Бексаротен

Описание

Bexarotene was launched in the US for the treatment of manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. The four step synthesis of bexarotene involves a double Friedel-Craft alkylation of toluene with 2,5-dichloro-2,5-dimethylhexane followed by acylation with monomethylterephthalic acid chloride, then Wittig methylidenation. Bexarotene is the first retinoid X receptor (RXR) agonist to be selective versus retinoid A receptors (RAR). Its activation of the three RXRα, β, γ isoforms induces cell differentiation and apoptosis and inhibits cell proliferation in several models of cancer. In phase ll/lll clinical trials, 48% of patients with refractory or persistent early-stage cutaneous T-cell lymphoma achieved a complete or partial response when treated with 300 mg/m2/day of bexarotene. It was shown in phase I trials that this second-generation retinoid was substantially less toxic than the broad-spectrum or RARselective retinoids.

Химические свойства

White Solid

Использование

Bexarotene is used as a Synthetic retinoid analog with specific affinity for the retinoid X receptor, an antineoplastic agent, already approved as an oral antineoplastic agent for cutaneous T cell lymphoma and being investigated against other cancers. A study has found that bexarotene in a mouse Alzheimer?s model lowered the most toxic form of β-amyloid peptide and increased cognitive ability.

Показания

Bexarotene (Targretin) belongs to a subclass of retinoids that selectively bind to and activates retinoid X receptors (RXRs), which have biological properties distinct from those of RARs. In vitro, bexarotene exerts antiproliferative effects on some tumor lines of hematopoietic and squamous cell origin.

Общее описание

Bexarotene is available in 75-mg capsules for oral administrationin the treatment of refractory cutaneous T-cell lymphoma.The agent is also available as a gel that may be usedtopically. The mechanism of action has not been fully establishedbut is thought to involve binding to retinoid receptorsresulting ultimately in the formation of transcription factorsthat promote cell differentiation and regulate cellular proliferation.168 Bexarotene has been demonstrated to activateapoptosis as a result of stimulation of caspase 3 and inhibitionof survivin, an antiapoptotic protein that would normallyinhibit caspase activity.Apoptosis is also stimulatedbecause of cleavage of poly(ADP-Ribose) polymerase,which is antiapoptotic. Reduced expression of the retinoidreceptor subtypes RXR and RAR has also been demonstratedfor the agent. Absorption is nearly complete afteroral administration and plasma protein binding is high(＜99%).There is extensive metabolism in the liver togive 6- and 7-hydroxy-bexarotene and 6- and 7-oxobexaroteneas well as glucuronides of these metabolites andthe parent. Elimination occurs via the feces with an eliminationhalf-life of 7 hours. Adverse effects include hypercholesterolemia,hypertriglyceridemia, hypothyroidism, myelosuppression,nausea, and skin rash.

Фармаколо?гия

Bexarotene is available in oral and topical formulations. Peak plasma levels are achieved within 2 hours of oral administration, although higher levels are obtained when the drug is ingested with a fatty meal. It is thought to be metabolized primarily by the hepatobiliary system, with a terminal half-life of approximately 7 hours. Topical and oral bexarotene are approved for earlystage (patch and plaque) cutaneous T-cell lymphoma that is refractory to at least one other therapy. Oral bexarotene is also approved for refractory cases of advanced disease; however, the best response has been noted in early disease. Local irritation, such as burning, pruritus, and irritant contact dermatitis, is common following topical application.

Побочные эффекты

Major side effects seen after systemic administration include dyslipidemia, leukopenia, liver function test abnormalities, and possibly development of cataracts. Unlike other systemic retinoids, oral bexarotene causes thyroid abnormalities in approximately half of patients, which may necessitate treatment for hypothyroidism. Bexarotene is teratogenic and should not be prescribed in topical or oral form to women of childbearing potential unless a negative serum pregnancy test has been obtained and the patient agrees in writing to use two effective forms of contraception from 1 month before to 1 month after treatment.