Rescue from the Ugliest Disease
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.