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Pyrimethamine (Daraprim®) is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention), and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals. more...

Dimethyl sulfoxide
Docusate sodium
Dornase alfa

Mechanism of action

Pyrimethamine interferes with folic acid synthesis by inhibiting the enzyme dihydrofolate reductase. Folic acid is needed for DNA and RNA synthesis in many species, including protozoa.

Mechanism of resistance

Resistance to pyrimethamine is widespread. Mutations in the gene for dihydrofolate reductase may reduce the effectiveness of pyrimethamine (PMID 15155209). These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase by steric interactions (PMID 14711307).

Clinical use

Pyrimethamine is typically given with a sulfonamide and folinic acid:

  • Sulfonamides inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
  • Folinic acid (Leucovorin) is a compound that can be converted into folic acid by the human body without relying on dihydrofolate reductase. By doing so, folinic acid reduces side effects related to folate deficiency.

Side effects

Pyrimethamine may deplete folic acid in humans, resulting in hematologic side effects associated with folate deficiency.

Side effects include:

  • hypersensitivity reactions
  • megaloblastic anemia
  • leukopenia
  • thrombocytopenia
  • pancytopenia
  • atrophic glossitis
  • hematuria
  • cardiac arrhythmias
  • pulmonary eosinophilia (rare)
  • hyperphenylalaninemia (particularly when used with a sulfonamide)


Pyrimethamine is contraindicated in patients with:

  • hypersensitivity to pyrimethamine
  • megaloblastic anemia - depletion of folic acid may aggravate this condition


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Obituary: Professor V. Ramalingaswami (1921-2001)
From Indian Journal of Medical Research, 6/1/01 by Sriramachari, S

For a really capable person, no job is a burden; for the industrious (farmer) no distance is too far For the learned man, no land is alien: for the sweet-tongued, there is no adversary

The passing away of Professor V. Ramalingaswami on May 28, 2001 marks the end of an era of medical research in post-independent India. Endearingly called 'Rama', he was universally acclaimed as the most eminent and well-known medical scientist in India and abroad during this period. At the time of death, he was a National Professor at the All India Institute of Medical Sciences, New Delhi.

Vulimiri Ramlingaswami was born on August 8, 1921 at Srikakulam in Andhra Pradesh. He had his early education in the historical town of Bobbili. He must have imbibed from his grandfather, a Shakespearean scholar, a passion for the written as well as spoken English and oratorical, and often theatrical, skills. This heritage was his incomparable forte in the analysis and exposition that carried conviction on even trite scientific issues, to any audience, be it learned scientists, administrators or even the lay public.

Although we were not then personally acquainted, Dr VRS happened to be my senior by about 4 years, in Mrs A.V.N.College, and later in the Andhra Medical College, Visakapatnam. As high school students, we had a glimpse of the brightness and dynamism of the future all-rounder, at once both book-bound and active in dramatics and sports. He obtained his MBBS in 1944 and MD in Internal Medicine of the Andhra University, in the very first attempt, considered a feat in those days. Very few people are aware that he switched over from Medicine to Pathology to become one of the most celebrated Pathologists of the country.

In the pre-independent India, there were few job opportunities in the Provincial Medical Services of the composite Madras Province. Historically, brighter students inspired by spirit of Investigative Medicine, used to migrate to the few medical research institutions, then located in Bombay, Calcutta, Kasauli and Coonoor. Either by choice or circumstances, a chain of enterprising graduates from the Andhra Medical College/ University in the moffusil town of Vishakapatnam trekked to the Nutrition Research Laboratories (NRL) of the Indian Research Fund Association (the forerunner of ICMR) or the Pasteur Institute, Coonoor, located in the salubrious Nilgiri Hills in south India. Dr VRS joined the impressive list of such pioneers like Drs N. Veeraraghavan, M. V. Radhakrishna Rao, M. N. Rao, and a stream of Parlakimidi scholars like Drs K.K.P. Rao V.V. Sriramamurthy, B.V. Rama Sastry and S.V.S. Rao. In turn, he also became a source of inspiration for many that followed like Dr K. S. Rao, myself, Dr M.K.Ramanathan and later Dr K.A.V.R. Krishnamachari.

