As 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.
It is 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 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:
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.
Hewitt 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 lungs.
84-L was 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.
SubbaRow 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
Dr 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.
Hewitt 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.
Hetrazan 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.
Although it certainly is less toxic than heavy metallic drugs
and dyes previously used in the treatment of the disease, there
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.
India expands mass chemotherapy to eradicate filariasis
Dinesh C Sharma
India-home to a third of the world's filariasis burden?has expanded
mass chemotherapy to cover about 400 million people in 201 endemic
districts in 20 states and federal territories during 2004. Mass
drug administration (M DA) was implemented in 74 districts during
June, while the remaining will be covered later this year.
Over 576 million tablets (100 mg.) of diethylcarbarnazine (DEC) were
supplied during the June campaign. More than another 500 million
tablets are meant for distribution during July. In seven endemic
districts in Tamil Nadu, and Kerala, albendazole (400 mg each) will
be co?administered along with DEC. The strategy involves using M DA
for interrupting transmission and spread to healthy individuals. The
drug kills microfilariae in symptomless people thus significantly
reducing the probability of mosquitoes propagating them in new
hosts. MDA requires administration of DEC tablets once a year for 5
years to all people in endemic areas. However, poor compliance
remains a major issue. The initial reports from 40 of the 74
districts covered under MDA in June indicated coverage of over 65%.
A study done earlier in Orissa where MDA was tried out on a pilot
scale found that 67% of the population older than 2 years received
drugs during MDA, but only 42% had consumed them (Trop Med Int
Health 2004; 9: 702?9). The rest had not consumed the tablets even
though they had received them.
Lack of awareness regarding prevention, and wrong perceptions about
the magnitude of adverse side effects lead to poor compliance, said
B V Babu (Regional Medical Research Centre, Bhubaneswar, India).
People are not aware that greater severity of adverse side reactions
may be caused by high levels of microfilariae and that it may
subside with each new round of MDA. But in the present campaign, two
or three deaths have been reported, allegedly resulting from DEC
administration. However, Derek Lobo (WHO, New Delhi) said
investigation by an expert team has concluded that the deaths were
not related to MDA.
Experts believe mass chemotherapy alone will not solve the problem.
1f it is combined with concurrent mosquito control measures such as
reducing human?mosquito contact, reducing adult mosquito population,
or cutting down larval density in breeding points, then the effect
would be synergistic, not merely additive," said India's public
health expert Jacob John. "People must participate with
understanding, not just 'do as you are told’ and swallow the pills
approach. It then becomes a pill distribution programme rather than
a filariasis control programme. Thus in effective tool or model
becomes a failure in upscaling", he added.
(from THE LANCET Infectious Diseases Vol 4 August 2004 page 478
THE HINDU in its July 1, 2004 issue editorially commented on the
Filariasis elimination programme in India and the lessons drawn from
the results so far. Following is the text of the editorial:
IT MAY NOT be a killer like malaria, but lymphatic filariasis is not
a disease to be taken lightly. Better known as elephantiasis, it can
lead to grotesquely enlarged arms, legs, genitalia, and breasts.
Over 128 million people are estimated to be suffering from the
disease worldwide, about 40 per cent of them in India. The disease
is caused by tiny, thread-like worms whose larvae are transmitted
from person to person by mosquitoes. The larvae make their way to
the lymphatic system, a network of nodes and vessels that returns
fluids from the tissues to the bloodstream and is a key part of the
body's immune system. There the larvae develop into male and female
worms that breed to produce millions of immature larvae, which then
circulate in the bloodstream. After a mosquito ingests the blood of
an infected person, these immature larvae develop further inside the
mosquito and reach the infective stage where they can set off
another cycle of infection. The development of the disease is not
still fully understood as it appears to be generally acquired in
childhood and manifests itself only many years later. Some infected
people may show no outward signs of the disease.
Countries where this dreadful disease is common have embarked on a
strategy that aims to eradicate it. The strategy is to administer
drugs that can kill the worms and the larvae they produce so that
the cycle of infection is broken. A single dose of the drug is
administered for at least five years to the entire population of an
endemic area. This strategy was ratified in 1997 by the World Health
Assembly, the supreme governing body of the World Health
Organisation, and the Global Programme for the Elimination of
Lymphatic Filariasis was established in 2000 to execute it. Mass
drug administration using diethylcarbamazine citrate (DEC) was tried
out in Cuddalore district in Tamil Nadu in 1996. Its success led to
the programme being, expanded and last year 31 districts in seven
States were covered. This year, however, the Government plans a
major expansion, with mass drug administration being carried out in
250 districts in 20 States where the disease is endemic.
But unless more is done to address public concerns and secure
widespread cooperation, such ~ an expansion could be
counterproductive. The safety and tolerability of the drug
combinations have been confirmed by their increasingly large scale
use, points out a paper published recently by a WHO expert; an
estimated 60 million people in 34 countries were administered the
medicines in 2002. However, experts say that adverse reactions,
which are not life threatening and are easily treated, are seen in a
small proportion of people as the drugs kill the worms and their
larvae. The most important thing is to prevent such occurrences from
setting off panic reactions. That is just what seems to have
happened in early June when the mass administration of DEC was
carried out in the endemic districts of Karnataka. Newspaper reports
spoke of several people taking ill, and of five deaths. Medical
investigators have since concluded that deaths were the result of
other ailments, and not related to the taking of DEC. The episode
shows the importance of educating the public and doctors in the area
where mass drug administration will be carried out, and enlisting
their support. Moreover, the Government must be in a position to
give credible assurances to people that medical help would be
readily available should they experience any adverse reaction after
taking the drug. Without sustained and widespread public support,
the anti-filariasis programme can fail.