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Weinschenk S, Weiss C, Benrath J, von Baehr V, Strowitzki T, Feißt M. Anti-Inflammatory Characteristics of Local Anesthetics: Inhibition of TNF-α Secretion of Lipopolysaccharide-Stimulated Leucocytes in Human Blood Samples. Int J Mol Sci 2022; 23:ijms23063283. [PMID: 35328706 PMCID: PMC8949497 DOI: 10.3390/ijms23063283] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44−61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, “responders”). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.
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Affiliation(s)
- Stefan Weinschenk
- Department of Gynecological Endocrinology and Fertility Disorders, Women’s Hospital, University of Heidelberg, D-69120 Heidelberg, Germany;
- Correspondence:
| | - Carsten Weiss
- Institute of Biological and Chemical Systems, Biological Information Processing, Karlsruhe Institute of Technology (KIT), Campus North, D-76133 Karlsruhe, Germany;
| | - Justus Benrath
- Pain Clinic, Mannheim University Hospital, Faculty of Heidelberg University, D-68167 Mannheim, Germany;
| | - Volker von Baehr
- Institute of Medical Diagnostics, Nicolaistraße 22, D-12247 Berlin, Germany;
| | - Thomas Strowitzki
- Department of Gynecological Endocrinology and Fertility Disorders, Women’s Hospital, University of Heidelberg, D-69120 Heidelberg, Germany;
| | - Manuel Feißt
- Institute of Medical Biometry (IMBI), Heidelberg University, Im Neuenheimer Feld 130.3, D-69120 Heidelberg, Germany;
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Zhang Y, Tao GJ, Hu L, Qu J, Han Y, Zhang G, Qian Y, Jiang CY, Liu WT. Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord. J Neuroinflammation 2017; 14:211. [PMID: 29096659 PMCID: PMC5667445 DOI: 10.1186/s12974-017-0983-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 10/18/2017] [Indexed: 12/29/2022] Open
Abstract
Background Morphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4). In Chinese pain clinic, lidocaine is combined with morphine to treat chronic pain. We found that lidocaine sufficiently inhibited neuroinflammation induced by morphine and improved analgesic tolerance on the basis of non-affecting pain threshold. Methods CD-1 mice were utilized for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of lidocaine. Neuroinflammation-related cytokines were measured by western blotting and real-time PCR. The level of suppressor of cytokine signaling 3 (SOCS3) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)-related signaling pathway was evaluated by western blotting, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. Results Lidocaine potentiated an anti-nociceptive effect of morphine and attenuated the chronic analgesic tolerance. Lidocaine suppressed morphine-induced activation of microglia and downregulated inflammatory cytokines, interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) via upregulating SOCS3 by activating AMPK. Lidocaine enhanced AMPK phosphorylation in a calcium-dependent protein kinase kinase β (CaMKKβ)-dependent manner. Furthermore, lidocaine decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear factor-κB (NF-κB) in accordance with the inhibitory effects to TLR4. Conclusions Lidocaine as a prevalent local anesthetic suppresses morphine tolerance efficiently. AMPK-dependent upregulation of SOCS3 by lidocaine plays a crucial role in the improvement of analgesic tolerance. Electronic supplementary material The online version of this article (10.1186/s12974-017-0983-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yan Zhang
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.,Research Division of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, 211100, China
| | - Gao-Jian Tao
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.,Department of Pain, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210008, China
| | - Liang Hu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Jie Qu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China
| | - Yuan Han
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Guangqin Zhang
- Research Division of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, 211100, China
| | - Yanning Qian
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Chun-Yi Jiang
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
| | - Wen-Tao Liu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. .,Department of Pharmacy, Sir Run Run Shaw Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, 210008, China.
