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 new diseases.
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 department.
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 the steroids.
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.