Miracle Man of Miracle Drugs
Dr. Yellapragada Subbarow

Rescue from the Ugliest Diseases

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 Madras.

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:

It was 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.

The 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" synthesised.

A compound, 84-L, made by substituting the two end hydrogen atoms with ethyl (-C2H5) groups was unmatched in its anti-filarial activity:

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 island.

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 http://infection.the lancet.Com)



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.