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Wickström K, Stavréus-Evers A, Vercauteren O, Olovsson M, Edelstam G. Effect of Lignocaine on IL-6, IL-8, and MCP-1 in Peritoneal Macrophages and Endometriotic Stromal Cells. Reprod Sci 2016; 24:382-392. [PMID: 27444775 DOI: 10.1177/1933719116657188] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE The objective was to evaluate the effect of lignocaine on cytokine expression and secretion in vitro in peritoneal fluid macrophages and endometriotic stromal cells. DESIGN Experimental in vitro study on human cells. POPULATION AND SAMPLE Peritoneal fluid (n = 10) and samples from endometriotic cysts (n = 7) were collected from 13 women (women with endometriosis n = 8, and healthy controls n = 5) during surgery for clinical reasons. METHODS Macrophages from the peritoneal fluid and cells from the inside of the endometriotic cysts capsules were isolated and cultivated for 24 to 48 hours in medium with and without the supplement of lignocaine 0.1 or 1.0 mg/mL. Relative gene expression of monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and IL-8 was evaluated with quantitative polymerase chain reaction and compared between treated and untreated cells with Wilcoxon matched pairs. The concentrations of MCP-1, IL-6, and IL-8 were measured using enzyme-linked immunosorbent assay and were compared between treated and untreated cells with Wilcoxon matched pairs. RESULTS The gene expression and protein secretion of IL-8 in endometriotic stromal cells after incubation with lignocaine 0.1 mg/mL were significantly decreased after 24 hours compared to the controls ( P = .028 and P = .018). Macrophages from healthy controls had a significant lower gene expression of all tested cytokines ( P = .043) after treatment with lignocaine, but there were no significant differences in protein level. Macrophages from women with endometriosis showed diverging results since 3 of 5 samples showed increased gene expression of 1 (n = 2) or 2 cytokines (n = 1) after lignocaine treatment. CONCLUSION Lignocaine can affect the gene expression and secretion of some proinflammatory cytokines in vitro.
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Affiliation(s)
- Karin Wickström
- 1 Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
| | | | - Olivier Vercauteren
- 2 Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Matts Olovsson
- 2 Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Greta Edelstam
- 2 Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.,3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Duman U, Yilmazlar A, Ozturk E, Aker S, Sarandol E, Yilmazlar T. Anti-inflammatory efficiency of levobupivacaine in an experimental colitis model. World J Gastroenterol 2010; 16:2537-41. [PMID: 20503454 PMCID: PMC2877184 DOI: 10.3748/wjg.v16.i20.2537] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the efficiency of levobupivacaine in treating experimentally induced colitis in rats.
METHODS: Colitis was induced by trinitrobenzene sulfonic acid and ethanol in 30 rats under general anesthesia, and 10 rats were used as a sham group. Subsequent to induction of colitis, rats were divided into three groups; budesonide group received 0.1 mg/kg budesonide, levobupivacaine group received 10 mg/kg levobupivacaine and saline group received 1 mL saline solution via rectal route for 7 d. In the sham group, only routine rectal catheterization was performed without use of any material. At the end of 7 d, laparotomy and total colectomy were performed for histopathological examination in all rats and blood samples were drawn for measurement of tumor necrosis factor (TNF)-α and interleukin (IL)-6 following cardiac puncture. Macroscopic and microscopic evaluations of the specimens were performed by a pathologist blinded to group assignment of the rats.
RESULTS: Weight loss (P = 0.016) and macroscopic examination scores (P = 0.001) were significantly higher in saline group than others. Histopathological scoring was comparable between all colitis groups (P = 0.350). There was no significant difference in TNF-α levels and IL-6 levels (P = 0.150).
CONCLUSION: The significant improvement in macroscopic scores suggests that levobupivacaine may have topical anti-inflammatory effects in an experimental colitis model; however, this finding was not supported by microscopic findings.
