(by Rajesh Bhatnagar MD)
Doctor Yellapragada SubbaRow’s direction of research at Lederle
Laboratories, Pearl River, New York, USA, led in the Nineteen Forties
to the discovery of four medical molecules which opened new approaches
to the treatment of nutritional, infectious, worm-transmitted diseases
and cancer. Perhaps the count should be reduced to three because
manipulation of a single molecule yielded first the vitamin folic
acid and then the cancer fighter anti-folic methotrexate. The uniqueness
of these molecules is that today, fifty years after their discovery,
they are being still researched for potential new benefits to humankind.
Aureomycin, with the tetracycline molecules, was derived from the
fungus Streptomyces sp. and proved for the first time that a single
drug can be used for controlling infections caused by both gram-positive
and gram-negative bacterial germs. The previously available penicillin
could battle only the former and streptomycin only the latter. Also
unlike penicillin and streptomycin, Aureomycin could be taken orally.
The second generation antibiotics with the tetracycline molecule
helped eradicate the plague which broke out in Gujarat and Maharashtra
just when SubbaRow's centenary year began in 1994. It was a debt
SubbaRow paid to his motherland almost half a century after death
which claimed him soon after the unveiling of Aureomycin before
a medical gathering at the New York Academy of Sciences. People
then said death was jealous of SubbaRow who was coming out with
a new potent drug every year and was set to conquer cancer. Death,
Be Not Proud! we can say with John Gunther. For the four molecules
he presented to the world in four years continue to battle ever
Aureomycin was sent soon after its medical release to the Haffkine
Institute in Bombay (now Mumbai). There the famed Dr Sahib Singh
Sokhey was able to save nine out of ten experimental animals suffering
from septicaemia caused by the plague germ Pasteurella pestis. Sokhey
incidentally was SubbaRow's senior at Harvard Medical School biochemistry
After Aureomycin proved itself in a plague case later that year
in the American state of Arizona, it was tried in 1951 in Latur,
a hyper-endemic plague area then in Hyderabad state but became part
of Maharashtra later. Of the 15 plague victims treated by Dr K Ramachandran
at the Isolation Hospital, 12 were cured and discharged. The three
who died had been brought in a serious condition and the drug had
no time to act. Tetracycline was therefore ready for plague in Latur
and Surat in 1994. It cannot resolve the debate whether the epidemic
was plague or falciparum malaria as it, particularly Doxycycline,
fights both the diseases.
Doxycycline, the third generation tetracycline, has now been cleared
by the US Food and Drug Agency (FDA) for prophylaxis of malaria,
especially the malignant variety caused by Plasmodium falciparum.
Unlike the traditional chloroquine and the new mefloquin, Doxycycline
is least toxic and is effective if taken just 24 hours before exposure.
Mefloquin needs at least 7 days to impart immunity against malaria.
In September 1999 when the United Nations Assistance Mission in
East Timor (UNAMET) was ordered into the region wrested from Indonesia,
its international staff packed Doxycycline in their survival kits.
Tetracycline is even today the only drug effective in Rickettsial
group of diseases, like scrub typhus and the Rocky Mountain spotted
fever, known as the scourge of war because of the heavy toll they
took of soldiers in the trenches of the First World War.
Folic acid, also fathered by SubbaRow, was initially used only
for the treatment of tropical sprue and the anaemias. Recently,
FDA approved it for expectant mothers and in fact recommended its
regular use a month before planning pregnancy to stave off neural
tube defects. The U.S. government has required that all flour, pasta
and other grain products manufactured after January 1, 1998 be enriched
with folic acid. In mid-1999 the New England Journal of Medicine
reported that this has already reduced homocysteine levels across
the board among the U.S. population. The report started a worldwide
debate focussing on homocysteine, an amino acid, as an independent
risk factor for coronary artery diseases. It has been statistically
seen that people with heart attacks fare poorly if they have also
high homocysteine levels associated. Folic acid reduces these homocysteine
levels and may improve the resistance of the general population
to ischemic heart diseases.
Aminopterin, the third brainchild of SubbaRow, has the folic molecule
with an amino radical replacing the hydroxy radical in the vitamin.
It reverses the vitamin action of folic acid and is called an anti-folic
or folic acid antagonist. It provided for the first time some semblance
of treatment for leukaemias. It initiated the chemotherapeutic approach
to treat widespread cancers or cancers not amenable to surgery.
Methotrexate the modified aminopterin has singly improved the survival
of young women suffering from choriocarcinoma the cancer of the
after-birth mimicking pregnancy.
In fact, methotrexate, used initially in cancer treatment, is finding
a new place in non-cancerous diseases. It has become a fairly standard
drug in treatment of rheumatoid arthritis and psoriasis, the two
chronic disabling conditions of joints and skin.
Though needing further evaluation, methotrexate has been used successfully
in chemotherapeutic treatment of ectopic pregnancy, chronic ulcerative
diseases and asthma. It may prove to be a boon to asthmatics as
it can reduce steroid dependency and thus the complications from
Di-ethylcarbamazine, the fourth molecule that SubbaRow pioneered,
has helped the afflicted nations fight the scourge of filaria which
leads to the extremely disfiguring elephantiasis disease. After
years of hesitation in employing it in mass campaigns, although
it has long been the only effective anti-filarial, it has now been
cleared for prevention of filariasis on a mass scale in endemic
areas. In an attempt to reduce the burden of the disease, WHO on
Indian Republic Day 1998 said it was now enough to administer only
a single dose of DEC, concurrently with ivermectin, to keep blood
free of filarial worms for a whole year. It said the unpleasant
side effects were due to unnecessarily high dosages previously prescribed.
There seems to be no end to such new SubbaRow miracles!
Dr. Rajesh Bhatnagar is Chief Medical Officer, CGHS, at Parliament
House Medical Centre.