Clofazimine

From Infogalactic: the planetary knowledge core
Jump to: navigation, search
Clofazimine
Structural formula of clofazimine
Space-filling model of the clofazimine molecule
Systematic (IUPAC) name
N,5-bis(4-chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine
Clinical data
Trade names Lamprene
AHFS/Drugs.com monograph
MedlinePlus a682128
Pharmacokinetic data
Biological half-life 70 days
Identifiers
CAS Number 2030-63-9 YesY
ATC code J04BA01 (WHO)
PubChem CID: 2794
DrugBank DB00845 YesY
ChemSpider 21159573 N
UNII D959AE5USF YesY
KEGG D00278 YesY
ChEMBL CHEMBL1292 YesY
Synonyms N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine
Chemical data
Formula C27H22Cl2N4
Molecular mass 473.396 g/mol
  • CC(C)/N=c/1\cc-2n(c3ccccc3nc2cc1Nc4ccc(cc4)Cl)c5ccc(cc5)Cl
  • InChI=1S/C27H22Cl2N4/c1-17(2)30-24-16-27-25(15-23(24)31-20-11-7-18(28)8-12-20)32-22-5-3-4-6-26(22)33(27)21-13-9-19(29)10-14-21/h3-17,31H,1-2H3 N
  • Key:WDQPAMHFFCXSNU-UHFFFAOYSA-N N
 NYesY (what is this?)  (verify)

Clofazimine is a fat-soluble iminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy (MDT) for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and Mycobacterium avium paratuberculosis infection in Crohn's disease patients. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema nodosum leprosum (ENL). (From AMA Drug Evaluations Annual, 1993, p1619). The drug is given as an alternative to patients who can not tolerate the effects of dapsone for tuberculosis.[1]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Side effects

Clofazimine produces pink to brownish skin pigmentation in 75-100% of patients within a few weeks, as well as similar discoloration of most bodily fluids and secretions. These discolorations are reversible but may take months to years to disappear. There is evidence in medical literature that as a result of clofazimine administration, several patients have developed depression which in some cases resulted in suicide. It has been hypothesized that the depression was a result of this chronic skin discoloration.[3]

Cases of icthyosis and skin dryness are also reported in response to this drug (8%-28%), as well as rash and pruritis (1-5%).

40-50% of patients develop gastrointestinal intolerance. Rarely, patients have died from bowel obstructions and intestinal bleeding, or required abdominal surgery to correct the same problem.

Mechanism

Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation.[4][5] It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids,[4][5] which are toxic and inhibit bacterial proliferation.[6][7]

Clofazimine is also a FIASMA (functional inhibitor of acid sphingomyelinase).[8]

Supply

Clofazimine is marketed under the trade name Lamprene by Novartis. One of the world's only producers of the clofazimine molecule is Sangrose Laboratories, located in Mavelikara, India.

Metabolism

Clofazimine has a biological half life of about 70 days. Autopsies performed on those who have died while on clofazimine show crystal-like aggregates in the intestinal mucosa, liver, spleen, and lymph nodes.[9]

Immunosuppressive effects

The immunosuppressive effects of clofazimine were immediately noticed when applied in animal model. Macrophages were first reported to be inhibited due to the stabilization of lysosomal membrane by clofazimine.[10] Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation,[11] mitogen-induced PBMC proliferation[12] and complement-mediated solubilization of pre-formed immune complexes in vitro.[13] A mechanistic studying of clofazimine in human T cells revealed that this drug is a Kv1.3 (KCNA3) channel blocker.[14] This indicates that clofazimine will be potentially used for treatment of multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Because the Kv1.3-high effector memory T cells (TEM) are actively involved in the development of these diseases,[15] and Kv1.3 activity is essential for stimulation and proliferation of TEM by regulating calcium influx in the T cells.[16] Several clinical trials were also conducted looking for its immunosuppressive activity even before it was approved for leprosy by FDA. It was first reported to be effective in treating chronic discoid lupus erythematosus with 17 out of 26 patients got remission.[17] But later another group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus.[18] Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis,[19] Miescher’s granulomatous cheilitis,[20] Crohn’s disease and ulcerative colitis.[21] A recent clinical study of clofazimine was done in post-bone marrow transplantation patients[22] with over 50% of them having skin involvement, flexion contractures or oral manifestations achieved complete or partial responses. 7 out of 22 patients were able to reduce other immunosuppressants such as cyclosporine A.

History

Clofazimine, initially known as B663, was first synthesised in 1954 by a team with the scientists J.G. Belton, M.L. Conalty, Seán O'Sullivan and Dermot Twomey led by Dr Vincent Barry, from Sunday's Well in Cork at Trinity College, Dublin as an anti-tuberculosis drug. The drug proved ineffective against tuberculosis but in 1959 a researcher named Y. T. Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, the Swiss pharmaceutical company Novartis launched the product in 1969 under the brand name Lamprene.

Novartis was granted FDA approval of clofazimine in December of 1986 as an orphan drug. The drug is currently no longer available in the United States.[23]

References

  1. ↑ Clinical Microbiology Made Ridiculously Simple
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Dennis, E. A. 1983. Phospholipases, p. 307-353. In P. D. Boyer (ed.), The enzymes, 3rd ed., vol. 16. Lipid enzymology. Academic Press, Inc., New York.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ http://reference.medscape.com/drug/clofazimine-342661

External links

Retrieved from "https://infogalactic.com/w/index.php?title=Clofazimine&oldid=2481720"