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)

Major neurologic complications secondary to cyclosporine are well documented and are known to include confusion, cortical blindness, seizure, spasticity, paresis, ataxia and coma. Most previous reports attribute these to white matter central nervous system (CNS) lesions or white/grey matter border lesions. Many predisposing factors have been identified, including: elevated levels of cyclosporine, hypomagnesemia, hypocholesterolemia, aluminium toxicity, high dose steroids, hypertension and infection. However CNS events attributed to cyclosporine have been reported without any of these risk factors. We report a case of a child developing multiple white and grey matter thalamic and cortical lesions along with acute neurologic deterioration, and then review cyclosporine mediated CNS injury, including the roles of P-glycoprotein and cyclophilin.
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PMID:Cyclosporine-induced white and grey matter central nervous system lesions in a pediatric renal transplant patient. 1008 60

A mutation in the canine MDR1 gene causes multiple drug sensitivity in dog breeds of the Collie lineage. Dogs with this genetic defect show severe neurotoxic adverse effects if they are treated with particular drugs. Clinical signs depending on the administered drug and its concentration vary from mild toxicosis with salivation and disorientation to severe effects with coma and finally death of the dog. Drugs which provoke adverse effects are structurally different. Although they are used for many different indications, all of these drugs are substrates of a transporting protein encoded by the MDR1 gene. This P-glycoprotein loses its normal protecting function at the tissue barriers in dogs with the mdrl-1Delta mutation. This article gives a short overview about the present state of analyses regarding the canine MDR1 gene. The genetic background, effects and prevalence in affected dog breeds of the mdrl-1Delta mutation are summarized. On the one hand, the overview might help practical veterinarians to understand the aetiology of drug sensitivity in dogs with the mdrl-1Delta mutation, and on the other hand, it might point out appendages for future research works about the canine MDR1 gene as well as for breeding strategies in affected dog breeds.
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PMID:Review of prevalence, genetic aspects and adverse effects of the mdr1-1Delta mutation in dogs. 1860 73

There is evidence to suggest that integrity of the neurovascular unit may be compromised in acute liver failure (ALF). In order to address this issue from a molecular standpoint, expression of an array of genes coding for key cerebrovascular endothelial cell and tight junction proteins were measured by reverse transcription-polymerase chain reaction in cerebral cortex of rats with ischemic liver failure resulting from hepatic devascularization (portacaval anastomosis followed 24h later by hepatic artery ligation) compared to appropriate sham-operated controls. Expression of P-glycoprotein, endothelin-1, von Willebrand factor, caveolin-1, occludin, and the endothelial nitric oxide synthase isoform (eNOS) were measured in brain extracts from rats with ALF at coma/edema stages of encephalopathy. The effects of mild hypothermia (35 degrees C) sufficient to prevent cerebral edema in ALF animals on the expression of these genes were also studied. Brain edema and hepatic coma in normothermic ALF rats was accompanied by selective increases in expression of eNOS. Expression of occludin and von Willebrand factor mRNAs were decreased at coma/edema stages of encephalopathy in ALF rats whereas, expression of other cerebrovascular endothelial cell markers endothelin-1, P-glycoprotein, and caveolin-1 were unaffected. Mild hypothermia led to normalization of brain water content and of eNOS mRNA. However, the correlation between increased eNOS expression and encephalopathy/edema grade was poor suggesting the existence of additional mechanisms. These findings underscore the multifactorial nature of brain edema/encephalopathy mechanisms in ALF and question the role of BBB breakdown as a major pathogenetic factor.
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PMID:Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. 2020 Nov 30

Clinical studies and case reports have identified a number of herb-drug interactions potentiated by the concurrent use of herbal medicines with prescription drugs. The purpose of this paper is to discuss the mechanisms and clinical implications of such herb-drug interactions by reviewing published human studies. Both pharmacokinetic and pharmacodynamic components may be involved in herbdrug interactions, although metabolic induction or inhibition is a common underlying mechanism for many herb-drug interactions. Drugs that have a high potential to interact with herbal medicines usually have a narrow therapeutic index, including warfarin, digoxin, cyclosporine, tacrolimus, amitriptyline, midazolam, indinavir, and irinotecan. Many of them are substrates of cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Herbal medicines that are reported to interact with drugs include garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), ginseng (Panax ginseng), and St. John's wort (Hypericum perforatum). For example, garlic has been shown to increase the clotting time and international normalized ratio (INR) of warfarin, cause hypoglycaemia when taken with chlorpropamide, and reduce the area under the plasma concentration-time curve (AUC) and maximum concentration of saquinavir in humans. Similarly, case reports have demonstrated that ginkgo may potentiate bleeding when combined with warfarin or aspirin, increases blood pressure when combined with thiazide diuretics, and has even led to a coma when combined with trazodone, a serotonin antagonist and reuptake inhibitor used to treat depression. Furthermore, ginseng reduced the blood levels of warfarin and alcohol as well as induced mania if taken concomitantly with phenelzine, a non-selective and irreversible monoamine oxidase inhibitor used as an antidepressant and anxiolytic agent. Lastly, multiple herb-drug interactions have been identified with St. John's wort that involve significantly reduced AUC and blood concentrations of warfarin, digoxin, indinavir, theophylline, cyclosporine, tacrolimus, amitriptyline, midazolam, and phenprocoumon. The clinical consequence of herb-drug interactions varies, from being well-tolerated to moderate or serious adverse reactions, or possibly life-threatening events. Undoubtedly, the early and timely identification of herb-drug interactions is imperative to prevent potentially dangerous clinical outcomes. Further well-designed studies are warranted to address the mechanisms and clinical significance of important herb-drug interactions.
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PMID:Clinical herbal interactions with conventional drugs: from molecules to maladies. 2191 44

Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy.
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PMID:Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2. 2308 5