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Lang A, Ben Horin S, Picard O, Fudim E, Amariglio N, Chowers Y. Lidocaine inhibits epithelial chemokine secretion via inhibition of nuclear factor κB activation. Immunobiology 2010; 215:304-13. [DOI: 10.1016/j.imbio.2009.05.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2008] [Revised: 05/14/2009] [Accepted: 05/17/2009] [Indexed: 12/15/2022]
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Effect of intravenous lidocaine administration on laminar inflammation in the black walnut extract model of laminitis. Equine Vet J 2010; 42:261-9. [DOI: 10.2746/042516409x475760] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Cywinski JB, Kusza K. Anesthesia and Critical Care. Plast Reconstr Surg 2010. [DOI: 10.1007/978-1-84882-513-0_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Barbara G, Stanghellini V, Cremon C, De Giorgio R, Corinaldesi R. What is the effect of inflammation on intestinal function? Inflamm Bowel Dis 2008; 14 Suppl 2:S140-4. [PMID: 18816685 DOI: 10.1002/ibd.20701] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Giovanni Barbara
- Department of Internal Medicine and Gastroenterology, University of Italy, Bologna, Italy
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Cook VL, Blikslager AT. Use of systemically administered lidocaine in horses with gastrointestinal tract disease. J Am Vet Med Assoc 2008; 232:1144-8. [DOI: 10.2460/javma.232.8.1144] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Lahat A, Ben-Horin S, Horin SB, Lang A, Fudim E, Picard O, Chowers Y. Lidocaine down-regulates nuclear factor-kappaB signalling and inhibits cytokine production and T cell proliferation. Clin Exp Immunol 2008; 152:320-7. [PMID: 18355353 DOI: 10.1111/j.1365-2249.2008.03636.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Lidocaine is a commonly used local anaesthetic agent which has also been found to possess anti-inflammatory activity in several disorders. However, the mechanism of this effect has been little explored. The aim of this study was to investigate the effect of lidocaine on stimulated human T cells. The effect of lidocaine on Jurkat T cells was examined by enzyme-linked immunosorbent assay (ELISA) to determine secretion of interleukin (IL)-2, and by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] viability assay. Tumour necrosis factor (TNF)-alpha and IL-2 mRNA expression was determined by reverse transcription-polymerase chain reaction. In addition, the effect of lidocaine on the proliferation of freshly isolated peripheral blood (PB) CD3(+) T cells was examined by carboxyfluorescein succinimidyl ester dilution. Apoptosis induction and cytokine production and secretion were determined by annexin V/PI assay, intracellular immunostaining and ELISA respectively. The results showed that lidocaine exerts a dose-dependent inhibition of IL-2 and TNF-alpha secretion by Jurkat T cells at the protein and mRNA levels. Moreover, lidocaine reduced nuclear factor-kappaB (NF-kappaB) signalling in clinically relevant concentrations. Similarly, proliferation of anti-CD3 stimulated PB T cells was abrogated significantly by lidocaine, and the percentage of interferon-gamma- and TNF-alpha-producing T cells was diminished after culture with this agent. In both experimental systems, lidocaine's effect was not mediated by cytotoxic mechanism, as no significant apoptosis or necrosis was demonstrated following co-culture of T cells with this drug. In conclusion, lidocaine's anti-inflammatory effect may be mediated by a drug-induced abrogation of T cell proliferation and cytokine secretion independent of cell death. These effects are mediated at least partly by inhibition of NF-kappaB signalling.
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Affiliation(s)
- A Lahat
- Department of Gastroenterology, Chaim Sheba Medical Center affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Travis SPL, Stange EF, Lémann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P, Kruis W, Mortensen NJM, Penninckx F, Gassull M. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis 2008; 2:24-62. [PMID: 21172195 DOI: 10.1016/j.crohns.2007.11.002] [Citation(s) in RCA: 365] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Accepted: 11/23/2007] [Indexed: 02/08/2023]
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Farhadi A, Keshavarzian A, Fields JZ, Jakate S, Shaikh M, Banan A. Reduced immunostaining for c-kit receptors in mucosal mast cells in inflammatory bowel disease. J Gastroenterol Hepatol 2007; 22:2338-43. [PMID: 17645464 DOI: 10.1111/j.1440-1746.2007.05011.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM The deleterious effects of stress in inflammatory bowel disease (IBD) have been attributed to activation of the brain-gut axis (BGA) and its end effectors, mast cells (MC). We previously showed that cold pressor stress test (CPT) results in increased activation and degranulation (but not increased proliferation) of mucosal MC, mitochondrial damage to epithelial cells and mucosal protein oxidation in both healthy controls and IBD patients. These changes are more marked in IBD patients. This increased activation of MC in IBD could be due to (i) greater activation of the BGA or (ii) inherited or acquired abnormalities in mucosal MC. In the current study we investigated the latter possibility. METHODS To assess the effects of stress on mucosal MC in patients with IBD, seven controls and 15 subjects with inactive IBD underwent 5 consecutive days of CPT to activate the BGA. Endoscopic mucosal biopsies of the distal sigmoid colon were taken during unprepared sigmoidoscopy before the first CPT and after the last CPT, and formalin-fixed samples were stained for both MC granules (MCg) and for the c-kit receptor, which is present on MC membranes (MCm). Mast cell degranulation was assessed using electron microscopy. RESULTS Mast cell granule staining suggested that IBD subjects do not have a significantly different number of MC compared with controls, either before or after stress. Mast cell membrane staining, in contrast, suggested that MC c-kit immunostaining was significantly reduced - at both baseline (P = 0.01) and post stress (P = 0.04) samples - in IBD patients compared to controls. MC c-kit immunostaining was independent of stress-induced MC degranulation. There was no significant change in MC number as a result of the stress intervention using either staining method in both groups. CONCLUSION These data support our previous report that the size of the mucosal MC population in patients with inactive IBD is not altered by disease or by stress, yet MC in IBD are different (fewer c-kit receptors) and respond differently (greater activation) than MC in control subjects. It remains to be seen whether this abnormality is an inherited or acquired one and to identify its role and mechanism in tissue injury in the pathogenesis of IBD.
