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AMERICAN
JOURNAL OF PHARMACY
AND THE SCIENCES SUPPORTING PUBLIC HEALTH
Since 1825
LINWOOD F. TICE, Ph. G., B. Sc., M. Sc., Editor
Austin A. Dodge, Ph. C., B. Sc., Ph. D., Assistant to the Editor
John E. Kramer, B. Sc., Business Manager
COMMITTEE ON PUBLICATION
E. Fullerton Cook, P. D., Ph. M., M.S., Chairman
Mitchell Bernstein, P. D., M. D., Louis Gershenfeld, P. D., Ph. M.,
F. A.C. P. D. Sc.
Marin S. Dunn, A. M., Ph. D. John K. Thum, Ph. G., Ph. M.*
J. W. Sturmer, Phar. D., Ph. M., D. Sc., Secretary
Ivor Griffith, P. D., Ph. M., D. Sc., F. R. S. A., ex officio
* Deceased.
Vol. 120 JUNE 1948 No. 6
CONTENTS
Editorial:
Disease, Warfare or Social Progress? .......... 186
Articles:
Studies of Pteroylglutamic Acid Displacing Agents. By
Navy Pharmacy—Past, Present and Future. By C. A.
Walter Reed and the Conquest of Yellow Fever.. By P. S.
Whiskey Is a Mere Byproduct. By T. Swann Harding.. 215
DISEASE, WARFARE OR SOCIAL PROGRESS?
HE conquest of the diseases which have for years affected man-
kind is not without serious complications. For centuries the al-
most inexorable rules of nature have regularly decimated whole popu-
lations by famine and disease thus relieving the population pressure.
With fewer people the competition for land and food became tess acute
and the economic pressure less intense.
Man in his technological advance has, one after another, con-
quered diseases which previously ran rampant with little that could
be done to save their victims’ lives; only the strong survived. The
first diseases the conquest of which produced an impact on society are
those of children. Visit any old cemetery and you will be amazed at
how few children, years ago compared with today, survived their
early years. You will also be impressed with how few people reached
the age of seventy. With small-pox, diphtheria, whooping-cough,
scarlet fever, and the like running almost unchecked through the
young, and pneumonia, typhoid, malaria, syphilis and others invading
both the young and the old it was small wonder that so many died
at an early age.
Today, none of de diseases is without either an efficient pro-
phylaxis or treatment and the mortality from them is low indeed.
The result is that more people reach maturity and even old age. Life
expectancy today in the U. S. is 67 years with all evidence pointing to
its steady increase as more attention is given to geriatrics. That this
rise in life-expectancy and the average age of the population has cre-
ated social problems cannot be denied. Witness the tremendous in-
crease in interest in old age security and the steps taken to assure it.
But there is an even larger aspect to this problem. American produc-
tion is of such magnitude that we can now envision supplying the
whole world, if need be, with the drugs used to prevent and treat al-
most all diseases. Drug production in almost every country is also on
the increase and the ultimate aim of most countties is to be self-suffi-
cient in this respect. With malaria, for instance, it is now well within
(186)
June, 1948 187
the realm of possibility that this disease, which for centuries has killed
and weakened millions, may be eradicated since potent antimalarials
can be produced in unlimited quantities. A good prophylactic is now
available for African Sleeping Sickness. Think of what this will
mean to the continent of Africa! With insect control and vaccines,
yellow fever and plague can be overcome—and so it goes. Thus we
see that the principal diseases which throughout the history of man
have been responsible for the periodic death of millions can be con-
quered.
That these drugs should be made: available to all the people of
the world is indisputable but if this is done without a simultaneous
effort to have the people of the world recognize the danger of popu-
lation increase beyond that level compatible with their agricultural
productivity then we are saving lives on the one hand only to have
these people starve or be killed by competitive warfare on the other.
Just as physical scientists are criticized for developing atomic
energy before civilization had made sufficient social progress to make
it safe we may be criticized for eradicating diseases which in the past
have kept population pressures down without supplying some substi-
tute measure. That great harm and serious consequences will result
is apparent to any objective thinker. As the number of people in any
geographical area reaches the point that they cannot be fed, clothed
and housed adequately there develops social unrest which finally
reaches the point that the political leaders are forced to try some
panacea that will, temporarily at least, placate the masses. They may
turn to some collectivist form of government but this is only a tempo-
rary expedient ; sooner or later a nation which is in a more favorable
position is envied, then hated and finally attacked. War then de-
stroys a large part of the population and all the blame is placed on
war for the suffering and the tribulation of the times. Actually the
economic pressure which led to war is to blame and behind this,
overpopulation which caused economic pressure. Those who think
that population increase is a healthy sign are deluding themselves.
Typical are a few narrow-minded industrialists who see only a
widened market for their products and the leaders of totalitarian coun-
tries who see larger armies in the making. In neither case is the
long term outlook sound or pleasant.
It will not be an easy matter to develop in the backward
countries where we now propose to check disease an understanding
188 Amer. Jour. Pharm.
of the problem of population. We do not even as a nation under-
stand it ourselves. Even here bigotry and human emotions rule our
reason and it is still thought something of an accomplishment when
a couple manages to have ten, twelve or fifteen children. Even in
our land of plenty and opportunity such a number of children can
rarely be given by their parents all the food, clothing, medical care
and education needed. Nor is it reasonable to expect society at large
to compensate for this intemperate fecundity on the part of the
parents any more than the drunkard or the indolent should be sup-
ported by their neighbors.
When we ourselves as well as others are prepared to recognize
that the goal of civilization should be a high living standard for an
optimum number of world inhabitants and not to see just how many
people can be crowded into a given space, disregarding living stand-
ards, we shall be ready to make real progress. What the world needs
is not more people but people who are healthy and happy. This can
come only by adequate food, clothing and medical care plus an eco-
nomic and social outlook that is both bright and based on sound
principles.
L. F. Tice
STUDIES OF PTEROYLGLUTAMIC ACID
DISPLACING AGENTS
By Gustav J. Martin, Robert Brendel, J. M. Beiler, Jack Moss,
Souren Avakian, Harold Urist, Leo Tolman and
Sidney Alpert *
ree chemical agents fall into several categories:
1. Parasympathetic drugs such as acetylcholine which act by
peripheral vasodilatation.
2. Histamine which acts thru dilation of capillaries.
3. Nitrites which act by vasodilatation thru an effect on tonus
of muscle.
4. Adrenolytic or sympatholytic agents of the type of di-
ethylamino-methylbenzodioxane (F883), piperidomethyl-3-benzo-
dioxane (F933) and dibenamine. These agents either block the pene-
tration of epinephrine into cells (1) or render the tissue itself in-
sensitive to epinephrine.
The metabolic channels in the formation of epinephrine are
probably initiated by decarboxylation of phenylalanine, tyrosine or
dihydroxyphenylalanine. Blockage of this mechanism should prevent
the building of pressor molecules. The observation that a pteroyl-
glutamic acid displacing agent specifically inhibited dopa decarboxyl-
ase (2) and that this same agent produced a marked drop in the
blood pressure of the intact animal (3) led to the study of a series
of these agents for their depressor activity.
Experimental
A series of chemicals were tested including many pteroyl-
glutamic acid displacing agents. The series included:
2-amino-4-hydroxy-6 or 7-methyl-pyrimido- (4,5-b) -pyrazine
2,4-diamino-6,7-diphenylpyrimido- (4,5-b) -pyrazine
2,4,5-triamino-6-hydroxypyrimidine
Xanthopterin
6-Chloroquinazoline
* Research Laboratories, The National Drug Company, Philadelphia, Pa.
(189)
-
-
190 Amer. Jour. Pharm.
N-(4-(6-aminoquinazoline )-p-aminobenzoyl ) glutamic acid
N-(4-( (4-quinazoline) amino ) benzoyl) glutamic acid
N-(4-quinazoline ) -p-aminobenzenesulfonamide
N-(4-(6-nitroquinazoline ) -p-aminobenzoy]) glutamic acid
N-(4-(6-chloroquinazoline ) -p-aminobenzoy]) glutamic acid
N-(4-(6-chloroquinazoline ) -p-amino) benzoic acid
4-( ( (2-amino-4-hydroxy-6-pteridyl ) methyl ) amino ) phenol
4-( ( (2-amino-4-hydroxy-6-pteridyl) methyl) amino) hippuric acid
N-(4-(( (2-amino-4-hydroxy-6-pteridy] ) methyl] ) amino )
benzoyl) glutamic acid. (pteroylglutamic acid)
N-(4(((2-amino-4-hydroxy-6-pteridyl) methyl) amino) benzoy!)
aspartic acid. (pteroylaspartic acid)
N-(4-(( (2-amino-4-hydroxy-6-pteridy]) methyl) amino)
benzene) sulfonamide (pteridyl sulfonamide )
N-(4-(( (2-amino-4-hydroxy-6-pteridy] ) methyl ) amino )
benzene sulfonic acid (sulfonic acid analogue of pteroic acid)
Methyl pteroate
(methyl ester of pteroic acid)
N-(2-methylbenzimidazole) p-aminobenzoic acid
N-(2-methylbenzimidazole) p-aminobenzene sulfonamide
N-(2-methylnaphthy] ) p-aminobenzoic acid
N-(4-(( (2,4-dihydroxy-6-pteridyl) methyl] ) amino) benzoyl )-1(-+-)
glutamic acid (oxypteroylglutamic acid)
N-(4-(( (2,4-dihydroxy-6-pteridyl ) methyl) amino) benzoic acid
(oxypteroic acid )
*Methylated oxypteroylglutamic :
Probable structure—
N-(4-(( (2,4-dihydroxy-7-methyl-6-pteridy] ) methyl ) amino )
benzoy] ) glutamic
N-(4-( (2,4-dihydroxy-6-pteridyl) methyl ) amino ) benzene
sulfonic acid
Methylated pteroylaspartic acid: ©
Probable structure—
*N-(4-( ( (2-amino-4-hydroxy-7-methyl-6-pteridy] ) methy] )
amino) benzoyl )aspartic acid
June, 1948 . 191
Methylated pteroylglutamic acid :
Probable structure—
*N-(4-( ( (2-amino-4-hydroxy-7-methyl-6-pteridy] ) methyl] )
amino ) benzoyl) glutamic acid
Pteroic acid
2-Chloro-4-( ( N-(2-amino-4-hydroxy-6-pteridy] ) methyl] )
amino) benzoic acid (chloropteroic)
*2-Chloro-4- ( ( )
methyl )amino benzoic acid
(chloromethylpteroic) (probable structure)
*N-(4-(( (2-amino-4-hydroxy-7-methyl-6-pteridyl ) methyl] ) amino)
benzoic. acid (methyl pteroic acid) (probable structure)
Chemical
For compactness in presentation, details of the synthesis of three
types of displacer will be given but not that of each compound in the
series. In general, the methods parallel that of Angier et al. (4)
for the preparation of pteroylglutamic acid. The compounds except
in specified instances were not obtained in pure form. Samples of
oxypteroic and of methylpteroic acids were obtained in pure form
and tested in the various systems. Results were identical with those
obtained using the unpurified chemical.
