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Ann Acad Med Stetin. 2006;52 Suppl 2:5-10.
Tlustochowicz W.
Klinika Chorob Wewnetrznych i Reumatologii Wojskowego Instytutu Medycznego CSK MON w Warszawie ul. Szaserow 128, 00-909 Warszawa.
[Rational therapeutic approach in rheumatoid arthritis][Article in Polish]
The author summarises treatment approaches for rheumatoid arthritis. Usually, early treatment with an appropriate drug or
drug-combination can suppress the disease activity.
The natural course of rheumatoid arthritis inevitably leads to joint damage and reduced life expectancy. Therefore,
active treatment of rheumatoid arthritis is indispensable. Although the etiology still remains unknown resulting in
unsuccessful prophylaxis and incurability of rheumatoid arthritis, learning more about its pathophysiology broadens
the spectrum of therapeutic possibilities. The aim of treatment is remission of the disease. Current standards of
treatment are based on the idea to start aggressive treatment as early as possible to suppress the activity of the
disease. This can be achieved by pharmacotherapy and rehabilitation. Physiotherapy is supplementary but there is no
room for spa treatment or alternative therapies. Treatment should be introduced immediately because the "window"
for successful change in the natural course of the disease covers the first three months since onset. Diagnostic
difficulties during this period support the idea of "early arthritis" and "early rheumatoid arthritis".
Glycocorticosteroids at a dose suitable to suppress inflammation represent the first-line treatment. Basic therapy
which usually is synonymous for methotrexate 15-25 mg once weekly should be introduced from the 4th month at the
latest. In case of methotrexate intolerance, leflunomide is an alternative. Lack of efficacy of monotherapy with
these drugs mandates the combination therapy of methotrexate with leflunomide, cyclosporine or sulphasalazine
together with hydroxychlorochine. The use of two latter drugs should be limited due to their low efficacy. Patients
refractory to combination therapy should be considered as candidates to anticytokine drugs or to lymphocyte B
depleting drugs. However, it should be emphasized that their high efficacy is achieved only in combination with
full doses of methotrexate. The same rules should be applied to therapeutic decisions in elderly patients and in
patients with long history of rheumatoid arthritis. However, lower doses of the drugs should be used at initiation
of therapy. Contraindications related to side effects and concomitant diseases should be considered. In these
groups, glycocorticosteroids play a more important role and cyclophosphamide is used more frequently. Surgical
treatment should be reserved for patients with advanced disease. Total joint replacement is an effective method for
large joints. Synovectomy should be done only exceptionally when all options of pharmacotherapy were ineffective.
Hepatology. 2007 Feb;45(2):412-21.
Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA.
Department of Pharmacology, Yong Loo Lin School of Medicine, Singapore.
Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury.
The authors in an experimental study on mice were able to confirm previous test-tube results. They showed that
leflunomide can protect against liver-damage which can result from high doses of the painkiller acetaminophen.
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses but which
can precipitate liver injury at high doses. We have previously found that the antirheumatic drug leflunomide is a
potent inhibitor of APAP toxicity in cultured human hepatocytes, protecting them from mitochondria-mediated cell
death by inhibiting the mitochondrial permeability transition. The purpose of this study was to explore whether
leflunomide protects against APAP hepatotoxicity in vivo and to define the molecular pathways of cytoprotection.
Male C57BL/6 mice were treated with a hepatotoxic dose of APAP (750 mg/kg, ip) followed by a single injection of
leflunomide (30 mg/kg, ip). Leflunomide (4 hours after APAP dose) afforded significant protection from liver
necrosis as assessed by serum ALT activity and histopathology after 8 and 24 hours. The mechanism of protection by
leflunomide was not through inhibition of cytochrome P450 (CYP)-catalyzed APAP bioactivation or an apparent
suppression of the innate immune system. Instead, leflunomide inhibited APAP-induced activation (phosphorylation)
of c-jun NH2-terminal protein kinase (JNK), thus preventing downstream Bcl-2 and Bcl-XL inactivation and protecting
from mitochondrial permeabilization and cytochrome c release. Furthermore, leflunomide inhibited the APAP-mediated
increased expression of inducible nitric oxide synthase and prevented the formation of peroxynitrite, as judged
from the absence of hepatic nitrotyrosine adducts. Even when given 8 hours after APAP dose, leflunomide still
protected from massive liver necrosis. Conclusion: Leflunomide afforded protection against APAP-induced
hepatotoxicity in mice through inhibition of JNK-mediated activation of mitochondrial permeabilization.
Arzneimittelforschung. 2007;57(3):155-63.
DuMez D, Venkatachalam TK, Uckun FM.
Paradigm Pharmaceuticals, 2139 Fourth Street, White Bear Lake, MN 55110, USA.
Large-scale synthesis of GMP grade alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a new anti-cancer drug candidate.
The leflunomide (CAS 75706-12-6) metabolite (LFM) analog
alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2), is a
rationally designed inhibitor of the anti-apoptotic enzyme Bruton's tyrosine kinase (BTK). LFM-A13 is being
developed as a novel dual-function anticancer drug with apoptosis-promoting and anti-thrombotic properties. LFM-A13
was prepared under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms.