At NRL, Coonoor, Dr VRS carried out pioneering studies on the role of essential fatty acids in phrynoderma, a peculiar clinical dermatological problem of nutritional origin. Lathyrism was rampant in India and the NRL was interested in establishing its causation. So, initially, Dr VRS was sent for preliminary training in Neuropathology at the Laboratories of the Armed Forces, at Pune, the forerunner of AFMC. He worked with Col. Leo Krainer, a traditional neuropathologist from Austria who migrated to India during II World War and worked for the old IMS (Indian Medical Service).

Before even completing the training in neuropathology at Pune, Dr.VRS was deputed by the Govt. of India to Oxford to undergo specialized training in nutritional pathology and worked under Dr Hugh M. Sinclair. On his own initiative, possibly as an extension of his earlier clinical work, he undertook a brilliant piece of experimental study on the role of essential fatty acids in the development of cutaneous lesions akin to phrynoderma. This work fetched him the D.Phil. degree of Oxford University and he was also elected a Fellow of Maugdlen College - a very coveted distinction. Later, he was also conferred the D.Sc. degree by Oxford. He also had an opportunity to meet often Sir Robert McCarrison in Oxford. Dr McCarrison earlier on did pionering work in India in the Area of Nutrition in general and Himalayan Goitre in particular. Towards the end of his stay in England, instead of whiling away his time, he seems to have pondered over the nutritional problems confronting India, like nutritional anaemias and iodine deficiency disorders. Always evincing keen interest and curiosity, he peeped into the London Office of the Chilean Iodine Bureau, which paved the way for his future work on Himalayan goitre, cretinism and the subtler manifestations of iodine deficiency. He also established a dynamic linkage with the Ciba Foundation that always focussed on the frontiers of medical research that continued with his association as Chairman of the Ranbaxy Foundation in later years..

Dr VRS returned to NRL, at Coonoor and rejoined Dr V.N. Patwardhan, Dr C. Gopalan and other colleagues. In spite of possessing double doctorates in Medicine and Science from Oxford, he continued for a few more years in the modest post of Research Officer. As his immediate junior colleague in the Pathology Department, I do not recall even a single instance when he complained about our relatively low posts or position in the scientific hierarchy. Instead, we always reveled in the realm of scientific fantasy through the microscope and our modest achievements. He addressed himself to quite a few issues of Nutritional Pathology, a list too formidable to be listed in a brief tribute. Nonetheless, a few topics merit mention. Due to limitations of accessibility to clinical material, he sought and fostered working arrangements with the distant clinicians in youth India, like Dr P.K. Kalyana Raman of Coimbatore and Dr Kalamegham and Dr Narayanan in Trichy for the study of nutritional anaemias, caused by deficiencies of iron and folic acid. Employing, daraprim, a folinic acid antagonist, together, we conducted bone marrow studies in our attempts to develop a model of pernicious anaemia in the primate.

With the liver biopsy technique developed by me at Visakapatnam, and with his skilled interpretation through the microscope, we published the first account of the pathology of kwashiorkor in India that led to extensive experimental studies on the different types of fatty livers, simulating kwashiorkor. In the true spirit of science. Dr VRS and I entertained even divergent views, at times. Later, along with Dr M.G.Deo, he succeeded in establishing a primate model of 'kwashiorkor'. The non-progression to hepatic fibrosis, in contrast with Indian childhood cirrhosis (ICC), led to the continued saga of Indian studies on hepatic pathology.

The pathology of nutritional deficiencies of vitamins A and D was yet another topic of his interest. Although it was well known that deficiency of vitamin A caused night blindness, we were the first to demonstrate the actual damage of the rods and cones of the retina of new born monkeys, following maternal deficiency of vitamin A. In those days, there were no ready suppliers of monkeys or of facilities for breeding them. Capturing monkeys from the hill slopes of Coonoor and Nilgiris was itself an adventuresome pastime! Yet another notable study was to provide histopathological and histochemical support for the classical work on the healing of rickets by Dr Patwardhan and Dr P.K.Dikshit. The mode of action of vitamin D was elucidated by the sequence of changes in tissue calcium and phosphorus at the biochemical and morphological and histochemical levels. His wide scientific background and personal charm, attracted the attention of the then leaders of medical research in India, like Dr V. R. Khanolkar, and Dr C. G. Pandit, who was then piloting the ICMR. Recognizing Dr VRS's potentialities and talents in diverse fields of medical sciences, Dr Pandit, then Secretary and later on Director of ICMR got him transferred from NRL to the Headquarters offices as a Senior Research Officer to give him support in the development of medical research, especially in the upcoming Medical Colleges and Institutions throughout India. Soon he was promoted as Assistant Secretary and later as the first Deputy Director of ICMR. In those early days, the trio of Dr Pandit, Dr VRS and Shri T. D. Joshi. chief of administration, nurtured the sapling ICMR in a small office then located on the Raising Road.

