- Email: [email protected]
Leflunomide as an antiatherogenic drug
Correspondence normal squamous epithelium to BO – dysplasia – OA. Therefore, we speculate that H. pylori might be involved in the GORD-BO-OA sequence and its eradication might inhibit the progress of this sequence.
References [1] Chatzopoulos D, Kyrgidis A, Kountouras J, Zavos C, Molyvas E, Venizelos I. Bax upregulation may provide a rationale for the low incidence of esophageal adenocarcinoma in a Greek cohort of patients with Barrett’s esophagus. Hepatogastroenterology, in press. [2] Kountouras J, Zavos C, Chatzopoulos D, Katsinelos P. Helicobacter pylori and gastro-oesophageal reflux disease. Lancet 2006;368:986. [3] Kountouras J, Zavos C, Chatzopoulos D. Induction of interleukin-8 expression by Helicobacter pylori infection in patients with endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol 2004;99:2500–1. [4] Abdel-Latif MM, Windle H, Terres A, Eidhin DN, Kelleher D, Reynolds JV. Helicobacter pylori extract induces nuclear
1175 factor-kappa B, activator protein-1, and cyclooxygenase-2 in esophageal epithelial cells. J Gastrointest Surg 2006;10: 551–62. [5] Nakajima S, Hattori T. Oesophageal adenocarcinoma or gastric cancer with or without eradication of Helicobacter pylori infection in chronic atrophic gastritis patients: a hypothetical opinion from a systematic review. Aliment Pharmacol Ther 2004;20(Suppl. 1):54–61.
Jannis Kountouras * Dimitrios Chatzopoulos Christos Zavos Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece * Tel.: +30 2310 892238; fax: +30 2310 992794. E-mail address: [email protected] (J. Kountouras).
doi:10.1016/j.mehy.2006.11.020
Leflunomide as an antiatherogenic drug Dear Editor, Although several drugs so far have been successful in the prevention of atherosclerotic vascular disease, it has been recently pointed out that the burden of cardiovascular morbidity and mortality is not likely to change in the near future unless fundamentally new therapeutic tools are found [1]. At this regard we speculate that leflunomide (LEF), a disease-modifying antirheumatic drug which is widely used in patients with rheumatoid arthritis (RA) [2], could also ameliorate vascular function by affecting several crucial mechanisms involved in the vessel wall pathobiology. Firstly, it has been shown that LEF has the ability to inhibit the nuclear factor kappaB signal transduction pathway [3], which is deemed to be critical in the development of a proinflammatory and proatherosclerotic phenotype in endothelial cells [4]. In addition, it has been demonstrated that leflunomide may reduce the subendothelial migration of peripheral blood mononuclear cells – an important event in early atherogenesis – by decreasing the cell surface expression of intercellular adhesion
molecules [5]. Third, LEF may cause functional impairment of antigen-presenting dendritic cells [6], whose activation has been recently demonstrated at sites of vascular pathology [7]. Altogether, these data may lead to the hypothesis that LEF could exert important vasculoprotective effects. In keeping with our hypothesis, preliminary results obtained in RA patients indicated that LEF use was associated with a significantly reduced risk of developing myocardial infarction [8]. Since the molecular actions of LEF indicate that its vasculoprotective effects may be independent of its antirheumatic properties, clinical testing of this compound as a cardiovascular medication in the general population may be worthwhile. Does treatment with LEF reduce the risk of ischemic cardiac events in the general population, and is it similar to that observed in RA? Does treatment with LEF have any beneficial effect on markers of endothelial function – such as flow-mediated vasodilation – in people with cardiovascular diseases? Is the tolerability profile of LEF in the general population similar to that observed in RA? We believe that clinical trials would be useful to answer to these
1176 important clinical questions, with the specific aim to investigate if low-dose LEF (e.g. 5–10 mg daily) can be used for vascular prevention even in patients without RA.
References [1] Mucke HA. Cardiovascular and renal developments: patent highlights January to June 2006. Curr Opin Investig Drugs 2006;7:792–8. [2] Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology (Oxford) 2005;44:280–6. [3] Feng H, Li XY, Zheng JR, et al. Inhibition of the nuclear factor-kappaB signaling pathway by leflunomide or triptolide also inhibits the anthralin-induced inflammatory response but does not affect keratinocyte growth inhibition. Biol Pharm Bull 2005;28:1597–602. [4] de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol 2005;25:904–14. [5] Grisar J, Aringer M, Koller MD, et al. Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells. Ann Rheum Dis 2004;63:1632–7.
Correspondence [6] Kirsch BM, Zeyda M, Stuhlmeier K, et al. The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function. Arthritis Res Ther 2005;7: R694–703. [7] Ranjit S, Dazhu L. Potential role of dendritic cells for progression of atherosclerotic lesions. Postgrad Med J 2006;82:573–5. [8] Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial infarction. Arthritis Rheum 2006;55:531–6.