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Affiliation(s)
- Ashkan Farhadi
- Section of Gastroenterology and Nutrition, and Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois 60612, USA.
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Farhadi A, Fields JZ, Keshavarzian A. Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: Stress, intestinal hyperpermeability and inflammation. World J Gastroenterol 2007; 13:3027-30. [PMID: 17589915 PMCID: PMC4172606 DOI: 10.3748/wjg.v13.i22.3027] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro-intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.
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Abstract
PURPOSE OF REVIEW We provide an overview of the immunological effects of commonly used anesthetic drugs and highlight their potential impact on long-term outcome after surgery. RECENT FINDINGS Clinical trials provide preliminary evidence that the perioperative process can influence long-term patient outcome. Immunology may begin to elucidate the biology of this safety concern and open new therapeutic opportunities. In this context, awareness of the immunological properties of drugs administered in the perioperative period may assist in their deliberate use to modulate this risk. Statins, beta-blockers, and clonidine can potentially improve long-term cardiac risk. Volatile anesthetics appear to suppress effector functions of both the innate and adaptive immunity, assist tumor growth in animal models, and facilitate aggregation of certain neurodegenerative disease proteins. Local anesthetics block neurons, but are also potent antiinflammatory drugs. Morphine has recognized immunosuppressive functions, which the newer, synthetic opioids don't seem to share. The cholinergic nervous system has antiinflammatory control functions that are largely unexploited. SUMMARY Long-term outcome after surgery is a new safety concern in perioperative care. We are faced with enormous challenges in healthcare and research. As providers, tailoring an anesthetic plan to patients' needs will become increasingly critical, and immunology should help in this pursuit.
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Affiliation(s)
- Jay A Homburger
- Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta, Georgia, USA
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Affiliation(s)
- A Nilsson
- Department of Medicine, University of Lund, Lund, Sweden.
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Sakaguchi M, Kuroda Y, Hirose M. The Antiproliferative Effect of Lidocaine on Human Tongue Cancer Cells with Inhibition of the Activity of Epidermal Growth Factor Receptor. Anesth Analg 2006; 102:1103-7. [PMID: 16551906 DOI: 10.1213/01.ane.0000198330.84341.35] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Local anesthetics suppress proliferation in several cancer cells. The mechanism of the suppression, however, is unknown. Our previous study shows that lidocaine, at the level of tissue concentration under topical or local administration, has a direct inhibitory effect on the activity of epidermal growth factor receptor (EGFR), which is a potential target for antiproliferation in cancer cells. Therefore, we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of EGFR activity. We investigated the effects of lidocaine (40-4000 microM) on proliferation of a human tongue cancer cell line, CAL27, which has a high level of EGFR expression, and also examined the effect of lidocaine on epidermal growth factor (EGF)-stimulated autophosphorylation of EGFR in CAL27 cells. A clinical concentration of lidocaine (400 microM) suppressed both serum-induced and EGF-induced proliferation of CAL27 cells and inhibited EGF-stimulated tyrosine kinase activity of EGFR without cytotoxicity. A larger concentration of lidocaine (4000 microM) showed cytotoxicity with an antiproliferative effect. We suggest that the inhibition of EGF-stimulated EGFR activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells. Lidocaine administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells.
