Gerd Geisslinger

Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, North Rhine-Westphalia, Germany

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Publications (427)1922.22 Total impact

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    ABSTRACT: Objective. Telaprevir (TVR)-based triple therapy has substantially improved cure rates of hepatitis C virus (HCV) genotype 1 infection but side effects are frequent and often severe. Therefore, response predictors are needed for early identification of patients not responding to TVR-based triple therapy. Material and methods. Forty-five patients (mean age: 54 ± 13 years; male gender: 60%; treatment-experienced: 82%; cirrhosis: 58%) with HCV genotype 1 infection were treated with a TVR-based triple-therapy regimen. TVR plasma levels were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry at weeks 2, 4, 8, and 12 of antiviral therapy. On-treatment HCV RNA response was assessed at weeks 4, 12, and 24 by real-time polymerase chain reaction. Results. An extended rapid virological response (eRVR) and sustained virological response (SVR) was achieved in 21 of 45 patients (47%) and 36 of 45 (80%) patients, respectively. Mean ± standard deviation TVR plasma levels at week 2 were 3.4 ± 0.2 log10 ng/ml and did not differ over time (when assessed at weeks 4, 8, and 12). TVR plasma levels at week 2 were significantly higher in patients who achieved an eRVR compared to those who did not achieve eRVR (3.5 ± 0.1 vs. 3.3 ± 0.2 log10 ng/ml; p = 0.003) but were neither associated with SVR nor with treatment-related anemia. Conclusion. TVR plasma levels are associated with on-treatment response but not with overall treatment efficacy. Given the high overall response rates to TVR-based triple therapy, our data suggest that TVR trough levels may not be a useful predictor of treatment response, and routine drug-level monitoring is not required.
    Scandinavian Journal of Gastroenterology. 11/2014;
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    ABSTRACT: Chemotherapy-induced peripheral neuropathic pain (CIPNP)-a severe adverse effect observed in up to 80% of patients during treatment with antineoplastic drugs-limits the tolerable dose of cytostatics, and can lead to discontinuation of chemotherapy. Many drugs that are approved for the treatment of other neuropathic pain states have shown little or no analgesic effect on CIPNP in large randomized, placebo-controlled clinical trials. Here, we review the known mechanisms of CIPNP induced by the three most commonly used cytostatics: paclitaxel, oxaliplatin and vincristine. These substances have distinct neurotoxic and neuroinflammatory properties, but they also have overlapping contributions to pathogenesis of CIPNP that could potentially be targeted for prevention or treatment of CIPNP. We discuss the failure of previously tested antioxidants, neuroprotective agents, anticonvulsants and antidepressants as therapeutic or preventative strategies, and suggest individualized, mechanism-based therapeutic options for CIPNP associated with each of the three main drug groups. We point out the necessity to assess drug efficacy in CIPNP independently of other neuropathic pain states, and emphasize the need for delineation of subpopulations of patients with CIPNP for more-efficient treatment. Finally, we discuss novel therapeutic strategies and recent progress in treatment of CIPNP, and evaluate the potential benefits of these recent proceedings for future therapies.
    Nature Reviews Neurology 11/2014; · 15.52 Impact Factor
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    ABSTRACT: Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2,-4, -5 and CerS6 promoter and 3’-UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERα/β) and MDA-MB-231 (ERβ) cells after 17β-estradiol treatment. Only the activities of CerS4 and CerS5 promoter Luc constructs, as well as CerS2- and CerS5 -3’UTR Luc constructs increased after estradiol treatment in MCF-7 cells, and this could be inhibited by the anti-estrogen fulvestrant. Co-transfection with the G protein-coupled estrogen receptor 1 (GPER1) also enhanced CerS2, CerS4 and CerS6 promoter activity whereas CerS5 promoter activity was inhibited in both cell lines. Promoter deletion and mutation constructs from CerS4- and CerS5 promoters revealed that estradiol and GPER1 mediate their effects on both promoters by activating AP-1, most likely through dimerization of c-Jun and c-Fos. At least we could show, that cell proliferation induced by estradiol could be blocked by co-treatment with Fumonisin B1, indicating that upregulation of CerS in breast cancer cells by estrogen is important for cell proliferation and possibly tumor development. In conclusion, our data highlight transcriptional and posttranscriptional mechanisms regulating CerS expression in human cells which provide the basis for further studies investigating the regulation of CerS expression and ceramide synthesis after diverse stimuli in physiological and pathophysiological processess.
