Bexarotene

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Bexarotene
Bexarotene2DACS.svg
Bexarotene3Dan.gif
Systematic (IUPAC) name
4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid
Clinical data
Trade names Targretin
AHFS/Drugs.com monograph
MedlinePlus a608006
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral and topical
Pharmacokinetic data
Protein binding >99%
Metabolism Hepatic (CYP3A4-mediated)
Half-life 7 hours
Excretion Parent drug and metabolites are eliminated primarily through the hepatobiliary system. Less than 1% is excreted in the urine unchanged.
Identifiers
CAS number 153559-49-0 YesY
ATC code L01XX25
PubChem CID 82146
IUPHAR ligand 2807
DrugBank DB00307
ChemSpider 74139 YesY
UNII A61RXM4375 YesY
ChEBI CHEBI:50859 YesY
ChEMBL CHEMBL1023 YesY
Chemical data
Formula C24H28O2 
Mol. mass 348.478 g/mol
 YesY (what is this?)  (verify)

Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent indicated 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).[1]

Medical uses[edit]

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).[2]

It has been used off-label for non-small cell lung cancer[3] and breast cancer.[4]

Alzheimer's disease[edit]

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.[5][6] 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.[7] 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.[8] 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.[9]

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.[10][11][12][13][14]

Adverse effects[edit]

Adverse effects by incidence[2][15][16]
Very common (>10% frequency):

Common (1-10% frequency):

  • Lymphoma Like Reaction
  • Lymphadenopathy
  • Hypochromic anaemia
  • Thyroid disorder
  • Weight Gain
  • SGOT Increased
  • SGPT Increased
  • Lactic Dehydrogenase Increased
  • Elevated serum creatinine
  • Hypoproteinaemia
  • Dizziness
  • Hypesthesia
  • Insomnia
  • Dry Eyes
  • Eye Disorder
  • Deafness
  • Peripheral oedema
  • Vomiting
  • Diarrhoea
  • Nausea
  • Anorexia
  • Abnormal LFTs
  • Cheilitis
  • Dry Mouth
  • Constipation
  • Flatulence
  • Skin Ulcer
  • Alopecia (hair loss)
  • Skin Hypertrophy
  • Skin Nodule
  • Acne
  • Sweating
  • Dry Skin
  • Skin Disorder
  • Bone Pain
  • Arthralgia (joint pain)
  • Myalgia (muscle aches)
  • Allergic reaction
  • Infection
  • Chills
  • Abdominal pain
  • Hormone Level Altered

Uncommon (0.1-1% frequency):

  • Blood Dyscrasia
  • Purpura
  • Coagulation Disorder
  • Coagulation Time Increased
  • Anaemia
  • Thrombocytopenia
  • Thrombocythaemia
  • Eosinophilia
  • Leukocytosis
  • Lymphocytosis
  • Hyperthyroidism (overactive thyroid)
  • Gout
  • Bilirubinaemia
  • Elevated BUN
  • HDL decreased
  • Ataxia
  • Neuropathy
  • Vertigo
  • Hyperaesthesia
  • Depression
  • Agitation
  • Cataract
  • Amblyopia
  • Visual Field Defect
  • Corneal Lesion
  • Abnormal Vision
  • Blepharitis
  • Conjunctivitis
  • Ear disorder
  • Tachycardia
  • Haemorrhage
  • Hypertension
  • Oedema
  • Vasodilatation
  • Varicose Vein
  • Pancreatitis
  • Hepatic Failure
  • Gastrointestinal disorder
  • Serous Drainage
  • Herpes Simplex
  • Pustular Rash
  • Skin discolouration
  • Hair disorder
  • Nail disorder
  • Myasthaenia
  • Albuminuria
  • Kidney function, abnormal
  • Fever
  • Cellulitis
  • Parasitic infection
  • Mucous Membrane Disorder
  • Back Pain
  • Lab test, abnormal


Summary:
Overall the most common adverse effects are skin reactions (mostly itchiness and rashes), leucopenia, headache, weakness, thyroid anomalies (which seems to be mediated by RXR-mediated downregulation of thyroid stimulating hormone) and blood lipid anomalies such as hypercholesterolaemia (high blood cholesterol) and hyperlipidaemia.[17]

Contraindications[edit]

Known contraindications include:[16]

  • 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

Interactions[edit]

It may have its plasma concentrations increased by concomitant treatment with CYP3A4 inhibitors like ketoconazole.[16] It may also induce CYP3A4 and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced.[16] Likewise consumption of grapefruit juice might reduce bexarotene's plasma concentrations, hence potentially also mitigating its therapeutic effects.[16]

Mechanism[edit]

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).[15][18][19] By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance.[20] It also has anti-angiogenic effects and inhibits cancer metastasis.[20] The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis.[21]

Physical properties[edit]

Bexarotene is a solid, white powder. It is poorly soluble in water; the solubility is estimated to be about 10-50 µM. It is soluble in DMSO at 65 mg/mL and in ethanol at 10 mg/mL with warming.[22]

History[edit]

SRI International and the La Jolla Cancer Research Foundation (now the Sanford-Burnham Medical Research Institute) collaborated on work that resulted in patent filings for the drug.[23]

The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999.[24] The FDA approved bexarotene on the 29th December 1999.[25]

Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006.[24] The FDA approved the drug in 1999. Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006.[24] In the United States, patents on the drug expire in 2016.[24]

It received EMA approval on the 29th of March 2001.[26]

Synthesis[edit]

Bexarotene can be synthesized from pentamethyltetralin.[27] The retinoid-like compound bexarotene (5) is approved for treating skin lesions associated with T-cell lymphomas.