Ann Pharmacother. 2006 Oct;40(10):1804-13.
Wilhelm SM, Taylor JD, Osiecki LL, Kale-Pradhan PB.
Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA.
Novel therapies for Crohn's disease: focus on immunomodulators and antibiotics.
The authors review the results of previous studies involving treatment of Crohn's disease with a range of different
drugs. Some of these appear promising, especially for patients not responding to other treatments.
OBJECTIVE: To review the literature on novel immunomodulators such as tumor necrosis factor alpha (TNF-alpha)- and interleukin (IL)-related agents, 6-thioguanine (6-TG), tacrolimus, and leflunomide, and antibiotics such as ornidazole, rifaximin, and ciprofloxacin for the treatment of Crohn's disease. DATA SOURCES: Literature was accessed through MEDLINE (1966-January 2006) using the terms Crohn's disease, novel therapies, immunomodulators, and antibiotics. Article references were hand-searched for additional relevant articles and abstracts. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Studies including greater than 5 patients with primarily adult populations were included in the review. DATA SYNTHESIS: There are a number of new TNF-alpha and IL-related agents that may be useful for management of Crohn's disease. They include CDP 571, CDP 870, etanercept, onercept, thalidomide, IL-10, and IL-11. Several studies have shown that CDP 571 decreases the Crohn's Disease Activity Index score and is promising, especially in patients with refractory disease. 6-TG, tacrolimus, and leflunomide are among other immunomodulators that appear to have a role in refractory/severe disease. Finally, ornidazole, rifaximin, and ciprofloxacin are antimicrobials that may be used in patients who have failed other therapies or as adjunctive therapies. CONCLUSIONS: A number of new treatment modalities are being investigated for Crohn's disease. Many of them are promising, and some of these agents may be considered in treatment-refractory patients in the future. However, some of the agents reviewed here are not available in the US. Future studies need to be double-blinded and placebo- or other treatment-controlled in a more homogeneous patient population.
Transplantation. 2005 Jan 27;79(2):135-41; discussion 133-4.
Yan Y, Verbeken E, Yu L, Rutgeerts O, Goebels J, Segers C, Lin Y, Waer M.
Laboratory for Experimental Transplantation, University of Leuven, Herestraat 49, Leuven, B-3000, Belgium.
Effects of a short course of leflunomide on T-independent B-lymphocyte xenoreactivity and on susceptibility of xenografts to acute or chronic rejection.
Leflunomide was found to be effectve as an immunosuppressive agent in animals subjected to heart-transplants.
BACKGROUND: Leflunomide is a novel immunosuppressive agent with promising activity for xenotransplantation. It is not clear yet which mechanisms of action of leflunomide are responsible for that. METHODS: In a hamster-to-C57BL/6 nude mouse heart transplantation model, a 2-week course of leflunomide was used after transplantation or for pretreating donors. Nontolerant B lymphocytes were transferred to recipients after transplantation of first or second xenogeneic heart grafts that were transplanted with or without leflunomide treatment. RESULTS: Hamster xenogeneic hearts transplanted into athymic C57BL/6 nude mice receiving leflunomide did not induce immunoglobulin (Ig) M xenoantibodies (XAb) and survived without signs of chronic rejection. Second xenogeneic hearts transplanted 4 weeks after withdrawal of leflunomide survived without induction of XAb but developed chronic vascular lesions. After injection of naive B lymphocytes at 6 weeks after grafting a first or second hamster heart, only in the latter case were XAb induced. These were deposited in, and provoked acute rejection of, only the second grafts. Pretreatment of donors with leflunomide decreased the ex vivo xenoantibody deposition on the xenogeneic heart endothelia. CONCLUSIONS: A short posttransplant course of leflunomide induces T-independent B-lymphocyte xenotolerance. Leflunomide treatment also influences xenoantigen expression, as nontolerant B lymphocytes provoke IgM XAb formation and rejection of only second xenografts (transplanted without leflunomide) and not of first xenografts (transplanted with leflunomide treatment). The ex vivo experiments that show that XAb deposition is decreased in leflunomide-pretreated xenografts further confirm this. The latter may also explain the resistance of first and not second xenografts against chronic rejection.
Transplantation. 2005 Jan 15;79(1):116-8.
Farasati NA, Shapiro R, Vats A, Randhawa P.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Effect of leflunomide and cidofovir on replication of BK virus in an in vitro culture system.
BACKGROUND: Cidofovir and Leflunomide are used empirically in the treatment of BK virus nephropathy. The aim of this study is to quantify the antiviral activity of these drugs. METHODS: BK virus was grown in a cell-culture system. The rate of viral replication in the presence or absence of the drug being tested was assessed using a quantitative polymerase chain reaction assay. RESULTS: The inhibitory concentration, effective concentration, and selectivity index for Leflunomide are 39.7+/-6.9, 11.3+/-2.8, and 3.8+/-0.8 microg/mL, respectively. For Cidofovir, these indices were, respectively, 63.9+/-17.2, 36.3+/-11.7, and 2.3+/-0.8 microg/mL. CONCLUSIONS: The in vitro activity of Cidofovir and Leflunomide is modest, and the selectivity index is low. There is a need to develop more effective and less toxic anti-BK virus drugs for clinical use.
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