    Biochemical Pharmacology. 10/2014;
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    ABSTRACT: Prostanoids, derivatives of arachidonic acid, are involved in inflammation and immune reactions. To understand the role of prostanoids produced by diverse immune cells, a highly sensitive quantitation method for prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), 6-keto prostaglandin F1α (6-keto PGF1α), prostaglandin F2α (PGF2α), and thromboxane B2 (TXB2) by means of nano-liquid chromatography-tandem mass spectrometry has been developed. It was validated according to the guidelines of the Food and Drug Administration (FDA) in terms of linearity, precision, accuracy, recovery, stability, and lower limit of quantitation (LLOQ). The LLOQ were 25 pg/mL in the injected solution (75 fg on column (o.c.)) for PGE2 and PGD2 and 37.5 pg/mL (112.5 fg on column) for 6-keto PGF1α, PGF2α, and TXB2, respectively. It was successfully applied to murine mast cells isolated from paws after zymosan injection and to CD4(+) and CD8(+) T lymphocytes from blood of sensitized versus non-sensitized mice in context of a delayed type hypersensitivity model. About 5,000 (T cells) to 40,000 (mast cells) cells were sufficient for quantitation. In the mast cells, the production of PGE2 increased at a significantly higher extent than the synthesis of the other prostanoids. The T lymphocytes did not show any difference in prostanoid production, no matter whether they were obtained from sensitized mice or non-sensitized mice.
    Analytical and Bioanalytical Chemistry 09/2014; · 3.66 Impact Factor
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    ABSTRACT: R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T cells, CTLA4+ inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial.
    EMBO Molecular Medicine 09/2014; · 7.80 Impact Factor
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    ABSTRACT: Ceramides (Cer) are mediators of inflammatory processes. In a chronic experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we observed a significant elevation of C16-Cer and its synthesizing enzyme, ceramide synthase(CerS)6, in the lumbar spinal cord. In the present study, we have confirmed that C16-Cer and CerS6 are also upregulated in the lumbar spinal cord in a spontanous relapse-remitting EAE model, using SJL mice overexpressing a transgenic T cell receptor (TCR1640). CerS6 was found to be expressed in macrophages, T cells and B cells in EAE lesions. In macrophages, we demonstrated that interferon gamma (IFN-γ)-induced CerS6 upregulation was amplified by 17ß-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-α). Accordingly, CerS6 and TNF-α expression was upregulated predominantly in the spinal cord in female TCR1640 mice, which usually develop the relapse-remitting form of EAE, while male TCR1640 mice showed an attenuated regulation of CerS6 and TNF-α and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-α, which is linked to neuroprotection and remyelination, was also upregulated to a greater extent during EAE in female TCR1640 mice in comparison to male TCR1640 mice. Taken together, our results confirm the upregulation of CerS6 and C16-Cer in an adjuvant-independent, physiological EAE model and further suggest an anti-inflammatory role of CerS6 in the regulation of the disease course in female TCR1640 mice via TNF-α/TNFR2.
    Biochemical Pharmacology 08/2014; · 4.58 Impact Factor
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    ABSTRACT: CYP inhibitors may reduce opioid analgesia by inhibiting CYP activity dependent post-opioid receptor signaling pathways in the brain. This suggestion was predicated on observations of highly attenuated morphine antinociception in rodents after intracerebroventricular injection of fluconazole or carrying a neuron-specific deletion of the cytochrome P450 reductase. However, based on assessments of thermal and electrical pain tolerance, respiratory function and side effects in 21 healthy volunteers, prior and during steady-state concentrations of remifentanil at effect site (CNS) of 1.5 ng/ml and 3 ng/ml, administration of 400 mg/d fluconazole for 8 days in a double-blind, placebo-controlled manner, failed to attenuate opioid effects. Although CYP inhibitors like fluconazole are unlikely to attenuate remifentanil analgesia in humans, extrapolation of the findings to other opioids is premature because opioid differences, like e.g. ligand-selective biased signaling at opioid receptors, leave the possibility that brain CYP dependent opioid signaling might be limited to morphine but not remifentanil.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 22 August 2014; doi:10.1038/clpt.2014.169.