Synthesis of N(4(((2-amino-4-hydroxy-6-pteridyl) methyl)
amino) hippuric acid.
To a solution of 10 g. of sodium glycine in 200 cc. of water, was
added 18.5 g. of p-nitrobenzoylchloride and 100 cc. of 1N sodium
hydroxide solution in half an hour. The mixture was stirred for
two hours, filtered, acidified, and the precipitate washed with cold
water. The air dried product melted at 127-129°.
The above nitro derivative was dissolved in 200 cc. of alcohol
and reduced at 60-30 Ibs. After filtration the solution was concen-
trated and the product filtered. This was used directly in the next
reaction.
* These preparations are used in a crude form and while they definitely
contain a compound with the methyl group at 7, they also contain other
molecular modifications the structure of which has not yet been determined.
They are prepared as described by Martin et al. (10). When used in impure
form, therefore, consideration must be given to the possibility that other
molecular configurations may play a role.
¢
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:
192 Amer. Jour. Pharm.
A solution of 21 g. of 1,2-dibromopropionaldehyde in 200 cc.
of ethyl alcohol was added slowly and with stirring to 21 g. of 2,4,5-
triamino-6-hydroxypyrimidine and 18 g. of p-amino hippuric acid
suspended in an acetate buffer (prepared by dissolving 54 cc. of acetic
acid and 57 g. of sodium acetate in one liter of water). The resulting
mixture was stirred for two hours at 30-35°, filtered, and the pre-
cipitate washed with water. The product was dissolved in dilute
sodium hydroxide solution and precipitated at pH3. The precipitate
was washed with water, alcohol, and ether to give a_ light
brown product, N (4( ( (2-amino-4- 6-pteridy] ) amino ) methy!)
hippuric acid.
Preparation of oxyfolic acid.
The following intermediates were mixed in a buffer solution for
three hours at room temperature: p-aminobenzoylglutamic acid, 26.6
gm. (.1 mole) ; 5,6-diaminouracil bisulphate, 33.6 gm. (.1 mole) ;
acrolein dibromide, 21.6 gm. (.1 mole).
The buffer solution was prepared as follows: a mixture of 66.9
gm. of anhydrous sodium acetate and 54.4 gm. gl. acetic acid was
diluted to 1 liter of water—600 ml. of this buffered solution was used
in the reaction.
The reaction mixture was allowed to stand overnight and the
brown precipitate which formed was collected and air dried. There
was obtained 23 gm. of crude product which was purified by dissolv-
ing in dilute sodium hydroxide, filtering and precipitating with di-
luted hydrochloric acid. There was obtained 10.35 gm. of a brown
powder. Yield 23.5%. Overall yield 4.5%. No m.p. could be ob-
tained.
Preparation of 2-chloro-4-((N-(2-amino-4-hydroxy-7-methyl-6-
pteridyl)methyl)amino)benzoic acid.
To 500 cc. of acetate buffer solution (pH 4) was added 12 g. of
2-chloro-4-aminobenzoic acid, 16 g. of 2,4,5-triamino-6-hydroxy-py-
rimidine bisulfite and 19 g. of dibromobutyraldehyde. This mixture
was stirred for three hours at room temperature. The red solid was
filtered and washed well with water and then with ethanol. This
material was dissolved in dilute sodium hydroxide and _ filtered.
Acidification of the filtrate gave 9.5 g. of brown powder after a
thorough washing with water and ethanol.
Ju
6-pte
phenc
4-( ((
6-pter
hippu
Meth:
June, 1948
This material had no melting point and appeared to be a mix-
ture of compounds.
Each member of the above series of compounds was tested in
three systems: 1. Metabolite displacement capacity against pteroyl
glutamic acid (5). 2. Capacity to specifically inhibit dopa decar-
boxylase (5). 3. Hypotensive action in the intact animal.
Bacteriological testing involved the use of S. faecalis (lactis)
R(8043) in the folic acid assay technique of Mitchell et al. (6).
Results are listed as Inhibitor/Metabolite ratios.
Studies of enzyme inhibition involved dopa decarboxylase which
was prepared according to the method of Holtz and Credner (7).
Rat kidney was ground with sand in five volumes of M/20 phos-
phate buffer pH 6.5. The suspension was centrifuged and the super-
natant assayed in the Warburg apparatus. Each cup contained 2
cc. of the enzyme preparation and 0.5 cc. of a solution of the dis-
placing agent in water. The side bulb contained 3 mg. of 1(-) dopa
dissolved in 0.5 cc. of water. The manometers were filled with
nitrogen and equilibrated at 37° C. for 15 minutes. At the end of
this time the substrate was tipped into the center compartment and
the reaction was run for 15 minutes. It was found that no COg was
evolved after this period. Results are listed in concentration per ml.
which produce a given degree of inhibition.
Hypotensive action was determined by standard pharmacological
technique on the dog. Results are listed as average drop in blood
pressure for six dogs following initial injection of compound.
The results are presented in Table I.
TABLE I
BroLocicAL ACTION OF VARIOUS CHEMICALS RELATED STRUCTURALLY TO
PTEROYLGLUTAMIC ACID
Inhibitor
Metabolite
Effect on Effect on Dopa Ratio for
Compound Dosage Blood Pressure Decarboxylase Strep. faecalis
4-(( (2-amino-4-hydroxy- 5 mg/kg —90 mm. 1 hr. 300y/cc 0% Probably in-
6-pteridyl ) methyl) amino) active. Too
phenol : insoluble.
4-(((2-amino-4-hydroxy- 5mg/kg —60mm.10min. 300y/cc 20% > 1000
6-pteridyl ) methyl) amino)
hippuric acid
Methyl pteroate 5 mg/kg Inactive 300y/cc 0% Inactive
.
193
ay
194
Dosage
5 mg/kg
Compound
(chloromethyl pteroic)
Probable structure
2-chloro-4- ( (N-(2-amino-
4-hydroxy-7-methyl-
6-pteridyl) methyl) amino)
benzoic acid
(chloropteroic ) 5 mg/kg
2-chloro-4- ( (N-(2-amino-
4-hydroxy-6-pteridy])
methyl) amino) benzoic acid
N-(4-(( (2,4-dihydroxy-
6-pteridyl ) methyl) amino)
benzoyl) 1(-+-) glutamic acid
(oxypteroylglutamic )
N-(4-(( (2,4-dihydroxy-
6-pteridyl ) methyl) amino)
benzoic acid
(oxypteroic)
N-(4-(( (2-amino-
4-hydroxy-6-pteridy])
methyl] ) amino) benzoyl)
aspartic acid
(pteroylaspartic acid)
N-(4-( ( (2-amino-
4-hydroxy-6-pteridy])
methyl) amino)
benzene) sulfonamide
(pteridylsulfonamide )
N-(4-( ( (2-amino-
4-hydroxy-6-pteridy])
methyl) amino)
benzene) sulfonic acid
5 mg/kg
5 mg/kg
5 mg/kg
1 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
6-chloroquinazoline
N-(4-(6-amino- 20 mg/kg
quinazoline ) -p-amino
benzoylglutamic acid
N-(4-( (4-quinazoline)
amino) benzoyl)
glutamic acid
N-(4-quinazoline) -
p-amino-benzene
sulfonamide
25 mg/kg
2 mg/kg
N-(4-(6-nitroquinazo- 100 mg/kg
line) p-aminobenzoyl)
glutamic acid
Effect on -
Blood Pressure
—45 mm. 30 min.
—40 mm. 25 min.
—30 mm. 10 min.
—80 mm. 10 min.
—50 mm. 15 min.
No effect
—80 mm. 30 min.
—80 mm. 12 min.
—40 mm, 2 min.
No effect
+25 mm. 35 min.
No effect.
Too insoluble
to test at
higher conc.
No effect
Amer. Jour. Pharm.
Inhibitor
Metabolite
Effect on Dopa Ratio for
Decarboxylase Strep. faecalis
300y/cce 35% 10
300y/cc 0%
Nonspecific Inactive
Nonspecific Inactive
300y/cc 50% 1-10
Inactive
Insoluble Inactive
No Test
300y/cc 0% Inactive
300y/cc 0% Inactive
|
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June, 1948
Compound Dosage
N-(4-(6-chloroquinazo- 100 mg/kg
line ) -p-aminobenzoyl
glutamic acid
N-(4-(6-chloroquin- 25 mg/kg
azoline ) -p-amino- 100 mg/kg
benzoic acid
Suramine 5 mg/kg
2-amino-4-hydroxy-6 5 mg/kg
(or 7)-methyl-pyrimido
(4,5-b) pyrazine
2,4,5-triamino- 20 mg/kg
6-hydroxypyrimidine
2,4-diamino-6,7-diphenyl 5 mg/kg
pyrimido (4,5-b) pyrazine 10 mg/kg
xanthopterin 17.2 mg/kg
2,4-dihydroxypteridine
(Lumazine)
2-amino-4-hydroxy-pyrimido
(4,5-b) pyrazine
*N-(4-( ( (2-amino-
4-hydroxy-7-methyl-
6-pteridy!l ) methyl ) amino)
benzoyl ) aspartic acid
(methyl pteroyl aspartic)
*N-(4-( ( (2-amino-
4-hydroxy-7-methyl-
6-pteridyl ) methyl ) amino)
benzoy1 ) glutamic
(methyl! pteroyl glutamic)
(methyl folic acid)
*N-(4-( (2-amino-
4-hydroxy-7-methyl-
6-pteridyl ) methyl ) amino)
benzoic acid
(methyl pteroic acid)
N-(4-( (2,4-dihydroxy-
6-pteridyl ) methyl) amino)
benzene sulfonic acid
*N-(4-( (2,4-dihydroxy-
6-pteridyl-7-methy])
methyl) amino) benzoyl)
glutamic acid
(methylated oxypteroylglutamic)
5 mg/kg
1 mg/kg
5 mg/kg
1 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
Effect on
Biood Pressure
No effect
No effect
—60 mm.
1 hr. 40 min.
—20 mm. 36 min.
—70 mm. 45 min.
No effect
No effect
—40 mm. 6 min.
No effect
mm. 10 min.
No effect
—40 mm. 30 min.
—60 mm. 3 min.
—74 mm. 30 min.
—40 mm. 5 min.
—80 mm. 15 min.
Effect on Dopa
Decarboxylase
300y/cc 75%
30y/cc 40%
300y/cc 0%
Too insoluble
to test at
higher conc.
Too insoluble
to test
300y/cc 0%
Suspension at
300y/cc 0%
30y/cc 30%
30y/cc 25%
30y/cc 17%
195
Inhibitor
Metabolite
Ratio for
Strep. faecalis
Inactive
Probably in-
active. Too
insoluble.
