Benzbromarone

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Benzbromarone
Benzbromarone.svg
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
  • (3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-1-benzofuran-3-yl)methanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.020.573 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H12Br2O3
Molar mass 424.088 g·mol−1
3D model (JSmol)
Melting point 161 to 163 °C (322 to 325 °F)
  • Brc1cc(cc(Br)c1O)C(=O)c2c3ccccc3oc2CC
  • InChI=1S/C17H12Br2O3/c1-2-13-15(10-5-3-4-6-14(10)22-13)16(20)9-7-11(18)17(21)12(19)8-9/h3-8,21H,2H2,1H3 Yes check.svgY
  • Key:WHQCHUCQKNIQEC-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benzbromarone is a uricosuric agent and non-competitive inhibitor of xanthine oxidase [1] used in the treatment of gout, especially when allopurinol, a first-line treatment, fails or produces intolerable adverse effects. It is structurally related to the antiarrhythmic amiodarone. [2]

Contents

Benzbromarone is highly effective and well tolerated, [3] [4] [5] [6] and clinical trials as early as 1981 and in April 2008 have suggested it is superior to both allopurinol, a non-uricosuric xanthine oxidase inhibitor, and probenecid, another uricosuric drug. [7] [8]

Mechanism of action

Benzbromarone is a very potent inhibitor of CYP2C9. [2] [9] Several analogues of the drug have been developed as CYP2C9 and CYP2C19 inhibitors for use in research. [10] [11]

History

Benzbromarone was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Europe, Asia and South America.

In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. [12]

Related Research Articles

<span class="mw-page-title-main">Gout</span> Form of arthritis causing swollen joints

Gout is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crystals. Pain typically comes on rapidly, reaching maximal intensity in less than 12 hours. The joint at the base of the big toe is affected (Podagra) in about half of cases. It may also result in tophi, kidney stones, or kidney damage.

<span class="mw-page-title-main">Xanthine oxidase</span> Class of enzymes

Xanthine oxidase is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Hyperuricemia</span> Medical condition

Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 mg/dL for men, and 5.5 mg/dL for youth are defined as hyperuricemia. The amount of urate in the body depends on the balance between the amount of purines eaten in food, the amount of urate synthesised within the body, and the amount of urate that is excreted in urine or through the gastrointestinal tract. Hyperuricemia may be the result of increased production of uric acid, decreased excretion of uric acid, or both increased production and reduced excretion.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.

<span class="mw-page-title-main">Cimetidine</span> Medication

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.

<span class="mw-page-title-main">Doxepin</span> Medication to treat depressive disorder, anxiety disorders, chronic hives, and trouble sleeping

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. Drugs that reduce blood uric acid are not all uricosurics; blood uric acid can be reduced by other mechanisms.

<span class="mw-page-title-main">Probenecid</span> Chemical compound

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

<span class="mw-page-title-main">Febuxostat</span> Chemical compound

Febuxostat, sold under the brand names Uloric among others, is a medication used long-term to treat gout due to high uric acid levels. It is generally recommended only for people who cannot take allopurinol. When initially started, medications such as NSAIDs are often recommended to prevent gout flares. It is taken by mouth.

<span class="mw-page-title-main">Hyperuricosuria</span> Medical condition

Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia. Notable indirect causes include uricosuric drugs, rapid breakdown of bodily tissues containing large quantities of DNA and RNA, and a diet high in purine.

<span class="mw-page-title-main">Oxipurinol</span> Chemical compound

Oxipurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels. By inhibiting xanthine oxidase, it reduces uric acid production. High serum uric acid levels may result in gout, kidney stones, and other medical conditions.

<span class="mw-page-title-main">Tisopurine</span> Chemical compound

Tisopurine is a drug used in the treatment of gout in some countries. It reduces uric acid production through inhibiting an early stage in its production.

A xanthine oxidase inhibitor is any substance that inhibits the activity of xanthine oxidase, an enzyme involved in purine metabolism. In humans, inhibition of xanthine oxidase reduces the production of uric acid, and several medications that inhibit xanthine oxidase are indicated for treatment of hyperuricemia and related medical conditions including gout. Xanthine oxidase inhibitors are being investigated for management of reperfusion injury.