    Clinical pharmacology and therapeutics. 08/2014;
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    ABSTRACT: Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating NADPH oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRGs) in mice. In response to peripheral nerve injury, Nox2-positive macrophages were recruited to DRGs, and ROS production was increased in a Nox2-dependent manner. Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent and ATF3-induction was reduced in DRGs of Nox2-deficient mice suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRGs contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.
    Pain 08/2014; · 5.64 Impact Factor
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    ABSTRACT: Pro-resolving lipid mediators are a class of endogenously synthesized molecules derived from different fatty acids, such as arachidonic, docosahexaenoic or eicosapentaenoic acid, which are derived into four different product families: lipoxins, resolvins, maresins and protectins. For quantitation of these compounds, a sensitive, selective and robust liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of lipoxin A4, 6-epi-lipoxin A4, lipoxin B4 and lipoxin A5, the D-series resolvins D1 and D2 as well as aspirin-triggered lipoxin A4 and resolvin D1, maresin and protectin and the pathway markers 17(S)-hydroxy-docosahexaenoic acid and 17(R)-hydroxy-docosahexaenoic acid in cell culture supernatants. For this purpose, a chiral column was connected in series with a reversed-phase column to achieve efficient analyte separation and high sensitivity. Sample pre-treatment included a fast and simple liquid-liquid extraction procedure. Limits of quantitation in the range of 0.1-0.5ng/mL cell culture media, absolute recoveries between 90 and 115%, intra- and interday precision of less than 13% and an accuracy of less than 11% were obtained. Stability of the samples after 60 days storage at -80°C, three freeze/thaw cycles and 4h at room temperature has been demonstrated for all analytes. Sample extracts can be stored at 7°C for 24h without degradation of the analytes. Deviations of less than 13% in the accuracy, evaluated in terms of relative error, were obtained. The suitability of the method has been demonstrated in cell culture supernatants of human polymorphonuclear leukocytes, stimulated with 15R-hydroxy-eicosatetraenoic acid and in cell culture media of human polymorphonuclear leukocytes co-incubated with human platelets. From all studied analytes, lipoxin A4 and 6-epi-lipoxin A4 were found in cell culture media under both incubation conditions, while 15-epi-lipoxin A4 was additionally detected in cell culture supernatants of polymorphonuclear leukocytes stimulated with 15R-hydroxy-eicosatetraenoic acid.
    Journal of chromatography. A. 07/2014;
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    ABSTRACT: Prostaglandins (PGs) act as potent local hormones in nearly all tissues of the human body and are used for various medical applications. Heterologous expression of PG endoperoxide H-synthase from the alga, Gracilaria vermiculophylla, into E. coli and the application of this strain in biotransformation experiments resulted in a highly efficient conversion of arachidonic acid (ARA) yielding up to 130 mg natural PGs l(-1) in a laboratory scale approach. Detailed analyses of the products and production kinetics were performed, confirming a rapid conversion of ARA to PGs.
    Biotechnology Letters 07/2014; · 1.85 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that various subtypes of purinergic receptors (P2X and P2Y receptor families) play an essential role in the development and the maintenance of neuropathic pain. However, there is only limited data available about the role of P2Y6 receptors in pain processing. Here we detected P2Y6 receptor immunoreactivity in primary afferent neurons of mice and observed an upregulation in response to peripheral nerve injury. However, systemic and intrathecal administration of the P2Y6 receptor antagonist MRS2578 failed to affect the injury-induced neuropathic pain behavior. Our results suggest that P2Y6 receptors, in contrast to other purinergic receptor subtypes, are not critically involved in nerve injury-induced neuropathic pain processing in mice.
    Pharmacology Biochemistry and Behavior 07/2014; · 2.82 Impact Factor
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    ABSTRACT: Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive. Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60-7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry. The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60-7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60-7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues. Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.
    Anesthesiology 04/2014; · 5.16 Impact Factor
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    ABSTRACT: AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have a therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.
