April 30, 2014
Anna Waszkielewicz. Ph.D., from the Jagiellonian University’s Medical College in Cracow, a coordinator of a project that aims to develop a range of chemical compounds that may in the future be used to produce a new drug for neuropathic pain and epilepsy, talks to Karolina Olszewska.
Your project is searching for what you term “an innovative group of compounds with a stabilizing effect on cell membrane potential.” Can you explain what that means?
We’re working on a group of compounds that in the future may be used for a drug for neuropathic pain and/or epilepsy. These compounds must be designed and then synthesized in the right way, and—because they are new chemical structures—they must be tested for inhibitory activity against convulsions and pain. First we need to test any new substances that have a stabilizing effect on convulsions resulting from excessive nerve cell activity. Then we need to look at the end result—namely the inhibition of pain. Unfortunately, this involves tests on animals. We want to minimize their suffering.
Why did you decide to focus on analgesics and antiepileptic drugs?
There is no medication for patients suffering from neuropathic pain. This disorder involves pathological changes in nerve cells. As a result of these changes, there is an excessive number of nerve cell projections and sigma receptors that cause pain when stimulated. The patient feels pain when touched and when there are temperature changes. Under normal physiological conditions, these two stimuli should be transmitted as a signal imperceptible to the brain. Neuropathic pain may be associated with different symptoms in different patients suffering from a range of diseases. But characteristically a touch and any slight changes in temperature are felt as pain. Sometimes there is even the occurrence of spontaneous pain not caused by any stimuli. For example, this may happen when the patient has cancer or undergoes cancer-related chemotherapy. This type of pain may also appear in the form of phantom pain after the patient loses a limb, as well as in the case of diabetic conditions or herpetic neuralgia.
What is a sigma receptor?
It is a protein that is responsible for transforming an ordinary stimulus into a pain stimulus. Usually, pain is a signal that there’s something wrong in the body. In this case, pain is a disorder in itself, and more precisely a collection of disorders. We call them neuropathic pain.
Neuropathic pain affects 5 percent of the population. The older the population, the more people tend to be affected, which is due to neurodegeneration processes. Epilepsy affects 1 percent of people. A major challenge for researchers is so-called drug-resistant epilepsy, which does not respond to any available drugs. This represents 30 percent of all seizures. So we have 0.3 percent of the population for which there is no cure.
Which partners are you working with?
The project is the result of nearly 20 years of collaboration (since 1996) between the Faculty of Pharmacy at the Jagiellonian University’s Medical College and the U.S. National Institutes of Health as part of a search for antiepileptic drugs. Research into neuropathic pain has also been carried out as part of this collaboration.
Generally, three groups of drugs are used in the treatment of neuropathic pain: anti-epileptic drugs, anti-depressants and local anesthetics. There is no pharmaceutical registered exclusively for neuropathic pain, so the search is being carried out as part of broader research programs.
Have you patented your compounds?
The project has yielded a number of patent applications. We have two applications for Europe, one for the United States, and three for Poland. In addition, we have secured patent protection in the European Union, in the BRIC countries (Brazil, Russia, India, China), and on the markets in Japan, Canada and South Korea—they cover a large part of the global pharmaceutical market. The United States alone accounts for 63 percent of the global market for prescription drugs for neuropathic pain. The patents are for the composition and structure of the chemical compound as well as the method with which it is obtained and its use in treatment.
What animals have been used for tests? Is it possible to reduce their suffering?
To begin with, the study includes administering a compound to mice, and then inducing convulsions. If the compound prevents their occurrence, that means it protects the animal. These initial tests were conducted in the United States. Then, rats were used for the tests. The change of the species tested and the method by which the preparation is administered provides a lot of information. The study also makes uses of isolated animal cells, for example neural cells and isolated enzymes of these, such as liver enzymes. Unfortunately, neurology is a complex field. So it may happen that you design compounds for specific, isolated cells and have very good results but fail to achieve a positive result on a living organism. Therefore, we cannot escape the need to administer the compounds to animals. The number of animals used in the experiment is monitored by the Animal Ethics Committee, and the application to this committee must justify the procedure. The tested compound is evaluated by the committee on each occasion—in terms of whether it is promising, offers the chance to yield positive results and whether such an experiment is rational and what’s the rationale for the tests. Only then does the committee grant its permission.
In addition to mice and rats, the compounds have been tested on guinea pigs in Poland. We have also managed to arrange tests on large mammals—miniature pigs weighing up to 40 kg. These tests were commissioned from a company in the United States—in order to see how the concentration of the compound in the blood changes with time. It’s only four species of animals, but quite a lot of them had to be sacrificed in many different experiments.
How close are you to putting drugs out on the market?
That takes time. Clinical trials on people alone will last seven years. We have already planned these in Poland, in three phases. We have drawn up the plan, calculated the budget and are in talks with investors. The tests cover not only the administration of the compound to people, but also collecting blood from them and analysis of the blood. We have patents and completed tests on animals, cells and enzymes. We still have to repeat some of the experiments for a single compound in line with Good Laboratory Practice standards, but we will outsource these along commercial lines to an institution that ensures such standards. This cannot be a university. A laboratory meets the GLP standards if all of its procedures meet the standards involved, and no experiment records can be removed from the documentation.
We still have chronic toxicity tests ahead of us. These last 28 days. The compound, in the form of pills, is administered to miniature pigs and rats. For 28 days bodily fluids are collected from them, and changes are examined in the concentration of the compound and in the metabolism. These animals are observed for their well-being, changes in weight and body temperature. The tests make use of synthesized compounds meeting the GLP standards. After that they can be administered to humans.
How will Polish researchers benefit if an innovative drug they’ve developed is produced by a foreign pharmaceutical company?
Formulas are developed at universities, which patent inventions. If a foreign company invests in such a project, it pays the university a license fee. Then the university shares part of this revenue with the researchers. Such a fee may be a one-off payment if it’s for the sale of a patent. Sometimes this may be an annual fee; sometimes the amount depends on the success of the later stages of research. All this is regulated by an agreement between the company and the university.
And what about the benefits for the Polish economy? Can the new drug be produced in Poland?
We want to manufacture our products in Poland. We plan the work in such a way so that as many organizational aspects of the project as possible are handled locally. Poland has an excellent business climate. The quality of services has improved, while the costs are still lower than abroad.
The “innovative group of compounds with a stabilizing effect on cell membrane potential” project has been financed with a zl.5 million grant from the National Center for Research and Development (NCBiR). Since the research is time-consuming—particularly at the stage of administering the new compounds to large mammals—the time frame for the project has been extended from three to four years.
The researchers have spent the money on laboratory equipment and hired qualified staff. For the purposes of their research, they have synthesized 100 new compounds and tested these on animals.
At various stages, the project has involved more than 30 researchers from the Faculty of Pharmacy at the Jagiellonian University’s Medical College.