-
- ,.' *l. '?.
HYDR-ATED MAGNESIUM TRISILICATEIN PEPTIC ULCERATION
blyN. MUTCH, M.D., F.R.C.P.
PHYSICIAN, GUY'S HOSPITAL, LONDON; LECTURER AND EXAMINER
INPHARMACOLOGY, LONDON UNIVERSITY
Synthetic magnesium trisilicate (Mg2Si3O8 nH1O) is atasteless
white insoluble powder, possessing adsorbent andantacid properties
of particular value in the treatmentof gastric hyperacidity and
chronic peptic ulceration ofthe stomach, duodenum, and jejunum. As
an adsorbentit far transcends bismuth salts, magnesia,
aluminiumhydroxide, prepared chalk, and other medicaments incommon
use in these conditions. In Table I are given
TABLE I.-Adsorption Poweys of Common Antacid Substances
Potency (Weight ofMethylene-blue
Adsorbent Removed per gram ofSubstance Testedthe Saturation
Poi
Magnesium trisilicate (synthetic sepiolite Type 11) 176Ditto
(allowing for loss on ignition) ... ...244Aluminium hydroxide
(B.P.C.)
... ... ... ...Less than 1
("alocol") 2Bismuth oxycarbonate (B.P.) ... ... ... ... Less
than 1Calcium phosphate (tribasic, 1B.P.) ... ... 0Chalk (prepared,
B.P.) ... ... ... ...3Kaolin suspended in aluminium hydroxide
(" kaldrox ")Kaolin suspended in aluminium hydroxide 2('
kaomagma ")An amount of " kaldrox " containing 1 gram of 8
-kaolinAn amount of " kaomagma " containing 1 gram 10
of kaolinKaolin (B. P.) ... .. , ... ... ... ...12
(purified "colloidal ") ... ... ... ... 14Maclean's powder "
(B.P.C.) ...0... ... ... 0
,, ,, (proprietary) . 0Magnesia (proprietary tablets) 0Magnesium
hydroxide (B.P.C.) ... ... Less than 1
,, oxide (heavy, B.P.) ... ... 0It it (light, B.P.) ... ... ...
... Less than 1
Talc (purified, B.P.C.) ... ... ... ...3
the relative adsorbent powers of such compounds, ex-pressed as
milligrams of methylene-blue removed by1 gram of each
substance.
Adsorption of HistamineAs described in a previous paper,* the
range of its
adsorptive affinities covers all basic dyes and in less
degreemany acidic ones also. It includes certain proteins,
pro-teoses, food poisons, bacterial toxins, putrefactive amines,and
alkaloids. Among the many interesting substancesadsorbed is
histamine ; 1 gram of magnesium trisilicateremoved 9 mg. of the
acid phosphate at the clearancepoint in three hours from an aqueous
solution. Thediazo-reaction and the response of the virgin
guinea-pig'suterus were used as. tests for the completeness of
theadsorption. More detailed study with dyes indicates thatat the
saturation point a much greater quantity wouldbe taken up ; if the
time lag about to be discussed istaken into account, the weight of
histamine removableper gram should probably be doubled again.
Histamine is a product of protein putrefaction, and incertain
states of intestinal stasis can be produced fromits parent
substance histidine by the bacteria of the small
* The first of this series of three articles appeared on January
25th,p. 143, and the second on February 1st, p. 205
intestine. When injected subcutaneously, it causes a flowof acid
gastric juice-a phenomenon which is the basis ofthe histamine test
meal, and may have an importantbearing on the causation of
hyperchlorhydria. Althoughsubstantial adsorption from aqueous
solution commencesas soon as the trisilicate is added, an even
greater second-ary adsorption follows and continues for a week or
more.
Delayed AdsorptionThis latency is of practical importance. It
permits a
continuous adsorption therapy on a scheme of inter-TABLE
II.-Illustrating Delayed Adsorption
Sample Methylene-blue (mg.) adsorbed per gram of theMagnesium
TrisihcateAfter 3 hours After 7 days1 40 100
2 50 1723 60 1694 108 1675 113 2186 121 1607 124 208
mittent dosage, the substances adsorbed during the firstthree
hours following ingestion being insufficient to satisfyeven
one-half of the total adsorptive affinities of thetrisilicate. This
is illustrated by the data in Table II,which relate to a variety of
dye concentrations in thesuperuatant fluid.
