3. The acid salt of tartaric acid is used In domestic economy
as cream of tartar or baking powder. The essentials of a baking
powder are: something that will liberate CO2 slowly and effi-
ciently, and will not leave a harmful or toxie residue in the food.
Cream of tartar fulfills these conditions. The reaction in this
case is:

CHOH.COOK CHOH— COOK

I + NaHCOa = + H2O + CO2

CHOH.COOH CHOH— COONa

Cream of tartar sodium potassium tartrate

CITRIC ACID

CH2— COOH
I/OH
Citric Acid, C{ occurs in the juice of many

I ^COOH
CH— COOH

plants, especially in lemon juice, where it may reach 5 per cent,
and in gooseberries, 1 per cent. It is also found in raspberries,
currants, and other acid fruits, and is said to be found in the
milk of animals, probably being derived from the food. It is
formed in the fermentation of glucose by citromycetes pfefiferi-
anus. In medicine its use is as a substitute for lemon juice; in
the syrup of citric acid as a vehicle and refrigerant. Magne-
sium citrate is a much used cathartic in iron and ammonium
citrate as a soluble form of iron in citrated caffeine, etc.

Citrophen or citrophenin is a combination of citric acid and
phenacetin:

CH2.CONHC6H4OC2H6

I
COH.CONHC6H4OC2HB

I

CH2CONHC6H4OC2H5. It • is used as an analgesic and
antipyretic.

The reactions of acetic acid, acetone, and citric acid are inter-

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74 CHEMICAL PHARHACOLOQY

esting, and tlie relationship also shows how the cyanides may be
disintoxicated by the body. Calcium acetate when distilled gives
acetone:

CH,.COO. CH,.

}C& = ^CO + CaCO,

CH,.CO(r ch/

If chlorine is conducted through cold acetone, dichlorace-
tone is formed:

CHjCl CHsCN

I I

C = + 2KCN -» C = + 2KC1

I I

CHsCl CHjCN

Dichloracetone Acetonedicyanide

When this is hydrolyzed it gives acetone dicarboxylic acid; and
this gives citric acid as follows:

CHjCOOH CHjCOOH CH»COOH

I I /OH I /OH

CO + HCN = C^ + 2H2O -» 6(

I I ^CN I ^COOH + NH3

CH2COOH CHjCOOH CHjCOOH

Acetone dicar- Cyanhydride Citric acid

boxyUc acid of citric acid

LACTIC ACID

Lactic acid, from (lac = milk) is but httle used in medicine.

It is somewhat used as a local appUcation to tuberculosis ulcers

of the nose and throat, especially on the larynx.

CH,

I
Lactic acid CHOH is of interest because of its relation to acetic

I
COOH

and formic acid and to glucose and amino acids derived from
protein. It is formed in the ^stomach in all fermentations
and dyspepsias when it may reach 0.4 per cent. There
is some doubt whether or not lactic acid exists in the
normal blood. It is present, however, in all cases where



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LACTIC ACID 75

there is asphyxiation or reduction of tissue respiration and in
such cases appears in the urine. It occurs especially after
poisoning with phosphorus, arsenic, hydrazines, chloroform, etc.,
i.e.y after those poisons which act on the liver causing hyper-
glycemia, reduction of glycogen, and fatty degeneration. It
may also occur in the course of diabetes and wasting diseases,
and is always present in cases of acidosis. Lacti<? acid since it
contains an asymmetric C atom exists in dextro, levo, and race-
mic or inactive forms. It was first discovered by Scheele in 1780,
who isolated it from sour milk. In the form of sour milk,
it was advocated by MetschnikoSF but without any sufficient
reason as a means of prolonging life. Since milk is an important
vitamin containing food, it per se would be of great benefit in
deficiency diseases and some of these benefits may have been
unduly credited to lactic acid. In the destruction of lactic acid
by bacteria, propionic, acetic and formic acids may be formed:

CHa CHa CHa H

I • I j I = CO2.H2O

CHOH CH2 COOH COOH

I I

COOH COOH

Lactic propionic acetic formic

Zinc lactate Zn(C3H503)2.3H20 is the most characteristic- salt of

lactic acid. The acid may be identified by the analysis of this salt.