Inactive
0.05
Inactive
10
* Probable structure.
i
1s
|
196 Amer. Jour. Pharm.
Table 2 shows the tachyphylaxis-like phenomena associated with
certain members of this series as reflected in their hypotensive action.
The table compares oxypteroic and methylpteroic acids and clearly
indicates the tremendous differences observed with different members
of the series. .
TABLE II
“TACHYPHYLACTIC”
PHENOMENA ASSOCIATED WITH THE PHARMACOLOGICAL
ACTION OF PTEROYLGLUTAMIC AciIpD DIsPLaciInc AGENTS
Blood pressure effect of 5 doses (5 mg/kg each)
given in sequence to a single animal
Compound 1 2 3 4 3
Oxypteroic acid —70 mm. —60 mm. —50 mm.
10 min. 10 min. 8 min.
—62 mm. —50 mm —42 mm. —28 mm. —24 mm.
15 min. 10 min. 10 min. 10 min. 10 min.
—110 mm. —86 mm. —82 mm. —44 mm.
10 min. 10 min. 10 min. 10 min.
Methylpteroic —60 mm. —20 mm. Noeffect Noeffect No effect
5 min. 3 min.
—74 mm. —28 mm. Noeffect Noeffect
30 min. 20 min.
—60 mm. —l6 mm. Noeffect Noeffect No effect
10 min. 3 min.
The tachyphylactic phenomena does not seem to be permanent
in nature. In two dogs, 5 mg/kg of oxypteroic acid was given at
10 A.M. and at 3 P.M. The next day at 10 A.M., these dogs re-
sponded to injections of oxypteroic acid (5 mg/kg) in a manner in-
distinguishable from that seen in a dog which had never received
such injections. The blood pressure dropped 64 mm. for 14 minutes
as an average for the two animals.
Orally, the agents are apparently inactive. One hundred sixty-
one mg. of oxypteroic acid per kilogram was administered to one
dog. The animal was checked for a period of four hours and during
that period the blood pressure had not been altered. Five hundred
mg. of methylpteroic per kilogram was administered orally to one
cat with no response in five hours.
Discussion
Effective displacing agents may be formed from the basic pteroyl-
glutamic acid molecule by modifying the pteridyl ring (methylpteroic
acid or oxypteroic acid), by modifying the p-amino-benzoic acid
j
June, 1948 ; 197
moiety (chloromethylpteroic and chloropteroic) or by modifying the
glutamic acid moiety (pteroylaspartic or 4-(( (2-amino-4-hydroxy-
pteridyl)methyl)amino)hippuric acid). Furthermore, the molecule
may be changed at several points and still remain an effective agent.
This is seen with chloromethylpteroic acid, methylpteroylaspartic
acid, and in methyloxypteroylglutamic acid.
While general correlation is obtained between the capacity of a
given molecule to inhibit dopa decarboxylase and its ability to lower
blood pressure, the correlation is not absolute. 4-(( (2-amino-4-hy-
droxy-6-pteridyl) methyl) amino) phenol is a powerful blood pressure
depressant but is inactive in the vitro enzyme system against dopa
decarboxylase. The oxypteroic acid molecule is another instance; it
is inactive as a displacer for folic acid in the S. faecalis system,
it is non-specific in its action on dopa decarboxylase, it is specific and
highly effective in its capacity to reduce blood pressure in the dog.
However, correlation of the activity of a molecule in the three systems
under test is generally found.
For hypotensive action, the pteroic acid analogues are superior
to the pteroylglutamic acid analogues. This is seen from Table I
by comparing methylpteroic and methylpteroylglutamic acids, oxyp-
teroic and oxypteroylglutamic acids, and N-(4-(6-chloroquinazoline )
p-aminobenzoic acid with N-(4-(6-chloroquinazoline) -p-amino-
benzoyl-glutamic acid. It is further true that the capacity to lower
blood pressure also resides in simpler compounds of the pyrimi-
dopyrazine type, thus, 2-amino-4-hydroxy-6(or 7)-methylpyrimido-
(4,5-b) pyrazine is active. Even a molecule quite far removed in
structure, such as 6-chloroquinazoline possesses a hypotensive action
in the dog.
Metabolite inhibitor ratios were determined for the three sys-
tems in the instance of the methylpteroylglutamic, methylpteroic,
oxypteroylglutamic and oxypteroic acid. For the S. faecalis system,
the metabolite inhibitor ratio is within the range of 1 to 10. In the
dopa decarboxylase system, the ratio is 0.1 to 0.01. In other words,
a concentration of folic acid from 10 to 100 times that of the displacer
nullifies the displacer action. The ratio for nullification of the
hypotensive action of a displacer parallels roughly that seen in the
dopa decarboxylase systems. Two hundred fifty mg. of folic acid per
kilogram nullify the hypotensive action of 10 mg. of displacer. This,
therefore, gives an inhibitor metabolite ratio of 0.04.
4
198 . Amer. Jour. Pharm.
The oral administration of methyl pteroylglutamic acid pro-
duced no effect even in doses of 500 mg. per kilogram. This could
mean either insolubility of the compound or its destruction in the in-
testinal tract. Pteroylglutamic acid itself is effective orally and is
comparable from a solubility and stability standpoint.
Another point of interest is the speed with which these de-
pressor agents produce tolerance or tachyphylaxis. It is well-known
that compounds of this general type are extremely difficult to purify.
Purification can be accomplished but losses are terrific and end
product amounts do not permit extended pharmacological testing.
The biological conversion of tyrosine to adrenaline has long been
regarded as probable (8). Recently, Gurin and Delluva (9) have
established the point by demonstrating the conversion of radioactive
phenylalanine to adrenaline. The decarboxylation of tyrosine to tyra-
mine is the probable first step in this mechanism. It is logical to
expect inhibition of this system to result in defective adrenaline for-
mation and consequent lowering of blood pressure. Pteroylglutamic
acid displacing agents are specific inhibitors of decarboxylase mechan-
isms (2). It is therefore not surprising that these agents produce
a drop in blood pressure when injected into the animal organism.
Summary
A series of pteroylglutamic acid displacing agents and related
compounds have been synthesized and tested in three systems: 1. dis-
placer in bacterial system, 2. displacer in dopa decarboxylase sys-
tem and 3. depressor agent in the dog.
REFERENCES.
(1946) Raab, W., and Humphreys, R. J.: J. Pharm. and Exp. Therap., 88, 268
% Martin, Gustav J., and Beiler, J. M.: Arch. Biochem., 15, 201 (1947).
(19475 Martin, Gustav J., Tolman, L., and Brendel, R.: Arch. Biochem., 15, 323
4. Angier, R. B., Boothe, J. H., Hutchings, B. L., Mowat, J. H., Semb, J.,
Stockstad, E. L. R., SubbaRow, Y., Waller, C. W., Cosulich, D. B., Fabren-
bach, M. J., Hultquist, M. E., Kuh, E., Northey, E. H., Seeger, D. R., Sickels,
J. P., and Smith, J. M.: Science, 103, 667 (1946).
5. Martin, Gustav J., Avakian, S., Tolman, L., Urist, H., and Moss, Jack:
112th A. C. S. Meeting, Sept. 15-19, 1947, page 2C.
(19415 Mitchell, H. K., and Snell, E. E.: Univ. Texas Pub. No. 4137, 36
7. Holtz, P., and Credner, K.: Arch. Exp. Path. Pharm., 199, 145 (1942).
(1936) Schuler, W., Bernhardt, H., Reindel, W.: Z. physiol. Chem., 243, 90
9. Gurin, S., and Delluva, A. M.: J. Biol. Chem., 170, 545 (1947).
“sey Martin, Gustav J., Tolman, L., and Moss, J.: Arch Biochem., 12, 318
NAVY PHARMACY—PAST, PRESENT AND FUTURE*
By C. A. Swanson, Rear Admiral, MC
Surgeon General, U. S. Navy
HE profession of Pharmacy has full reason to be proud of this
historic occasion. It is fitting and proper that American Phar-
macy dedicate a memorial to its members who have served in the
wars of our country. This imposing memorial, standing beside your
National Headquarters, appropriately reflects the high place of
Pharmacy in peace and in war—in the past, the present and the
future. This recognition of the services of. pharmacists to the armed
forces is especially timely and impressive. Wars are rarely fought
by professional military men alone. In times of national emergency
the services have always called upon reserve units and trained
civilians to complement the regular fighting forces. By necessity
this has meant that many pharmacists have served in our wars in
capacities foreign to their chosen civilian vocation. It is for this
reason I make the observation that this occasion is of more than
ordinary significance. Your actions here recognize the fine American
spirit of team play in a common cause, as well as particular devotion
to your profession.
The Navy Medical Department is justifiably proud of its record
in caring for the sick and injured—in peace and in war. No small
part of this enviable accomplishment is associated with the use of
effective drugs and the skills of Pharmacy. The Navy has long recog-
nized the essential place of the functions of Pharmacy in medical
practice.
The forced utilization of pharmacists by the Navy in other than
their professional capacity parallels the situation in scores of other
professional fields which are not directly related to warfare. I
know that this circumstance caused your profession much concern
during both world wars. It has also concerned the other professions
confronted with the same problem. While military necessity will
always govern the utilization of manpower the position of Pharmacy
is more favorable than that of most of the other non-military pro-
fessions.
* Address given at the A. Ph. A. Conference on Pharmacy in Peace and
War, May 6, 1948, Washington, D. C
(199)
200 Amer. Jour. Pharm.
The Past
The essential practices of what we know today as Pharmacy
were carried on by all of the ancient civilizations centuries before
Pharmacy possessed a name; a literature; an educational program
or a respected position in organized society. On the valiant ships
of the Revolutionary War Navy, functional Pharmacy was practiced
more than half century before the American Pharmaceutical Associa-
tion was organized; the U. S. Pharmacopoeia issued, or a College
of Pharmacy established in America.
In contrast to the elementary Pharmacy services as a functional
necessity in the early Navy, the distinguished Dr. E. R. Squibb
placed Navy Pharmacy on a professional plane while serving as
Assistant Director of the Navy Pharmacy Laboratory from 1852 to
1857. Following Dr. Squibb’s return to civil life to found the
pharmaceutical house bearing his name today, Navy Pharmacy re-
verted to a good quality, but very practical level, of routine operations.
Incomplete records indicate that the Navy attempted, without success,
to replace Dr. Squibb as director, and to interest pharmacists generally
in Naval service. Failure in this effort forced upon the Navy the
practice of in-service training of functional pharmacists.