Experiments with powders of different grades indicatedthat the
lag was not determined by the size of theparticles, provided that
the whole would pass a 200-meshsieve. It was still observable in
magnesium trisilicatewhich had been allowed to stand under water
for a week;
FIG. 1.
therefore it cannot be explained as due to progressivehydration
of the silicate. One gram (ignited weight)removed 244 mg. of
methylene-blue in seven days(saturation point determination). A
similar amount oftrisilicate was left under distilled water at room
tempera-ture for the same period ; methylene-blue was then addedto
secure a concentration and total equal to that of thedye in the
control tubes. During the next three hoursonly 126 mg. of dye were
removed, but a week later theamount adsorbed was 242 mg., a close
approach to thecontrol figure
-
-~~~
- NMDJEIbL j5&a-;t--s--z--*6'.rX -A,,L $ fy 0 ,
Antacid ValueAs an antacid, I gram (ignited weight) of the
trisilicate
neutralizes 310 c.cm. of N/20 HCI, the approximateequivalent of
normal gastric juice. The ultimate inter-action is a chemical one,
producing magnesium chlorideand an insoluble residuum of hydrated
silica. Neutraliza-tion proceeds with a lag analogous to that
observed during-the adsorption of methylene-blue. A rapid initial
neutral-ization uses up 75 to 80 per cent. of the
availablemagnesium during tne first hour. A slower
secondaryneutralization util-izes the remaining HCi CONTROL20 to 25
per cent. ENTof magnesium at .146a steadily diminish- TEST MEAL+ing
rate. The pro- . WATER 2 OZ.cess is substantially .073complete in
three 0.036or four hours, but oa trace amountingto 0.5 per cent. of
- k i 1 *1 i 22*2*magnesium remainsminundissolved even FIG.after a
week.The magnitude of CONTROL
this lag is shown HCIclearly in Fig. 1, CENT TEST MEAL +where
neutraliza- 0.219 WATER 2 OZ.tion curves are 0.182given for several
1-different batches 0.14of material indi- 0.1Q9vidually prepared.
0.073The quick primary 0neutralization and 4the progressive
0.000secondary one make
~1* 1* 2 .2*it possible to secure FASTING HOURSa continuous
ant-acid effect through-out the whole -
H Clnormal period of PERgastric digestion by CEN; CONTROLthe
administration 0.364of a single dose. 0.321The validity of 0.29 T
NEAL ethis deduction was 0.255 WATER 2 o. /A%Z / ctested by,
gastric
.29analysis. .219An ordinary o.8-is
stomach tube was 0.14passed, and the 0109 /resting juice
wassampled (acidity = 0.073 /0.13 per cent. HCl). 0.036 \Three
grams of the 0.00trisilicate suspended _ _ _ _ _ _in 4 oz. of water
+2 i *1*i*22*zfwere then intro- FASTINGduced through the FIG.tube.
One hourlater the stomach was. evacuated as completely as
possible,and its contents were quickly filtered (acidity of
filtrate= 0.11 per cent. HCl). The washed residue (0.19
gram)contained only a small portion of the remains of
thetrisilicate administered, but on standing in contact withan
excess of N /20 HCI for a week it neutralized 12.4 c.cm.of the
acid. The residue recovered from another in-dividual with similar
acidity controls neutralized 9.6 c.cm.N / 20 HCI.
Clearly magnesium trisilicate after remaining in thestomach for
an hour still retains antacid potentialities,
even when there is a positive acidity in the gastric juicebefore
the introduction of the trisilicate and at the timeof its removal.
The effect of a small dose of the trisilicateon the standard test
meal curve is demonstrated inFigs. 2, 3, and 4.Further details from
a series of cases appear in Table
III. Reduction in acidity is apparent throughout thewhole
three-hour period in each instance, but is mostmarked during the
first one and a half hours. With thedosage used (35 grains, ignited
weight basis) acidity was
kept down to a sub-HCI WITH MAGNESIUM TRISILICATE normal figure
when-PER ever the maximumCENT0.146 TEST NEAL+ acidity in the
con-
WATER 2 OZ.+ to etma a0.109 MAGNESIUM TRISILICATE trol test meal
wasGRAINS 35 not greater than0.07 j, 0.28 per cent. With0.036
higher degrees of
- hyperchlorhydriaup to 0.33 per cent.
