Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1Delta) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1Delta dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.
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PMID:P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model. 1833 85

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. Limited clinical trials suggest that hypericum and standard antidepressants have similar beneficial effects, but current evidence regarding the antidepression effects of SJW extracts is inconsistent. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs. This review highlights and updates the knowledge regarding drug interactions with SJW by a systematic review of all the available evidence, including worldwide published literature and spontaneous case reports. A number of clinically significant interactions of SJW have been identified with conventional drugs. These interactions often result in a decrease in the concentration or effect of the combined drug, most probably due to the induction of cytochrome P450s (CYPs) and the key drug transporter P-glycoprotein (P-gp) by the major active constituents in SJW. SJW is a potent inducer of human CYP3A4 and P-gp in vitro and in vivo. In addition, pharmacodynamic interactions of SJW with some drugs (e.g. selective serotonin re-uptake inhibitors) have been identified, which are associated with an increased risk of adverse reactions. Since potential interactions of SJW with conventional drugs is a major safety concern, it is important to minimize and avoid these interactions by taking appropriate approaches. These include systematic research to identify SJW-drug interaction; close therapeutic drug monitoring when SJW is combined with conventional drugs with a narrow therapeutic window; proper dose and regimen adjustment; patient education and communication between the patient and physician; design of new preparations of SJW without inducing ability of CYP3A4 and P-gp while retaining its bioactivity; and appropriate regulation in herbal safety and efficacy. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and clinical significance.
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PMID:An update on clinical drug interactions with the herbal antidepressant St. John's wort. 1853 76

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.
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PMID:Clinical drugs that interact with St. John's wort and implication in drug development. 1867 95

The concept of individualized drug therapy on the basis of pharmacogenetics has become a central focus in the treatment of depression. There is an increasing agreement about the importance of polymorphisms in cytochrome P450 enzymes and the effects of drug-drug interactions in relation to the incidence of adverse effects. There has been also increasing focus on the role of the drug transporter P-glycoprotein (P-gp) with regard to drug penetration into the brain. P-gp at the blood-brain barrier can exert a profound effect on the ability of some antidepressants to enter the brain. In addition, genetic polymorphism of the serotonin transporter has been investigated in relationship to the therapeutic response to several antidepressants, especially SSRIs. However, prediction of response on the basis of variants of candidate genes is incipient and remains elusive.
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PMID:Pharamacogenetics and antidepressant treatment in integrative psychiatry perspective. 1882 70

P-Glycoprotein-mediated multidrug resistance (MDR) is a major hurdle in cancer therapy. P-Glycoprotein is a 170 KD protein encoded by the MDR1 gene. Over-expression of P-glycoprotein is considered one of the characteristics of the MDR phenotype, thus down-regulation of the MDR1 gene expression will circumvent MDR partly. RNA interference (RNAi) is a process that can result in sequence-specific gene silencing by cleavage target mRNA. Electroporation has been demonstrated to be a promising and efficient method for gene delivery and has been successfully applied in gene therapy. In our study, by using electric pulse to delivery Stealth RNAi into nude mice NCI-H460 tumour xenografts, we successfully inhibited MDR1 both at the mRNA level as determined by reverse transcription-polymerase chain reaction and at the protein level as determined by immunohistochemistry. Furthermore, by administration of navelbine after transfection with Stealth RNAi targeted on the MDR1 gene, its depression to tumour xenografts dramatically improved by nine times. These studies demonstrate that through electrotransfection of Stealth RNAi, P-glycoprotein-mediated MDR can be reversed.
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PMID:In vivo reversal of P-glycoprotein-mediated multidrug resistance by efficient delivery of stealth RNAi. 1883 55

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography was used to measure brain uptake of [11C]verapamil, which is normally expelled from the brain by P-gp. Cerebral volume of distribution (V(T)) of [11C]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to healthy controls showed a significant decrease of [11C]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [11C]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs. Our results may explain why treatment-resistant depression can develop.
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PMID:Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood-brain barrier. 1922 56

