When cells are hyperactive

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Scientists from the Faculty of Pharmacy at the Jagiellonian University Medical College are working on new potential drugs against neuropathic pain and/or epilepsy.

Searching for new drugs is an important challenge in a society where the lifespan of humans has significantly increased. Patients' expectations concerning their health are also growing. In this context, neurological diseases have become a particular problem whose treatment and rehabilitation are costly, and the purchase of medications quite often leads to financial ruin. This is why it is a particular social responsibility to carry out chemical and pharmacological studies whose results may contribute to improving the outlook of people's lives.

Development of new drugs can be divided into two stages: pre-clinical and clinical. The first one encompasses, among others, studies related to structural design and synthesis, physical, chemical and biotechnological analyses, and tests on animals. The clinical stage consists of tests on humans. Due to the number of aspects that have to be taken into account when planning the possibilities of therapeutic application of new compounds, both stages usually last for 7–10 years each.

Broad spectrum of analyses

Epilepsy and neuropathic pain (pain caused by damage or dysfunction of the nervous system) are different ailments, which have, however, one essential trait in common: excessive activity of neural cells. Plenty of analgesics and anti-convulsives have been registered throughout the world, although their insufficient efficacy and toxicity are unsatisfactory for both patients and doctors.

At the same time, knowledge about the causes and the course of these diseases not only at the anatomical level but also at the cellular or even molecular levels is growing, which gives us increasing hope of finding new, efficient and safe drugs. A team at the Department of Bioorganic Chemistry (Jagiellonian University Medical College), supervised by Professor Henryk Marona, has been designing and synthesizing new, potentially therapeutically active chemical compounds, which might be approved for the pre-clinical testing stage. Compounds selected in this manner were the subject of pharmacological analyses at the American National Institute of Health, which tested their activity in preventing seizures caused by various factors, e.g., electric current or compounds such as metrazol, picrotoxin or bicuculline, which are used in experimental pharmacology among others to cause seizures. Substances that prevented seizures, and at the same time were free of neurotoxicity, were then subject to detailed tests aimed at the analysis of the mechanism of action. The most promising compounds were also subject to tests consisting of evoking neuropathic pain in rats and then checking how the given compound influences the feeling of pain by the animal.

Towards trials on humans

As a result of the research discussed above, substances were obtained that were active both in neuropathic pain and in epilepsy, which gives hope for their application in the treatment of neurological diseases. The activity of these compounds consists mainly of inhibiting the sigma receptor, which is suggestive of their high potential, precisely in the treatment of neuropathic pain. Two prerequisites pointing to the truthfulness of this opinion are important: first, higher numbers of sigma receptors exist in the body in the case of previous neural cell damage, and their stimulation causes a pain reaction; and second, currently there are no drugs acting only on this receptor available on the market.

The pharmacological activity discussed has been described in further detail. Mandatory chemical tests have been conducted and the methods of analysis of these compounds in the bloodstream have been developed. Scientists have also determined their functioning and changes in concentration as well as their metabolism in the body and they have described most of the necessary studies on their toxicity. Tests were conducted using receptors, enzymes and whole cells as well as different species of animals: mice, rats, guinea pigs and miniature pigs. Also, the initial oral formulation, i.e., the composition of the tablet that will be swallowed by future patients has been developed.

"We want to continue our efforts. The next stage will be synthesis on a larger scale (i.e., the increase in the size of batches of the compound synthesized each time) and transferring the works to the GLP standard (Good Laboratory Practice – a set of criteria that a laboratory conducting the given types of analysis must meet in order to provide adequate research quality), which is obligatory for this type of project at this stage of research. Then our aim will be to conduct an analysis of chronic toxicity on miniature pigs and to administer the drug to humans for the first time," explained Anna Waszkielewicz, PhD, co-creator and expert coordinator of the project.

Towards trials on humans

Research team: Professor Henryk Marona – Project Manager; Anna M. Waszkielewicz, PhD – Project Coordinator; Natalia Szkaradek, PhD; Karolina Słoczyńska, PhD; Agnieszka Gunia, PhD; Dorota Żelaszczyk, PhD and employees of other departments at the Faculty of Pharmacy (Jagiellonian University Medical College).