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Affiliation(s)
- Masahiro Sakaguchi
- Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Greenwood-Van Meerveld B, Johnson AC, Foreman RD, Linderoth B. Spinal cord stimulation attenuates visceromotor reflexes in a rat model of post-inflammatory colonic hypersensitivity. Auton Neurosci 2005; 122:69-76. [PMID: 16182612 DOI: 10.1016/j.autneu.2005.08.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Revised: 08/04/2005] [Accepted: 08/06/2005] [Indexed: 12/22/2022]
Abstract
Spinal cord stimulation (SCS) has been found to relieve neuropathic and ischemic pain clinically and to attenuate a nociceptive reflex in an animal model of acute colonic hypersensitivity. The goal of the present study was to determine the effect of SCS in a rat model of post-inflammatory colonic hypersensitivity. Acute inflammation was induced in rats by a single enema of trinitrobenzenesulfonic acid (TNBS) (50 mg/kg, 0.5 ml, 25% EtOH). Control rats received a single saline enema. A visceromotor behavioral response (VMR), induced by innocuous colorectal distention (30 mm Hg, 10 min) was used to quantify the level of colonic sensitivity on day 3 and 30 post-enema. Prior to VMR testing, under general anesthesia, an electrode (cathode) was placed epidurally on the dorsal surface of the spinal cord at L1 with a paravertebral anode plate. Three to 7 days after implantation of the SCS electrode, the effect of SCS (50 Hz, 0.2 ms, amplitude 90% of motor threshold for 30 min) on colonic sensitivity was determined. On day 30, rats that had received a single TNBS enema were hypersensitive to innocuous colonic distention when compared to rats that received a saline enema (VMR/10 min: TNBS: 17.2+/-0.8 vs. Saline: 9.6+/-1.1, p<0.01). Spinal cord stimulation significantly reduced the VMR in the TNBS-enema group to a value that resembled the saline-enema group (VMR/10 min: TNBS: 11.2+/-1.2 vs. Saline: 10.0+/-1.0). This study provides the first evidence that SCS might be a potential therapeutic for the treatment of abdominal pain observed in patients with post-inflammatory irritable bowel syndrome.
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Farhadi A, Keshavarzian A, Van de Kar LD, Jakate S, Domm A, Zhang L, Shaikh M, Banan A, Fields JZ. Heightened responses to stressors in patients with inflammatory bowel disease. Am J Gastroenterol 2005; 100:1796-804. [PMID: 16086717 DOI: 10.1111/j.1572-0241.2005.50071.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Several studies suggest that stressful situations (stressors) worsen the course of inflammatory bowel disease (IBD), but the mechanism is not known. Based on several lines of evidence, we hypothesized that psychosocial stress activates the brain-gut axis (BGA) and mucosal mast cells (MC), and activated MC produce proinflammatory cytokines. To test this hypothesis, we determined whether stressor-induced activation of BGA is exaggerated in IBD patients. METHODS Stress was induced in 15 IBD patients who were in remission (inactive IBD) and in seven controls by a widely used stressor, the cold pressor test (CPT), daily for five consecutive days. Induction of stress was confirmed objectively by measurement of stress hormones (serum cortisol and ACTH), and hemodynamic parameters and subjectively by questionnaire. Activation of the BGA by this stressor was assessed by evaluating colonic mucosal MC histology and degranulation, using electron microscopy (EM). The effects of the stressor on the intestinal mucosa were assessed by changes in inflammatory cell histology, epithelial mitochondria (EM), and oxidative tissue injury (assays for protein oxidation). RESULTS In both study groups, the stressor resulted in (1) increased levels of stress hormones, (2) the expected changes in hemodynamic parameters, (3) activation and degranulation of MC, (4) mitochondrial damage to epithelial cells, and (5) mucosal protein oxidation. These changes were more marked in IBD patients. CONCLUSIONS The heightened response to the stressors and the greater epithelial damage in IBD patients suggests that stress-induced activation of the BGA and of mucosal MC is important in the initiation and/or flare up of IBD.