Shri Joshi used to narrate how Dr VRS would cycle daily all the way from Karol Bagh and back late in the nights at the end of the day's work. Often the team worked till late in the night in drawing up plans for the growth and development of the ICMR. The original concepts of IRFA were enlarged and the map of Indian Medical Research was progressively redrawn against many obstacles. Dr VRS acted as the main link between ICMR and the Ministry of Health and the rising aspirations and expectations of the scientific community within and outside the rapidly expanding medical colleges throughout India.

With the establishment of the Planning Commission, the ICMR was associated with drawing up the National Health Programmes and especially promotion of new medical research. Dr VRS played a notable role in laying the foundations of ICMR. and he actively helped Dr Pandit in drawing up the Health Plans from the 11 Five-year Plan onwards. The unique combination of Dr Pandit's wisdom and tact and Dr VRS's charming manners. as a virtual PRO. proved formidable. As the Volume of work increased, the Council was shifted form P Block, Raisina Road to the Type D 11 Quarters in the AHMS Campus and still later, to its own permanent premises. In spite of administrative duties, Dr VRS played a significant role in elucidating the epidemiology and pathology of the 1954 epidemic of hepatitis in Delhi.

He cultivated the abiding friendship of visiting scientists Drs Lucien Gregg and LeRoy Allen of the Rockefeller Foundation and WHO and was largely responsible for selection and deputation of Rockefeller fellows through the ICMR - Rockefeller Fellowships thereby achieving a pool of talented and trained new generation of middle-level scientists. With his clinical moorings, he envisaged the need for epidemiological studies in the country. As a first step, he was responsible for initiating the core idea of an Indian Registry of

Diseases on the lines of the American Registry of Pathology and Armed Forces Institute of Pathology, with an integral statistics division. Later, these concepts fructified in the form of the Statistical Unit at ICMR Headquarters and the creation of the Indian Registry of Pathology. Up to the mid-sixties, Dr VRS played a crucial role in the combined Annual Meetings of the ICMR and the Indian Association of Pathologists & Microbiology and thus fostered research in Medical Colleges.

Dr Pandit was a co-author of the historical Pandit-Hance Report which recommended the establishment of the All India Institute of Medical Sciences (AIIMS) at New Delhi as a parting gift of the British Empire, at the behest of Lord Wavell. With the recruitment of its faculty in the offing, Dr VRS's interest in pursuing a scientific and academic career was rekindled. He was the obvious and natural choice for the position of Research Professor of Pathology at AIIMS. Soon, he was also entrusted with responsibilities of regular Professor of Pathology & Head of the Department. This gave him a rare opportunity to develop a school of excellence in pathology. Several eminent colleagues like Drs H. D. Tandon, N. C. Nayak, M. G. Deo and S. K. Sood joined him as members of his staff. An array of brilliant students, too many to be enumerated here, spread his name and fame throughout the world.

The new opportunity enabled him to pursue vigorously, some of his earlier studies on nutrition pathology, such as development of a model of kwashiorkor. He pursued with his colleagues further studies on ICC. In close collaboration with the clinical colleagues, he established the new entity of NCPF (non cirrhotic portal fibrosis). Some of the unique features which DrVRS introduced as professor of pathology, was the optimal utilization of autopsies, both clinical and medico-legal. The latter dealt with the prevalence of cardiovascular diseases, particularly of the aorta and coronary vessels, a work, which is extensively cited.

A reference has already been made to the original interests of Dr VRS in iodine metabolism. Subsequently, in close association with Drs Karmarkar, N. Kocchupillal and Dr VRS undertook extensive laboratory studies on Himalayan goitre, cretinism, and mental retardation not only in the sub-Himalayan region but in other parts of the country. It paved the way for the recognition of goitre as a national problem and development of effective counteractive measures culminated in the National Goitre Control Programme through iodination of common salt. Studies on dengue and epidemic hemorrhagic fever were other significant contributions of Dr VRS.