HYDROCYANIC ACID

Hydrocyanic acid is usually considered with the paraffin acids,
but it is not a derivative of the paraffins. It is of direct interest
to the paraffins because it forms addition products with aldehydes
and ketones. These can be hydrolyzed, enabling the formation
of a product richer in carbon than the initial e.g. :
CH3I + KCN = CHsCN + KI

CH3CN + 2H2O = CH3COOHNH3

The relation of HCN to formic acid is shown by the following:
HCN + H2O -> HCOONH4 (ammonium formate)
It is, therefore, the nitril of formic acid. Hydrocyanic acid 2
per cent., dilute hydrocyanic, is used in medicine as an antemetic
and in cough mixtures, as a depressant of the respiratory centre.
On account of the readiness with which it decomposes, it is not so



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76 CHEMICAL PHARMACOLOGY

much used as formerly. It ako exists in wild cherry, in amygdalin,
in KCN, Hg(CN)2 and other compounds used more or less.

Because of its toxic action this drug is falling into disuse
It is of considerable importance in toxicology. It is absorbed
even from the skin. It is toxic to all ferments and tissues. It
first stimulates then paralyzes the central nervous syistem. The
peripheral mtlscles and nerves are weakened and eventually para-
lyzed. The tissues cannot use oxygen and soon die from asphyxia.
In such cases lactic acid may be found in the blood and urine.
The oxidative processes of the blood are also checked and the color
of the blood is bright red due to oxyhemoglobin as is to the fact
that the tissues from internal asphyxia cannot take oxygen from
the blood. Whether or not such a compound as cyanhemoglobin
is formed is still disputed. It is probably formed and readily
decomposed, though it is harder to reduce than oxyhemoglobin.

Hydrocyanic acid, if it does not kill is changed to sulphocy-
anides in the tissues. This seems to be a simple chemical process
which occurs without the action of living protoplasm. The
sulphocyanate test for hydrocyanic test is based on this fact. It
is as follows:

To a dilute solution of hydrocyanic acid, or a distillate sus-
pected of containing it, add a few drops of a solution of potassium
hydroxide, and twice as much yellow ammonium sulphide.
Evaporate to dryness on a water bath; dissolve in a Uttle water
and acidify with dilute hydrochloric acid. Filter to remove
sulphur. If the solution contained hydrocyanic acid the filtrate
will give a blood red color on the addition of a drop of dilute ferric
chloride, this is due to the formation of ferric sulphocyanate.

Hydrocyanic acid occurs in many plants, in the form of
glucosides — cyanogenetic glucosides. It is present principally
in the seed, buds, leaves and bark. The cyanide is held to be a
direct product of photosynthesis, and may be of fundamental
importance in the metabolism of the plant and perhaps in the
evolution of life processes. Gautier thinks that prussic acid and
its compounds may be formed in the plant by the reduction of
nitrates by formaldehyde. This theory agrees with the distri-
bution of both nitrates and cyanides in the plant. Th^ amount
of cyanide in plants varies greatly and may amount to as much
as 0.3 per cent. In many cases free hydrocyanic will be liberated



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LACTIC ACID 77

from such plants on chewing — owing to digestion of the glucoside
— and can be detected in this way.

To isolate hydrocyanic acid from a plant or tissue: digest the
finely pulverized substance mixed with water in an incubator or
on a water bath for two hours at a temperature of 40°C. If the
temperature is raised much above this, it will kill the ferment and
prevent the setting free of HCN. Acidify the digest with tar-
taric acid and distil with steam. Test the distillate by:

1. Prussian Blue Test.— Add a trace of KOH, then a few drops
of freshly prepared ferrous sulphate solution and a drop of dilute
ferric chloride solution. Shake well and warm gently. Finally
acidify with dilute hydrochloric acid. A blue color is formed at
once if the quantity of HCN is considerable, if only a minute
amount is present a bluish green color only develops.

2. Hydrocyanic acid gives a white precipitate with AgNOa.

3. Vortmann's Nitro-prusside Test. — To a dilute solution of
hydrocyanic acid add a few drops of potassium nitrate solution,
then a few drops of ferric chloride and enough dilute sulphuric
acid to give a yellow color. Heat to boiling and add enough
ammonium hydroxide to remove excess of iron, filter, and add a
few drops of very dilute ammonium sulphide. A violet color
passing through blue green and yellow, indicates hydrocyanic
acid. It is due to the conversion of the cyanide into potassium
nitro-prusside — K2Fe (NO) (CN)6 which changes color when
ammonium sulphide is added.