Although effective treatment for mood and anxiety disorders have been available for more than 40 years, 30-50% of depressed patients and 25% of patients with anxiety disorder do not respond sufficiently to first-line treatment with antidepressants. Genetic factors are supposed to play a major role in both variation of treatment response and incidence of adverse effects to medication. So far, candidate genes of pharmacokinetic and pharmacodynamic pathways of antidepressants have been investigated, and associations between several candidate genes and response to antidepressants are reported. Two functional polymorphisms of the serotonin transporter gene, 5-HTTLPR and STin2 have been investigated in a large number of pharmacogenetic studies of depression; other candidate genes include serotonin receptor genes, brain-derived neurotrophic factor, P-glycoprotein (located in the blood-brain barrier), G-proteins, TPH1 and TPH2, MAOA, the noradrenaline transporter gene, FKBP5, or cytochrome P450 (CYP450) genes. CYP450 genes play a major role in the metabolism of a substantial part of psychotropics, including antidepressants, and the first estimates of dosage adjustments for antidepressants have been provided based on metabolizer status. Genome-wide association studies that use large numbers of single-nucleotide polymorphisms to screen the entire genome for alleles that influence a trait are now feasible, and the results of the first genome-wide association studies of antidepressant treatment outcome will soon be available. The current review not only updates pharmacogenetic research in depression but also focuses on antidepressant treatment response in anxiety disorders.
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PMID:The role of pharmacogenetics in the treatment of depression and anxiety disorders. 1973 81

St John's wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John's wort, is also strongly suspected to be responsible of most of the described interactions.
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PMID:Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations. 1985 15

The multi-drug efflux transporter P-glycoprotein is expressed in high concentrations at the blood-brain barrier and has a major function in the transport of drugs. In a recent PET-study evidence was found for an increased function of P-glycoprotein at the blood-brain barrier in medicated patients suffering from major depressive disorder. We used small-animal PET and [(11)C]-verapamil to study P-glycoprotein function at the blood-brain barrier of rats, either being administered as venlafaxine, an antidepressant, or subjected to chronic stress, a factor contributing to the development of depression. In a first experiment, male Wistar rats underwent a three-week foot shock procedure as a model of human depression. In a second experiment, rats were chronically treated with the antidepressant venlafaxine (25 mg/kg/d via an implanted osmotic minipump). In both experiments, a [(11)C]-verapamil PET scan was performed. In the chronically stressed rats, the distribution volume (V(T)) of [(11)C]-verapamil was significantly increased, whereas treatment with venlafaxine had the opposite effect and caused a significant reduction in V(T). The changes in V(T) could not be attributed to the influx rate constant (K(1)). Our data suggest that P-glycoprotein function at the blood-brain barrier is inhibited by chronic stress and increased by chronic administration of venlafaxine.
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PMID:Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood-brain barrier: an experimental PET study in rats. 1994 35

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Sedatives are often used to control anxiety and depression in cancer patients. In this in vitro study we investigated the effects of three plant derived sedatives such as apigenin (Api), fisetin (Fis), flavonoids and honokiol (Hnk) on Pgp activity and cellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each sedative alone (10 microM) or in combination with different doxo concentrations (2-8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2 and 8 microM doxo concentrations in the presence of Api, Fis and Hnk enhanced significantly doxo accumulation by 29+/-3.3, 20+/-4.8, 24+/-6.6 percent and 14+/-1.7, 8.3+/-4.2, 10.7+/-3.1 percent, respectively, when compared with doxo alone. These results were consistent with the increase of sensitivity towards doxo in MES-SA/Dx5, resulting in 1.7, 1.2, 1.4-fold and 1.2, 1.0 and 1.1-fold increases, respectively. Moreover, treatment with Api decreased markedly cellular GSH content (18 percent) and increased ROS production (greater than 20 percent) on MES-SA/Dx5 cells, while a significant reduction in ROS levels was observed in Hnk and Fis treated cells, when compared to untreated control. Our in vitro findings provide a rationale for innovative clinical trials to assess the use of natural sedatives or their derivatives as potential adjuvants to anticancer treatment for overcoming multidrug resistance Pgp-mediated in cancer patients.
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PMID:Modulation of multidrug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin- resistant sarcoma cells (MES-SA/DX-5): implications for natural sedatives as chemosensitizing agents in cancer therapy. 2048 33


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