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Affiliation(s)
- Ashkan Farhadi
- Department of Internal Medicine, Section of Gastroenterology and Nutrition, Rush University Medical Center, Chicago, Illinois 60612, USA
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Marteau P, Beaugerie L, Bouhnik Y, Flourié B, Gambiez L, Reimund JM, Seksik P. [Introduction of the evidence]. ACTA ACUST UNITED AC 2005; 28:961-3. [PMID: 15672567 DOI: 10.1016/s0399-8320(04)95173-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Philippe Marteau
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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Seksik P, Contou JF, Ducrotté P, Faucheron JL, de Parades V. [The treatment of distal ulcerative colitis]. ACTA ACUST UNITED AC 2005; 28:964-73. [PMID: 15672568 DOI: 10.1016/s0399-8320(04)95174-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Philippe Seksik
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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Klotz U, Schwab M. Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease. Adv Drug Deliv Rev 2005; 57:267-79. [PMID: 15555742 DOI: 10.1016/j.addr.2004.08.007] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2004] [Accepted: 08/11/2004] [Indexed: 01/18/2023]
Abstract
For targeting local and systemic inflammatory processes in inflammatory bowel disease (IBD) therapeutic agents of first choice (e.g. aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn's disease) and/or the colon (Crohn's disease and ulcerative colitis). However, it has to be realized that intestinal physiology (e.g. motility, intraluminal pH profiles), extent and pattern of IBD as well as drug disposition demonstrate large interindividual differences resulting in variable clinical response rates between about 35% and 75%. 5-Aminosalicylate (5-AS) can be delivered to the colon either by azo-prodrugs (e.g. sulfasalazine, olsalazine or balsalazide) or by direct rectal administration of 5-AS in form of enemas, foam or suppositories. Such formulations will be only effective in patients with ulcerative colitis (UC). Various slow/controlled release preparations of 5-AS have been developed for oral use. Some of them (e.g. Pentasa, Salofalk) release sufficient 5-AS already in the small bowel which could provide some additional benefit in Crohn's disease (CD). As urinary and faecal recoveries of total 5-AS are similar for all oral formulations, no major clinical differences can be expected. Extent of the disease, profile of adverse effects and patient's acceptance provide some guidance for selection of the particular agent. Rectal installation of several glucocorticosteroids has been employed for many years. More recently scientific and clinical interest has been focused on budesonide which is extensively presystemically metabolized in the intestinal wall and the liver. Therefore, its systemic availability is low (10-15%) independent whether budesonide is administered orally as controlled release formulation in patients with CD or rectally as enema in patients with UC. Numerous pharmacokinetic and clinical studies have documented the anticipated topical delivery and clinical efficacy of this corticosteroid without serious side effects such as cushingoid features. It can be assumed that for any novel therapeutic principle in IBD the approach of topical delivery will be also tried.
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Affiliation(s)
- Ulrich Klotz
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany.
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24
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Chevalier E, Pétoux F, Chovet M, Langlois A. Beneficial effect of trimebutine and N-monodesmethyl trimebutine on trinitrobenzene sulfonic acid-induced colitis in rats. Life Sci 2004; 76:319-29. [PMID: 15531383 DOI: 10.1016/j.lfs.2004.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2004] [Accepted: 08/03/2004] [Indexed: 10/26/2022]
Abstract
The use of local anesthetics, such as lidocaine, has been proposed in the treatment of distal ulcerative colitis. Trimebutine maleate (TMB) displays a local anesthetic activity higher than that of lidocaine in rabbit corneal reflex. TMB and nor-TMB its main metabolite in human show similar affinity to that of bupivacaine toward sodium channel labeled by [3H]batrachotoxin and block sodium currents in sensory neurons from rat dorsal root ganglia. The aim of this study was to evaluate the effects of TMB and nor-TMB in comparison to lidocaine and bupivacaine in a rat model of acute colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS). A single intracolonic instillation of TNBS (50 mg/kg dissolved in ethanol 30%) led to early plasma extravasation then macroscopic damage (hyperemia and necrosis), increased colonic weight and tissular MPO, a marker of neutrophilic infiltration. Local administration of TMB at dose of 3 to 60 mg/kg, 30 min before, 24 and 48 h after colitis induction, significantly reduced the severity of colitis. Nor-TMB (1, 3, 10, 30 mg/kg) as well as lidocaine (1, 3, 10 mg/kg) dose-dependently reduced colitis while bupivacaine at 10 mg/kg did not affect it significantly. In contrast systemic administration of TMB, nor-TMB and lidocaine at 10 mg/kg had no significant effect. Furthermore, local administration of TMB (30 mg/kg) and lidocaine (10 mg/kg) significantly reduced plasmatic extravasation. In conclusion, intracolonic treatment with TMB and nor-TMB improved acute experimental TNBS-induced colitis in rat and these effects could be explained by their local anesthetic activity.