Picric Acid Test. — When a solution of hydrocyanic acid is
made alkaline with KOH and heated in a water bath at 50°-60°C.
with a few drops of picric acid, it gives a blood red color due to
the formation of potassium isopurpurate — C8H4N5O6K. Sul-
phides present in decomposing organic matter will also give
this test and sugars under similar conditions will give a red
color due to the formation of picramic acid — which is 2 amino 3.
4, di-nitro phenol C6H2(NH2).(N02)2.0H. This last is the basis
of Benedict's method for the estimation of blood sugar.

Isopurpuric acid does not exist in the free state, but only as the
potassium salt. Nietzki and Petri (Ber d. deutsch. Chem.
Gesellschaft 1900-33-1788)— think isopurpuric acid (CsHsOeNs)
is dicyano-picraminic acid = 5 oxy. 6 amino — 2, 4 di nitro
isophthalic nitrile: see page 98.



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78 CHEMICAL PHARMACOLOGY

Purpuric acid, the formula of which is not definitely known, is
of biological interest in that its ammonium salt,

C8H4(NH4)Nb06 + H,0 is the dye stuff murexide. The
murexide test is given by uric acid caffeine, xanthine, theobro-
mine and many nuclein bases (see p. 288).

GENERAL PHARMACOLOGY OF THE ACIDS

The introduction of COOH into the Marsh Gas series gives
rise to acids with relatively sUght toxicity. The anesthetic
action of the alkyl radicals is lessened by combination with car-
boxyl. The introduction of carboxyl into the aromatic series
lessens the toxicity of the benzyl group. In addition to the car-
boxyl group the acyl groups exert an action. Acetyl salicylic
acid is more effective as an antipyretic and analgesic than is
salicylic acid. Acetyl atoxyl is said to be less toxic than atoxyl.

The replacement of the hydrogen of the amino group in para-

/ \

mino phenol with an acetyl group, HOC ^NH.CGCHa



lessens the toxicity, and gives a compound with greater anti-
neuralgic properties.

Lactyl phenetidine (lactophenin)

C2H5< > NH— CO— CH— CH3



OH

IS more soluble, and has a less antipyretic action than phenacetin.
Ecogonine-methyl ester has no anesthetic action but its benzoyl
derivative, cocaine is noted for its local anesthetic effect. Most
artificial cocaines contain the benzoyl group. The toxicity of
aconitine is closely related to the benzoyl and acetyl groups present
in the alkaloid. The mechanism of the action of these and many
other similar compounds is little understood, but the total
action in each case seems to be the algebraic sum of the actions
of the component chemical groups of the drug. In addition
to these there is a molecular action and a hydrogen ion action.
For the effects of the hydrogen ion, see acidosis, p. 350; see also
amino acids, p. 304,



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IODOFORM 79

Vm. IODOFORM AND PHYSIOLOGICAL SUBSTITUTES

Iodoform, or triodomethane, was the first solid antiseptic known.
It is prepared by the action of iodine upon alcohol or acetone, in
the presence of an alkali or an alkaline carbonate. Its formation
is also used to test for the presence of alcohol or acetone. A solu-
tion of I in KI is added to the solution of alcohol, or acetone, and
warmed, then dilute NaOH or KOH is added, drop by drop
until the color has disappeared. Iodoform is formed :

CH3COCH8 + 3KI0 = CH3COCI3 + 3K0H
CH3COCI3 + KOH = CHsCOOK + CHIs

The potassium hypoiodite KIO is formed when dilute KOH
is added to the I in KI solution : 2 KOH + 21 -^ KIO + KI + H2O.
The hypoiodites are easily decomposed into iodides, ^nd iodates:
3 KIO = KIO3 + 2KI. Both the iodate and iodide are usually
formed in the solution with the iodoform, even when KI has
nofbeen added. Strong alkalies cause the formation of the io-
date; and, therefore, if a too strong alkali is added, it interferes
with the reaction. For this reason, sodium carbonate or potas-
sium carbonate instead of the hydrate is sometimes recommended
in making the iodoform test. From alcohol, iodoform is pre-
pared, possibly according to the following reaction:

C2H6OH+I8+6KHCO3 = CHI3+5KI + KCOOH+6CO2+5H2O

Ethyl iodide, acetic ether, and other compounds are probably
also produced. The result appears to be greatly influenced by
the temperature, and the relative amounts of the materials used.
Iodine is an oxidizing agent and the probable mechanism is:

.0
C2H5OH +0 = CH3C/ + H2O

^H
O

GHzCe + le = CI3C/ + 3HI
^H ^H

CI3C/ + KOH = CHI3 + KCOOH
^H

Iodoform melts at about 115°C. It is nearly insoluble in
water, but soluble in alcohol, glycerine, carbon bisulphide, ether



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80 CHEMICAL PHARMACOLOGY

and in fats. In medicine it is sometimes used in the form of
an ointment.

