Diacerein

Spencer, Caroline M.; Wilde, Michelle I.

doi:10.2165/00003495-199753010-00007

Cited by 93 publications

(45 citation statements)

References 15 publications

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“…Our finding of considerable potentiation of the activities of plant antimicrobials by MDR inhibitors opens the possibility for the development of combination therapy. For example, rhein becomes an effective broad-spectrum antibiotic in the presence of MDR inhibitors, and it is approved for systemic use for the treatment of osteoarthritis (administered as a prodrug, diacerein [42]). …”

Section: Discussionmentioning

confidence: 99%

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Tegos

Stermitz

Lomovskaya

et al. 2002

Antimicrob Agents Chemother

423

317

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Plant antimicrobials are not used as systemic antibiotics at present. The main reason for this is their low level of activity, especially against gram-negative bacteria. The reported MIC is often in the range of 100 to 1,000 g/ml, orders of magnitude higher than those of common broad-spectrum antibiotics from bacteria or fungi. Major plant pathogens belong to the gram-negative bacteria, which makes the low level of activity of plant antimicrobials against this group of microorganisms puzzling. Gram-negative bacteria have an effective permeability barrier, comprised of the outer membrane, which restricts the penetration of amphipathic compounds, and multidrug resistance pumps (MDRs), which extrude toxins across this barrier. It is possible that the apparent ineffectiveness of plant antimicrobials is largely due to the permeability barrier. We tested this hypothesis in the present study by applying a combination of MDR mutants and MDR inhibitors. A panel of plant antimicrobials was tested by using a set of bacteria representing the main groups of plant pathogens. The human pathogens Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica serovar Typhimurium were also tested. The results show that the activities of the majority of plant antimicrobials were considerably greater against the gram-positive bacteria Staphylococcus aureus and Bacillus megaterium and that disabling of the MDRs in gram-negative species leads to a striking increase in antimicrobial activity. Thus, the activity of rhein, the principal antimicrobial from rhubarb, was potentiated 100-to 2,000-fold (depending on the bacterial species) by disabling the MDRs. Comparable potentiation of activity was observed with plumbagin, resveratrol, gossypol, coumestrol, and berberine. Direct measurement of the uptake of berberine, a model plant antimicrobial, confirmed that disabling of the MDRs strongly increases the level of penetration of berberine into the cells of gram-negative bacteria. These results suggest that plants might have developed means of delivering their antimicrobials into bacterial cells. These findings also suggest that plant antimicrobials might be developed into effective, broad-spectrum antibiotics in combination with inhibitors of MDRs.

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Section: Discussionmentioning

confidence: 99%

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Tegos

Stermitz

Lomovskaya

et al. 2002

Antimicrob Agents Chemother

423

317

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“…Rhein has antibacterial (11), antitumor and anti-inflammatory properties (12). Notably, rhein inhibits superoxide anion production in a Protective effect of rhein against oxidative stress-related endothelial cell injury XIAN-FENG ZHONG 1 , GUI-DONG HUANG 2 , TING LUO 1 , ZE-YUAN DENG 1 and JIANG-NING HU dose-dependent manner (13) and the proliferation of vascular smooth muscle cells (14). In the vascular system, rhein is beneficial for the prevention of AS by protecting endothelial cells from damage (15).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of rhein against oxidative stress-related endothelial cell injury