Tsai-Fan Yu was a Chinese-American physician, researcher, and the first woman to be appointed as a full professor at Mount Sinai School of Medicine. She helped to develop an explanation for the cause of gout and experimented with early drugs to treat the disease which are still in use today.

<span class="mw-page-title-main">Lesinurad</span> Pharmaceutical drug for the treatment of gout

Lesinurad is a urate transporter inhibitor for treating high blood uric acid levels associated with gout. It is recommended only as an adjuvant with either allopurinol or febuxostat when these medications are not sufficient.

<span class="mw-page-title-main">Nordoxepin</span> Active metabolite of antidepressant drug doxepin

Nordoxepin, also known as N-desmethyldoxepin, is an organic compound. A colorless solid, it attracted attention as the major active metabolite of the tricyclic antidepressant (TCA) doxepin (Sinequan). It has been found to play a significant role in the antidepressant effects of doxepin.

<span class="mw-page-title-main">Gout suppressants</span>

Gout suppressants are agents which control and prevent gout attacks after the first episode. They can be generally classified into two groups by their purpose: drugs used for induction therapy and that for maintenance therapy.

References

  1. Sinclair DS, Fox IH (December 1975). "The pharmacology of hypouricemic effect of benzbromarone". The Journal of Rheumatology. 2 (4): 437–45. PMID   1206675.
  2. 1 2 Kumar V, Locuson CW, Sham YY, Tracy TS (October 2006). "Amiodarone analog-dependent effects on CYP2C9-mediated metabolism and kinetic profiles". Drug Metabolism and Disposition. 34 (10): 1688–96. doi:10.1124/dmd.106.010678. PMID   16815961.
  3. Heel RC, Brogden RN, Speight TM, Avery GS (November 1977). "Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia". Drugs. 14 (5): 349–66. doi:10.2165/00003495-197714050-00002. PMID   338280. S2CID   8198915.
  4. Masbernard A, Giudicelli CP (May 1981). "Ten years' experience with benzbromarone in the management of gout and hyperuricaemia" (PDF). South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde. 59 (20): 701–6. PMID   7221794.
  5. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E (September 1998). "Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout". Annals of the Rheumatic Diseases. 57 (9): 545–9. doi:10.1136/ard.57.9.545. PMC   1752740 . PMID   9849314.
  6. Reinders MK, van Roon EN, Houtman PM, Brouwers JR, Jansen TL (September 2007). "Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients". Clinical Rheumatology. 26 (9): 1459–65. doi: 10.1007/s10067-006-0528-3 . PMID   17308859.
  7. Schepers GW (1981). "Benzbromarone therapy in hyperuricaemia; comparison with allopurinol and probenecid". The Journal of International Medical Research. 9 (6): 511–5. doi:10.1177/030006058100900615. PMID   7033016. S2CID   33337546.
  8. Reinders MK, van Roon EN, Jansen TL, Delsing J, Griep EN, Hoekstra M, et al. (January 2009). "Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol". Annals of the Rheumatic Diseases. 68 (1): 51–6. doi:10.1136/ard.2007.083071. PMID   18250112.
  9. Hummel MA, Locuson CW, Gannett PM, Rock DA, Mosher CM, Rettie AE, Tracy TS (September 2005). "CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variant". Molecular Pharmacology. 68 (3): 644–51. doi:10.1124/mol.105.013763. PMC   1552103 . PMID   15955872.
  10. Locuson CW, Rock DA, Jones JP (June 2004). "Quantitative binding models for CYP2C9 based on benzbromarone analogues". Biochemistry. 43 (22): 6948–58. CiteSeerX   10.1.1.127.2015 . doi:10.1021/bi049651o. PMID   15170332.
  11. Locuson CW, Suzuki H, Rettie AE, Jones JP (December 2004). "Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors". Journal of Medicinal Chemistry. 47 (27): 6768–76. doi:10.1021/jm049605m. PMID   15615526.
  12. Lee MH, Graham GG, Williams KM, Day RO (2008). "A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients?". Drug Safety. 31 (8): 643–65. doi:10.2165/00002018-200831080-00002. PMID   18636784. S2CID   1204662.