Hazardous cocktails

Pertti Neuvonen is a whizz at tracking down dangerous drug interactions. The pharmaceutical industry anxiously watches out for his latest findings.

It was 1993 when a female patient returned to a physician she had just seen, complaining about swollen feet. The woman had been prescribed antifungal medication for athlete’s foot, and suddenly her boots no longer fit.

The physician treating her contacted the University of Helsinki – the Department of Clinical Pharmacology at the Meilahti medical campus, to be specific – to seek the advice of Pertti Neuvonen. Now a holder of the honorific Professor Emeritus, Neuvonen has for nearly 40 years been the person to call when a patient reacts unexpectedly to medication.

The physician suspected that the symptoms were caused by a drug interaction, since the patient also used a calcium channel blocker for high blood pressure.

Neuvonen’s research group carried out additional tests on the patient and also used test subjects to study the case. It turned out that the antifungal medication led to a tenfold increase in the concentration of the calcium channel blockers. This rapidly caused the feet to swell and blood pressure to plunge.

Instead of arranging press conferences or meetings with the authorities, Neuvonen’s team submitted an article to Clinical Pharmacology and Therapeutics, the leading journal in the field.

The news spread rapidly around the world. The medical authorities in the US and the EU, among others, have since listened keenly to the results and recommendations published by Neuvonen’s team.

Death investigator

Investigations into drug interactions are, in fact, often motivated by patient observations, but their impact may be extremely wide.

A little more than a decade ago, a new cholesterol drug caused nearly one hundred deaths in the US in only a few years, half of them due to drug interactions.

Neuvonen’s team unravelled the mechanism causing the concentration of certain cholesterol-lowering drugs — statins — to spike and even lead to death. The shocking results and the ensuing compensation claims very nearly brought a large German pharmaceutical company to its knees.
The pharmaceutical industry has learned to keep close tabs on the activities of Neuvonen, now a research director, and his team. It even includes the team’s results in its product information.

Though drug interaction observations reduce the sale of pharmaceuticals, the safety of medicinal products must take precedence. However, in the case of drugs that generate annual sales of billions of euros, companies sometimes try to protect their product sales and formulate statements that repudiate the findings made by Neuvonen’s team.
“Nevertheless, our results have always proved to be true,” says Neuvonen.

Riding to fame with activated carbon

Neuvonen was drawn to pharmaceuticals early on.  At the beginning of the 1970s, he showed that iron preparations and milk products inhibited the absorption of tetracycline antibiotics. First repudiated by a major pharmaceutical company this observation has now become standard textbook material.

The field wasn’t particularly popular back then. “Some physicians seemed to think that patients could endure pretty much anything,” recalls Neuvonen.

In 1972, when Neuvonen was a young docent, he was hired as a clinical instructor by the recently established Department of Clinical Pharmacology. His reputation began to increase hand in hand with the studies of activated carbon launched in the late 1970s.

Activated carbon, used to treat intoxication, was originally administered in small doses as tablets. Used this way, its effect was small. Neuvonen and his team developed a water-soluble carbon powder that enabled a tenfold increase in the dosage. In addition, Neuvonen demonstrated that a large dosage worked for many different types of intoxication. Thanks to Neuvonen’s work, stomach lavage and emetics have now taken a back seat.

References are still made to these studies, as well as to many of Neuvonen’s other findings. Over the years, Neuvonen and his team members have become some of the most cited researchers in the field of pharmacology and of the University of Helsinki.

Business rules

During the recent decades Neuvonen’s group has identified dozens of life-threatening drug interactions. However, this is not the only reason for his awe-inspiring scores in citation indexes. Nor is the fact that Department of Clinical Pharmacology is one of the best in the field worldwide.
The work group has also gained a great deal of publicity because of the scarcity of competitors. The topic is not popular among researchers in the pharmaceutical industry.

Once a pharmaceutical has been granted marketing authorisation, the manufacturer rarely shows much interest in studying possible interactions with other drugs. “From its own point of view, industry has nothing to gain from interaction research in the short term,” Neuvonen explains.

After all, serious interaction issues could lead to a pharmaceutical being withdrawn from the market or at least to its demand dropping. “Some industrial players have actually admitted that they suspected the interaction we later detected, but left it at that.”

However, Neuvonen is careful not to create too great a divide between his research and business. “The academic world can only dream about the research budgets of companies,” he points out. “I believe society should invest more in drug interaction research. It is integrally related to the safety of medicinal products.”

Neuvonen has received a few offers for the position of research director in pharmaceutical companies, but academic freedom has ultimately prevailed.

The impact factory

Around the world, Neuvonen’s team is known by the playful name the “impact factory”. Not only does this refer to impact factor, a measure of the importance of research, but also to the factory-like pace at which the team pumps out significant publications.

Neuvonen has also received an award from the US Food and Drug Administration (FDA), in addition to being granted the first Nordic Prize for lifelong efforts in the field by the journal Basic & Clinical Pharmacology & Toxicology.

The biggest prize, however, lies elsewhere. Cautious estimates put annual drug interaction-related deaths at tens of thousands, a figure that keeps growing as the numbers of pharmaceuticals and their users increase.

This is where Neuvonen and his team want to make a difference – and have already done so.

Text: Juha Merimaa
Photo: Wilma Hurskainen
Translation: Language Services / Language Centre of  the University of Helsinki