The Navy has had the advantage of good practical Pharmacy
for many years. All members of the Hospital Corps receive basic
training in the science of Pharmacy and selected men have received
extensive specialized training in this field. Your profession has
understandably objected to use by the Navy of the terms “Phar-
macist’s Mate,” “Pharmacist” and “Chief Pharmacist,” for in-serv-
ice trained men who have not, in all cases, qualified under civilian
standards for such title. However, the early adoption by the Navy
of the designation “Pharmacist,” and the long continued use of the
title, is evidence of the high regard in which the skills of your pro- —
fession are held by the Navy Medical Department. This also denotes
recognition of the essentiality of operating Pharmacy services in
the care of the sick and injured. .
During World War II hundreds of pharmacists served with
credit in the Navy Medical Department. The insatiable demands
of war and absence of appropriate legislation forced the vast majority
of these pharmacists to serve as enlisted men or Warrant and Chief
Warrant Officers in the Hospital Corps. Additional hundreds of phar-
macists, through military necessity, served the Navy as officers in the
i
June, 1948 201
line or in other non-pharmaceutical pursuits. While all of these phar-
macists undoubtedly contributed to the final victory, it is possible the
Navy did not achieve the maximum advantage from these profession-
ally educated men because of their assignment to duties which did not
utilize their extensive civilian training.
The Present
The present place of Pharmacy in the Navy raises a real chal-
lenge for both the Navy and your profession. By cooperative effort,
legislation was enacted last August, which established a definite place
for limited numbers of pharmacists as officers in the Medical Serv-
ice Corps of the Medical Department. This marks the accomplish-
ment of a long standing objective, opening the way for Pharmacy
Officers to take their proper place in the Medical Department of the
Navy. Last month the use of the former titles “‘Pharmacist’s Mate”
and “Pharmacist,” for hospital corps personnel, was discontinued.
Thus the Navy has abandoned use of a title for in-service trained
personnel which was in conflict with the generally accepted standards
for civilian trained pharmacists. Since the American Pharmaceutical
Association in 1894 created a “special committee on the status of
pharmacists in the Army and Navy,” you have sought to achieve these
circumstances. The present position of Navy Pharmacy holds abun-
dant opportunities for the mutual gain of the Navy and your profes-
sion. Parallel responsibilities are inherent in all opportunities. The
challenge before us is.the prompt acceptance of the responsibilities and
the implementation of these new opportunities.
I have forcefully indicated my confidence in the capacities of
pharmacists to contribute to the further accomplishments of the
Navy Medical Department. I have spelled out in some detail the type
of professional services we expect from Pharmacy Officers. We have
laid down a general pattern for the duties of Pharmacy Officers in
various types of Naval medical activities. We have established an
orientation course for newly integrated Pharmacy Officers to facilitate
their assimilation into the Medical Department. We have proposed
an amendment to the Medical Service Corps Act which would permit
qualified pharmacists to be commissioned in the regular Navy, directly
from civil life. We have created a Pharmacy section in the pro-
fessional division of the Bureau of Medicine and Surgery, with re-
sponsibility for Navy Pharmacy matters. We have announced a
a:
202 Amer. Jour. Pharm.
program for the Inactive Volunteer Medical Reserve, including billets
for 480 Reserve Pharmacy Officers in the 240 divisions. Other
progressive plans are rapidly taking form for the full and proper
utilization of the services of professional Pharmacy in the Medical
Department of the U. S. Navy. We believe that our development of
the place of Pharmacy in the Navy will be both sound for the service
and gratifying to your profession. The challenging responsibility
for action to accomplish our joint objectives now rests with Phar-
macy.
The Future
Within the immediate future we hope to have a Pharmacy
Officer in charge of all pharmaceutical operations in each of our major
hospitals and dispensaries. When this has been accomplished we
expect our present good Pharmacy to become outstanding Pharmacy.
We will always need enlisted pharmacy technicians who must be
trained by the Navy. To produce the best qualified men for this type
of service we want to assign Pharmacy Officers, with teaching ex-
perience, to our Pharmacy Technicians School and to the several
basic Hospital Corps Schools. Our materiel division is concerned
with technical operations requiring the services of officers with a
broad understanding of pharmacy, chemistry, scientific equipment
and related fields of knowledge. Where Pharmacy Officers with ex-
perience in these areas are feasibly available they will be so utilized.
Pharmacy Officers with appropriate backgrounds can be assigned,
with mutual advantage, in connection with drug and chemical pro-
curement, testing and usage. There are unfilled needs for Pharmacy
Officers on Hospital Ships and in certain research projects. Some
Medical Department publications on subjects related to Pharmacy
await availability of qualified officers to undertake revision.
It is not news to tell you that we need manpoéwer—in particular,
Pharmacy manpower. The filling of a Navy manpower shortage, how-
ever, is completely secondary to professional and personal qualifica-
* tion. All Navy standards are high. Navy Medical Department per-
sonnel standards are beamed at perfection. While we need Phar-
macy Officers, we can not profitably use mediocre men. We need
outstanding men. We are seeking men with vision, with inspira-
tion, with potential capacities for leadership. Our Pharmacy Officers
must have creative ability and broad interests. They must adjust
themselves to a wholly new career—the proud profession of the Navy.
|
June, 1948 203
They must on occasion undertake with enthusiasm military activities
far afield from Pharmacy. Pharmacy, as a new professional member
of the Medical Department, will join in the building of a monumental
medical service. We can build only as fast and as high as the flow
and the strength of our material permits. __
Conclusion
The legislatively created Pharmacy section of the Medical Service
Corps is not a mere gesture. Navy medicine can not meet the high
trust and grave responsibility imposed by the people through tempo-
rizing with expediency. The Medical Department urgently needs the
contributions of your professional talents in the building of an even
greater medical service. Professional Pharmacy has made notable
progress during recent years, abreast with developments in Medical
Science. The time is opportune for the Navy to take full advantage
of the capacities of modern Pharmacy to aid in advancing Navy
medical care to a pre-eminent position. We dare not fail in our joint
mission. I am confident Pharmacy will rise to this challenge. The
destiny of Pharmacy in the Navy is in your keeping.
=
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. “7%
WALTER REED AND THE CONQUEST OF
YELLOW FEVER*
By Philip S. Hench, M. D.**
T the close of the Spanish-American War thousands of American
soldiers returned home to be received like conquering heroes. But
others returned home not so gloriously. Some returned in hospital
ships, soldiers whose bodies had been weakened by fever. Some
were in coffins, soldiers who had met death at the hands of an enemy
more powerful than any Spaniard. For disease, especially yellow
fever, had killed more soldiers than had the bullets of the enemy.
Day after day, strong young men became hot with fever and wracked
with pain: then they turned yellow, suffered with the dreaded “black
vomit” and died at the rate of as many as 200 a day.
“We'll stop that,” said the United States Government, and with
its Army of Occupation it sent physicians whose duty it was’ to con-
trol yellow fever which had been endemic in Havana for about 300
years. Among these physicians were Major Gorgas, who was re-
sponsible for the health of the soldiers and civilians in the city of
Havana, and Major Jefferson R. Kean whose chief responsibility
was the health of the American soldiers at Columbia Barracks on the
outskirts of Havana in the little suburban town of Quemados de
Marianao, near the famous bathing beach, La Playa.
Despite the vigorous sanitary methods which were instituted,
yellow fever continued to spread, and in May and June, 1900, Major
Kean, a worried man, compiled a tragic list of the names of soldiers
and civilians, of fellow-officers, and their wives, all living in the
neighboring streets of Quemados and all victims of yellow fever.
The mortality rate among the officers on the headquarters staff of
Generals Wood and Lee was alarming. The clerks in General Wood’s
office burned sulfur candles on their desks as a prophylactic measure,
but the candles burned in vain, and in the officers’ mess they drank
a gruesome toast, “Here’s to the ones who have gone. Here’s to
the next one to go!”
* Address given at the Walter Reed Memorial Celebration of the Inter-
national Congresses on Tropical Medicine and Malaria, Washington, D. C
May 10-18, 1948.
** Mayo Clinic, Rochester, Minn.
(204)
June, 1948 205
One of the earliest to go was Major Edmunds, a friend of Major
Kean. Because General Lee had already lost so many officers and
men he ordered all those not immediately in charge of the sick to
stay away from the sickrooms of those with yellow fever. Thus
Major Keen could not visit Major Edmunds who lay sick unto death
in the front room of a little house. But on the last dawn that
Major Edmunds was to see, Major Kean, torn between the con-
flicting obligations of obedience to his commanding officer and loyalty
to his dying friend, rose about 4 A. M. and went to the porch where,
technically not in the patient’s room, he spent a last few minutes.
During that short visit Major Kean was bitten by mosquitoes from
the sick room but thought little of it. But a few days later on June
21 Major Kean suddenly developed yellow fever.
As if to ridicule the puny efforts of the army medical corps, the
disease was now striking down the physicians themselves! Could no-
body stop this evil thing? What was its cause anyhow? One of
the commonest ideas was that the mysterious cause of yellow fever
arose like an evil spirit ; an airborne poison from the tropical swamps.
An Italian physician, Sanarelli, insisted it was due to a special germ
which he had discovered. But nobody really knew the cause, and
when a person died of yellow fever his home was often purified by
fire to destroy his presumably infected furniture, clothing and other
personal belongings, called “fomites.’””’ Thus hundreds of thousands
of dollars worth of military and civilian equipment went up in smoke
in an attempt to control the disease. But it was all in vain.
The old tragic story of yellow fever was being enacted again in
the first year of the 20th century as it had been enacted throughout
the world for 300-400 years of recorded history. Year after year
“Yellow Jack” had invaded wide regions of the earth, spreading north
and south, east and west from its lair in the tropics. The West
Indies were continually infected with the plague, and from thence
it traveled periodically and seasonably, first knocking at the doors of
America’s great ports such as New Orleans, Charleston, Norfolk,
Philadelphia, Boston and New York. When the first cases appeared
each season, these great cities tried frantically to quarantine them-
selves to shut out the terrible plague. But no doors were high enough |
or thick enough to bar it, and up and down the streets of villages,
towns and cities of the South rode “the saffron horror,” spreading
fear and death. :
206 Amer. Jour. Pharm.
From these doomed cities the panic-stricken people fled by every
available means. Some tried to escape by railroad, but often only the
immune, who had previously survived yellow fever, were allowed to
disentrain. More likely the refugees were turned back by fearful
neighbors armed with rifles. When the trains stopped running, the
refugees set out on foot. Fortunate were those who could flee in
the luxury of carriages. But, as panic mounted, the stricken districts
were quickly segregated by armed patrols who turned back those
who would escape the spreading death. Sometimes the quarantine
worked two ways and when certain immune persons tried to enter
a stricken city on errands of profit or even of mercy they also had
to run the armed blockade.
For those unable to escape but unwilling to remain in their
plague-ridden homes only one recourse remained, mass migration into
camps, generally set up on open high ground outside the city limits.