_* * 1*1*1*2 22* the trisilicate keptFAST ING HOUR8 the acidity
down2. below normal for
one and a halfWITH MAGNESIUM TRISILICATE hours, but some
MCi TEST llEAL + rise occurred later.PE5 WATER2 OZ.+CENT
MAGNESIUM TRISILICATE At extreme figures0.21 GRAINS 35 even up to
an0.182 I acidity of 0.41 per
I1 cent. the antacid0.148 * raction was per-0.1 _ ceptible
throughoutO.0 the whole three-0.03 hour period, butthe dose used
wasQ .000 _ _ _ _ insufficient to pre-
+ ~~~~~ ~ vent some degreeFASTING HOURS of hyperacidity in
the earlier phases3. as well as in the
later ones. It seemsHCP probable, therefore,CENT WITH MAGNESIUM
TRISILICATE that the dosage for1.364 full control should0.327 be 35
grains three-
TEST MEAL+O0.292 WATEST 2EAL.+ hourly for acidities
MAGNESIUM TRISILICAT20.255 GRAINS TS up to 0.3 per cent.,
a similar dose two-0.11 19 hourly for aciditiesD.182 \1 t }
between 0.3 per0.146 /,JK cent. and 0.35 per0.109 t, cent., and a
higher1.10,, dose for extreme0.073 - cases
).036 A' \ /~~~~~~Clinical Potentialities
The presumptive* *v 1* ' 2- 2 suitability of thisFASTING HOURS
substance for the
4. treatment of chronicpeptic ulceration in
the stomach, duodenum, and jejunum depends on aparticular
combination of properties:
1. Its antacid power is sustained for hours even in thepresence
of an excess of acid. Not only does this facili-tate the continuous
control of hyperchlorhydria in thegastric contents as a whole, but
it furnishes a basis fora local antacid therapy in the floor of the
ulcer itself.In the presence of acid the trisilicate acquires a
gelatinousconsistency, and if any of the mass lodges in the
ulcercrater it will progressively neutralize the acid whichdiffuses
through it. It should not be impossible, there-
I
I
c
c
c
c
m
II
0
0
0
0
0
0
0
0
0
0
0
m
-
- k 7fore, to secure a local hypochlorhydria at the ulcer
site,even when the acidity in the main gastric contents ishigh.
2. Its adsorbent power is sustained, and cannot beexhausted in a
few hours or even in a few days. For
TABLE III.-Effect of Synthetic Magnesiutm Trisilicate on
theFractional Test Meal Curve
Maximum Acidity (% HCI Test Meal)Resting
Case Juice 1st Periol (0 to 1l hours) 2nd Period (1l to 3
hours)%CHCl .__CControl Using Control UsingTrisilicate
Trisilicate
Normal 0.08 0.17 0.151 0.01 0.10 0.04 0.01 0.002 0.08 0.22 0.04
0.19 0.023 0.19 0.28 0.09 0.25 0.154 0.33 0.30 0.11 0.33 0.225 0.25
0.32 0.14 0.32 0.266 0.27 0.36 0.28 0.36 0.327 0.31 0.41 0.30 0.38
0.37
this reason it cannot be saturated with foodstuffs adsorbedfrom
the gastric contents. - A great reserve will alwaysbe left for the
removal of soluble necrotic products at theulcer site and of toxic
substances in general.
3. It has strong antipeptic powers available for theprotection
of the ulcer base from destructive digestion.Since its adsorptive
action is sustained, and cannotquickly be used up, trisilicate
arrested in the crater shouldestablish a local pepsin-free zone
even when pepticdigestion is proceeding freely in other parts of
thestomach.
4. As its antacid power is utilized, hydrated silica isliberated
in a form possessing strong adsorptive affinitiesfor pepsin, food
poisons, and other substances.* Thisactivity of the end-product
intensifies the adsorbent effectof the parent substance, magnesium
trisilicate.
5. It can be given in large doses without disturbingthe general
motility of the digestive tract. It does notcause either
constipation or diarrhoea.
6. No matter how great a quantity may be given itcannot reduce
the gastric reaction materially below theneutral point.
7. Being completely insoluble in water any unusedexcess is
voided in the stools. It cannot be absorbed,and so produce direct
alkali poisoning.
Illustrative CasesFifteen patients in whom the existence of
chronic peptic
ulceration in stomach, duodenum, or jejunum had beenestablished
by clinical examination, x-ray visualization,and by the association
of hyperchlorhydria, with evidenceof high alimentary bleeding, were
treated with syntheticmagnesium trisilicate. No Qther antacid
preparation wasemployed, either in the form of buffer salts or of
alkalis.The patients were kept in bed on two-hourly feeds. Assoon
as pain was under control, and tests for occult bloodin the stool
were negative, a three-hourly regimen wassubstituted. Feeds at
first consisted of milk preparedwith Irish moss, custard, junket,
cream, milk jelly, eggbeaten in milk and proprietary milk foods
wi-th theaddition of a little orange juice, grape fruit
juice,vegetable pur6e, and marmite as soon as all pain
haddisappeared.
