Chemistry:Clofazimine

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Short description: Medication
Clofazimine
Structural formula of clofazimine
Space-filling model of the clofazimine molecule
Clinical data
Trade namesLamprene
Other namesN,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine
AHFS/Drugs.comMonograph
MedlinePlusa682128
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life70 days
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC27H22Cl2N4
Molar mass473.396 g·mol−1
3D model (JSmol)
Melting point210 to 212 °C (410 to 414 °F)
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Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy.[1] It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum.[2] Evidence is insufficient to support its use in other conditions[1] though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol,[3] as well as the drugs amikacin and clarithromycin.[4] However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration.[5] It is taken orally.[1]

Common side effects include abdominal pain, diarrhea, itchiness, dry skin, and change in skin color.[1] It can also cause swelling of the lining of the gastrointestinal tract, increased blood sugar, and sensitivity to the sun.[2] It is unclear if use during pregnancy is safe.[1] Clofazimine is a phenazine dye and is believed to work by interfering with DNA.[1]

Clofazimine was discovered in the 1950s at Trinity College, Dublin,[6] and approved for medical use in the United States in 1986.[1] It is on the World Health Organization's List of Essential Medicines.[7] In the United States it is not available commercially but can be obtained from the US Department of Health and Human Services.[1]

Medical uses

The primary use of clofazimine is for the treatment of leprosy.[1] Other uses have not been proven to be safe or effective.[1]

It has been studied in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in people with HIV/AIDS and Mycobacterium avium paratuberculosis. 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 people who can not tolerate the effects of dapsone for leprosy.[8]

Early research suggested clofazimine inhibits the replication of SARS-CoV-2 in vitro and reduce viral load and inflammation in the lung in animal models [9]

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.[10]

Cases of icthyosis and skin dryness are also reported in response to this drug (8%-28%), as well as rash and itchiness (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.[11][12] It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids,[11][12] which are toxic and inhibit bacterial proliferation.[13][14]

Clofazimine is also a FIASMA (functional inhibitor of acid sphingomyelinase).[15]

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.[16]

History

Clofazimine, initially known as B663, was first synthesised in 1954 by a team of scientists at Trinity College, Dublin: Frank Winder, J.G. Belton, Stanley McElhinney, M.L. Conalty, Seán O'Sullivan, and Dermot Twomey, led by Vincent Barry. Clofazimine was originally intended as an anti-tuberculosis drug but proved ineffective. In 1959, a researcher named Y. T. Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, Swiss pharmaceutical company Novartis launched the product in 1969 under the brand name Lamprene.[citation needed]

Novartis was granted FDA approval of clofazimine in December 1986 as an orphan drug. The drug is currently no longer commercially available in the United States as Novartis has discontinued production of clofazimine for the US market and no generic or other brand names are marketed in the US although it retains FDA approval.[17]

Society and culture

Clofazimine is marketed under the trade name Lamprene by Novartis although its discontinued in some countries like the US. Other brands are also available in many countries. Another producer of the clofazimine molecule is Sangrose Laboratories, located in Mavelikara, India .[citation needed]