During this period at AIIMS, Dr VRS made the second major contribution by fostering scientific interaction between Indian and eminent pathologists of the West. Scientists invited by him to spent time at AIIMS in his department reads like a virtual Who is Who in pathology - Drs Benjamin Castleman of Harvard, Hans Smetana, Lolla Iverson of AFIP, Walter Putschar of Harvard. Hans Popper of Montefiore Hospital. Dame Sheela Sherlok of the Royal Free Hospital, London, in addition to several other visitors in transit who delivered advanced lectures on different topics of pathology. In recognition of his contributions at the national and international levels, Dr VRS succeeded Dr K. L. Wig as the Director of the All India Institute of Medical Sciences, a post he executed with great finesse and won accolades by the entire faculty and the Government.

At the height of his reputation as Director of ARMS, and his background in medical research for several decades, he was chosen as the Director-General of ICMR in 1979. He lived up to the expectations of the Government as well as the scientific community. During his tenure of about 7 years, Dr VRS enlarged the activities of ICMR in many directions. Apart from the setting up of new institutions, he developed the concept of Regional Medical Research Centres for tackling the local health problems in specific and far-flung areas. He implemented the recommendations of the first and second ICMR Review Committees and greatly contributed to the reorganization of ICMR specially through introduction of a rigorous peer review system for all intramural and extramural research programmes. The mechanisms that he laid down are of an enduring nature, being practiced even now.

Dr VRS had the scientific spirit, temper and urge, to rise to the occasion on many a national crisis and emergency. A notable example is the manner in which he had mobilized and organized the resources and manpower for the conduct of scientific studies in the wake of the Bhopal Gas disaster. Even after he retired. his initiative and role in the outbreak of plague in Surat exemplifies his commitment and systematic and scientific approach to national health problems and crises. Indeed, his period could be considered as a high watermark in the annals of the ICMR.

During his long sojourn at the ICMR, he continued and accelerated the ongoing efforts in making the Council a forum and venue in the city of Delhi, for scientific meetings and discussions. He strengthened several scientific activities such as ICMR Award Lectures and Orations, that were greatly appreciated by medical profession and the public at large.

Even after the formal end of his tenure in the ICMR, Dr VRS evinced keen scientific interests which were fully appreciated by International bodies and agencies. Thus, he was invited as a Fogarty Fellow and later as a Special Professor of Toxicology at Harvard. Subsequently, he was on an assignment with the UNICEF for a period of 5 years. He was actively associated with national bodies like, Rajiv Gandhi Foundation & Cancer Research Institute, Center for Science and Environment, Ranbaxy Foundation etc. Thus, his scientific exertions found natural fulfillment in his ceaseless endeavors towards perfection in the cause of medical research in India and abroad. To the very end of his life when he was the National Professor at the AIIMS, New Delhi he retained his academic and research interests. The First Pushpa Sriramachari Memorial Oration at the Institute of Pathology, New Delhi on June 1, 2000, arranged as a mark of my personal tribute to our scientific association spanning five decades, perhaps was his last Public Oration.

Dr VRS was among the most honoured medical scientists of India from a Bhatnagar award (CSIR) to Padma Bhushan conferred on him by the Govt. of India. To recall a few others, he was a Fellow of the Royal Society, Fellow of all the three National Academies of Sciences in India (President of the INSA - 197980), Fellow of the National Academy of Medical Sciences, Foreign Associate of the US and Russian Science Academies and Fellow of the Royal Colleges of Physicians and Pathologists. He was awarded D.Sc. (honoris causa), Karolinska Institute, Sweden, Basanti Devi Amir Chand Award (ICMR), Silver Jubilee Award (Medical Council of India), Jawahar Lal Nehru Memorial Lecture, Jacque Parisot lecture of WHO, first R.D. Birla National Award, J.C. Bose Medal of INSA and crowned by the National Professorship of the Government of India. He was also Chairman of the Global Advisory Committee on Medical Research, WHO besides advising other international organisations in various capacities.

Dr VRS was also blessed with a happy family. His wife Surya Prabha retired as a Professor in the Centre for Social Medicine and Community Health at the Jawahar Lal Nehru University, New Delhi, son Dr V. Jagdish is currently Chairman of the voluntary agency South Asia Against AIDS based in Bethesda and daughter, Dr Lakshmi, Assistant Director of Clinical Laboratories at Mount Sinai Hospital, New York.

May his spirit be a source of inspiration for successive generations of biomedical scientists of India.

Dr S. Sriramachari

Former Addl Director-General, ICMR and now INSA Honorary Scientist Institute of Pathology (ICMR) New Delhi 110029

Copyright Indian Council of Medical Research Jun 2001
Provided by ProQuest Information and Learning Company. All rights Reserved

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