Bexarotene synthesis: Ligand Pharmaceuticals Inc. U.S. Patent 5,780,676 (1998).

The starting tetralin (1) is probably obtained by alkylation of toluene with dichloride (see under Tamibarotene). Friedel–Crafts acylation with the acid chloride (2), gives the ketone (3). This intermediate is then treated with the ylide from triphenylmethylphosphonium bromide. The carbonyl oxygen in the product (4) is now replaced by a methylene group. Saponification of the ester affords the free acid and thus (5).

References[edit]

  1. ^ Gniadecki, R; Assaf, C; Bagot, M; Dummer, R; Duvic, M; Knobler, R; Ranki, A; Schwandt, P; Whittaker, S (2007). "The optimal use of bexarotene in cutaneous T-cell lymphoma". British Journal of Dermatology 157 (3): 433–40. doi:10.1111/j.1365-2133.2007.07975.x. PMID 17553039. 
  2. ^ a b "TARGRETIN (BEXAROTENE) CAPSULE [CARDINAL HEALTH]". DailyMed. Cardinal Health. March 2006. Retrieved 12 January 2014. 
  3. ^ Dragnev, KH; Petty, WJ; Shah, SJ; Lewis, LD; Black, CC; Memoli, V; Nugent, WC; Hermann, T; Negro-Vilar, A; Rigas, JR; Dmitrovsky, E (2007). "A proof-of-principle clinical trial of bexarotene in patients with non-small cell lung cancer" (PDF). Clinical Cancer Research 13 (6): 1794–800. doi:10.1158/1078-0432.CCR-06-1836. PMID 17363535. 
  4. ^ Esteva, FJ; Glaspy, J; Baidas, S; Laufman, L; Hutchins, L; Dickler, M; Tripathy, D; Cohen, R; DeMichele, A; Yocum, RC; Osborne, CK; Hayes, DF; Hortobagyi, GN; Winer, E; Demetri, GD (March 2003). "Multicenter Phase II Study of Oral Bexarotene for Patients With Metastatic Breast Cancer" (PDF). Journal of Clinical Oncology 21 (6): 999–1006. doi:10.1200/JCO.2003.05.068. PMID 12637463. 
  5. ^ Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L. et al. (2012). "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models". Science 335 (6075): 1503–1506. doi:10.1126/science.1217697. PMC 3651582. PMID 22323736. 
  6. ^ MedicalXpress (9 February 2012). "FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer's symptoms in mice". MedicalXpress. Retrieved 14 February 2012. 
  7. ^ Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (9 February 2012). "ApoE-directed therapeutics rapidly clear β‑amyloid and reverse deficits in AD mouse models" (epub ahead of print). Science Express 335 (6075): 1503–6. doi:10.1126/science.1217697. PMC 3651582. PMID 22323736. 
  8. ^ Jaslow, Ryan (10 February 2012). "Cancer drug reverses Alzheimer's disease in mice: Hope for humans?". CBS News. Retrieved 10 February 2012. 
  9. ^ Shirley S. Wang (11 February 2012). "Alzheimer's Families Clamor for Drug". The Wall Street Journal. Retrieved 11 February 2012. 
  10. ^ Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924. doi:10.1126/science.1235809. 
  11. ^ Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt, D. R.; Golde, T. E.; Felsenstein, K. M. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924. doi:10.1126/science.1234089. 
  12. ^ Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D. et al. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924. doi:10.1126/science.1233937. 
  13. ^ Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M. et al. (2013). "Comment on "ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models"". Science 340 (6135): 924. doi:10.1126/science.1235505. 
  14. ^ "Anti-Cancer Drug Reverses Alzheimer's Disease In Mice". Medical News Today. 25 May 2013. 
  15. ^ a b "Targretin (bexarotene) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 31 January 2014. 
  16. ^ a b c d e "Targretin Capsules - Summary of Product Characteristics". electronic Medicines Compendium. Eisai Ltd. 4 April 2013. Retrieved 14 January 2014. 
  17. ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.  edit
  18. ^ Rowe, A (February 1997). "Retinoid X receptors". The International Journal of Biochemistry & Cell Biology 29 (2): 275–278. doi:10.1016/S1357-2725(96)00101-X. PMID 9147128.  edit
  19. ^ Dawson, M. I.; Xia, Z. (2012). "The retinoid X receptors and their ligands". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821 (1): 21–56. doi:10.1016/j.bbalip.2011.09.014. PMID 22020178.  edit
  20. ^ a b Qu, L; Tang, X (January 2010). "Bexarotene: a promising anticancer agent". Cancer Chemotherapy Pharmacology 65 (2): 201–205. doi:10.1007/s00280-009-1140-4. PMID 19777233. 
  21. ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.  edit
  22. ^ "Bexarotene MSDS". LC Labs. 
  23. ^ "Lymphoma Treatment: Targretin® (bexarotene)". Timeline of Innovation. SRI International. Retrieved 2013-09-20. 
  24. ^ a b c d Vinluan, Frank (2011-10-12). "Generic cancer drug from Banner aims to take on Eisai's Targretin". MedCity News. Retrieved 2012-02-11. 
  25. ^ "Bexarotene". Drugs.com. Retrieved 12 January 2014. 
  26. ^ "Targretin : EPAR - Product Information" (PDF). European Medicines Agency. Eisai Ltd. 3 April 2013. Retrieved 12 January 2014. 
  27. ^ M. F. Boehm, R. A. Heyman, L. Zhi, C. K. Hwang, S. White, A. Nadzan, U.S. Patent 5,780,676 (1998)