Research

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.[18] Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation,[19] mitogen-induced PBMC proliferation[20] and complement-mediated solubilization of pre-formed immune complexes in vitro.[21] A mechanistic studying of clofazimine in human T cells revealed that this drug is a Kv1.3 (KCNA3) channel blocker.[22] 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,[23] and Kv1.3 activity is essential for stimulation and proliferation of TEM by regulating calcium influx in the T cells.[24] 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.[25] But later another group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus.[26] Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis,[27] Miescher's granulomatous cheilitis.[28]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Clofazimine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/clofazimine.html. 
  2. ↑ 2.0 2.1 WHO Model Formulary 2008. World Health Organization. 2009. p. 132. ISBN 9789241547659. 
  3. ↑ "Long-term Follow-up of Mycobacterium avium Complex Lung Disease in Patients Treated With Regimens Including Clofazimine and/or Rifampin". Chest 149 (5): 1285–1293. May 2016. doi:10.1378/chest.15-0543. PMID 26513209. 
  4. ↑ "Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin". https://aac.asm.org/content/60/2/1097. 
  5. ↑ "Clofazimine in the Treatment of Pulmonary Mycobacterium Avium Complex (MAC) | Clinical Research Trial Listing ( Mycobacterium avium Complex | MAC Infection (Mycobacterium Avium Complex) | Mycobacterium avium-intracellulare Infection ) ( NCT02968212 )". https://www.centerwatch.com/clinical-trials/listings/185340/clofazimine-in-the-treatment-of-pulmonary-mycobacterium-avium-complex-mac/. 
  6. ↑ (in en) Antimicrobial Drugs: Chronicle of a Twentieth Century Medical Triumph. OUP Oxford. 2008. p. 200. ISBN 9780199534845. https://books.google.com/books?id=i4_FZHmzjzwC&pg=PA200. "By 1954 related molecules known as iminophenazines were being investigated... one of the first ones to be made, originally given the laboratory code B663 ... B663—subsequently called clofazimine" 
  7. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  8. ↑ Clinical Microbiology Made Ridiculously Simple
  9. ↑ "Clofazimine broadly inhibits coronaviruses including SARS-CoV-2". Nature 593 (7859): 418–423. May 2021. doi:10.1038/s41586-021-03431-4. PMID 33727703. Bibcode: 2021Natur.593..418Y. 
  10. ↑ Psychiatric Side Effects of Prescription and Over-the-counter Medications: Recognition and Management. American Psychiatric Pub. 1998. ISBN 9780880488686. https://books.google.com/books?id=K7kevbILCuQC&q=clofazimine+suicide&pg=RA2-PA1985. 
  11. ↑ 11.0 11.1 "Clofazimine: a review of its medical uses and mechanisms of action". Journal of the American Academy of Dermatology 32 (2 Pt 1): 241–247. February 1995. doi:10.1016/0190-9622(95)90134-5. PMID 7829710. 
  12. ↑ 12.0 12.1 "The mode of action of clofazimine DNA binding studies". International Journal of Leprosy and Other Mycobacterial Diseases 44 (1–2): 133–134. 1976. PMID 945233. 
  13. ↑ 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.
  14. ↑ "Tocopherol stabilizes membrane against phospholipase A, free fatty acids, and lysophospholipids". Annals of the New York Academy of Sciences 570 (1): 121–135. 1989. doi:10.1111/j.1749-6632.1989.tb14913.x. PMID 2698101. Bibcode: 1989NYASA.570..121K. 
  15. ↑ "Identification of novel functional inhibitors of acid sphingomyelinase". PLOS ONE 6 (8): e23852. 2011. doi:10.1371/journal.pone.0023852. PMID 21909365. Bibcode: 2011PLoSO...623852K. 
  16. ↑ "Molecular imaging of intracellular drug-membrane aggregate formation". Molecular Pharmaceutics 8 (5): 1742–1749. October 2011. doi:10.1021/mp200101b. PMID 21800872. 
  17. ↑ "Lamprene (clofazimine) dosing, indications, interactions, adverse effects, and more". http://reference.medscape.com/drug/clofazimine-342661. 
  18. ↑ "The antileprosy agent B.663 (Clofazimine) and the reticuloendothelial system". International Journal of Leprosy and Other Mycobacterial Diseases 39 (2): 479–492. Apr 1971. PMID 4948088. 
  19. ↑ "The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals". Leprosy Review 53 (2): 85–90. June 1982. doi:10.5935/0305-7518.19820010. PMID 7098757. 
  20. ↑ "Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy". Antimicrobial Agents and Chemotherapy 21 (5): 693–697. May 1982. doi:10.1128/aac.21.5.693. PMID 7049077. 
  21. ↑ "Anti-leprosy drugs inhibit the complement-mediated solubilization of pre-formed immune complexes in vitro". International Journal of Immunopharmacology 14 (2): 269–273. February 1992. doi:10.1016/0192-0561(92)90039-N. PMID 1624226. 
  22. ↑ "Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes". PLOS ONE 3 (12): e4009. Dec 2008. doi:10.1371/journal.pone.0004009. PMID 19104661. Bibcode: 2008PLoSO...3.4009R. 
  23. ↑ "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences of the United States of America 103 (46): 17414–17419. November 2006. doi:10.1073/pnas.0605136103. PMID 17088564. Bibcode: 2006PNAS..10317414B. 
  24. ↑ "The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS". The Journal of Clinical Investigation 111 (11): 1703–1713. June 2003. doi:10.1172/JCI16921. PMID 12782673. 
  25. ↑ "Clofazimine in the treatment of discoid lupus erythematosus". The British Journal of Dermatology 91 (1): 93–96. July 1974. doi:10.1111/j.1365-2133.1974.tb06723.x. PMID 4851057. 
  26. ↑ "Antileprosy drugs and lupus erythematosus". Annals of Internal Medicine 97 (5): 788. November 1982. doi:10.7326/0003-4819-97-5-788_2. PMID 7137755. 
  27. ↑ "Treatment of pustular psoriasis with clofazimine". The British Journal of Dermatology 99 (3): 303–305. September 1978. doi:10.1111/j.1365-2133.1978.tb02001.x. PMID 708598. 
  28. ↑ "Clofazimine--an effective treatment for Melkersson-Rosenthal syndrome or Miescher's cheilitis". Clinical and Experimental Dermatology 11 (2): 173–178. March 1986. doi:10.1111/j.1365-2230.1986.tb00443.x. PMID 3720016. 

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