It is volatile at ordinary temperatures and distils readily in
steam. When it is suspected in organic matter, and its separa-
tion is desired, acidify with tartaric acid and distil with steam.
Extract the distillate with ether and evaporate the ether in a
suitable dish. Iodoform remains as yellow hexagonal plates
with a characteristic odor.

Tests: Lustgarten's. — In a test tube warm a little iodoform
solution in alcohol with a few drops of sodium phenolate — made
by dissolving 2 parts of phenol, 4 parts of sodium hydroxide and
7 of water. A red precipitate is formed which settles to the bot-
tom. Pour olBf the supernat^t fluid and dissolve the precipi-
tate in dilute alcohol — a carmine red color results.

Phenylisocyanide Test. — Add a few drops of aniline to a little
iodoform solution in alcohol, then a few drops of alcohoUc KOH
solution. When heated gently, phenylisocyanide — CeHsNC is
produced. This is recognized by its very characteristic and
repulsive odor. For reaction see page 43.

Iodoform is sometimes used as a disinfecting dusting powder,
and any action it has is due to the liberation of iodine. It has
two serious disadvantages:

1. Its disagreeable and persistent odor.

2. In cases of abraded surfaces, suflScient may be absorbed to
produce toxic symptoms. For these reasons its use is becoming
restricted.

Various other iodine compounds have been devised, with the
idea of securing the iodine effect, without the disadvantages of
iodoform. The following are the most common:
Aristol, or dithymol-di-iodide.

The stearoptene, thymol, from oil of thyme has the formula:

CHa
/\



OH



\/



CH

/\
CHg CHs



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IODINE COMPOUNDS 81

It is a solid crystalline body, which is used in medicine, especially
in the treatment of hook-worm disease. It has also been much
used in biological chemistry as a preservative for urine and other
fluids. Since it combines with iodine-also an antiseptic — it was
thought that a valuable iodine compound could be obtained
without the disadvantages of iodoform. Eichkoflf in 1890 pre-
pared aristol or thymol iodide by the action of iodine on thymol
in alkaline solution.

C6H2r~CH3

\oi

CeHas-OI

V3H7
This is a chocolate colored powder and contains about 45 per
cent, iodine. It has been used as a dusting powder especially
in soft ulcers, eczema, psoriasis, lupus, burns, infections of ear,
nose and throat and in many other cases where the odor of iodo-
form has been a drawback. Its action- is similar to iodoform,
and its only advantage is that it is odorless.

EUROPHEN-OR-DI-ISO-BUTYL ORTHOCRESOL IODIDE.

This is analogous to thymol iodide. It has the. formula:

•C4H9

C6H2r~"CH3

C6H2r— CH3
\C4H9

and is a condensation product of two molecules of isobutyl-ortho
cresol with one atom of iodine. The action is similar to thymol
iodide. It contains about 28 per cent, iodine.

lODOL OR TETRAIODO PYRROL.

I.C — C.I

II II

I.Cv/C.I
NH



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82



CHEMICAL PHARMACOLOGY



was one of the first iodoform substitutes. It is prepared by the
action of iodine on alkaline solutions of pyrrol or indirectly by
the action of KI on tetrachlor-pyrrol.

C4H4NH + 8C1 = C4CI44NH + 4HC1

pyrrol tetra-chlor-pyrrol

C4CI4.NH + 4KI = C4I4.NH + 4KC1

lodol is a tasteless and odorless poivder with an action similar
to iodoform.

Besides the above iodine containing bodies, from which iodine
is liberated readily in the body, others have been prepared, but
since these do not liberate iodine in the body, they cannot be
classified as true iodoform substitutes.

In the iodoform substitutes the iodine is not attached directly
to the benzene ring but replaces the H of the hydroxyl group.
In Loretin, 1 oxy, 2-iodo — 4 sulphonic acid,

SO2OH




4 chlor quinoline



N and vioform 1, oxy, 2-iodo,




and nosophen or tetraiodophenol phthalein C20H10I14O4 and

/OH



Losophan — or tri-iodo di-metacresol — CeHIs



\



CH3



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IODINE COMPOUNDS



83



and sozoiodol (iodo para phenol sulphonic acid)

.OH
C6H2I2V

^SOaOH

the I is attached to the ring.

