Unexpected effects of old drugs – antihypoxic properties of lactulose
Authors: Соловйов А. , Мончак І. , Козловський В. , Ольшевська О. 
Published: January 2025

Faced with soaring costs of developing new drugs, researchers are looking for ways to repurpose old ones, that is «...the most fruitful basis for discovering a new drug is to start with an old drug». Lactulose is a well-known synthetic sugar used to treat constipation. It is not absorbed in the small intestine and is not broken down by human enzymes. Lactulose is metabolized in the colon by bacterial flora to short-chain fatty acids, monosaccharides, lactic and acetic acids, volatile fatty acids, hydrogen and methane. The problem is that all of this happens in the colon. Could something similar happen in Krebs solution under in vitro conditions?The aim of study – to test experimentally the hypothesis about the possible antihypoxic effect of the drug lactudose in vitro. However lactulose unexpectedly demonstrated a clear ability to restore spontaneous activity of the rat portal vein inhibited under hypoxia in vitro. Lactulose effectively restores the amplitude of vascular contractions caused by field electrical stimulation that was inhibited by hypoxia. When lactulose was added to the organ bath both before hypoxic exposure and electrical stimulation, stimulation caused a paradoxical increase in isometric tension. Preliminary data obtained suggest that the plasma membrane of vascular smooth muscle cells may primarily participate, and the mechanisms of energy supply to the contractile apparatus do not take such a large part in the response to hypoxia. The experiments showed, that one of the most vulnerablel inks in the excitation-contraction coupling chain in vascular tissues during hypoxia is the system of passive transmembrane Ca2+ transport. Probably, sugars that are not hydrolyzed by a living cell can have biological effects during hypoxia that are not related to their substrate influence. As an object of study, we focused on the disaccharide lactulose, which contains fructose and galactose. In the body, outside the intestines, there are no enzymes that could metabolize this bond and hydrolyze this compound. It seems that if lactulose has an antihypoxic effect, then this effect will depend exclusively on non-metabolic factors, which will make a significant contribution to the understanding of the fundamental mechanisms of the development of hypoxic conditions. The voltage-sensing domain of voltage-gated ion channels is a protein structure important for membrane voltage sensing that is characterized by specific, conserved, and charged amino acid residues. It is generally assumed that molecules are neutral and do not carry unpaired electrons. Charged molecules are called molecular ions, molecules with a multiplicity other than unity (i. e., with unpaired electrons and unsaturated valences). Thus, under certain changes in environmental conditions (for example, a change in pH), a previously neutral molecule can become electrically charged and thus acquire the ability to interact with a potential sensor in ion channels. Interestingly, even if a carbohydrate does not carry a formal charge, when bound it will change the dielectric environment, since the region previously filled with water (in the absence of significant conformational changes) will be occupied by an environment with a much lower dielectric constant. Thus, carbohydrates can act as universal electrostatic modulators of protein function, even if their binding causes little or no conformational change in the protein molecule. In conclusion, it should be noted, the fact that lactulose has antihypoxic properties is beyond doubt. From a clinician's point of view, this is already good. The compound is well known and completely harmless. But pharmacology is the science of the mechanisms of action of chemicals on living systems, and therefore we are obliged to propose such mechanisms. If not absolutely demonstrative, then at least theoretically acceptable. A possible metabolic shift towards glycolysis would be a good potential candidate for evidence, but is currently difficult to substantiate. It remains only to assume the possible interaction of the electrically modified (under conditions of hypoxia and associated acidosis) lactulose molecule with voltage-dependent calcium channels and the restoration of their activity, suppressed during hypoxia.