One of the ongoing challenges with neglected tropical diseases (NTDs) is that the discovery of medicines to treat them has been very slow. Current global programmes for NTDs largely depend on donated medicines, primarily to treat the world’s poorest people – most of whom live in remote rural or in deprived urban settings.
Due to a lack of incentives to develop new chemical matter or apply target knowledge, many medicines intended for veterinary use have been “adapted” or “repurposed”, while others have been “combined” for better efficacy – the majority from last century.1
In 1981, albendazole was adapted and approved as a deworming medicine for human use. It has since benefited billions of people, bringing health benefits to pregnant women and children especially.
The World Health Organization’s (WHO’s) global deworming programmes recommend periodic deworming without previous individual diagnosis for all at-risk people living in endemic areas.
We recently spoke to Mr Robert J. Gyurik, who discovered albendazole in 1972. He took us through the journey that led him to develop the compound.
© Bob Gyurik // Bob Gyurik giving a symposium presentation in La Grand Motte, France, 2001
Mr Gyurik, how did you get into medical research?
I always thought I would be involved in science and became interested in chemistry around the age of 12. My father encouraged me in that direction.
I scored very high in the college entrance exams and went to Rutgers University in New Jersey. After completing a 2-year scholarship, I dropped out – I felt that I had learned enough and did not want to borrow money (my family was poor).
For 3.5 years, I worked as an Assistant Medicinal Chemist at Schering Corporation in New Jersey, working on memory and learning drugs and anti-Parkinson drugs.
Following a year of travel in Northern Canada, I returned to the United States of America and was hired by SmithKline Animal Health Products (now Glaxo) in 1971.
Was this the right working environment and job?
Interestingly, benzimidazole anthelmintics were not part of our team’s mandate. We were focused on other molecule classes .
Over the preceding decades, 190+ individual benzimidazole molecules had been synthesized and tested for anthelmintic activity, resulting in parbendazole and oxibendazole – commercial successes for veterinary applications.
I was discouraged from synthesizing albendazole. The perception was that the benzimidazole class had been exhausted. Furthermore, the albendazole structure was demonstrated to have no better activity than oxibendazole.
At the time, investigators could spend 10% of their time on “skunkworks” projects. So, I decided to make the molecule. Since my focus was supposed to be on other potential drug classes, I often stayed late or used the weekend to finish making the molecule in the shortest order. Also, sulfur chemistry was not loved at the time – the intermediates were often odorific, to say the least.
However, my supervisor, who had been trained in sulfur chemistry, provided encouragement and synthetic direction.
About 2 months and 7 successful synthetic steps later, I had 3.5 grams of a pure white powder. It was 1972. Next, I had next to prove its structure, which took another month. But finally, albendazole was here!
© Bob Gyurik // Pennsylvania 1972, the year of the invention of ABZ (Albendazole), Bob-Gyurik and his wife Wendy and their pet steer, Mark.
Exciting times – what were the next steps?
The excitement was somewhat dampened, when my company announced that the parasitology effort was being discontinued in favor of animal nutrition research.
Research staff were relocated or terminated, and most chemists were moved to the main branch in Philadelphia. The remaining staff in parasitology biology stayed on for a month. The only test animals left were 3 sheep, which had been infected with all 3 classes of helminths, nematodes, cestodes and trematodes.
I handed the vial to my friend, the testing biologist, who gave 2 of the infected sheep a dose of the albendazole. (This was slightly “under the table”, as we had been told to suspend efforts on parasitology.)
A week later, the results came in – the 2 treated sheep had zero worms on necropsy! No roundworms, tapeworms or flukes remained. The control animal was still heavily parasitized with all classes.
Albendazole was the “next generation” of anthelmintics we had been searching for!
Next you had to go through the formal approval process. How did this unfold?
My new job was to get albendazole approved by the United States Food and Drug Administration (FDA).
My team dosed 4 species of animals (cattle, sheep, rats and mice) with radioactive 14C albendazole. We then isolated and identified the “hot” metabolites in urine from each. Chromatography identified 9 metabolites of unknown structure. Next, I had to isolate the metabolites and elucidate the structures.
The result was published in the Journal of Metabolism and the paper presented to the FDA. This was key to albendazole being approved for the treatment of meat-producing animals. Once identified, each metabolite had to be synthesized for further study. This development effort took a further 2 years.
What were the challenges during this phase? How did you overcome them?
The main toxicity issue was teratology, which is common to the benzimidazole class of compounds. With my supervisor and a professor from the University of Lyons, we undertook embryotoxicity and teratology studies in rats in France.
How was albendazole approved for use in animals?
To obtain approval for meat-producing animals from the FDA, a withdrawal time for the drug had to be developed. This was critical to the safety package and involved creative solutions, which took a long time.
Following on from the metabolism work, we not only knew what the active principle was (ABZSO), but from tissue work, which metabolite was the longest residing one in liver tissue.
At the desired withdrawal time, only parts per billion (ppb) of this entity remained. Measurable and reproducible levels in liver tissue were established using novel extraction methods, followed by high-performance liquid chromatography (HPLC) with fluorescence detection accurate at 50 ppb.
The method accuracy and precision were confirmed by inverse isotope dilution methods that were worked out concomitantly in our laboratory. The results satisfied the FDA, allowing a withdrawal time of 27 days for cattle and 7 days for sheep.
Albendazole was quickly approved for veterinary use after the submission.
© Bob Gyurik // Bob Gyurik standing in front of an HPLC (high performance liquid chromatography). HPLC is now one of the most powerful tools in analytical chemistry, 1976.
How was albendazole adapted for treatment in humans?
Credit goes to Dr Jean-Francois Rossignol and James Murphy, who worked with WHO to hold trials in Thailand, West Africa and Latin America.
In 1981, albendazole was finally approved for human treatment. I thank all my colleagues for their excellent work in taking my discovery to new heights.
Almost half a century after my synthesis, and 39 years after the human launch, albendazole continues to change the lives of hundreds of millions of people, especially children and women.
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Another milestone
Another relevant medicine used against NTDs is ivermectin.
It was discovered through close collaborative work started in the 1960s by Japanese microbiologist Satoshi Ōmura and Irish biologist William Campbell, who worked on a veterinary project against parasitic worms. The outcome of their research was an active component called “avermectin”. This was further chemically modified to produce ivermectin, which was approved to treat animals in 1981.
Campbell convinced his colleagues that ivermectin could work in the treatment of human diseases, and onchocerciasis was a disease candidate. They ran successful trials in Senegal.
Ivermectin was approved for human use in 1987. It has since been used in mass treatment programmes worldwide.
Decades later, Campbell and Ōmura were awarded the 2015 Nobel Prize in Physiology or Medicine2 for their “discoveries concerning a novel therapy against infections caused by roundworm parasites”.
NTDs
NTDs comprise a group of mainly chronic, debilitating and often stigmatizing diseases that primarily affect the world’s poorest people, living in remote rural and deprived urban settings.
Typical features include their complex interrelationship with poverty and socio-economic and ecological systems. NTDs are often linked with the course and outcome of pregnancy and stunted growth in children due to parasitic worm infection (loads).
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1 Some examples: suramin, an anti-trypanosomal (discovered in 1920s) used to treat sleeping sickness; pentamidine, part of a class of compound used to treat equine trypanosomiasis; melarsoprol, an arsenical used to treat sleeping sickness.
2 The 2015 Nobel Prize in Physiology or Medicine was shared with Youyou Tu, who discovered the antimalarial, artemisinin.