|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Oral and topical|
|Excretion||Parent drug and metabolites are eliminated primarily through the hepatobiliary system. Less than 1% is excreted in the urine unchanged.|
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Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent approved by the U.S.Food and Drug Administration (FDA) (in late 1999) and the European Medicines Agency (EMA) (early 2001) for use as a treatment for cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid.
Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical).
In 2012, researchers reported that bexarotene reduced amyloid plaque and improved mental functioning in a small sample of mice engineered to exhibit Alzheimer's-like symptoms. Three different mouse models (APP/PS1, APPPS1-21, Tg2576) were used. It is thought that bexarotene stimulates expression of apolipoprotein E (ApoE), which leads to intracellular clearance of β-amyloid. The authors of the research article said, "We've fixed Alzheimer's in mice lots of times, so we need to move forward expeditiously but cautiously", and expect to start a safety study with healthy human subjects by February 2013. The chief executive of the Alzheimer's Foundation of America said that people desperate to find a treatment for Alzheimer's should not take matters into "their own hands" or rush to take the medication.
In 2013, several research groups reported on their attempts to reproduce these findings. The results were mixed: none of the studies found a reduction in amyloid plaques, but several of the studies found that soluble forms of β-amyloid were reduced.
Known contraindications include:
- Hypersensitivity to the active substance or to any of the excipients in the preparation(s).
- Pregnancy and lactation
- Women of child-bearing potential without effective birth-control measures
- History of pancreatitis
- Uncontrolled hypercholesterolaemia
- Uncontrolled hypertriglyceridaemia
- Hypervitaminosis A
- Uncontrolled thyroid disease
- Hepatic insufficiency
- Ongoing systemic infection
Overall the most common adverse effects are skin reactions (mostly itchiness and rashes), leucopenia, headache, weakness, thyroid anomalies (which seem to be mediated by RXR-mediated downregulation of thyroid stimulating hormone) and blood lipid anomalies such as hypercholesterolaemia (high blood cholesterol) and hyperlipidaemia.
Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole. It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced. Likewise consumption of grapefruit juice might reduce bexarotene's plasma concentrations, hence potentially also mitigating its therapeutic effects.
Bexarotene is a retinoid that selectively activates retinoid X receptors (RXRs), as opposed to the retinoic acid receptors, the other major target of retinoic acid (the acid form of vitamin A). By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance. It also has anti-angiogenic effects and inhibits cancer metastasis. The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis.
The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999. The FDA approved bexarotene on the 29th December 1999.
It received EMA approval on the 29th of March 2001.
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