Indication: For the treatment of active rheumatoid arthritis (RA)
Pharmacology: Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7 - to 8 -fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide’s inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.
Mechanism Of Action: Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Specifically Leflunomide blocks the de novo synthesis of pyrimidines, thus preventing the proliferation of activated T cells. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 which is responsible for essentially all of its activity in vivo
Absorption: Well absorbed, peak plasma concentrations appear 6-12 hours after dosing
Interactions:
DrugBank: Interactions for Leflunomide
Interactions for Leflunomide:
Cholestyramine and Charcoal
Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid
and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration .
Hepatotoxic Drugs
Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to
be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small
(n=30) combination study of ARAVA with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30
patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A
>3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and
3 after discontinuation of leflunomide. Three patients met "ACR criteria" for liver biopsy (1: Roegnik Grade I, 2:
Roegnik Grade IIIa). No pharmacokinetic interaction was identified.
NSAIDs
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of diclofenac
and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however,
there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.
Tolbutamide
In in vitro studies, M1 was shown to cause increases ranging from 13 - 50% in the free fraction of tolbutamide
at concentrations in the clinical range. The clinical significance of this finding is unknown.
Rifampin
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1
peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA
levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both
ARAVA and rifampin.
Warfarin
Increased INR (International Normalized Ratio) when ARAVA and warfarin were co-administered has been rarely
reported.
Chemical IUPAC Name: 5-methyl-N-[4-(trifluoromethyl)phenyl]-oxazole-4-carboxamide
Chemical Formula: C12H9F3N2O2
Half Life: 2 weeks
Drug Type: Approved Drug
# Accession No: APRD00205
CAS Registry Number: 75706-12-6
Leflunomide News (When available)
A passage to the Holy Land (1)15 Jan 2006 Nigeria Daily Independent, Leaving Eilat to the north the following day, through the Arava (plain of Jordan) and along the shores of the Dead Sea, we passed Sodom and Gomorrah by the ...
Dr. Alon Tal Awarded the Bronfman Prize15 Jan 2006 Israel Ministry of the Environment, Ten years ago, he founded the Arava Institute of Environmental Studies at Kibbutz Ketura in Israel's south, a multidisciplinary program in which Israeli ...
Israeli-Palestinian jv bearing fruit15 Jan 2006 Freshinfo, Adafresh, which is managed by Avi Kadan, who founded Arava Growers some eight years ago, specialises in exporting fresh produce to Europe and the North ...
Nature’s attorneyJan 12, 2006 Globes, ...his doctorate in political science and the environment there, and returned to Israel with his wife in 1990, settling on Kibbutz Ketura in the Arava region. ...
Three people killed in traffic accidents in south of countryJan 14, 2006 Ha'aretz (subscription), In an accident on the Arava Highway two youngsters were killed and another person was lightly hurt after a minibus and car collided some 80 kilometers north of ...
3 killed, including a child, in two car accidentsJan 14, 2006 Jerusalem Post, Two youths were killed in a traffic accident between a private car and a minivan on Saturday near Ketora Junction along the Arava Road in the Negev. ...
The Charles Bronfman Prize Awards $100,000 to Dr. Alon Tal ...Jan 11, 2006 Emediawire (press release), The Charles Bronfman Prize, a $100,000 humanitarian award, named Dr. Alon Tal, Founder and Director of Research for the Arava Institute for Environmental ...
An Israeli perspectiveJan 1, 2006 Israel 21C, ...cycle events I recently attended. Roi's family is living for two years on Kibbutz Ketura in the Arava Desert. For his bar mitzvah ...
Israeli environmentalist Alon Tal won the $100,000 Charles ...Jan 3, 2006 Jewish Telegraphic Agency, Tal, 45, who immigrated to Israel from the United States, founded the Arava Institute for Environmental Studies and the Israel Union for Environmental Defense. ...
Soldiers with Pneumonia Still in Serious ConditionJan 1, 2006 Arutz Sheva, ...(IsraelNN.com) Two soldiers who contracted a severe form of pneumonia at the Tsukei Ovda military base in the Arava are still in serious condition. ...
Southern observations - Late December 2005Dec 26, 2005 Kibbutz Lotan Center for Birdwatching, In the southern Arava clouds covered the sky and temperatures stayed in the low teens throughout the days. I spent some time birding ...
Menorah on the MountainDec 29, 2005 The Jewish Journal of greater L.A, The view from the top of the cliff is stunning, particularly at sunset, when the red mountains of Jordan on the opposite side of the Arava Valley turn radiant ...
Dr. Alon Tal awarded Bronfman PrizeJan 9, 2006 Globes, ...organization. In 1996 he founded the Arava Institute, where he served as director and more recently as director of research. Tal ...
The flood channelJan 1, 2006 Ynetnews, The best observation points in the Faran River area are the bridge south of the Moshav Faran in the Arava desert (route 90), or on route 40 between Mitzpe ...
A Look at the ForecastDec 27, 2005 Arutz Sheva, ...(IsraelNN.com) Tuesday night’s forecast calls for a risk of frost in the Negev and Arava. Wednesday calls for fair skies with ...
VMC: Uproar over meagre funds to divisionsDec 30, 2005 Newindpress, Even some Congress corporators like, Venkata Satyanarayana (Arava Satyam) too expressed their displeasure over the meagre allocations to their divisions. ...
Peres: “Jerusalem will remain the united capital of Israel�Dec 17, 2005 International Middle East Media Center, Solana will also discuss Europe’s willingness to advance the Israeli-Jordanian economic partnership in the Dead Sea and Arava regions. ...
Bicycling for peace in the Middle EastDec 18, 2005 San Mateo County Times, The ride will raise scholarship money for the Arava Institute for Environmental Studies in Israel, which brings Christian, Jewish and Muslim students and ...
Whiny Whistleblower of the Year AwardDec 30, 2005 American Council on Science and Health, ...bans. Graham has made a career out of calling for the banning of drugs, including Accutane, Arava, Meridia, Serevent, and Bextra. ...
Breakthrough in protection of e-PassportsDec 24, 2005 I-Newswire.com (press release) The company was founded in 1993 in Israel and is located in Rotem Industrial Park, Arava. For more than 10 years, MicroTag TEMED Ltd. ...
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