Innovative analytical methods for Central Nervous System Drug analysis in biological fluids

During recent years a consistent number of central nervous system (CNS) drugs have been approved and introduced on the market for the treatment of many psychiatric and neurological disorders, including psychosis, depression, Parkinson disease and epilepsy. Despite the great advancements obtained in the treatment of CNS diseases/disorders, partial response to therapy or treatment failure are frequent, at least in part due to poor compliance, but also genetic variability in the metabolism of psychotropic agents or polypharmacy, which may lead to sub-therapeutic or toxic plasma levels of the drugs, and finally inefficacy of the treatment or adverse/toxic effects. With the aim of improving the treatment, reducing toxic/side effects and patient hospitalisation, Therapeutic Drug Monitoring (TDM) is certainly useful, allowing for a personalisation of the therapy. Reliable analytical methods are required to determine the plasma levels of psychotropic drugs, which are often present at low concentrations (tens or hundreds of nanograms per millilitre). The present PhD Thesis has focused on the development of analytical methods for the determination of CNS drugs in biological fluids, including antidepressants (sertraline and duloxetine), antipsychotics (aripiprazole), antiepileptics (vigabatrin and topiramate) and antiparkinsons (pramipexole). Innovative methods based on liquid chromatography or capillary electrophoresis coupled to diode-array or laser-induced fluorescence detectors have been developed, together with the suitable sample pre-treatment for interference removal and fluorescent labelling in case of LIF detection. All methods have been validated according to official guidelines and applied to the analysis of real samples obtained from patients, resulting suitable for the TDM of psychotropic drugs.

Flow of Complex Fluids in Geological Fractures

In this study, the lubrication theory is used to model flow in geological fractures and analyse the compound effect of medium heterogeneity and complex fluid rheology. Such studies are warranted as the Newtonian rheology is adopted in most numerical models because of its ease of use, despite non-Newtonian fluids being ubiquitous in subsurface applications. Past studies on Newtonian and non-Newtonian flow in single rock fractures are summarized in Chapter 1. Chapter 2 presents analytical and semi-analytical conceptual models for flow of a shear-thinning fluid in rock fractures having a simplified geometry, providing a first insight on their permeability. in Chapter 3, a lubrication-based 2-D numerical model is first implemented to solve flow of an Ellis fluid in rough fractures; the finite-volumes model developed is more computationally effective than conducting full 3-D simulations, and introduces an acceptable approximation as long as the flow is laminar and the fracture walls relatively smooth. The compound effect of shear-thinning fluid nature and fracture heterogeneity promotes flow localization, which in turn affects the performance of industrial activities and remediation techniques. In Chapter 4, a Monte Carlo framework is adopted to produce multiple realizations of synthetic fractures, and analyze their ensemble statistics pertaining flow for a variety of real non-Newtonian fluids; the Newtonian case is used as a benchmark. In Chapter 5 and Chapter 6, a conceptual model of the hydro-mechanical aspects of backflow occurring in the last phase of hydraulic fracturing is proposed and experimentally validated, quantifying the effects of the relaxation induced by the flow.