Here mysteriously they usually found safety. To these camps were
carried also the aged and infirm. As their tumbrels traversed the
narrow streets acrid smoke rose from cans of tar set ablaze “to purify
the death-laden air.” And like a grim salute to the dead that were
and were to be, cannon boomed as helpless, ignorant, foolish man
tried to stir up the stagnant air in a vain attempt to dissipate its
mysterious poison.
During the great southern epidemics of the 1870’s river steam-
boats shunned afflicted cities like Memphis. But to help the harassed
population the steamboats paused above the city, then let loose barges
laden with food and supplies which floated downstream, were caught
and made safe at the otherwise abandoned wharves.
But before they could escape to safety hundreds of thousands
developed the disease, and thousands died. Some had at least the
comfort of dying in their own bed surrounded by their grief-stricken ~
family. But to many others even this comfort was denied; stricken
suddenly they fell in the streets or in the parks, shunned by frightened
passers-by. Some, seeking mere shelter in lieu of a Samaritan,
crawled into abandoned cellars to die alone in the darkness, their
bodies being discovered days later.
In this fearful manner great cities like Philadelphia and New
Orleans were repeatedly attacked to become desolate, shunned by the
quick, abandoned to the dead and the dying. Along the lengths of
such great thoroughfares as Canal Street there fell a prolonged
June, 1948 207
hush. Overhead the smoke from the tar pots and cannon fire spread
an appropriate shroud. Coffins multiplied and were quickly carried to
cemeteries by hearse, by wagon or by hand. Undertakers and grave
diggers became totally inadequate, or fled for their own lives. Then
the dead were abandoned or carried off by a surviving relative who
may well have lost his whole family.
Such were the horrors of yellow fever prior to 1900 in which -
year, long-suffering Havana, now host to a conquering American
army, was stricken again. As Major Kean and other military per-
sonnel succumbed to yellow fever their recent victories “dried in their
mouths.” But on June 25, the fourth day of Major Kean’s illness,
Major Reed arrived in Havana, rushed to Major Kean’s bedside,
and in him saw his first case of yellow fever. Later that day Major
Reed met with three others on the veranda of the officers’ quarters at
Columbia Barracks Post Hospital. The three others were Drs. James
Carrell, Aristides Agramonte and Jesse W. Lazear and the four men
thus ended their first day’s work as the members of the United States
Army Special Yellow Fever Board.
They first attempted to find Sanarelli’s germ in the bodies of
those sick or dead of yellow fever, but this search soon ended in
failure. Perhaps, after all, no germ was responsible for the disease.
Why in Quemados had the disease progressed so erratically down
the streets, striking first in this house, skipping the next few houses,
then hopping around the corner to this house, rather than crossing
the affected street? Another curious fact was noted when Reed,
Agramonte and Lazear went to study an epidemic which broke out
among the soldiers at Pinar del Rio. A soldier in a prison cell fell
sick and died of yellow fever but his cell mates, exposed to the same
food and atmosphere, remained well. Could something have entered
between the bars of the open window, struck one man down and gone
away? Could yellow fever be caused by a winged agent? Could
Dr. Carlos Finlay be right after all?
For nineteen long years this kind, elderly Havana physician had
been trying to convince his medical colleagues that yellow fever was
caused by a common house mosquito. Absolutely sure of the truth
of his doctrine, Dr. Finlay often sent reprints of his work first to his
Cuban colleagues, later to high-ranking American medical officers
who replied with courteous little notes but did no more. Nobody
believed Finlay simply because, although he had inoculated over 100
208 Amer. Jour. Pharm.
volunteers with mosquitoes between 1881 and 1896, he hadn’t pro-
duced a single case of the disease which Cuban or other physicians
regarded as unquestionably induced or experimental rather than
probably spontaneous. For Finlay’s volunteers were not quarantined
and those few who later developed yellow fever were believed (by
everyone except Finlay) to have gotten yellow fever the ordinary
way.
When Reed, Agramonte and Lazear returned from Pinar del
Rio the Board decided on August lst to try to prove or disprove
Finlay’s theory once and for all. They visited Dr. Finlay who
graciously gave all the help he could including a supply of mosquito
larvae of the suspected species. Thereupon a momentous and heroic
decision had to be made because no animal was then known to be
susceptibie to yellow fever. Human volunteers were required. Un-
willing to ask others to do what they themselves would not do the
Board decided to inoculate each other among the first. At this junc-
‘ture Reed was unfortunately ordered to Washington to finish an
important medical report. Carroll and Agramonte continued re-
spectively their bacteriologic and pathologic studies and it fell to
Lazear’s lot to begin the mosquito work. This was fortunate because
he of all the Board was most sympathetic to the Finlay theory. In-
deed for some time Lazear had been trying (so far unsuccessfully )
to prove a relationship between mosquitoes and yellow fever. Thus
on the very day the Army Board was officially named in Washington,
Lazear in Quemados, Cuba, was catching mosquitoes in the room
of a patient with yellow fever and (as shown from notes in his labora-
tory notebook) was examining their bodies for agents responsible
for the disease.
Lazear began to breed Finlay’s mosquitoes in their little camp
laboratory and then tried to infect them by allowing them to bite
yellow fever patients at Las Animas Hospital. Between August 11
and 25 these presumably infected mosquitoes were applied to nine
American soldiers including Drs..Lazear and Pinto, but nothing
happened. They all remained well.
Two days later, on August 27, discouraged and doubting, Carroll
permitted Lazear to inoculate him again. In a few days Carroll de-
veloped a severe and almost fatal attack of yellow fever. On the
way from Carroll’s bedside Lazear (without the knowledge of his
colleagues) inoculated a scoffing volunteer soldier who “wasn’t
June, 1948 209
afraid of any little old gnat.” When yellow fever hit him six days
later this soldier became a very surprised hero whose widow later
received his Congressional Medal, and a memorial bridge in Grand
Rapids, Michigan was named for him.
Having accomplished two very successful inoculations Lazear
wrote his wife (September 8) : “I rather think I am on the track of
the real germ. But nothing must be said as yet, not even a hint. I have
not mentioned it to a soul.” How right he was was tragically proven
by what happened ten days later when he himself developed the
dreaded disease. During his illness Dr. Lazear told two visitors,
Drs. Carroll and Gorgas, that a few days before, while feeding his
mosquitoes on yellow fever patients at Las Animas Hospital a stray
mosquito had alighted on his hand. Engaged in this manner, Lazear
had allowed it to take its fill of his own blood. From the first he
was very ill and died September 25, 1900, officially listed as a victim
of “accidental yellow fever” but none the less a true martyr to science.
Such is the official version of this tragic incident. But I am about to
tell you another version of the affair, one which was kept secret for
forty years, and which was not even known to Dr. Lazear’s widow
until I was permitted to tell her of it in 1940 through the courtesy of
those who revealed it to me: Walter Reed’s. colleagues, Generals
Truby and Kean, and Dr. Agramonte’s daughter.
Reed hastened back to Havana (October 4) filled with mingled
-emotjons. He was greatly depressed at Lazear’s death, yet elated
that success at last seemed at hand. But he was also confused. Why
did the first nine inoculations fail and the next ones succeed? The
second successful case seemed incontrovertible: having been quaran-
tined at the otherwise fever-free Post Hospital, the scoffing private
(Private Dean—‘“case XY”) had had no other conceivable source
of infection than via the applied infected mosquito. But could one
be sure that Carroll’s disease had come from the experimental mos-
quito bite and not from some other source to which he might have
exposed himself while going about town? And how could Lazear’s
tragic case be used to prove anything unless somebody knew what
kind of a mosquito had bitten him?
In the side pocket of the uniform blouse which Lazear had re-
cently worn Lieutenant Truby, at that time commanding officer of
the Columbia Barracks Post Hospital, had found a small notebook
containing entries about Lazear’s experiments. Reed eagerly
210 Amer. Jour. Pharm.
studied these and other notes. Herein was the solution of the age-
old mystery, a solution which became crystal clear to the brilliant
mind of Walter Reed. Finlay’ s mosquito (the culex fasciatus or
Aedes Aegypti) could indeed cause yellow fever but only under
certain special conditions:
By carefully noting the relative timings of each step in the
successful and unsuccessful experiments it became obvious that
patients with yellow fever have the agent or virus of their disease
circulating in their blood only the first three days of their illness;
later when they are sicker, even sick unto death, the agent has
strangely disappeared from the blood. Therefore, a mosquito to be-
come “infected” must bite a yellow fever victim during these first
three days. But even then that “infected mosquito” cannot transmit
its deadly load or infect another person until the virus has had a chance
to develop or “ripen” within the mosquito’s body for at least twelve
days.
All of the failures of Finlay and of the Board were thus ex-
plained: those volunteers who had not developed yellow fever had
either been bitten by mosquitoes which had really never been i in-
fected (having bitten patients too late) or had been bitten by “*
fected mosquitoes” which were still temporarily harmless ~ilot
they had not been allowed to “ripen.”
Thus Lazear’s little notebook was vitally useful in solving one
mystery but it posed another mystery,-for in it Reed found some in-
complete entries which appeared to indicate that Lazear had secretly
submitted himself to other experimental inoculations. Reed pondered
long over these entries and then concluded that when Lazear was
taken sick he must have worried lest his life insurance become for-
feited if it became known that he had deliberately infected himself
with a fatal disease. Actually this explanation was incorrect; Mrs.
Lazear told me that Dr. Lazear left no life insurance. But did he for
some other reason at the last fateful hour withhold facts to protect
his loved ones? Was this why he had told Gorgas and Carroll that
he had been bitten by a stray mosquito at Las Animas? Reed be-
lieved that it was. Having produced two cases of yellow fever and
knowing the danger, Lazear would surely never have allowed a
mongrel mosquito to bite him and vitiate his otherwise meticulously
controlled experiments. Reed confided his suspicions only to two
or three colleagues and then decided to permit the official records to
June, 1948 211
read that Lazear had become accidentally infected while in the per-
formance of duty. Having made his quiet and heroic gesture Lazear
had sought to carry his secret to a better world. Out of respect for
the unspoken wishes of their friend, Lazear’s colleagues have kept
that secret all these years, Reed and others having carried it to their
graves.
In so doing they eminently proved their loyalty to him. But it
apparently disturbed them to deprive Lazear of a greater fame and
in the following unpublished remarks of Agramonte I sense a wistful
desire to rectify matters. At a Havana banquet in honor of Drs.
Gorgas and Kean in June 1902 Agramonte’s speech contained this
tribute: ‘““The one of us who’ from the very inception of our work so
strenuously believed in the mosquito theory in connection with the
propagation of yellow fever, the one of us who was best fitted by his
training in the line of our investigation to successfully carry out
the work, who in fact performed the first successful inoculation un-
known to his co-workers, Jesse W. Lazear, gave up his life in the
pursuit of knowledge which shall immortalize his name. May he in
the Regions of the Unknown find the glory that is his due which so
unjustly has been witheld by man on earth.”
