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.

Effect of solder volume on joint shape with variable chip-to-board contact pad ratio

The objective of this paper is to investigate the effect of the pad size ratio between the chip and board end of a solder joint on the shape of that solder joint in combination with the solder volume available. The shape of the solder joint is correlated to its reliability and thus of importance. For low density chip bond pad applications Flip Chip (FC) manufacturing costs can be kept down by using larger size board pads suitable for solder application. By using “Surface Evolver” software package the solder joint shapes associated with different size/shape solder preforms and chip/board pad ratios are predicted. In this case a so called Flip-Chip Over Hole (FCOH) assembly format has been used. Assembly trials involved the deposition of lead-free 99.3Sn0.7Cu solder on the board side, followed by reflow, an underfill process and back die encapsulation. During the assembly work pad off-sets occurred that have been taken into account for the Surface Evolver solder joint shape prediction and accurately matched the real assembly. Overall, good correlation was found between the simulated solder joint shape and the actual fabricated solder joint shapes. Solder preforms were found to exhibit better control over the solder volume. Reflow simulation of commercially available solder preform volumes suggests that for a fixed stand-off height and chip-board pad ratio, the solder volume value and the surface tension determines the shape of the joint.