Director of Research at Lederle, SubbaRow established
a project for protecting American soldiers fighting
in the Pacific from malaria and Filariasis. He found
in Hetrazan the cure for Filariasis.�
today the most widely used drug against Filariasis
which leads to the deformity-causing elephantiasis.�
The Second World War made the United States Army get
interested in drugs to treat diseases the American
soldiers would be exposed to in the tropics.
This was opportunity for SubbaRow to conduct in the
United States research to fight Filariasis and other
tropical diseases he had seen causing great suffering
among people in India.�
It was, however, only in the spring of 1944 that he
could organise a "parasitology" group at Pearl River.
He brought Dr Redginal Irving Hewitt doing research
on bird malaria in Alabama and set him screen
chemical and other material for their effectiveness
in ducklings infected with experimental malaria.
Within five months SubbaRow talked Hewitt into
switching research from malaria to Filariasis.
Filariasis is the underlying illness in what
manifests itself as elephantiasis or the ugly
swelling of legs. SubbaRow had seen the agony and
shame of the sufferers and had conducted some
research into the disease at the Ayurvedic College in
In the United States, only the isolated community of
Charleston, South Carolina, was troubled by
Filariasis but Hewitt was soon as enthusiastic as
SubbaRow in finding a cure for soldiers returning
home from the Pacific with the dreaded disease.
The young filarial larva, discharged by the mother
into the blood stream, usually causes no
complications. The real trouble starts when it is
sucked by a mosquito, in whose body it matures, and
is subsequently discharged into humans by the
mosquito. It now makes for the lymph ducts in large
numbers, concentrating particularly in the lymph
glands. Lymph fluid, thus blocked, flows into
connective tissue and causes it to grow in size. The
skin in affected parts thickens. There is muscular
pain and fever.
Dogs infected with the heart‑worm, which is
related to the parasite in man, were till then used
for screening compounds against Filariasis. But they
were too expensive, required large amounts of test
chemicals and had to be returned to owners after
treatment. Luckily, they learnt that large percentage
of cotton rats in the Florida wilds is already
infected with a filarial parasite. They started with
a screening programme that required 20 to 40 cotton
rats a week and soon needed a weekly supply of 200.
SubbaRow sent Hewitt any and every chemical he came
across -- organic eyes, sulphonamides, quinolines,
sulphones, cyanamides and piperazines. As many as 517
chemicals went through the cotton rat screen before
Hewitt found what SubbaRow wanted.
In April 1945, six months after the screening began,
Hewitt found the compound code numbered "180‑C"
somewhat reduced the filarial larva count in the
blood of a cotton rat. It was not a dramatic
reduction but Hewitt decided to test the chemical
again in a number of cotton rats. 180‑C was a
chemical synthesised by a Calco chemist as a possible
analgesic and had been sent over to Hewitt because
its pain‑killing power was negligible.
Hewitt went wild with excitement when the repeat
tests showed that 180‑C, whether injected or
given by mouth, caused a rapid reduction in
microfilaria or young worms in blood. But 180‑C
had very little effect on the adult worm.
SubbaRow had chemists both at Pearl River and Bound
Brook synthesise a number of piperazines to which
group of chemicals 180‑C belongs. Since the
parent piperazine, once used in gout, was inactive in
the rats, the anti-filarial activity did not lie in
the piperazine nucleus but either in the "methyl" or
"carbethoxy" side-chain of 180-C:
theoretically possible to make 256 different
piperazines by substituting the side chains with
other alkyl (alcohol) groups, since piperazines with
which the carbethoxy side-chain were more filaricidal
than those which did not have it, a whole series of
compounds were prepared substituting the "methyl"
side-chain with other "alkyl'' groups. None of the 35
piperazines so prepared was better than 180-C.
chemists therefore turned to the carbethoxy chain and
prepared a number of acid derivatives. The
anti‑filarial activity shown by a compound
related to the carbamic acid (HO.CO.NH2)
derivative encouraged SubbaRow to get all possible
chemicals related to this "carbamine"
compound, 84‑L, made by substituting the two
end hydrogen atoms with ethyl (‑C2H5)
groups was unmatched in its anti‑filarial
Diethyl-carbamyl-4-methyl piperazine -- to spell out
the chemical name of 84-L synthesised by Dr Sam
Kushner in SubbaRow's group of organic chemists at
Pearl River -- immobilised filarial worms in rats,
dogs and frogs in a dramatic fashion. A larva dropped
into a test‑tube full of the chemical would
contract in spasms, its whip would contract into a
tight coil within five to fifteen minutes and then
straighten out to remain completely motionless.
tried various doses and treatment times in 212 cotton
rats and 25 dogs. Adult worms in cotton rats
succumbed with oral treatment of several weeks. Dog
owners exasperated Hewitt by demanding the return of
their pets after treatment. But in a few dogs he
could sacrifice, the hearts were free of worms.
The worms were found dead in the blood vessels of the
tested in animals by pharmacologists and found to
have low toxicity. It was moreover rapidly excreted
by kidneys and hence posed little danger of
accumulating in the body in toxic concentrations.
Hewitt and his colleagues swallowed 84‑L in
high doses and suffered only a little nausea.
sent Hewitt and Kushner to Puerto Rico to personally
deliver 84‑L to Dr Jose Oliver‑Gonzales
of San Juan's School of Tropical Medicine, and then
have a three‑week holiday in that Caribbean
Gonzales and Dr Santiago-Stevenson, his colleague,
administered 84-L to 26 Puerto Ricans and reported
that it caused rapid disappearance of microfilariae
from the blood stream, possibly acted on the adult
worm as well and caused no serious side effects.
took Hetrazan, as the drug was now named, to all
parts of the world. In St. Croix, one of the Virgin
Islands where generations have suffered from
Filariasis, he initiated in 1951 a programme in which
the drug was given virtually to the whole population.
Some 85 per cent of those treated were found free of
microfilariae when a check was made a year later.
received its most extensive trial between 1955 and
1959 when six million people in twelve states of
India were given the full five-day course. A
committee of the Indian Council of Medical Research
ruled against mass programme with Hetrazan as it
causes unpleasant, although transitory, reactions
from nausea and stomach upset to body-ache and fever.
These reactions result from the sudden release of
protein when microfilariae are killed effectively
within such a short time. It has therefore to be used
under medical supervision and is positively
beneficial in early diagnosed cases of Filariasis,
the ICMR ruled.
it certainly is less toxic than heavy metallic drugs
and dyes previously used in the treatment of the
was therefore hesitation for many years, in
employing di-ethylcarbamazine (DEC), the generic
name for Hetrazan, in mass campaigns against the
scourge of elephantiasis. A few years ago, on
India's Republic Day January 26, 1998, the World
Health Organisation (WHO) found that the side effects
were due to unnecessarily high dosages prescribed and
that it was enough to administer only a single dose
of DEC, concurrently with ivermectin, to keep blood
free of filarial worms for a whole year. And WHO has
since then made DEC a key element of its worldwide campaign for the
elimination of elephantiasis.