Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gallbladder cancer (GBC) is the most common biliary tract malignancy. There is a tremendous regional variability in its incidence. Risk factors include genetic susceptibility, gender, presence of gallstones, chronic biliary infections, diet and some anatomical anomalies. Several genetic abnormalities have been described which may be aetiologically important as well as carry prognostic significance. These include mutations in the proteins K-RAS and P53, and altered expression of P-glycoprotein, COX-2 and epidermal growth factor receptor. Most patients present at an advanced stage, overall prognosis is very poor. TNM stage and the extent of surgical resection are the most important prognostic factors. Surgery is the only curative therapy reserved for patients with early-stage disease. The role of adjuvant therapy is not fully defined. Patients with advanced disease are managed with systemic chemotherapy that is primarily palliative. Although 5-fluorouracil alone, or in combination, has been most commonly utilised, there is much greater enthusiasm for the combination of cisplatin and gemcitabine. The availability of better drugs and combinations may affect the use of chemotherapy in neoadjuvant and adjuvant settings. Novel targeted therapies require exploration alone or in combination with chemotherapy.
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PMID:Gallbladder cancer: current status. 1516 72

The standard treatment for genotype 1 chronic hepatitis C consists of the peginterferon alfa + ribavirin combination taken for 24 to 48 weeks. When added to this combination, boceprevir, an inhibitor of hepatitis C virus (HCV) NS3/4A serine protease, increases virological efficacy at a cost of generally acceptable adverse effects (mainly anaemia). However, more trials are needed to assess its impact on morbidity and mortality. Telaprevir was authorised in the European Union soon after boceprevir, also as an adjunct to standard therapy. A double-blind randomised trial in 1088 previously untreated patients showed that adding telaprevir to the peginterferon alfa-2a + ribavirin combination, as compared with adding placebo, led to a significantly higher rate of sustained virological response (about 79% versus 46%). In another randomised but unblinded trial in 540 patients, the rates of sustained virological response did not differ whether patients who had an early virological response were treated for 24 or 48 weeks. A double-blind randomised trial including 662 patients in whom initial treatment with peginterferon alfa-2a + ribavirin had failed showed that further treatment with the standard regimen plus telaprevir resulted in a significantly higher rate of sustained virological response compared to adding placebo, regardless of the type of failure (relapse: 86% versus 22%; partial response: 59% versus 15%; nonresponse: 32% versus 5%). There are no head-to-head comparisons between telaprevir and boceprevir. No firm conclusions on respective efficacy can be drawn from an indirect comparison of the data. The most common adverse effects associated with the addition of telaprevir, as compared to adding placebo, were rash (55.2% versus 32.7%), anaemia (32.1% versus 14.8%), and anorectal disorders (26% versus 5%). Severe rash occurred in 0.4% of patients receiving telaprevir, and severe anaemia in 4.9%. Telaprevir is metabolised by and inhibits cytochrome P450 isoenzyme CYP 3A4. Telaprevir is also a P-glycoprotein substrate, resulting in a high risk of pharmacokinetic interactions. The adverse effects of telaprevir are more difficult to manage than those of boceprevir. This means that telaprevir should be reserved for patients in whom boceprevir fails, at least until the respective long-term effects of the two drugs are better documented.
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PMID:Telaprevir. 2251 33

Patients with rare homozygous familial hypercholesterolaemia are at risk of dying at a very young age. When liver transplantation is not feasible, treatment is based on regular LDL apheresis sessions, a burdensome and inconvenient procedure, and on high-dose statins in combination with ezetimibe. Lomitapide acts by inhibiting the synthesis of LDL constituents. It has been granted EU marketing authorisation as adjunctive therapy for homozygous familial hypercholesterolaemia. Clinical evaluation of lomitapide is based on a non-comparative trial in 29 adults. When added to standard therapy, lomitapide led to about a 40% reduction in absolute LDL cholesterol levels. Longer follow-up is needed to determine whether this is sufficient to prevent cardiovascular complications. Seven of the 13 patients under-going LDL apheresis were able to increase the interval between sessions or stop them altogether. Nearly all patients treated with lomitapide experienced gastrointestinal adverse effects, including diarrhoea, nausea, vomiting and dyspepsia. Lomitapide was associated with hepatic abnormalities in about one-third of patients in the short-term. It remains to be seen whether the hepatic steatosis observed in some patients progresses to fibrosis or cirrhosis with long-term use. Lomitapide is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 and also inhibits P-glycoprotein, hence a risk of multiple pharmacokinetic interactions. In particular, lomitapide increases the plasma concentrations of statins, and their toxicity. Lomitapide was teratogenic in experimental animals. In practice, lomitapide should be strictly reserved for patients with homozygous familial hypercholesterolaemia. Clinical evaluation must continue in these rare patients at high risk of early death.
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PMID:Iomitapide (Lojuxta). Use only in homozygous familial hypercholesterolaemia, with caution. 2624 Aug 81