Piercarlo Minoretti Anna Bruno Clara Di Vito Enzo Emanuele * Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli, 24, I-27100 Pavia, Italy * Tel.: +39 0382 528 341; fax: +39 0382 526 259. E-mail address: [email protected] (E. Emanuele).
doi:10.1016/j.mehy.2006.10.036
Are lung cancers triggered by stopping smoking? The clinically high correlation between smoking and carcinoma of the lungs has been the focal point in societal campaigns against the habit and the tobacco lobby. In an overview of personal history in a number of lung cancer patients locally, we are struck by the more than casual relationship between the appearance of lung cancer—and an abrupt and recent cessation of the smoking habit in many, if not most cases. The association is more than just casual-development of cancer within a few months of eschewing cigarette smoking. Over a period of 4 years, a total of 312 cases were treated for carcinoma of pulmonary origin: of this number, 182 patients had quit smoking within 5–15 months prior to their being diagnosed with lung cancer. Of the 182 patients 142 were male and 40 were females, with ages ranged between 47 and 74. Each one of had been addicted to the habit for no less than 25 years, smoking in excess of 20 sticks a day. The striking direct statistical correlation between cessation of smoking to the development of
lung malignancies, more than 60% plus, is too glaring to be dismissed as coincidental. It is our premise that a surge and spurt in re-activation of bodily healing and repair mechanisms of chronic smoke-damaged respiratory epithelia is induced and spurred by an abrupt discontinuation of habit, goes awry, triggering uncontrolled cell division and tumor genesis. In normal tissue healing, anabolic and catabolic processes achieve equilibrium approximately 6– 8 weeks after the original insult. When an imbalance occurs between these phases occur in the healing process, disruptions in repair limitations occur leading to tumor genesis—this sequence is best exemplified in the formation of keloids from scars [1]. Nicotine stimulates corticotrophin-releasing factor (CRF) besides increasing the level of adrenocorticotropic hormone (ACTH), both of which interfere with immune systems [2]. Abrupt withdrawal of the addictive drug could trigger derangement of the ‘smoking-steroid’ conferred immunity, priming the healing lung epithelia to dangerous levels uncontrolled cell division.
References [1] Chatzopoulos D, Kyrgidis A, Kountouras J, Zavos C, Molyvas E, Venizelos I. Bax upregulation may provide a rationale for the low incidence of esophageal adenocarcinoma in a Greek cohort of patients with Barrett’s esophagus. Hepatogastroenterology, in press. [2] Kountouras J, Zavos C, Chatzopoulos D, Katsinelos P. Helicobacter pylori and gastro-oesophageal reflux disease. Lancet 2006;368:986. [3] Kountouras J, Zavos C, Chatzopoulos D. Induction of interleukin-8 expression by Helicobacter pylori infection in patients with endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol 2004;99:2500–1. [4] Abdel-Latif MM, Windle H, Terres A, Eidhin DN, Kelleher D, Reynolds JV. Helicobacter pylori extract induces nuclear
1175 factor-kappa B, activator protein-1, and cyclooxygenase-2 in esophageal epithelial cells. J Gastrointest Surg 2006;10: 551–62. [5] Nakajima S, Hattori T. Oesophageal adenocarcinoma or gastric cancer with or without eradication of Helicobacter pylori infection in chronic atrophic gastritis patients: a hypothetical opinion from a systematic review. Aliment Pharmacol Ther 2004;20(Suppl. 1):54–61.
Jannis Kountouras * Dimitrios Chatzopoulos Christos Zavos Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, 8 Fanariou St, Byzantio, 551 33 Thessaloniki, Macedonia, Greece * Tel.: +30 2310 892238; fax: +30 2310 992794. E-mail address: [email protected] (J. Kountouras).