    Biochemical and Biophysical Research Communications 04/2014; · 2.28 Impact Factor
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    ABSTRACT: Background/AimsRecurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virologic response rates in patients after OLT in combination with pegylated-interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT-patients with IS are unknown. Aim of the present study was to analyze telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS.Methods Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1 infected patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily, and pegylated-interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase-chain-reaction.ResultsMedian (range) telaprevir plasma concentrations of TW 4, 8, and 12 were 3970 (1980-4430) ng/mL and 2520 (1870-8730) ng/mL in patients after OLT and ciclosporin or tacrolimus based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (p=0.3). In one patient with tacrolimus based IS, telaprevir dose had to be adjusted to achieve virologic response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8, and 12 in patients with and without IS.Conclusions Telaprevir drug monitoring may be necessary in patients with tacrolimus based IS in patients with HCV graft infection after OLT.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 03/2014; · 3.87 Impact Factor
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    ABSTRACT: Inflammatory pain is based on stimulation and sensitization of peripheral endings of sensory neurons (nociceptors) by pronociceptive mediators. These mediators can be released by resident cells, as well as invading immune cells. Although neutrophils are known to release various mediators, which can stimulate or sensitize nociceptors, the extent of their contribution to nociceptive responses is unclear. Here, we studied the contribution of neutrophils to zymosan-induced inflammatory pain, which is characterized by an early recruitment of high numbers of neutrophils. Surprisingly, antibody-mediated neutrophil depletion caused a complete loss of edema formation but had no effect on mechanical pain thresholds. Blockage of the interaction between neutrophils and platelets or endothelial cells using antibodies directed against CD11b and CD162 reduced neutrophil recruitment to the site of inflammation. Again, the treatment decreased zymosan-induced edemas without altering mechanical pain thresholds. Also, HLB-219 mice, which have five to 10 times less platelets than WT mice, showed reduced neutrophil recruitment to the site of inflammation and decreased edema sizes, whereas, again, mechanical thresholds were unaltered. The effects observed in HLB-219 mice were relatively small and not reproduced in vWF-deficient mice or after antibody-mediated blockage of GPIbα. Flow chamber and transmigration assays showed that platelets were not necessary for neutrophil adhesion to endothelial cells but increased their transmigration. Taken together, zymosan-induced mechanical allodynia is, in contrast to edema formation, independent of neutrophils, and recruitment of neutrophils is only partly influenced by interactions with platelets.
    Journal of leukocyte biology 02/2014; · 4.99 Impact Factor
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    ABSTRACT: Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid β-oxidation (FAO) affects macrophage responses to SFA. We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. To inhibit FAO, we created THP-1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO.
    Diabetologia 02/2014; · 6.49 Impact Factor
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    ABSTRACT: Once daily doses of 100-400 mg lumiracoxib have been proposed to inhibit local prostaglandin synthesis longer than systemic prostaglandin synthesis due to local accumulation in inflamed, acidic tissue. Lower, less toxic doses, however, might still achieve the clinical goal and merit further contemplation. In a randomized, double-blind, placebo-controlled, three-way cross-over study, 18 healthy men received, with an interval of 24 h, two oral doses of 50 mg lumiracoxib or for comparison, 90 mg etoricoxib, for which local tissue accumulation has not been claimed as therapeutic component. Systemic and local drug concentrations, assessed by means of subcutaneous in-vivo microdialysis, were related to COX-2 inhibiting effects, quantified as inhibition of prostaglandin ex-vivo production in whole blood as well as local tissue prostaglandin (PG) concentrations. Twenty-four hours after the first dose, only etoricoxib was detectable in plasma and inhibited PGE2 production. In contrast, after the second dose, systemic PGE2 concentrations were significantly reduced by both coxibs, indicating similar maximum systemic effects of the selected doses. The local COX-2 inhibition by etoricoxib was most pronounced for PGD2. To the contrary, no indication was given of local inhibition of PG production by lumiracoxib at the dose tested. Doses of 50 mg lumiracoxib and 90 mg etoricoxib produced similar maximum inhibition of systemic COX-2 function whereas 50 mg lumiracoxib was ineffective in producing local COX-2 inhibition. At a 50 mg dosage, lumiracoxib does not provide peripheral effects that outlast its systemic actions in therapies of rheumatic diseases such as osteoarthritis.
    Pharmaceutical Research 01/2014; · 4.74 Impact Factor
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    ABSTRACT: Aims: Emerging lines of evidence indicate that oxidants such as hydrogen peroxide exert specific signaling functions during the processing of chronic pain. However, the mechanisms by which oxidants regulate pain processing in vivo remain poorly understood. Here, we investigated whether cGMP-dependent protein kinase Iα (cGKIα), which can be activated by oxidants independently of cGMP, serves as a primary redox target during pain processing. Results: After peripheral nerve injury, oxidant-induced cGKIα activation is increased in dorsal root ganglia of mice. Knock-in mice in which cGKIα cannot transduce oxidant signals demonstrated reduced neuropathic pain behaviors after peripheral nerve injury, and reduced pain behaviors after intrathecal delivery of oxidants. In contrast, acute nociceptive, inflammatory, and cGMP-induced pain behaviors were not impaired in these mice. Innovation: Studying cGKIα knock-in mice, we provide the first evidence that oxidants activate cGKIα in sensory neurons after peripheral nerve injury in vivo. Conclusion: Our results suggest that oxidant-induced activation of cGKIα specifically contributes to neuropathic pain processing, and that prevention of cGKIα redox activation could be a potential novel strategy to manage neuropathic pain.
