P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps

2021 ◽  
Vol 0 (0) ◽  
pp. 0-0
Author(s):  
M.S. Taha ◽  
A. Nocera ◽  
A. Workman ◽  
M.M. Amiji ◽  
B.S. Bleier
Keyword(s):  
Combination Therapy ◽  
Nasal Polyps ◽  
Efflux Pump ◽  
Test Results ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Fold Reduction ◽  
Anti Inflammatory ◽  
Type 2 Inflammation

Background: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. Methodology: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 μg/mL) and verapa- mil (125 μg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. Results: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. Conclusions: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.

P505 DUPILUMAB EFFECT ON TYPE 2 INFLAMMATION BIOMARKERS IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS AND NSAID-ERD

2020 ◽  
Vol 125 (5) ◽  
pp. S48
Author(s):  
A. White ◽  
S. Fujieda ◽  
T. Takabayashi ◽  
N. Daizadeh ◽  
Y. Deniz ◽  
...  
Keyword(s):  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Type 2 Inflammation

scholarly journals Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Pierre-Francois Ceccaldi ◽  
Laurent Gavard ◽  
Laurent Mandelbrot ◽  
Elisabeth Rey ◽  
Robert Farinotti ◽  
...  
Keyword(s):  
Internal Control ◽  
Efflux Pump ◽  
Placental Transfer ◽  
Ex Vivo ◽  
Glycoprotein P ◽  
Control Phase ◽  
P Glycoprotein ◽  
Ciclosporin A ◽  
High Albumin

Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on placental transfer of lopinavir with ritonavir at different albumin concentrations.Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases.Results. In the control phase, the clearance index of lopinavir decreased from 0.401±0.058 to 0.007±0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [−0.156,−0.002],P=.046) and became positive for ritonavir.Conclusions. Even at high albumin concentrations, inhibition of placental P-glycoprotein increased placental transfer of lopinavir, suggesting that this efflux pump actively reduces placental transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy.

scholarly journals Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia.

1989 ◽  
Vol 9 (10) ◽  
pp. 4357-4363 ◽  
Author(s):  
H Galski ◽  
M Sullivan ◽  
M C Willingham ◽  
K V Chin ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Bone Marrow Cells ◽  
Efflux Pump ◽  
Multidrug Resistance Gene ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Leukocyte Counts ◽  
Actin Promoter

The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.

scholarly journals Dupilumab: new opportunities for the treatment of asthma and chronic rhinosinusitis with nasal polyps

2021 ◽  
Vol 18 (1) ◽  
pp. 18-31
Author(s):  
Miramgul E. Dyneva ◽  
Gulyumkhan E. Aminova ◽  
Oksana Kurbacheva ◽  
Natalya I. Il'ina
Keyword(s):  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Human Monoclonal Antibody ◽  
High Rate ◽  
Cytokine Signaling ◽  
Main Task ◽  
Receptor Complexes ◽  
Target Individual ◽  
Type 2 Inflammation

Airway inflammation plays a key role in asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The inflammatory process can vary in intensity thus affecting the clinical picture of the disease and, most importantly, the effectiveness of therapy. Today, there is still a high rate of growth in the incidence of asthma and CRSwNP and dissatisfaction with the effectiveness of existing therapy for severe forms of asthma, especially when asthma is associated with CRSwNP, so the main task is to find new approaches to diagnosis and therapy. The development of biologics is a promising step forward in achieving control of severe and poorly controlled asthma and recurrent CRSwNP that target individual and specific components of inflammation. One of the latest monoclonal antibodies is Dupilumab that has shown significant success in the treatment of asthma and CRSwNP. Dupilumab is a fully human monoclonal antibody directed against the -subunit of the Il-4 interleukin receptor (IL-4R), common to both IL-4 and IL-4/IL-13 receptor complexes. This contributes to the suppression of type 2 cytokine signaling (IL-4 and IL-13), since the IL-4/IL-13/STAT6 signaling pathway plays a crucial role in type 2-inflammation. Currently, Dupilumab is approved for the treatment of severe asthma and CRSwNP, so this article summarizes the main information about Dupilumab and its effectiveness in these diseases, as well as presents the results of clinical observation.

scholarly journals An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products

2020 ◽  
Vol 12 (540) ◽  
pp. eaay0605 ◽  
Author(s):  
Marta de los Reyes Jiménez ◽  
Antonie Lechner ◽  
Francesca Alessandrini ◽  
Sina Bohnacker ◽  
Sonja Schindela ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Mitogen Activated Protein Kinase ◽  
Metabolic Enzyme ◽  
Prostaglandin E ◽  
Lipoxygenase Pathway ◽  
Anti Inflammatory ◽  
Type 2 Inflammation ◽  
Allergy And Asthma

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E2 (PGE2) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE2-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.

scholarly journals Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues

2020 ◽  
Vol 13 (12) ◽  
pp. 453
Author(s):  
Małgorzata Anna Marć ◽  
Annamária Kincses ◽  
Bálint Rácz ◽  
Muhammad Jawad Nasim ◽  
Muhammad Sarfraz ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Drug Candidates ◽  
P Glycoprotein ◽  
Efflux Pump Inhibitors

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1–3) or a bioisosteric analogue core (compounds 4–6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia

1989 ◽  
Vol 9 (10) ◽  
pp. 4357-4363
Author(s):  
H Galski ◽  
M Sullivan ◽  
M C Willingham ◽  
K V Chin ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Bone Marrow Cells ◽  
Efflux Pump ◽  
Multidrug Resistance Gene ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Leukocyte Counts ◽  
Actin Promoter

The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.

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