doi:10.1016/j.mehy.2006.11.020
Leflunomide as an antiatherogenic drug Dear Editor, Although several drugs so far have been successful in the prevention of atherosclerotic vascular disease, it has been recently pointed out that the burden of cardiovascular morbidity and mortality is not likely to change in the near future unless fundamentally new therapeutic tools are found [1]. At this regard we speculate that leflunomide (LEF), a disease-modifying antirheumatic drug which is widely used in patients with rheumatoid arthritis (RA) [2], could also ameliorate vascular function by affecting several crucial mechanisms involved in the vessel wall pathobiology. Firstly, it has been shown that LEF has the ability to inhibit the nuclear factor kappaB signal transduction pathway [3], which is deemed to be critical in the development of a proinflammatory and proatherosclerotic phenotype in endothelial cells [4]. In addition, it has been demonstrated that leflunomide may reduce the subendothelial migration of peripheral blood mononuclear cells – an important event in early atherogenesis – by decreasing the cell surface expression of intercellular adhesion
molecules [5]. Third, LEF may cause functional impairment of antigen-presenting dendritic cells [6], whose activation has been recently demonstrated at sites of vascular pathology [7]. Altogether, these data may lead to the hypothesis that LEF could exert important vasculoprotective effects. In keeping with our hypothesis, preliminary results obtained in RA patients indicated that LEF use was associated with a significantly reduced risk of developing myocardial infarction [8]. Since the molecular actions of LEF indicate that its vasculoprotective effects may be independent of its antirheumatic properties, clinical testing of this compound as a cardiovascular medication in the general population may be worthwhile. Does treatment with LEF reduce the risk of ischemic cardiac events in the general population, and is it similar to that observed in RA? Does treatment with LEF have any beneficial effect on markers of endothelial function – such as flow-mediated vasodilation – in people with cardiovascular diseases? Is the tolerability profile of LEF in the general population similar to that observed in RA? We believe that clinical trials would be useful to answer to these
1176 important clinical questions, with the specific aim to investigate if low-dose LEF (e.g. 5–10 mg daily) can be used for vascular prevention even in patients without RA.
References [1] Mucke HA. Cardiovascular and renal developments: patent highlights January to June 2006. Curr Opin Investig Drugs 2006;7:792–8. [2] Maddison P, Kiely P, Kirkham B, et al. Leflunomide in rheumatoid arthritis: recommendations through a process of consensus. Rheumatology (Oxford) 2005;44:280–6. [3] Feng H, Li XY, Zheng JR, et al. Inhibition of the nuclear factor-kappaB signaling pathway by leflunomide or triptolide also inhibits the anthralin-induced inflammatory response but does not affect keratinocyte growth inhibition. Biol Pharm Bull 2005;28:1597–602. [4] de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol 2005;25:904–14. [5] Grisar J, Aringer M, Koller MD, et al. Leflunomide inhibits transendothelial migration of peripheral blood mononuclear cells. Ann Rheum Dis 2004;63:1632–7.
Correspondence [6] Kirsch BM, Zeyda M, Stuhlmeier K, et al. The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function. Arthritis Res Ther 2005;7: R694–703. [7] Ranjit S, Dazhu L. Potential role of dendritic cells for progression of atherosclerotic lesions. Postgrad Med J 2006;82:573–5. [8] Suissa S, Bernatsky S, Hudson M. Antirheumatic drug use and the risk of acute myocardial infarction. Arthritis Rheum 2006;55:531–6.
Piercarlo Minoretti Anna Bruno Clara Di Vito Enzo Emanuele * Interdepartmental Center for Research in Molecular Medicine (CIRMC), University of Pavia, Viale Taramelli, 24, I-27100 Pavia, Italy * Tel.: +39 0382 528 341; fax: +39 0382 526 259. E-mail address: [email protected] (E. Emanuele).
doi:10.1016/j.mehy.2006.10.036
Are lung cancers triggered by stopping smoking? The clinically high correlation between smoking and carcinoma of the lungs has been the focal point in societal campaigns against the habit and the tobacco lobby. In an overview of personal history in a number of lung cancer patients locally, we are struck by the more than casual relationship between the appearance of lung cancer—and an abrupt and recent cessation of the smoking habit in many, if not most cases. The association is more than just casual-development of cancer within a few months of eschewing cigarette smoking. Over a period of 4 years, a total of 312 cases were treated for carcinoma of pulmonary origin: of this number, 182 patients had quit smoking within 5–15 months prior to their being diagnosed with lung cancer. Of the 182 patients 142 were male and 40 were females, with ages ranged between 47 and 74. Each one of had been addicted to the habit for no less than 25 years, smoking in excess of 20 sticks a day. The striking direct statistical correlation between cessation of smoking to the development of
lung malignancies, more than 60% plus, is too glaring to be dismissed as coincidental. It is our premise that a surge and spurt in re-activation of bodily healing and repair mechanisms of chronic smoke-damaged respiratory epithelia is induced and spurred by an abrupt discontinuation of habit, goes awry, triggering uncontrolled cell division and tumor genesis. In normal tissue healing, anabolic and catabolic processes achieve equilibrium approximately 6– 8 weeks after the original insult. When an imbalance occurs between these phases occur in the healing process, disruptions in repair limitations occur leading to tumor genesis—this sequence is best exemplified in the formation of keloids from scars [1]. Nicotine stimulates corticotrophin-releasing factor (CRF) besides increasing the level of adrenocorticotropic hormone (ACTH), both of which interfere with immune systems [2]. Abrupt withdrawal of the addictive drug could trigger derangement of the ‘smoking-steroid’ conferred immunity, priming the healing lung epithelia to dangerous levels uncontrolled cell division.