* British Medical Journal, February 1st, p. 205.
The dosage of magnesium trisilicate was kept low in thehope that
a sufficient acid-free and pepsin-free zone mightbe established
locally in the ulcer crater, as already dis-cussed, without there
being any necessity to neutralizethe gastric contents as a whole.
The clinical resultsencourage one to believe that such actually was
the case.The preparation of magnesium trisilicate used was
mag-sorbent, which on drying lost 10 per cent. of moisture,and on
ignition an additional 15 per cent. of more closelycombined water.
It was given in doses ranging from 7 to28 grains midway between
each feed, so that the patientsreceived only 5 to 21 grains of the
anhydrous sub-stance at a time. These are relatively small
doseswhen compared with the data in Table III for thecontrol of the
acid response to a standard test meal.Nevertheless they were
adequate to secure satisfactoryclinical results.In only one
instance did any persistent difficulty arise.
The patient was a man aged 38, with recurrent deepduodenal
ulceration confirmed radiographically and withan exceptionally
severe hyperchlorhydria, the total acidityrising above 0.4 per
cent. The full 21 grain, dose wasrequired to control his pain
symptomatically, and sevenweeks' treatment was needed to rid him of
his painpermanently and of traces of " occult " blood from
thestool.
In every other case the desired result was obtainedwith doses
not exceeding 16 grains (anhydrous weight),but with very high acid
figures it would appear advisableto use a higher scheme of dosage.
Half an hour beforeeach feed one to four teaspoonfuls were given
(dose deter-mined by bowel action) of an emulsion of paraffin in
awatery dispersion of colloidal kaolin, in order to
eliminateattrition at the ulcer site and impedance at the
pylorusand duodeno-jejunal flexure. Regular bowel action
wasmaintained carefully, colon lavage being used as a rulein
preference to purgatives.Three brief case histories will suffice to
indicate the
type of patient treated.
CASE I.-Duodenal UlcerC. H., aged 24, with five years' history
of attacks of pain
one to one and a half hours after meals, relieved by
food.Occasional vomiting. An x-ray photograph in May, 1934,showed
deformity of duodenal bulb. Another in September,1934, confirmed
it. The test meal revealed a moderate hyper-chlorhydria, no gastric
delay.
Occult Blood Test, (Faeces)
Date Pain X-RayGuaiac Haemato-porphyrin
October 15 ... ... 2 + 2 + + Duodenal defect,, 18 ...... 2+ 2+
+
Magnesium trisilicatecommenced
October 25 ... ... 2+ 2+,, 29 + 2+_
it 30 .. ... + + _November 2 ... ... +
it 7 _ ...
to 12 ... ... Normal14 (discharged) - _
CASE II.-Gastric UlcerWV. E., aged 28, had recurrent attacks of
epigastric pain
half an hour after meals. There had been severe haema-temesis
and a secondary anaemia. There was well-markedhyperchlorhydria, but
no gastric delay.
4. .., I- - .. - I. " I,. I - --1
-
-37.
Occult Blood Test(Faecs) HaemoglobinDate (Blood)
Haemato- Per Cent.Guaiac porphyrin
September 23-haematemesis (No iron or trans-fusion givcn)
October 9 ... ... ... 2+ 2+ 3813. ... ... 2f 2+ - 3915 ... ... +
+ 3816 '
...+ + 36
19 miagnesium tri- + + 38silicate commenced20 ... ... - + 4521
... ....... - 5524
......
- 5626 ... ... - 5531
... ........- co
Novembvr 5... ... ... 70
9 ... ... - 75
CASE III.-Jejunal UlcerJ. B. B., aged 48, had suffered from
dyspepsia since 1925.
In 1927 appendicectomy was performed. In 1930 an investi-gation
revealed hyperchlorhydria and gastric bleeding. In1931 he had
posterior gastro-jejunostomy for a chronic pre-pyloric ulcer. In
1933 the ulcer was still active, and apartial gastrectomy was
undertaken. In 1934 there were dailybouts of left epigastric pain,
not closely related to meals.The patient had severe constipation,
general exliaustion, andloss in weight. An x-ray examination showed
the deep craterof a jejunal ulcer. There was much occult blood in,
the faeces.
