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53 :279, 1947. 




< ering POSITION 


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 

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 
Disease, Warfare or Social Progress? .......... 186 

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 


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 


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- 

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 

L. F. Tice 


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. 


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 



* Research Laboratories, The National Drug Company, Philadelphia, Pa. 


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) 


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 

* 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. 

| | 

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- 

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. 



4-( (( 



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. 



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 



5 mg/kg 


(chloromethyl pteroic) 

Probable structure 
2-chloro-4- ( (N-(2-amino- 
6-pteridyl) methyl) amino) 
benzoic acid 

(chloropteroic ) 5 mg/kg 
2-chloro-4- ( (N-(2-amino- 

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 


N-(4-(( (2-amino- 
methyl] ) amino) benzoyl) 
aspartic acid 
(pteroylaspartic acid) 

N-(4-( ( (2-amino- 
methyl) amino) 
benzene) sulfonamide 
(pteridylsulfonamide ) 

N-(4-( ( (2-amino- 
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 


N-(4-(6-amino- 20 mg/kg 
quinazoline ) -p-amino 

benzoylglutamic acid 

N-(4-( (4-quinazoline) 
amino) benzoyl) 
glutamic acid 
N-(4-quinazoline) - 

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. 


Effect on Dopa Ratio for 
Decarboxylase Strep. faecalis 
300y/cce 35% 10 
300y/cc 0% 
Nonspecific Inactive 
Nonspecific Inactive 

300y/cc 50% 1-10 

Insoluble Inactive 
No Test 
300y/cc 0% Inactive 
300y/cc 0% Inactive 


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 
2,4-diamino-6,7-diphenyl 5 mg/kg 

pyrimido (4,5-b) pyrazine 10 mg/kg 

xanthopterin 17.2 mg/kg 


(4,5-b) pyrazine 

*N-(4-( ( (2-amino- 
6-pteridy!l ) methyl ) amino) 
benzoyl ) aspartic acid 
(methyl pteroyl aspartic) 

*N-(4-( ( (2-amino- 
6-pteridyl ) methyl ) amino) 
benzoy1 ) glutamic 

(methyl! pteroyl glutamic) 
(methyl folic acid) 

*N-(4-( (2-amino- 
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- 
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 

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% 


Ratio for 
Strep. faecalis 


Probably in- 
active. Too 




* Probable structure. 


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. . 




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. 


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 


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. 


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. 

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. 


(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 


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 

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- 

* Address given at the A. Ph. A. Conference on Pharmacy in Peace and 
War, May 6, 1948, Washington, D. C 


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 


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 


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- 
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. __ 


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. 


. “7% 


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. 


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 

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 

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 

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 

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. 



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 

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 

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 


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. 


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- 

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 
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 


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 

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 

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! 


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 

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 


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. 


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. 


OL - CH2 - - COOH (1) 



N-[4-( (2-benzimidazoly1) -methyl } -amino)-benzoyl]-glutamic acid 

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. 


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 

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 


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- 

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- 

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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| tn Clinical Diagnosis 

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. 

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pected to cost somewhat more than the rates given. 

2 pp. 4 pp. 8 pp. 16 pp. Covers WITH TITLES 
50 copies ..... $3.50 $6.00 $10.50 $11.25 50 copies ..... $ 5.00 
4.25 7.00 14.00 6.50 
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| <4