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On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8–21.5] compared with 14.1 months (95% CI: 12.5–16.2; HR, 0.74; 95% CI, 0.61–0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer's disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD.

Alzheimer's disease (AD) is known for its hallmark features such as increased levels of tau hyperphosphorylation and amyloid-beta (Aβ) deposition. Cerebral vascular dysfunction constitutes an important feature of AD as well, which includes amyloid angiopathy and impaired clearance of Aβ across the blood-brain barrier (BBB). In the search for potential drugs that may enhance or maintain the BBB integrity and function, we screened the Sigma Lopac®1280 compound library using a high-throughput screening (HTS) assay developed in our laboratory. In the process of identifying a hit compound, an in-vitro BBB model monolayer utilizing bEnd3 cells was constructed. Compounds were first identified as hits if they were able to enhance the monolayer's integrity by decreasing Lucifer Yellow (LY) permeation. Next, hit compounds were secondary screened for their effect on BBB model function. Utilizing the same cell line, western blot analysis for major transport proteins of Aβ and the tight junction proteins ZO1, Occludin, and Claudin-5 was performed. Finally Aβ transport study was conducted to measure the effect of hit compounds on Aβ transport across the membrane. The HTS assay identified 3 unique compounds that decreased LY permeation, indicating enhancement of the in-vitro BBB model integrity. Western blot analysis showed these hit compounds to deferentially alter transport and tight junction protein expression indicating increased phenotypic function. In addition, hit compounds enhanced the Aβ transport across the monolayer in this model. In conclusion, these hit compounds are compelling candidates for further in vivo investigation in AD animal models.

The blood-brain barrier (BBB) controls the content of brain interstitial fluid due to the presence of high-resistance tight junction proteins between the endothelial cells of brain capillaries. Severalmodels using different cell-lines were developed to study the BBB biology, these models werecomplex and their use for high-throughput screening (HTS) has proven to be challenging. Therefore, we developed an in-vitro BBB model that is practical and reliable for HTS. The mouse brainendothelial cells (bEnd3) grown on 96-well plate inserts were upgraded and optimized for HTSassay. Using Lucifer Yellow (LY) permeation assay, 3 different compounds libraries that include3000 compounds were screened for hits that have the potential to modulate the BBB model integrity. To evaluate the model ability to identify compounds that increase LY permeation, mannitol wasused as a positive control for disruptors. The model performance in this assay was high with Z'factor above 0.5 and high S/N and S/B ratios. Alternatively, hydrocortisone was used as a positivecontrol for compounds that enhance the barrier function as it is known to improve endotheliumtightness. The Z' factor determined with hydrocortisone was 0.3 with lower S/N and S/B ratioscompared to mannitol. The primary screen has identified several hundred of modulators. Thesecondary screen could identify 13 compounds as potent enhancers of the monolayer integrity withEC50 values less than 10 μM. In conclusion, an HTS-BBB model was developed and used forcompounds screening to identify compelling hits for further evaluation for their effect on the BBB.

Mediterranean diet (MD) is considered one of the most health promoting diets adopted initially by the Mediterranean population. Recent studies showed a link between MD and lowering the incidence of mild cognitive impairment and Alzheimer's disease (AD). Clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO), a major component of MD, that could protect and decrease the risk of developing AD. Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. Here we provide evidence to support the role of EVOO and oleocanthal in enhancing the clearance of amyloid-beta (As), a major pathological hallmark in AD, and reducing the overall inflammatory burden on the brain. In our study, both EVOO and oleocanthal treatment significantly decreased As load in the hippocampal parenchyma and microvessels. Furthermore, our mechanistic studies demonstrated an effect on increasing the expression of important amyloid clearance proteins at the blood-brain barrier (BBB) including P-glycoprotein (P-gp) and low density lipoprotein receptor-related protein 1 (LRP1), and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. Additionally, oleocanthal was able to reduce astrocytes activation and IL-1s levels. The reduction in As levels and microvessels deposition could be explained, at least in part, to the enhanced As clearance across the BBB and by ApoE-dependent pathway. In addition, oleocanthal demonstrated an anti-inflammatory effect by reducing astrocytes activation and IL-1s brain levels, which emphasize the importance of considering EVOO and oleocanthal as a potential therapeutic interventions in AD.

The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of γ-tocotrienol (γ-T3) and α-tocopherol (α-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of γ-T3 or α-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of γ-T3 in the aqueous phase, the oral bioavailability of α-Tph (36%) was significantly higher than γ-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for α-Tph compared with γ-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for α-Tph compared with γ-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of α-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of γ-T3, suggesting that enhancing its permeability would increase its oral bioavailability. Copyright © 2012 John Wiley & Sons, Ltd.

The effect of bioactive plant natural products on the expression and functional activity of P-glycoprotein (P-gp) is poorly understood. Interactions of bioactive plant-based food and dietary supplements with P-gp can cause significant alteration of pharmacokinetic properties of P-gp substrate drugs when used in combination. This can augment toxicity and/or interfere with the drug’s therapeutic outcomes. This study investigated the effects of diverse commonly used plant natural products on the expression and activity of P-gp in human adenocarcinoma cells (LS-180). These natural products included the tobacco cembranoid (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (cembratriene), the palm oil-derived γ-tocotrienol, the extra-virgin olive oil-derived secoiridoid oleocanthal, and the triterpene acid asiatic acid derived from Melaleuca ericifolia and abundant in several other common plant dietary supplements. Treatment with 25 μM of cembratriene, oleocanthal, γ-tocotrienol, or asiatic acid showed 2.3-3.0-fold increase in P-gp expression as demonstrated by Western blotting. These results were consistent with those obtained by quantitative analysis of fluorescent micrographs for P-gp. Accumulation studies demonstrated 31-38% decrease in rhodamine 123 intracellular levels when LS-180 cells were treated with the investigated compounds as a result of P-gp induction. Bioactive natural products can up-regulate the P-gp expression and functionality, which may induce herb/food-drug interactions when concomitantly used with P-gp substrate drugs.

The known mechanism by which orlistat decreases the absorption of dietary cholesterol is by inhibition of intestinal lipases. The aim of this study was to investigate the ability of orlistat to limit cholesterol absorption by inhibition of the cholesterol transport protein Niemann-Pick C1-like 1 (NPC1L1) as another mechanism of action. In situ rat intestinal perfusion studies were conducted to study the effect of orlistat on jejunal cholesterol absorption. Inhibition kinetic parameters were calculated from in vitro inhibition studies using Caco2 and NPC1L1 transfected cell lines. The in situ studies demonstrated that intestinal perfusion of orlistat (100µM) was able to reduce cholesterol absorption by three-fold when compared to control (i.e. in the absence of orlistat, P

Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer's disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of (125)I-Aβ40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced (125)I-Aβ40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing (125)I-Aβ40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in (125)I-Aβ40 degradation as a result of the up-regulation of Aβ degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of Aβ clearance from the brain.

Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer's disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ± 6.1%, p < 0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.