Inactive ingredients in medicine can be biologically active!

Inactive ingredients in medicine can be biologically active!

Some supposedly inactive ingredients in common drugs - such as dyes and preservatives - can possibly be biologically active and lead to unexpected side effects. This emerges from a preliminary new study by researchers from UC San Francisco School of Pharmacy and the Novartis Institute for Biomedical Research (NIBR).

Some supposedly inerts in common drugs may be biologically active

Most medication contains only a relatively small amount of their pharmaceutical active ingredient (e.g. paracetamol in Tylenol and other medications). The rest of a pill, liquid or injectable can consist of components, including preservatives, dyes, antimicrobial means and other compounds known as auxiliary materials. These ingredients play a crucial role in ensuring that the active ingredient of a drug is reliably and effectively released, and give important properties such as storage stability and the ability to quickly distinguish pills according to color.

It is generally assumed that auxiliary substances are considered to be biologically inactive due to their long use of use or because they do not cause obvious toxicity in animal experiments. Only a few studies have searched for a long -term exposure to these compounds or their interaction in people who take several different drugs that contain these ingredients.

The researchers Brian Shoichet, PhD, from the UCSF department for pharmaceutical chemistry and Laszlo Urban, PhD, Global Head of Preclinical Safety Profiling on NIBR, had started to ask whether all of these substances were really used and teamed up to examine them. They began working in 2017 with a database in which the easiest accessible auxiliary substances are documented, which the UCSF group had put together in a user-friendly auxiliary browser that was based on a more specialized FDA database for inactive ingredients (IID) supported by the FDA financed by the FDA financed and Innovation (Cersi).

As reported in her new study, which was published online in Science on July 23, 2020, the researchers have now systematically scanned 3296 in the database for inactive ingredients and identified 38 auxiliary material molecules that interact with 134 important human enzymes and receptors.

The team of researchers emphasizes that in their study, in which the actual effects on human patients were not searched for, only molecules should be marked that may have negative effects on Health. The examples listed must be further examined to understand how they may contribute to side effects of drugs in which they are found.

The data illustrate the following:

"This data show that many auxiliary molecules are actually inserted, but a good number of possibly not recognized effects on human proteins that are known to play an important role in health and illness," said Shoichet. "We show an approach with which pharmaceutical manufacturers can rate the auxiliary substances used in their formulations and replace biologically active connections with equivalent molecules that are really inactive."

The team pursued various approaches. On the UCSF, Shoichet's team examined mathematically auxiliary material molecules, which physically resemble the well-known biological binding partners of 3117 different human proteins in the public chembl database. The team then reduced 2 million possible interactions of these aids and human target proteins to 20,000 chemically plausible interactions. Based on a visual examination, the researchers identified a sub -group of 69 auxiliary substances with the highest probability of interaction with human target proteins and tested these interactions experimentally in laboratory bowls in cooperation with the groups of Bryan Roth, PHD, Professor of Pharmacology at the University of North Carolina, Chapel Hill, and Kathy Giacomini, PHD, Professor for Bio engineering at the UCSF and co-director of the UCSF-Stanford Cersi Center.

In experiments, various biological interactions with auxiliary molecules and pharmacologically important human proteins were identified

These experiments identified 25 different biological interactions in which 19 auxiliary material molecules and 12 pharmacologically important human proteins were involved.

In a supplementary series of experiments on the NIBR, the researchers examined 73 frequently used aids against a group of human protein goals that are involved in the medication -induced toxicity and were used regularly to test medication candidates for safety. They identified an additional 109 interactions between 32 auxiliary substances and these security goals for humans.

"Our study should build on anecdotic evidence that auxiliary substances can be the cause of unexpected physiological effects that occur in certain pharmaceutical formulations," said the study manager Joshua Pottel, PhD, a former postdoctoral student in Shoichet-Labor, which is now the President and CEO from Molecular Forecaster Inc. It was not so surprising to find new properties of examined connections that have been classified as "inactive" for decades, but it was surprising to see how effective some of these molecules are, especially in view of the rather high amounts that are sometimes used in typical medicinal formulations. “

biologically active auxiliary substances The study identified in laboratory bowls deserves further examinations

The biologically active auxiliary substances that were identified in the study in laboratory bowls earn another examination in animal models to determine whether one of them can actually cause unwanted side effects in human patients, according to the authors. Many should easily be interchangeable with really advertised auxiliary substances with a similar function, they said, but for others, new replacement connections may have to be developed.

"After decades with little innovation in the formulation of medicinal products, we see this as an opportunity for a public-private partnership between academic, official and pharmaceutical communities to look for new and better auxiliary materials, and we demonstrate an approach to this," said Shoichet. "In view of the challenge that this work represents for the pharmaceutical status quo, we are grateful for the forward -looking support that the project has received primarily from the FDA and through our collaboration with Novartis and the National Institutes of Health."