This work presents the GnG-PK/PD-AD study-a pharmacokinetics/pharmacodynamics (PK/PD) analysis of the impact of genetic and nongenetic factors on the treatment with the antidepressant fluoxetine (FLU)-with a focus on potential biomarkers. Seventy-nine depressed patients treated with FLU were recruited and clinically characterized in the scope of the study. Clinical outcomes, including remission and antidepressant adverse effects were assessed by means of the Hamilton Depression Rating Scale and the Antidepressant Side-Effect Checklist, respectively. Patients were submitted to therapeutic drug monitoring of FLU and norfluoxetine and genotyping of the CYP2C9, CYP2C19, CYP2D6, and ABCB1 genes. A multivariate analysis was used to evaluate the impact of genetic and nongenetic factors on the drug plasma concentrations and clinical outcomes and to identify potential biomarkers. Genetically determined CYP2D6 activity was found to be a predictor of FLU and norfluoxetine concentrations (p < .05). In turn, genetic and nongenetic factors related to CYP2D6 and P-glycoprotein were found as potential biomarkers of the clinical outcomes of FLU (p < .05). Specifically, the potential of the CYP2D6 to be inhibited by drug-induced phenoconversion was associated with a higher severity of depression (p < .05). Moreover, ABCB1 TTT-haplotype was favorable to better clinical outcomes with FLU (higher likelihood of remission and lower severity of adverse effects; p < .05). The potential of the P-glycoprotein to be inhibited by drug-induced phenoconversion was also related to a worse tolerability profile (higher severity and number of adverse effects; p < .05). Lastly, the presence of nervous system comorbidities was associated with a higher severity of adverse effects and aging and the female gender with a higher severity of depression and lower probability of remission (p < .05). (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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PMID:Pharmacogenetics and therapeutic drug monitoring of fluoxetine in a real-world setting: A PK/PD analysis of the influence of (non-)genetic factors. 3175 Jun 87

The non-vitamin K antagonist oral anticoagulant, rivaroxaban, is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically-based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild-to-moderate renal impairment had a minor effect on area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters versus normal renal function. AUC and Cmax increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately. This article is protected by copyright. All rights reserved.
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PMID:Applications of Physiologically-Based Pharmacokinetic Modeling of Rivaroxaban - Renal and Hepatic Impairment and Drug-Drug Interaction Potential. 3320 49

In this study, we prepared ferulic acid (FA) and paclitaxel (PTX) co-loaded polyamidoamine (PAMAM) dendrimers conjugated with arginyl-glycyl-aspartic acid (RGD) to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). FA was released in greater extent (80%) from the outer layer of the dendrimers compared to PTX (70%) from the interior of the dendrimers. FA improved intracellular availability of PTX via P-gp modulation in drug-resistant cells. In vitro drug uptake data show higher PTX delivery with RGD-PAMAM-FP than with PAMAM-FP in drug resistant KB CH-R 8-5 cell lines. This indicates that RGD facilitates intracellular PTX accumulation through active targeting in multidrug-resistant KB CH-R 8-5 cells. The terminal deoxynucleotidyl transferase (TdT) 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay data and membrane potential analysis in mitochondria confirm the enhanced anticancer potential of RGD-PAMAM-FP nanoaggregates in drug-resistant cells. We also confirmed by the increased protein levels of proapoptotic factors such as caspase 3, caspase 9, p53, and Bax after treatment with RGD-PAMAM-FP nanoaggregates and also downregulates antiapoptotic factors. Hence, FA-PTX co-loaded, RGD-functionalized PAMAM G4.5 dendrimers may be considered as an effective therapeutic strategy to induce apoptosis in P-gp-overexpressing, multidrug-resistant cells. This article is protected by copyright. All rights reserved.
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PMID:PAMAM G4.5 dendrimers for targeted delivery of ferulic acid and paclitaxel to overcome P-glycoprotein-mediated multidrug resistance. 3328 76