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Affiliation(s)
- Eric Chevalier
- Department of Biology, Pfizer Global Research and Development, Fresnes Laboratories, 3-9 rue de la loge, 94265 Fresnes Cedex, France.
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25
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Siveke JT, Folwaczny C. Medical approaches and future options in chronic active ulcerative colitis. Int J Colorectal Dis 2004; 19:297-307. [PMID: 14727131 DOI: 10.1007/s00384-003-0569-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND Immunosuppressive therapy employing purine analogues is the therapeutic mainstay in patients with chronic active ulcerative colitis. However, despite therapeutic optimization according to thiopurine-methyltransferase activity or red blood cell 6-thioguanine levels, a substantial proportion of patients does not tolerate azathioprine or 6-mercaptopurine or relapses during this treatment. In the latter multiple therapeutic regimens comprising 6-thioguanine, cyclosporin or tacrolimus, methotrexate, cyclophosphamide, infliximab, interferons, heparin, leukocyte apheresis, and various other regimens might be considered aiming at long-term remission. Many of these treatment forms have only been evaluated in small mostly uncontrolled trials. OBJECTIVE In this review existing treatment modalities and future options for patients with chronic active ulcerative colitis will be discussed focusing on immunomodulating approaches.
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Affiliation(s)
- J T Siveke
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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26
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Abstract
The following article summarizes different aspects of local anesthetic effects that cannot be explained purely by a sodium channel blockade. Particularly remarkable is hereby their antiinflammatory activity, e.g. the inhibition of pathological changes such as excessive stimulation of the inflammatory system, without compromising the host defense system. In contrast to other immunosuppressive drugs commonly used for treating such conditions, local anesthetics look promising for the future as a new therapeutic option. Besides general anesthetic activity, local anesthetics exert cerebroprotective effects and are furthermore, in consideration of their cardiovascular stability, of interest during neuroanesthetic procedures. In addition, local anesthetics are known for their potency to minimize bronchial hyperreactivity, although details of the underlying mechanisms are not yet elucidated. These effects of local anesthetics may represent interesting prospects for which their relevance has to be determined.
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Affiliation(s)
- S Pecher
- Universitätsklinik für Anaesthesiologie, Universität Heidelberg
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Abstract
Treating inflammation in the equine gastrointestinal tract remains a challenge. Our most potent anti-inflammatory drugs, COX inhibitors and glucocorticoids, have unwanted effects on the gastrointestinal tract and host defense that often limit their use. Newer strategies targeting specific cells and molecules that regulate a subset of the events occurring during inflammation are rapidly becoming available and should allow clinicians to reduce the detrimental effects of inflammation without inhibiting the beneficial aspects.
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Affiliation(s)
- Samuel L Jones
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
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Hollmann MW, Strümper D, Durieux ME. The poor man's epidural: systemic local anesthetics for improving postoperative outcomes. Med Hypotheses 2004; 63:386-9. [PMID: 15288353 DOI: 10.1016/j.mehy.2004.02.057] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2004] [Accepted: 02/22/2004] [Indexed: 11/21/2022]
Abstract
The inflammatory response is an important determinant of outcome after major surgery. Perioperative excessive stimulation of the inflammatory and hemostatic systems plays a role in the development of postoperative ileus, ischemia-reperfusion syndromes (e.g. myocardial infarction), hypercoagulation syndromes (e.g. deep venous thrombosis) and pain; together, these represent a significant fraction of major postoperative disorders. Epidurally administered local anesthetics prevent or modulate many of these processes. Since local anesthetics show inflammatory modulating properties in vitro and in vivo, they might also prevent these postoperative inflammatory processes when administered intravenously. Clinical studies have shown that perioperative local anesthetic administration significantly reduces the incidence of thrombosis and postoperative pain, shortens postoperative ileus and decreases hospital stay. On this basis we hypothesize that continuous intravenous administration of local anesthetic perioperatively might prevent or reduce several postoperative disorders resulting from excessive stimulation of inflammatory and hemostatic systems, and thereby improve surgical outcome.
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Affiliation(s)
- Markus W Hollmann
- Department of Anesthesiology, University Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany.
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