Such compounds are practically undecomposed by the body,
and of little value as antiseptics so far as the iodine content is
concerned. They are therefore not real substitutes for
iodoform.

All phenols have a high antiseptic value, and the introduction
of iodine increases this to some extent. The increase is not
sufficient to warrant approval.

Besides the above iodoform substitutes, organic combinations
of iodine have been prepared for administration internally to take
the place of potassium iodide. Iodides in the form of potassium
or sodium are sometimes too rapidly absorbed, cause irritation
of stomach, skin eruptions and other untoward manifestations.
Many attempts have been made to avoid these complications by
combining the iodine with organic substances that will be slowly
decpmposed in the body and slowly absorbed. The combinations
are usually with protein matter, and the composition in most
cases is not fixed or definite as in the iodoform substitutes.

THYREOi&LOBULiN is the normal iodine-containing body of the
thyroid gland. The active ingredient of this has recently been
isolated by E. I. Kendall and has the formula:

HI



HI



HI



-C - CH2 - CH2 - COOH



-N-



-CO



H or thyro-oxy-indole

loDO-spoNGiN is the iodine compound of the sponge.

loDOALBiN is a compound of iodine and blood albumin, con-
taining approximately 21 .5 per cent, of iodine. It passes through
the stomach unchanged, but is decomposed in the intestine.

loDOPiN is iodized sesame oil. As is well known, unsaturated



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84 CHEMICAL PHARMACOLOGY

oils may absorb or add iodine — the iodine number. Two prepa-
rations of iodopin are on the market — one 10 per cent, and
one 25 per cent. The action is the same as that of potassium
iodide, but it is claimed that iodism is less likely to develop.

loDocASBiN is a compound of iodine with milk casein, contain-
ing about 18 per cent, of iodine, in organic combination. Many
other such potassium iodide substitutes have been prepared, but
the principle is the same as the above.

The supposed or claimed advantage of these organic prepara-
tions is that iodism is less likely to develop. By iodism is meant
the untoward symptoms that develop after the prolonged use of
iodides, the most common being catarrh of the respiratory pass-
ages and adnexa, bronchitis, salivation, skin eruptions, eczema,
bull®, pemphigus, purpura, fetid breath, nausea and general
malaise. A dermatitis resembling ivy poisoning is sometimes
seen after iodoform has been used.

The fatal dose of iodoform or its substitutes is not definitely
known. Barois (Arch, de Med. et de Pharm. MiUtare, 1890)
records the death of a woman on the 9th day after the injection
of 3 grams of iodoform in ether. Gaillard (Bull, de Chirurg.,
1889) records a comatose condition and apparent death (but ff om
which recovery took place) after the injection of about 6 grams
iodoform into an abscess, v. Bonsdorfif (Jour. Am. Med. Assoc,
67, 1916, 1052) reports death due to the use of about 40 cc. of
10 per cent, iodoform solution, 10 cc. at a time being injected into
the pleural cavity in a case of tuberculosis in an alcoholic. The
death in this case was probably due to other causes. Much larger
doses than any here recorded have been injected without apparent
injury.

The symptoms of poisoning in addition to iodism are diuresis,
somnolence, hallucinations, delirium, lassitude, diminished re-
flexes, convulsions, paralysis. As in many cases, of poisoning,
sodium carbonate in 1 gram doses may be beneficial, because of
its e^ect on the acidosis which develops.

The Fate of Iodoform in the Body

Iodoform and its substitutes are readily decomposed in the
alkaline fluids of the body, and the iodine is excreted as iodides.
Some decomposition takes place when it is used on wounds as



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BROMINE COMPOUNDS 85

a dusting powder. The iodides formed after the administration
of iodoform have been found in the saliva, perspiration, bronchial
secretions, urine and other fluids, just as aftei: the administration
of potassium iodide. lodo albuminates are also formed as after
the use of iodides, and the final excretion of the total iodine as
sodium or potassium iodide, may be long delayed.

Some iodide undergoes decomposition in the body and free
iodine is said to have been found in the stomach. If this were
absorbed however it must circulate as an albuminous compound
until converted into the inorganic form in which it i^ excreted.



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