    Antioxidants & Redox Signaling 01/2014; · 8.20 Impact Factor
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    ABSTRACT: AMP-activated kinase is a cellular energy sensor which is activated in stages of increased ATP consumption. Its activation has been associated with a number of beneficial effects such as decreasing inflammatory processes and the disease progress of diabetes and obesity, respectively. Furthermore, AMPK activation has been linked with induction of cell cycle arrest and apoptosis in cancer and vascular cells, indicating that it might have a therapeutic impact for the treatment of cancer and atherosclerosis. However, the impact of AMPK on the proliferation of macrophages, which also play a key role in the formation of atherosclerotic plaques and in inflammatory processes, has not been focused so far. We have assessed the influence of AICAR- and metformin-induced AMPK activation on cell viability of macrophages with and without inflammatory stimulation, respectively. In cells without inflammatory stimulation, we found a strong induction of caspase 3-dependent apoptosis associated with decreased mTOR levels and increased expression of p21. Interestingly, these effects could be inhibited by co-stimulation with bacterial lipopolysaccharide (LPS) but not by other proinflammatory cytokines suggesting that AICAR induces apoptosis via AMPK in a TLR4-pathway dependent manner. In conclusion, our results revealed that AMPK activation is not only associated with positive effects but might also contribute to risk factors by disturbing important features of macrophages. The fact that LPS is able to restore AMPK-associated apoptosis might indicate an important role of TLR4 agonists in preventing unfavorable cell death of immune cells.
    Biochemical and Biophysical Research Communications 01/2014; · 2.28 Impact Factor
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    ABSTRACT: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity. Olfactory function and nociception was compared between carriers (n = 38) and non-carriers (n = 43) of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2). Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2) were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049). Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations) and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006), which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced. The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.
    PLoS ONE 01/2014; 9(4):e95592. · 3.53 Impact Factor

Publication Stats

9k Citations
1,922.22 Total Impact Points

Institutions

  • 2014
    • Fraunhofer Institute for Molecular Biology and Applied Ecology IME
      Aachen, North Rhine-Westphalia, Germany
  • 2005–2014
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 1999–2014
    • Goethe-Universität Frankfurt am Main
      • • Institut für Klinische Pharmakologie
      • • Institut für Pharmazeutische Biologie
      • • Institut für Allgemeine Pharmakologie und Toxikologie
      • • Zentrum der Pharmakologie
      Frankfurt, Hesse, Germany
  • 2012
    • University Health Network
      Toronto, Ontario, Canada
  • 2008–2011
    • University of Toronto
      Toronto, Ontario, Canada
    • Kerckhoff Klinik
      • Department of Cardiology
      Stadt Bad Nauheim, Hesse, Germany
  • 2000–2011
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
    • Stanford University
      • Department of Anesthesia
      Palo Alto, CA, United States
  • 1989–2006
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Department of Ophthalmology
      • • Department of Experimental and Clinical Pharmacology and Toxicology
      • • Department of Anaesthesiology
      Erlangen, Bavaria, Germany
  • 1989–2000
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 1998–1999
    • Hadassah Medical Center
      • Department of Medicine
      Jerusalem, Jerusalem District, Israel
  • 1996
    • Karl-Franzens-Universität Graz
      Gratz, Styria, Austria
    • University of New South Wales
      Kensington, New South Wales, Australia
  • 1992–1995
    • St. Vincent's Hospital Sydney
      • Clinical Pharmacology and Toxicology
      Sydney, New South Wales, Australia
    • Max Planck Institute for Biophysical Chemistry
      Göttingen, Lower Saxony, Germany
  • 1994
    • Ruhr-Universität Bochum
      • Institute of Pharmacology and Toxicology
      Bochum, North Rhine-Westphalia, Germany