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The team from the Institute of Experimental Pharmacology and Toxicology of the Centre of Experimental Medicine SAS has been studying mechanisms of pathological changes affected by long-term hyperglycemia, which are considered to be a key factor in the development of late diabetic complications. A ray of hope is the promising new drug cemtirestat. The team is in the stage of "comprehensive pre-clinical evaluation” and even won the SAS Award for 2023 for the results of the research work so far.  We spoke to Marta Prnová about the drug, as well as the entire research.

• Cemtirestat is supposed to be helpful in the treatment of late diabetic complications. Can you specify them?

Patients who suffer from diabetes (diabetes) are affected by late diabetic complications, which include, for example: neuropathy (gangrene, allodynia, incontinence, impotence...), nephropathy (kidney damage leading to dialysis), angiopathy (vessel damage), retinopathy (eye disease that can lead to blindness), cataracts, gingivitis, non-specific inflammation, recurrent infections, osteoporosis, cardiovascular diseases and many others. Late diabetic complications occur slowly and unnoticed. They also occur in patients who are relatively well compensated.

• What influences their origin?

The increased flow of glucose, the so-called Polyol pathway, plays one of the main roles in the development of these complications.  If we have normal blood glucose levels, roughly three percent of glucose is metabolized through this pathway, but if the body is affected by hyperglycemia, the proportion of glucose metabolized through this pathway can reach up to 33 percent. The first metabolite (metabolism product) of this pathway is sorbitol, whose increasing concentration in the cell can lead to damage to the cell itself or even to its rupture. In turn, an increased level of the second metabolite - fructose, can lead to increased glycation of proteins, and to their damage and loss of regulatory and functional abilities. In addition, this pathway indirectly produces a larger amount of free radicals, which induce the production of the so-called antioxidant enzymes (glutathione, peroxidase, superoxide dismutase, catalase...) and subsequently the so-called detoxification enzymes, including the very first enzyme of the Polyol pathway. This mechanism creates an endless cycle that accelerates pathological processes in the affected cells and silently leads to the development of late diabetic complications.

• What makes cemtirestat special - what are its properties?

There is no drug on the Euro-American market that would prevent the development of late diabetic complications. There is an epalrestat on the Asian market, which did not reach our market due to adverse effects. When comparing the effects of these two substances, cemtirestat is a more effective inhibitor (reduces the activity of the target enzyme), is more soluble in water, has a lower molecular weight, and acts as an antioxidant on several levels. It not only scavenges free radicals but also regenerates glutathione, an antioxidant enzyme that maintains balance in the cell. So cemtirestat, with its multiple mechanisms, acts on multiple levels and prevents the development of late diabetic complications.

• At what stage is your research? When can it be expected on the market?

In pharmacological research, it is generally very difficult to predict how long it will take for the investigated potential medicine to be launched on the market, and if at all. With each experiment, we may discover some features that could cause a serious adverse effect. On the other hand, cemtirestat has already gone through many preclinical tests and we have not seen such a feature so far. However, to enter the clinical market, we would need an industrial partner - a pharmaceutical company that could perform clinical tests and other actions necessary for drug validation and registration.

Edited by Andrea Nozdrovická

Foto: ÚETaF CEM SAV, v. v. i. a Martin Bystriansky