P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.

The Vikings in ninth-century Ireland: Sources and settlements

Archaeological excavations, particularly those of the last fifty years, have greatly advanced our understanding of Viking settlement in Ireland, and this study sets out to present a complementary analysis of the historical sources. Increasingly, evidence suggests that Viking occupation encompassed a more diverse range of settlement types than previously acknowledged. Major urban excavations such as those carried out in Dublin and Waterford, are now complemented by small scale excavations and studies of sites such as: Cherrywood, Co Dublin, a rural settlement; Beginish, Co Kerry, a maritime haven; Truska, Co Galway, a possible farmstead; longphort-settlements at Dunrally, Co Laois and Athlunkard, Co Limerick; and significant Viking settlements at Woodstown, Co Waterford and at Annagassan, Co Louth. This thesis sets out to examine patterns of Viking settlement in ninth-century Ireland; an interdisciplinary approach is adopted that attempts to combine evidence from both the extant primary sources and the archaeological evidence. It is argued that the Vikings had bases in Ireland even in the earliest period of activity 795-836, traditionally characterised as the ‘hit-and-run’ phase. The downturn discernible in Viking-related annalistic entries occurs at a time when there are increased references to Viking settlements in the Irish annals; therefore, it is proposed that this change in the ninth-century recorded pattern of Viking activity reflects their increased involvement in trade and settlement. To support this hypothesis, the evidence for settlement, settlement patterns and trade at Dublin and Waterford in the ninth century is then discussed.

Reading Lydgate's Troy Book: patronage, politics, and history in Lancastrian England

This thesis, Reading Lydgate's Troy Book: Patronage, Politics and History in Lancastrian England, discusses the relationship between John Lydgate as a court poet to his patron Henry V. I contend that the Troy Book is explored as a vehicle to propagate the idea that the House of Lancaster is the legitimate successor to King Richard II in order to smooth over the usurpation of 1399. Paul Strohm's England's Empty Throne was a key influence to the approach of this thesis' topic. I examine that although Chaucer had a definitive impact on Lydgate's writing, Lydgate is able to manipulate this influence for his own ambitions. In order to enhance his own fame, Lydgate works to promote Chaucer's canon so that as Chaucer's successor, he will inherit more prestige. The Trojan war is seen in context with the Hundred Years War, and can be applied contextually to political events. Lydgate presents characters that are vulnerable to human failings, and their assorted, complicated relationships. Lydgate modernises the Troy Book to reflect and enhance his Lancastrian society, and the thesis gives a contextual view of Lydgate's writing of the Troy Book. Lydgate writes for a more varied target audience than his thirteenth-century source, Guido delle Colonne, and there is a deliberation on the female characters of the Troy Book which promulgates the theory that Lydgate takes a proactive and empathetic interest in women's roles in society. Furthermore Lydgate has never really been accepted as a humanist, and I look at Lydgate's work from a different angle; he is a self-germinating humanist. Lydgate revives antiquity to educate his fifteenth-century audience, and his ambition is to create a memorial for his patron in the vernacular, and enhance his own fame as a poet separate from Chaucer's shadow.