Knowing that a skeptical world would demand more proof than
that afforded by these three successful but relatively uncontrolled
inoculations, Reed now conceived, and with Carroll and Agramonte
_ executed, a series of brilliant experiments which were to write the
final chapter of this story. On the advice of Major Kean, Reed
asked General Leonard Wood, Governor General of Cuba for money
with which to set up an experimental camp and to pay what Ameri-
cans and Spanish volunteers might be secured. To the lasting credit
of General Wood who had himself been a physician, he promptly
granted Reed’s request and threw behind Reed all the authority of
the governor’s high office.
Yellow fever was to be given away free with premiums of
$200.00. The victims could spend the money any way they wanted
to—if they survived; a rather big if, considering that the mortality
rate of epidemic yellow fever was about 40 per cent. But before any
paid volunteers were secured two American soldiers, John R. Kiss-
inger and John H. Moran volunteered their services only on condition
that they could do so without pay and in the interests of science.
Legend has it that Major Reed, profoundly affected, rose and said,
212 Amer. Jour. Pharm.
“Gentlemen, I salute you.” Both Kissinger and Moran told me that
actually, the legend is not true, which Reed’s widow and children
were sorry to learn from me a few years ago. But as one writer
said, “If Reed didn’t salute them, he should have!” The world is
still saluting them with many honors. :
A specially guarded and quarantined experimental station named
Camp Lazear was set up in a secluded spot a mile from Camp
Columbia. There John Kissinger bared, his arm in this manner for
the bites of five infected mosquitoes, and promptly developed the first
case of deliberately accepted and completely controlled experimental
yellow fever in history. Of this Reed wrote, “In my opinion-this ex-
hibition of moral courage has never been surpassed in the annals of
the army of the United States.”
Then two small specially constructed wooden buildings were
erected. The first was called Building Number One or the “Infected
Clothing and Bedding Building.” It comprised one room, 14 x 20
feet, had only two small windows and was heated by a stove to a
tropical temperature. Three cots were set up and into this sweltering
room were brought the soiled and foul-smelling bed clothes of yellow
fever victims. Night after night Dr. Robert Cooke and other soldier-
volunteers (who included Folk, Jernegan, Weatherwalks, Hilde-
brand, England, and Mr. Hanberry) hung these offensive clothes
around the walls and on their beds, and then lay down fo try to sleep
on stinking pillows and sheets soiled with blood and vomitus. Stom-
achs rebelled, but spirits remained firm and not one of these volunteers
developed yellow fever, simply because there were no mosquitoes in
the room. Thus was exploded the notion that “fomites” carried the
disease.
The second building of similar size (Building Number Two or
the “Infected Mosquito Building”) was divided into two parts sep-
arated merely by a wire screen. On a cot in one side of this room,
John Moran, exposed his body to the bites of fifteen loaded mos-
quitoes let loose in the room. He was in the room only a little over
an hour in all, but promptly developed yellow fever, while other
volunteers who stayed long hours on the other side of the screen
where there were no mosquitoes remained well.
Moran took sick on Christmas day. His yellow fever was a
wonderful Christmas gift to Walter Reed, to Carlos Finlay and to all
the world. A few days later on New Year’s Eve, Reed in a mood of
‘June, 1948 213
exultation and humble gratitude to God, wrote his family a much
quoted letter which has become famous:
“11:50 P.M. December 31st, 1900—only 10 minutes of the
old century remain. Here I have been sitting reading that most
wonderful work—LaRoche on yellow fever, written in 1853.
Forty-seven years later it has been permitted to me and my as-
sistants to lift the impenetrable veil that has surrounded the
causation of this most dreadful pest of humanity and to put it on
a rational and scientific basis. I thank God that this has been
accomplished during the latter days of the old century.
—The prayer that has been mine for twenty or more
years, that I might be permitted in some way or sometime to do
something to alleviate human suffering, has been answered.
12 midnight !—Hark! There go the 24 buglers, all in con-
cert, sounding “Taps” for the old year! How beautiful it floats
on the midnight air—.”
Dr. Finlay’s 20 year old prayer had also been answered. How
proud he had a right to be, and at a banquet given in his honor (Dec.
22, 1900) by Havana physicians and American medical officers (in-
cluding-Major Reed and Major Kean) Dr. Finlay voiced his hap-
piness thus: “Twenty years ago, guided by indications, which I
deemed certain, I sallied forth into an arid and unknown field; I dis-
'. covered therein a stone, rough in appearance; I picked it up and
with the assistance of my efficient and faithful co-laborer—Dr. Claudio
Delgado, polished and examined it carefully, arriving at the conclu-
sion that we had discovered a rough diamond. But nobody would
believe us, till years later there arrived a commission, composed of
intelligent men, experts in the required kind of work, who in a short
time extracted from the rough shell the stone to whose brilliancy none
can now be blind.”
After this brief pause for rejoicing, Reed and his colleagues con-
tinued their work. In the bodies of twelve more American and
Spanish volunteers (Benigno, Fernandez, Presedo, Martinez, Jer-
negan, Oson, Folk, Forbes, Andrus, West, Hanberry and Sonntag)
yellow fever was produced at will, either through the medium of
mosquito bites or by injections of infected blood or serum. For-
tunately all these volunteers survived, thanks to the excellent care of
Dr. Roger Post Ames. Their problem solved after just eight months
214 Amer. Jour. Pharm.’
of work, the Board disbanded Camp Lazear on March 1, 1901. Now
armed with precise knowledge, Gorgas within three months freed ©
Havana of its age-old scourage. Later, with this and other knowledge
he made safe the Isthmus of Panama for the passage of the commerce
of the world.
And what became of their battlefield, Camp Lazear? Revert-
ing to commonplace uses it was lost for forty years until Mr. John
Moran, Mr. Luis Pogolotti (of Havana) and I hunted for it and re-
discovered it in 1940. Building Number Two is gone, but Build-
ing Number One still stands, creaking with age and sleeping in the
Cuban sun. At its back is an encroaching quarry; in front a field
of corn.
.I re-visited’ it a few weeks ago with Mr. Moran and Dr. Pedro
Noguera. You will be interested to know that the Cuban govern-
ment has now designated this “old warrior” as a national monument
and we are hoping that it will be properly preserved.
In these days when man’s inhumanity to man is still so pa-
thetically apparent, it is well for us to note the example of these men
who banded together for high adventure, not to kill or even to die
for one country but to die if need be for their fellow men of all
countries. These 25 men included 3 Cubans, 16 Americans, one
Englishman, one Irishman and 4 Spaniards. Some were Catholic,
some Protestant, some were Hebrews. United in a common cause
they demonstrated magnificently the human capacity for greatness
and courage. It is such as they who reassure us of the inherent
decency and dignity of man.
’
WHISKEY IS A MERE BYPRODUCT
By T. Swann Harding
ESEARCH is rapidly making whiskey a mere byproduct of the
R grain distillation industry. This is done by elevating the former
byproducts to the status of coproducts. But just how requires more
detail.
Assume, then, that qualified scientists in well-equipped labora-
tories are confronted by certain cereal grains—wheat, oats, barley,
rye, or grain sorghum, and are told to do their stuff. What do they
do?
To the layman grain is grain, wheat is wheat. It can be made
into bread or transformed into a mash and fermented to produce
alcohol or whiskey, which are commonly regarded as the primary
products. There is a residue, a byproduct which makes excellent live-
stock feed. But, to a research worker at the Department of Agricul-
ture’s Northern Regional Research Laboratory, at Peoria, grain is
not just grain.
He first picks the grain to pisces. He finds considerable quantities
of starch, protein, and oil. For what can these be used? The starch
may be used directly for food, feed, adhesives, textile size or launder-
ing, or converted into corn sugar, dextrin, sirup, alcohol, butyl
alcohol, or even an extremely durable varnish. The protein is good
‘for food or feed, but may be converted into textile fibers, plastics, or
adhesives, or made to yield a meat flavor. While corn oil is directly
useful as food, wheat oil, because high in vitamin E, is usually too
valuable to use merely as food or in industry and it enters the field
of therapy.
All this is admittedly sketchy, but it serves to show that the
research worker initially regards a grain of wheat as a mixture of
starch, protein, and oil. It is not just grain to him and, naturally, he
digs more deeply than that. He studies the structures of the various
grains, the exact locations of their components within them, and their
spatial relationships.
Thus, in the endosperm of corn, starch grains lie in a matrix of
protein and this presents special problems in milling. Wheat grains
are hard to separate with the minute knives used because the protein
(215)
216 Amer. Jour. Pharm.
strings out along the knife-blade! Some molecules have that habit.
Some molecules are straight-line affairs and others are bunched up;
this fact makes big differences in starches. Barley presents more
problems than corn but fewer than wheat. In any case each grain
must be analyzed chemically and physically to see what makes it tick
and exactly how its constituents are arranged.
Then each variety of a grain must be examined separately. To
this end, 480 pure-variety wheats were grown at 63 different loca-
tions in the United States and Canada, over a period of 5 years, and
the grain was then analyzed to find out just how much of each of the
following it contained: Protein, starch, oil, sugar, ash, biotin, ribo-
flavin, niacin, pantothenic acid, and pyridoxine. The last 5 are a
few fractional parts of the vitamin B complex which has been divided
about 16 ways also.
The protein content of the wheat varieties varied from 13.6 and
21.8 per cent; the starch from 54.2 to 71.1; and the oil from 1.37 to
2.56 per cent. The sugar content of the wheats ranged from a low
of 1.6 per cent for a Krahkof variety to a high of 5.9 for a Baart
variety. Moreover, geographical location affects sugar content; soil
and climatic conditions affect content of other constituents. Ash
varied from 1.35 to 2.66 per cent, indicating considerable range in
the dietary mineral value of the varieties.
The vitamin content of grains also varies. Some work along
this line has been done on all grains, but most of it on wheat, corn,
and grain sorghums. The differences are wide, again largely due to
soil and climatic influences. Spring wheats average higher than
winter wheats in the five vitamins mentioned above. Some individual
variations were inconsequential ; some quite striking. Grain sorghums
vary so widely that breeding for high vitamin content is possible.
Breeding wheats for a high oil or protein content is also possible.
By this time the research worker begins to think of primary
products, byproducts and coproducts. The Northern Laboratory has
developed a special batter process for the better separation of wheat
starch from protein or gluten. This permits recovery of a gluten
which, when dried, has. special value for improving and fortifying
the quality of flour used in bread and macaroni. But the gluten can
also be utilized to produce glutamic acid which, when converted into
monosodium glutamate, becomes a meat-flavoring condiment which
puts chicken into lots of soup.
