The objective of this study was to test the hypothesis that serotonin O-sulphate (5-HT-SO4) could be quantified in human plasma using modern liquid chromatography–mass spectrometry (LC-MS) method as well as develop and validate that method. First, a suitable LC-MS method for detection of 5-HT-SO4 in human plasma samples was developed and validated. Second, a Pilot phase involving four healthy volunteers was executed, where a basal plasma level of 5-HT-SO4 was measured for all subjects and for one after the intake of 100 mg of a 5-hydroxytryptophan (5-HTP) -containing food supplement used to promote serotonergic stimulation of the central nervous system. The basal level of 0.9–2.8 ng/mL of 5-HT-SO4 was observed. The changes of plasma 5HT-O-SO4 showed 1.2 ng/mL before and 22.6 ng/mL 1 h after stimulation. Finally, nine healthy volunteers were selected for the Study phase, where a basal plasma level of 5-HT-SO4 was measured before and after the intake of 5-HTP. One hour after stimulation, six study subjects showed a decrease in 5-HT-SO4 levels while three subjects showed an increase. The changes of plasma 5HT-O-SO4 from the Study phase showed an average 5-HT-SO4 level of 19.2 ng/mL before and 15.7 ng/mL 1 h after stimulation indicating ability of method to emphasize quantitative changes. This was the first study in which naturally occurring 5-HT-SO4 was detected in the samples of human plasma obtained from healthy volunteers. The method developed herein is specific to the measurement of 5-HT-SO4, sensitive enough to quantify intra-individual changes in the samples of plasma and opens up new possibilities to evaluate pathways of serotonin metabolism by minimally invasive methods. The discovery of novel biomarkers using such approaches is increasingly required to expedite development of mechanism-based therapeutics and patient stratification.

According to the latest European regulatory policy a close attention is paid to research into the use of biomarkers and surrogate markers in the development of pharmaceuticals. Since early sixties of the last century when a sulphation of serotonin was described from which the biotransformation product serotonin-O-sulfate (5-HT-SO4) was formed, is assumed it accentuates the intensity of serotonin metabolism in the central nervous system. Not so many researches are done with this compound particularly in humans, but taking into account serotonin-o-sulfate is able to reflect serotonin pathways it has a potential to be employed as a surrogate biomarker to follow the effects of a specific serotonergic treatment. Hereby we summarize the literature evidence of 5-HT-SO4 appearance in vivo. So far this indolemine was found in animal neurons, endothelial cells, urine and the only site of detection in humans was cerebrospinal liquid. Probably due to its absence in the easy accessible body fluids the clinical significance of 5-HT-SO4 has thus far been lessened. In result of our latest research we developed a suitable liquid chromatography-mass spectrometry (LC-MS) method, found this neurotransmitter degradation product in the human plasma and performed the first in humans clinical trial detecting it in healthy volunteers. According to the earlier animal research it is hypothised that 5-HT-SO4 release is site specific and emphasizes central nervous system specific serotonin metabolism, therefore a further research is necessary to define the origin of plasmatic 5-HT-SO4 in humans.

Until the change in drug legislation in 2010, the Russian Federation (RF) tried to follow the world-recognised guidelines of the US and European food supplement and drug registration legislation. After introducing the new pharmaceutical law (NPL), a unique legal system was created that did not correspond to international practice. At the same time, legislation on food supplements (FSs) remained the same corresponding to worldwide accepted practice. Consequently, restructuring of regulatory authorities was implemented. There was no pathway or authority restructuring for FSs in the same period. The present study aimed to analyse the legislative change burden on the availability of food supplements and medicines in the RF during the most turbulent period from 2010 to 2012. Before the NPL, 20,836 drugs and 5000 food supplements (FSs) were registered. After the NPL, the number of registered drugs significantly fell, while the number of registered FSs grew, showing a 90% increase. During the observational period, the number of registered FSs grew, and the registration process was stable. Meanwhile, a reduced quantity of registered medicines was observed, and the decline was −21.25%. Moreover, decreased productivity of regulatory authorities was noted, and the drug MAs issued per year fell by −64.11%.