et al. 2012

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Abstract. Endothelial cell injury caused by reactive oxygen species (ROS) plays a critical role in the pathogenesis of atherosclerosis. Therefore, phytochemicals or antioxidants that inhibit the production of ROS have clinical value for the treatment of atherosclerosis. Rhein is one of the most important active components of rhubarb (Rheum officinale), a famous traditional Chinese remedy that possesses potent antioxidant properties through undefined mechanism(s). The aim of the present study was to determine whether rhein inhibits hydrogen peroxide (H 2 O 2 )-induced injury in human umbilical vein endothelial cells (HUVECs). The oxidative injury model was established with H 2 O 2 . HUVECs were treated with different concentrations of rhein in the presence/absence of H 2 O 2 . The protective effects of rhein against the injury caused by H 2 O 2 were evaluated. HUVECs incubated with 200 µmol/l H 2 O 2 had significantly decreased cell viability, which was accompanied by cell apoptosis and upregulated Bid and caspase-3, -8 and -9 mRNA expression. Meanwhile, H 2 O 2 treatment induced a marked increase in malondialdehyde (MDA) and lactate dehydrogenase (LDH) content and decreased the nitric oxide (NO) content and nitrogen oxide synthase (NOS), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity. However, pre-treatment with different rhein concentrations (2, 4, 8 and 16 µmol/l) significantly increased the viability of H 2 O 2 -injured HUVECs, decreased the MDA and LDH content, increased the NO content and NOS, SOD and GSH-PX activity in a dose-dependent manner and resulted in significant recovery from H 2 O 2 -induced cell apoptosis. In addition, the results of the qRT-PCR indicated that pre-treatment with rhein downregulates the expression of Bid and caspase-3, -8 and -9 mRNA, which plays a key role in H 2 O 2 -induced cell apoptosis. The present study shows that rhein protects endothelial cells against oxidative injury induced by H 2 O 2 , suggesting that rhein is a potential compound for the prevention and treatment of atherosclerosis. IntroductionCardiovascular disease (CVD) is the primary cause of morbidity and mortality worldwide (1). Atherosclerosis (AS), a chronic inflammatory disease that results in the deposition of oxidized lipoproteins that form fatty plaques, accounts for nearly 75% of all deaths from CVD (2,3). Vascular inflammation, especially at the endothelium cell level, has been shown to play a pivotal role in the initiation, progression and clinical complications of AS (4).Endothelial cells regulate cardiovascular health and control the elasticity of vessels. Injury of endothelial cells is the first stage of AS, and oxidative stress is regarded as a critical pathogenic factor in endothelial cell injury (5). Oxidative stress is mainly caused by the excessive accumulation of reactive oxygen species (ROS), which include hydrogen peroxide (H 2 O 2 ), superoxide anions (O 2-·) and hydroxyl radicals (·OH).ROS are continuously produced in cells as products of cellular oxidation-reductio...

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“…Many active components found in R. palmatum L.-including aloe-emodin, emodin, and rhein-have pharmacologic effects. For example, rhein has moderate anti-inflammatory, analgesic activity, and weak laxative effects (Spencer and Wilde, 1997). Simultaneous monitoring of brain monoamine level changes by the in vivo microdialysis sampling technique is an important tool in the discovery of new drug therapies for a large number of neurologic disorders, such as Parkinson's disease, Alzheimer's disease, epilepsy, and neuropsychiatric disorders (Garrison et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis

Hou

Lin

et al. 2015

J Pharmacol Exp Ther

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Clozapine, an atypical antipsychotic agent, is highly effective in treatment-resistant schizophrenia; however, its major side effect is constipation. Instead of laxatives, rhein is a pharmacologically active component found in Rheum palmatum L., a medicinal herbal remedy for constipation. The purpose of this study is to determine whether rhein impacts the pharmacokinetics (PK) and pharmacodynamics (PD) of clozapine in brain when used to relieve clozapine-induced constipation. Here, we have investigated not only the PK of clozapine in blood but also the effects of rhein on the PK of clozapine in blood and in brain extracellular fluid together with the PD effects on neurotransmitters in extracellular fluid. The concentrations of clozapine and norclozapine in biologic samples were measured by ultra-performance liquid chromatography-tandem mass spectrometry. The drug-drug effects of rhein on extracellular neurotransmitter efflux in the rat medial prefrontal cortex (mPFC) produced by clozapine were assayed by highperformance liquid chromatography-electrochemical detection. The results demonstrate that the clozapine PK was nonlinear. Pretreatment with rhein for 7 days increased the total blood concentration of clozapine, but significantly reduced the unbound clozapine concentrations in the mPFC by approximately 3-fold. Furthermore, 7 days of rhein pretreatment thoroughly abolished the efflux of dopamine and its metabolite (3,4-dihydroxyphenylacetic acid) and altered the profile of homovanillic acid, another metabolite of dopamine, in the mPFC. In conclusion, rhein was found to substantially decrease clozapine and norclozapine concentrations in the mPFC dialysate, and this is accompanied by lower concentrations in the neurotransmitters in the same biophase. These findings suggest that a detailed clinical study for drug-drug interactions is recommended.

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Diacerein

Cited by 93 publications

References 15 publications

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Protective effect of rhein against oxidative stress-related endothelial cell injury

The Drug-Drug Effects of Rhein on the Pharmacokinetics and Pharmacodynamics of Clozapine in Rat Brain Extracellular Fluid by In Vivo Microdialysis

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