1
|
June, 1948 217
But when gluten is made by this method from 6 to 8 times as
much starch as gluten is also produced. To cheapen the gluten, uses
have to be found for all that starch. Indeed the use of the gluten
may be limited by the ability to find a profitable market for all the
starch, some of which can go into the making of dextrose sugar or
glucose, sirup for the pancakes, and fuel or industrial alcohol by
fermentation. Step up the uses of the starch, enhance its value,
make it a coproduct rather than a byproduct, and the gluten becomes
cheap. |
To this end the starch itself is torn to pieces and examined
under the microscope. Wide differences exist in starches from
different sources. The size of the cells, the molecular structure, and
the physical properties all differ. Starch from common wheats, corns,
and other cereals contains two kinds of molecules, linear and non-
linear. Starch from wax or glutinous types of cereals—the
sorghums, waxy corn, rice, and barley—contains practically no linear
molecules. But starch from wrinkled-type garden peas contains
them richly.
Each kind of starch has special uses. Linear-molecule starch
only can be used to make starch acetate from which can be produced
strong fibers similar to those of cellulose acetate film. Since cereals
are cheaper than garden peas and contain twice as much starch it
would be a good thing to breed more linear molecules into cereals.
. As the research worker proceeds, the possibilities increase all the
time. But his problem is also to find uses for culls, surpluses, and
what would otherwise be wasted.
So the Northern Laboratory has worked out a method of making
good-quality starch from damaged and stored wheats, using the wet-
milling process. Excellent starch has been made from wheat that
was heavily damaged by frost or must, that was weathered eight
weeks, that contained some scab and blight, that was infested with
weevils, was heat-damaged, or had largely sprouted, or that was full
of dead germs. Only when the wheat was badly damaged by excessive
heat was the starch discolored and. of low paste viscosity.
In general, however, wheat that has been stored too long, or
been heavily damaged in storage, can be employed for the produc-
tion of starch which can be used as such, or can be converted into
sirup or dextrose sugar, or fermented into alcohol. But, not only
must methods be devised of putting damaged grain to use, byproducts
218 | Amer. Jour. Pharm.
and coproducts must be nurtured all along the way to make indus-
trial processing profitable.
In this connection someone recently stated that whiskey might
soon become a mere byproduct of the fermentation industry. That
was no drunkard’s dream. Some distillers even now recover one-
half their original grain costs through the sale of fermentation by-
products as livestock feed. Could that be stepped up? Industrial
alcohol is quite as important a primary product of the fermentation
industry as is whiskey but to make it cheap for fuel purposes, the
byproducts must become coproducts. The research worker now
tackles that problem. .
Scientists at all four of the Regional Research Laboratories, for
there are three others in addition to the one at Peoria, are past
masters at this business of making byproducts sustain and lower the
costs of primary products, thus becoming transformed into coproducts.
In working on agricultural materials the laboratories aim not so
much at making from farm products commodities that are already
economically available from other sources. They are interested in
wholly new products for wholly new uses, rather than in mere substi-
tutes.
They do not sneer at byproducts, of course, but they seek to
transform them into coproducts. If you are going to make cheap
liquid fuel from agricultural wastes, for instance, you have to develop
valuable coproducts to sustain part of the production costs. Thus
the cost of making the primary product is drastically reduced. This
makes our scientist regard the recovery of distillers’ feed grains in
a wholly new light.
Generally speaking, the absolute quantity of the B-complex vita-
mins, and of the protein and its constituent amino acids in the original
fermentation mash ingredients, is fully recovered in the feed by-
product. We have seen that grains and grain varieties vary in their
content of different ingredients. Thus grain sorghums in some in-
stances contain large quantities of nicotinic acid and they can be bred
to contain more. Any nutritional improvement in the quality of the
mash ingredients improves the byproduct finally left for feed.
How effect this improvement? For one thing more nutritious
mash ‘ingredients could be selected in the first place. Then, via con-
centration during the fermentation process, better feed byproducts
are obtained. Again, it is known that certain micro-organisms ac-
June, 1948 219
tually synthesize certain vitamins and may also produce other nu-
tritional elements. Then the still residues could be processed in a
variety of ways, chemically, biologically, by fermentation, to enhance
their nutritional value.
In this way the concentration in the final feed byproduct of
several of the vitamin-B complex fraternity, or of certain essential
amino acids in the proteins, can be improved. Of course, the obvious
way to start out would appear to be by having more vitamins in the
grain used originally. Then, if possible, other vitamins still could
be synthesized during the fermentation or during a refermentation
process. This brings us to a waxy sorghum which is singularly rich
in nicotinic acid.
Waxy sorghum varieties were introduced here as long ago as
1854, and 200,000 acres were planted to them in 1942. They first
assumed striking importance during the war when tests by Depart-
ment of Agriculture scientists had demonstrated that they could sub-
stitute as sources of a starch as good as the hitherto imported root
starches which were used in foods (tapioca), in the textile industry,
and in making special adhesives. Waxy sorghum starch has many
of the desirable qualities of tapioca and root starch, and there are
also waxy corns and barleys.
If high nicotinic acid content is desired in distillers’ byproducts,
corn is a poor source. Wheat, barley, rice, and sorghum are much
_ better. Wheat, rice, oats, and rye outrank corn in pantothenic acid
content ; sorghum and oats have high biotin value—sorghum in par-
ticular, and oats is lower than other grains in vitamin Bg or pyri-
doxine. Cody sorghum, a waxy variety, is of especial interest be-
cause it contains very considerably more nicotinic acid than its parent
varieties.
Hence high nicotinic acid content can be perpetuated and en-
hanced by breeding. Therefore, not only could the scientist substi-
tute grains of higher for those of lower vitamin content, but varieties
could be bred for use in fermentation which were especially rich in
certain vitamins. Some substitution of Cody sorghum for wheat in
the mash would obviously improve the quality of the feed byproduct
and tend to make it a coproduct.
Next the research worker looks into the amino acid composition
of the proteins in different grains and grain varieties. For proteins
are made up of various combinations of some twenty-odd simpler
bd
°
220 Amer. Jour. Pharm.
compounds called amino acids, some of which the body must have
in the diet, because it cannot itself make them. Building proteins
up in their content of these essential amino acids makes them very
much more valuable nutritionally. Moreover the content of essential
amino acids may also be stepped up by hybridizing promising grain
varieties.
Meanwhile refermentation with different organisms offers pos-
sibilities and the Northern Laboratory has the finest collection of
valuable beneficial micro-organisms in existence anywhere on earth.
Certain fungi, when cultured on thin stillage, step up its vitamin B-
complex value. Indeed micro-organisms display great versatility in
making products useful to man if grown on particular cultures, so
another avenue of investigation opens to the scientists.
Many of these micro-oranisms have been cultured in still resi-
dues and have increased their nutritive value. Different molds work
on different patterns in synthesizing the B vitamins, but out of 250
mold strains under test by the laboratory some very proficient ones
may be found. Also slight changes in or additions to the still
residues may make them excellent for the growth of other organisms
which can produce still more valuable products—antibiotics perhaps.
After the mold strains get through with the residues feeding tests
on animals demonstrate their proficiency. The nutritive qualities of
still residues can be greatly modified and enhanced by such refer-
mentations carried on under careful control. Finally there remains
the possibility of utilizing still residues for the production of individual
vitamins like riboflavin. A yeast sporting the rather gaudy name
Ashbya gossypii has been shown capable of a high rate of riboflavin
production.
The rate of production depends, of course, upon what the yeast
gets to eat to make it grow; properly fed it works wonders. Nor
does it have the same nutritional requirements for mere growth
that it does when it gets to work at vitamin production. But the
composition of some of the media upon which it produces riboflavin
like fury indicates that a yeast strain may be found which will per-
form this same job in still residues. Ashbya gossypii grows well in
thin stillage diluted with an equal part of water; it even produces
some riboflavin. That is making constructive use of an organism
which is a pathogene of the cotton plant!
ie
June, 1948 221
Only recently the Northern Laboratory has announced that,
by developing a fungal amylase, which is produced by a mold that can
be grown on distillers’ stillage, to serve as a substitute for com-
monly used malt, ethyl alcohol can be made from grain at a cost of
3 cents a gallon Jess than heretofore. Again grain residues are used
to grow the amylase. Moreover, if 1 gallon of this alcohol is
blended with 9 gallons of low-grade gasoline, 10 gallons of premium-
grade antiknock motor fuel are produced!
As motor fuel, alcohol approaches isooctane, which has an oc-
tane rating of 100. It therefore increases the octane number of any
gasoline below 92. Gasoline of 60 octane rating becomes 79 when
blended with 25 per cent of ethyl alcohol, and a 10-per cent alcohol-
gasoline blend performs as well as premium gasoline in engines. Re-
cently a small gadget has been commercialized which automatically
injects an alcohol-water mixture into the engine when it is under
heavy load, thus enabling a truck driver to negotiate hills at high
speed.
The adoption of engine devices already available would enable
drivers of passenger cars to get a similar advantage from alcohol-
water mixtures while using low-octane gasoline as their major fuel.
Finally, not only is alcohol being made cheaper at the Northern
Laboratory by using amylase, but considerable progress has been
made in rendering the production of alcohol from such farm wastes
as corncobs far more economical on semicommercial scales than ever
before.
Obviously many things have yet to be learned to make whiskey
a mere byproduct of the alcoholic fermentation industry. But
enough has been said here to show how scientists tackle the problem
by tearing the various grains to pieces, using them in unusual ways
for novel types of fermentation, increasing the value of the byproducts
of alcoholic fermentation and gradually transforming them into ‘co-
products. This reduces the cost of the primary product and may in
time give it a secondary rating itself.
SELECTED ABSTRACTS
The Folic Acid Activity and Antagonism of Two Struc-
turally Related Derivatives of Benzimidazole. P. C. Edwards, D.
Starling, A. M. Mattocks and H. E. Skipper. Science 107, 119
(1948). Although folic acid is an essential growth factor for Strep-
tococcus fecalis R. and other lactic acid bacteria, these organisms are
capable of development if certain pyrimidine and purine bases are
present in place of folic acid. ”
The structural similarity of benzimidazole to purine and its re-
ported competitive action with amino purines led the authors to sub-
stitute this nucleus for the pyrimido-(4,5)-pyrazine (or pterin)
nucleus of pteroylglutamic acid. The resulting compound (I) was
found to possess some activity in promoting growth. In contrast,
compound II, which differs from I only in that a sulfonyl group has re-
placed the carbonyl in the p-aminobenzoic acid portion of the mole-
cule, was found to be a metabolite antagonist.
H
cooH
OL - CH2 - - COOH (1)
=
N
N-[4-( (2-benzimidazoly1) -methyl } -amino)-benzoyl]-glutamic acid
H
N cooH
N O
N-[4-( (2-benzimidazolyl) -methy] -amino) -benzenesulfonyl]-
glutamic acid
Data supporting this observation are presented in tabular form.
The authors suggest that their results cast additional doubt on the
specificity of the pteridin nucleus for the folic acid system.
(222)
June, 1948 223
Mechanism of Penicillin Action. R. Pratt and J. Dufrenoy.
