Herein the interactions of etamicastat nepicastat and zamica
Herein, the interactions of etamicastat, nepicastat and zamicastat with P-gp and BCRP were evaluated. Although recent investigations have been performed to assess the involvement of P-gp in the moxalactam sale exposure of nepicastat and etamicastat (Loureiro et al., 2015), the contribution of BCRP remains undetermined. Moreover, there is yet no available information in literature concerning the interaction of zamicastat with these transporters. Intracellular accumulation and bidirectional permeability assays were performed using Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes as surrogate BBB models. In addition to fast growth and low metabolic activity, MDCK cells can form polarized monolayers with tight junctions when grown on semipermeable supports and possess BBB-like passive permeability, being able to accurately distinguish passive from effluxed compounds (Hellinger et al., 2012). The stability of the DBH inhibitors was determined beforehand and the quantification of these compounds was achieved using validated high-performance liquid chromatography (HPLC) techniques with diode-array detection (DAD).
Results and discussion
Conclusion The following is the supplementary data related to this article.
Acknowledgements This work was funded by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and national funds by FCT - Foundation for Science and Technology under the project (SFRH/BD/78256/2011). This work was also supported by BIAL-Portela & Ca S.A.
Introduction A number of medications have been evaluated in clinical trials for cocaine use disorder, including antidepressants, antipsychotics, stimulants, and anticonvulsants (Haile and Kosten, 2013, Moeller et al., 2008, Vocci and Elkashef, 2005), although no medication has gained approval from the Food and Drug Administration (FDA) for this indication. Disulfiram (Antabuse®), the first FDA-approved medication for the treatment of alcohol use disorder, was initially reported to reduce concomitant cocaine and alcohol use (Carroll et al., 1998, Carroll et al., 2000, Higgins et al., 1993). Subsequently, disulfiram was shown to be at least equally effective, and possibly even more beneficial, at reducing cocaine use (self-report and/or cocaine-positive urine screens) in subjects not meetingalcohol use disorder criteria (Carroll et al., 2004, George et al., 2000, Petrakis et al., 2000). More recent data show that disulfiram reduced the positive subjective effects produced by cocaine (Baker et al., 2007) and higher doses of disulfiram (mg/kg basis) reduced cocaine self-administration (Haile et al., 2012a, Haile et al., 2012b). These studies suggested that the efficacy of disulfiram to suppress alcohol vs. cocaine consumption may involve differential underlying mechanisms. Disulfiram suppresses alcohol intake by inhibiting hepatic aldehyde dehydrogenase which is required to effectively metabolize alcohol; in the face of this inhibition, the accumulated acetaldehyde burden causes the unpleasant disulfiram ethanol reaction (e.g., flushing, nausea, vomiting, sweating, headache) which deters continued drinking (Haley, 1979). However, disulfiram is a non-selective, irreversible inhibitor of sulfhydryl-containing enzymes, which encompass several plasma esterases, including those that metabolize cocaine. It also inhibits the enzyme dopamine β hydroxylase (DβH) (Goldstein et al., 1964, Musacchio et al., 1966) and this is specifically hypothesized to account for its efficacy for reducing cocaine consumption (Gaval-Cruz and Weinshenker, 2009). The enzyme DβH, expressed in synaptic vesicles of central nervous system noradrenergic neurons, converts dopamine (DA) into norepinephrine (NE) (Kaufman and Friedman, 1965), two neurotransmitters important in mediating the subjective and rewarding properties of cocaine (Sofuoglu and Sewell, 2009, Haile et al., 2012a, Haile et al., 2012b). Thus, while the exact mechanism by which DβH inhibition reduces cocaine use remains elusive (Gaval-Cruz and Weinshenker, 2009), decreased NE production and enhanced DA levels that occur as a result of DβH inhibition (Bourdelat-Parks et al., 2005, Goldstein et al., 1964, Musacchio et al., 1966) are likely involved. Indeed, disulfiram blocked cocaine-primed reinstatement of cocaine-seeking in rats extinguished from repeated self-administration at a dose that significantly reduced brain NE levels (Schroeder et al., 2010). Blockade of post-synaptic NE α1a receptors by doxazosin significantly reduced the positive subjective effects produced by cocaine in an inpatient study (Newton et al., 2012) and reduced cocaine use in an outpatient study (Shorter et al., 2013), while the α1 antagonist prazosin attenuates cocaine-seeking behavior in rats (Zhang and Kosten, 2005). Thus, clinical and preclinical findings suggest that pharmacological inhibition of DβH may offer a viable therapeutic strategy for the treatment of cocaine use disorder.