OIl the routine treatment previously outlined, and a doseof 5
grains (anhydrous weight) of the trisilicate between everyfeed, the
pain quickly disappeared and the general conditionimproved.
Although the pain had recurred daily for morethan six months, he
was able to start convalescence with apain-free abdomen and a
radiologically normal jejunum aftersixteen days of treatment.The
clinical results were equally satisfactory in the
remaining cases, and further detailed descriptions wouldbe
wearisome. Synthetic hydrated trisilicate of mag-nesium quite
clearly supplied an effective medicinal con-trol for all. The
special features of its employment are:(1) The combination of three
therapeutic actions in asingle substance-namely, antacid,
antipeptic, and anti-toxic, each of which fulfils a useful role in
the stomachand duodenal bulb. (2) A sustained action
wherebyhydrochloric acid, destructive ferments, and toxins canbe
removed continuously for several hours after the ad-ministration of
a single dose. (3) The possibility of alocal therapy at the ulcer
base independently of changesoccurring in the gastric contents as a
whole. (4) Freedomfrom the risk of inducing toxic alkalosis.
Summary1. Synthetic hydrated magnesium trisilicate possesses
antacid and general adsorbent properties, readily applica-ble to
the treatment of chronic peptic ulceration andhyperchlorhydric
dyspepsia (discussed more fully in thetwo preceding papers).
2. It differs from all other antacids in clinical use inthe
vigour of its adsorbent action, as measured by themethylene-blue
method (Table I).
3. Its neutralizing action continues for several hourseven in
the presence of an excess of acid, and exerts asustained control
over gastric hyp-eracidity (test mealgnaly-ses, Table II, and
curves).
4. This prolonged neutralizing action enables a mini-mum amount
of mineral base to control hyperchlorhydria
continuously. The quantity. required is far .below thatwhicdi
has been known to produce toxic -symptoms ofalkalosis. The
trisilicate itself is insoluble in water andweak alkalis, so that
any unused excess remains un-absorbed.
5. The possible local therapeutic action in the ulcercrater is
discussed.
6. A series of successfully treated cases of chronic
pepticulceration is quoted in which the only antacid
substanceadministered was synthetic hydrated trisilicate
ofmagnesium.
OESTROGENIC ACTION OF COMPOUNDSOF THE ANDROSTERONE-TESTOSTERONE
SERIES
BY
R. DEANESLY, D.Sc.AND
A. S. PARKES, Sc.D., F.R.S.(From the National Institute for
Medical Research, London)
It has been known for some years that extracts oftestis and male
urine may show oestrogenic activity,"but this has usually been
ascribed, to the presence inthe extracts of oestrogenic substances,
probably of theoestrone group, in addition to male hormone. The
factthat large amounts of oestrone can be isolated fromstallion
urine by mild chemical treatment is, of course,strong evidence in
favour of this view,2 but a purelyoestrogenic substance has never
actually been isolatedfrom other male mammals. It is now recognized
thatsubstances of a more or less similar chemical nature tooestrone
may have some degree of oestrogenic power,even if their primary
biological activity is-of quite adifferent nature.; Further, it has
been found possibleto hydrogenate testrone, which itself shows no
malehormone activity, to a substance having male hormoneactivity
but no oestrogenic power.4 It is not unlikely,therefore, that
substances having both male hormoneand oestrogenic properties may
occur naturally. The firstmale hormone obtained, androsterone,
isolated from maleurine by Butenandt5 and prepared artificially
from chole-sterol by Ruzicka and his co-workers,6 was found to
benon-oestrogenic by the vaginal cornification test7 and bya
plumage test.8 Butenandt and Kudszus,9 however, haverecently
reported that tranis-dehydroandrosterone, andro-stenedione, and
testosterone cause opening of the vaginain the intact immature rat.
The first of these substancesis present in human male urine and has
some malehormone activity (Butenandt and Dannenbaum) .1
Testo-sterone, however, isolated from testes by Laqueur andhis
co-workers," is the most active male hormone sofar described.
Saturated and Unsaturated CompoundsButenandt's work provided the
first evidence that
naturally occurring compounds might show the activitiesof both
ovarian and male hormones. The three com-pounds found to be
oestrogenic by Butenandt are allunsaturated, and therefore more
similar to oestrone thanis androsteroxe, but certain saturated
compounds of theseries, including androstanediol (the dihydroxy
derivativeof androsterone), are also oestrogenic on the intact
im-mature rat.'2 Moreover, androstanediol increases the sizeof the
uterus and vagina' of the adult ovariectomize'drat. 13