Bacteriol. Rev. 12:79 (1948). Under the influence of bactericidal
concentrations of penicillin susceptible bacteria undergo distortion,
swelling, ultimate lysis, and concatenation in some cases.
Cytochemical studies indicate that penicillin exerts its bacterio-
static action by promoting dehydrogenation of -SH protein groups
to S-S groups more rapidly than the organism can restore the active
sulfhydryl group. Sulfhydryl bearing proteins have been found to
act in the aerobic bacterial cell as reservoirs of H. ions. These H
ions are capable of promoting rehydrogenation of the dienol or —
aldehydic groups which are essential in aerobic cell respiration. There
is evidence that the -SH groups are most reactive at the time of cellu-
lar division. Therefore it would be expected that penicillin would
be most active during cellular division. This expectation has been
fulfilled by experimental evidence. Thus penicillin appears to check
the organism in an early stage of cell division.
An organism is therefore penicillin sensitive when penicillin
stimulates dehydrogenation of its functional sulfhydryl groups faster
than they can be stored. Conversely, an organism may be assumed
to be non-sensitive to penicillin when it is able to restore -SH groups
faster than penicillin causes dehydrogenation.
Making extraneous -SH groups available nullifies the effect of
penicillin. Substances which expose the -SH groups formerly pro-
tected within protein molecules increase the sensitivity of the organ-
ism to penicillin. Examples of such substances are detergents and
bacteriophage.
The Toxicology, Absorption, and Excretion of Miracil D.
F. Hawking and W. F. Ross. Brit. J. Pharmacol 3:167 (1948).
The authors present an outline of the behavior of the hydrochloride
of (Miracil D)
when given to laboratory animals and to human volunteers. The
compound has been developed for use in the treatment of schistoso-
miasis (bilharziasis). In mice and monkeys experimentally infected
with Schistosoma mansoni it has been found to be highly effective.
The drug is given orally because it causes marked irritation to
tissues when given parenterally. It is rapidly and completely ab-
sorbed from the alimentary canal. Only very small amounts of the
aie
224 Amer. Jour. Pharm.
compound are excreted in the faeces and only about 7 per cent in
the urine. The compound is degraded in the body quite rapidly and
there is no apparent accumulation following repeated doses. It is
eliminated from the body in about 3 days after cessation of adminis-
tration.
Deliberate prolonged overdosage in animals may cause de-
generative changes in the liver and renal tubules but these toxic
manifestations are often very slight. The toxic symptoms in man
were noted as nausea, prostration, headache, insomnia, and yellow
coloration of the skin, sclerotics, and urine. None of the symptoms
reached dangerous proportions. There was a latent period of 18
to 24 hours before the symptoms appeared in man. Thus it was sug-
gested that they may have been caused by a degradation product
rather than the compound itself.
A dose of 0.2 Gm. a day was well tolerated by human volun-
teers. Rabbits tolerated daily doses of 50 mg. per Kg. and monkeys
tolerated 200 mg. per Kg. four times a week.
Streptomycin in Bubonic Plague. Ch. Haddad and A.
Valero. Brit. Med. J. No. 4560, 1026 (1948). The outbreak of
bubonic plague reported by the authors was quickly suppressed by
the ‘extensive use of D. D. T. Sulfadiazine was administered as a
routine to all cases in which the disease developed. The usual
initial dose was 2 Gm. given orally, followed by 1 Gm. every four
hours during the acute stage. The dose was then reduced according
to the needs of the patient but continued until the bubo healed. This
regimen was effective in the treatment of most cases.
Three patients who were very seriously ill when admitted did
not respond to the above treatment. Consequently, streptomycin was
administered in doses of 200 to 300 mg. every three hours. Response
was rapid with marked improvement within 24 hours in each case.
Incision and drainage of the bubo was necessary in two of the cases
before recovery progressed to completion.
Sodium Sulfacetamide Eye Drops. M. I. Anthony. Pharm.
J. 160 :360 (1948). Solutions of sodium sulfacetamide are too al-
kaline for use in the eye without causing irritation. Therefore a
buffer should be used. The author cites the pH of various concen-
June, 1948 225
trations of this compound. It was found that a 0.5 per cent solution
had a pH of 7.5, a 10 per cent solution had a pH of 8.8, and a 30
per cent solution had a pH of 9.0, with a corresponding pH for con-
centrations between those cited.
A buffer composed of 19.11 Gm. of borax, 12.40 Gm. of boric
acid and 2.93 Gm. of sodium chloride per liter of solution was found
to be satisfactory as a vehicle for the sodium sulfacetamide. The
pH of the buffer alone was 7. In combination with this buffer the
sulfonamide gave a pH of 7.2 with a concentration of 2.5 per cent
up to a pH of 7.6 with a concentration of 30 per cent. The author
stated that no discomfort was felt in the eye from these buffered solu-
tions.
New Salicylate Derivative. G. J. Martin and S. Byers.
Am. J. Digestive Dis. 15:127 (1948). In order to provide adequate
blood levels of sodium salicylate in the treatment of acute rheumatic
fever the daily oral administration of 10 Gm., equally divided into
four-hour-doses, is necessary. It would be desirable to have avail-
able a compound which would give prolonged blood levels with a
minimum of fluctuation of blood concentration. A series of deriva-
tives of salicylic acid were studied in this connection.
The most effective single compound was found to be nicotinyl
salicylate. This compound is insoluble in water. It was therefore
‘administered to rabbits in the experiments by means of a stomach
tube in the form of aqueous suspension. The dose given was
100 mg. per Kilogram of body weight. The appearance of the
salicylate in the blood plasma was somewhat delayed but was high
and fairly constant when it did appear. The blood level of nicotinyl
salicylate was still at 4 mg. per cent after 40 hours. In contrast,
acetylsalicylic acid tested in the same manner had entirely disappeared
from the blood in 26 hours.
Chloromycetin in the Treatment of Scrub Typhus. J. E.
Smadel Fourth National Congress on Tropical Medicine and Malaria
(through Drug Trade News 23:31 (May 31, 1948). Malaya was
selected as a test base for the study of the effect of chloromycetin on
scrub typhus, also known as rickettsial tsutsugamushi and Japanese
226 Amer. Jour. Pharm.
River Fever, because of a high incidence of the disease. Preliminary
clinical trials revealed that the antibiotic was effective in treating
25 patients ill with the disease.
Chloromycetin was administered orally to a total of 8 to 15 Gm.
over a period of six days, but this was later reduced to about 6
Gm. over a period of 24 hours.
The average duration of fever in the ranted group was 714 days,
no complications developed, and the average period of hospitaliza-
tion was 19 days. In an untreated control group one died, one de-
veloped serious complications, the average duration of fever was 18
days, and the average period of hospitalization was about 31 days.
Phenol Derivative in Germicidal Soap. E. F. Traub. Society
of American Chemists Meeting (Through Drug Trade News 23:30
(May 31, 1948). A new phenol derivative incorporated in soap may
reduce. the prolonged scrubbing ritual customarily enacted by sur-
geons before performing an operation. The phenol derivative, known
as G-11, has the chemical formula 2,2’-dihydroxy-3,5,6,3’,5’,6’-hexa-
chlorodiphenyl methane. The author described a series of experi-
ments in which a group of subjects used ordinary soap in cleansing
their hands for a period of one week. The subjects then went
through an elaborate scrubbing procedure in which they used, suc-
cessively, ten basins of water. The water in each basin was then
subjected to bacteria! counts in order to determine the number of
bacteria in each.
Another group of subjects followed the same procedure but used
a soap impregnated with 2 per cent of G-11. The number of organ-
isms found in the water of each of the basins from the latter group
was far below that of the first group.
In another study involving 389 persons, a record was kept of
the number of skin infections-of all types which were contracted
during a one-year period. The next year a record was again kept
but the ordinary soap which had been used for washing was replaced
with a soap containing G-11. There was a marked reduction of all
types of skin infections, ranging up to 80 per cent.
‘
|
June, 1948 227
Malignant Mouse Tumors in Mice Treated With KR Endo-
toxin. T. S. Hauschka and M. B. Goodwin. Science 107 :600
(1948). A cancerolytic toxin, KR, prepared from the lysed cells
of Trypanosoma cruzi has received some acclaim as a biotherapeutic
agent in the treatment of malignant tumors experimentally induced
in mice. These authors report largely negative findings.
Tumor growth was consistently inhibited by infections in mice
of various 7. cruzi strains, such as that causing Chagas’ disease.
However, the tumor growth did not regress and the infected mice
often died sooner from the. disease than the non-infected mice did
from the cancerous growth. The apparent cause of the inhibition
of the tumor growth is competition for essential dietary factors.
Lysates were prepared from Soule (s) strains and from Well-
come (W-BH) strains of T. cruzi. These strains and also the sar-
coma strains duplicated as nearly as possible those of previous in-
vestigators who had reported positive claims for the endotoxin. The
authors tested these whole culture lysates against spontaneous adeno-
carcinoma in 40 mice and noted no sign of cancerolytic effect nor
prolongation of survival time. They therefore concluded that the
endotoxin of T. cruzi does not appear to hold much promise for
effective cancer therapy.
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American Journal of Pharmacy
The American Journal of Pharmacy is the oldest continuously pub-
‘lished scientific periodical of its kind in America, having been established by
the Philadelphia College of Pharmacy in 1825. After the original issue there
were three other preliminary numbers until 1829, when regular publication
began. From then until 1852 four issues were published annually, with the
single exception of 1847, when an additional number appeared. Six issues a
year were printed from 1853 to 1870, at which time the Journal became a
monthly publication.
Former Editors of the Journal have been: Daniel B. Smith, 1825-1828;
Benjamin Ellis, 1829-1831; Robert E. Griffith, 1831-1836; Joseph Carson,
1836-1850; William Procter, Jr., 1850-1871; John M. Maisch, 1871-1893;
Henry Trimble, 1893-1898; Henry Kraemer, 1898-1917 ; George M. Beringer,
1917-1921, and Ivor Griffith, 1921-1941.
Established and maintained as a record of the progress of pharmacy and
the allied sciences, the Journal’s contents and policies are governed by an
Iditor and a Committee on Publications elected by the members of the
College.
Manuscripts should be sent to the Editor, who does not assume any re-
sponsibility in connection with the views or investigations of contributors of
accepted manuscripts, other than to exercise general care in selection.
Contributors are allowed a reasonable number of copies of this Journal,
free of charge, if applied for when the proof is returned.
Reprints, if desired, should be ordered when the proof is returned.
The table below shows the approximate cost of reprints, the make-up of the
pages to be identically the same as in the Journal. The actual cost may
vary from the fizures given, and will depend upon the amount of presswork,
paper, binding, and other factors. Reprints containing half-tones may be ex-
pected to cost somewhat more than the rates given.
2 pp. 4 pp. 8 pp. 16 pp. Covers WITH TITLES
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