Jump to content

Clofazimine: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
{{Reflist}}
Yren1 (talk | contribs)
15 edits
Line 41: Line 41:


==Immunosuppressive effects==
==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.<ref name="pmid4948088">{{cite journal |author=Conalty ML, Barry VC, Jina A |title=The antileprosy agent B.663 (Clofazimine) and the reticuloendothelial system. |journal=Int J Lepr Other Mycobact Dis. |volume=39 |issue=2 |pages=479-92 |year=1971 |month=Apr |pmid=4948088 |doi= |url=}}</ref> Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation <ref name="pmid7098757">{{cite journal |author=Gatner EM, Anderson R, van Remsburg CE, Imkamp FM. |title=The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals. |journal=Lepr Rev. |volume=53 |issue=2 |pages=85-90 |year=1982 |month=Jun |pmid=7098757 |doi= |url=}}</ref>, mitogen-induced PBMC proliferation <ref name="pmid7049077">{{cite journal |author=van Rensburg CE, Gatner EM, Imkamp FM, Anderson R. |title=Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy. |journal=Antimicrob Agents Chemother. |volume=21 |issue=5 |pages=693-7 |year=1982 |month=May |pmid=7049077 |doi= |url=}}</ref> and complement-mediated solubilization of pre-formed immune complexes in vitro <ref name="pmid1624226">{{cite journal |author=Kashyap A, Sehgal VN, Sahu A, Saha K. |title=Anti-leprosy drugs inhibit the complement-mediated solubilization of pre-formed immune complexes in vitro. |journal=Int J Immunopharmacol. |volume=14 |issue=2 |pages=269-73 |year=1992 |month=Feb |pmid=1624226 |doi= |url=}}</ref>. Several clinical trials were also conducted looking for its immunosuppressive activity even before it was approved for leprosy by FDA. Dr. Barnes first reported it was effective in treating chronic discoid lupus erythematosus with 17 out of 26 patients got remission <ref name="pmid4851057">{{cite journal |author=Mackey JP, Barnes J. |title=Clofazimine in the treatment of discoid lupus erythematosus. |journal=Br J Dermatol. |volume=91 |issue=1 |pages=93-6 |year=1974 |month=Jul |pmid=4851057 |doi= |url=}}</ref>. But later aother group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus <ref name="pmid7137755">{{cite journal |author=Jakes JT, Dubois EL, Quismorio FP Jr. |title=Antileprosy drugs and lupus erythematosus. |journal=Ann Intern Med. |volume=97 |issue=5 |pages=788 |year=1982 |month=Nov |pmid=7137755 |doi= |url=}}</ref>. Clofazimine also has been sporadically reported with some success in a limited number of autoimmune diseases such as psoriasis <ref name="pmid708598">{{cite journal |author=Chuaprapaisilp T, Piamphongsant T. |title=Treatment of pustular psoriasis with clofazimine. |journal=Br J Dermatol. |volume=99 |issue=3 |pages=303-5 |year=1978 |month=Sep |pmid=708598 |doi= |url=}}</ref>, Miescher’s granulomatous cheilitis <ref name="pmid3720016">{{cite journal |author=Podmore P, Burrows D. |title=Clofazimine--an effective treatment for Melkersson-Rosenthal syndrome or Miescher's cheilitis. |journal=Clin Exp Dermatol. |volume=11 |issue=2 |pages=173-8 |year=1986 |month=Mar |pmid=3720016 |doi= |url=}}</ref>, Crohn’s disease and ulcerative colitis [http://gut.bmj.com/cgi/reprint/23/5/A432]. Antin's group did most systematic immuno-clinical study of clofazimine in post-bone marrow transplantation patients <ref name="pmid9116272">{{cite journal |author=Lee SJ, Wegner SA, McGarigle CJ, Bierer BE, Antin JH. |title=Treatment of chronic graft-versus-host disease with clofazimine. |journal=Blood. |volume=89 |issue=7 |pages=2298-302 |year=1997 |month=Apr |pmid=9116272 |doi= |url=}}</ref> 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.
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.<ref name="pmid4948088">{{cite journal |author=Conalty ML, Barry VC, Jina A |title=The antileprosy agent B.663 (Clofazimine) and the reticuloendothelial system. |journal=Int J Lepr Other Mycobact Dis. |volume=39 |issue=2 |pages=479-92 |year=1971 |month=Apr |pmid=4948088 |doi= |url=}}</ref> Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation <ref name="pmid7098757">{{cite journal |author=Gatner EM, Anderson R, van Remsburg CE, Imkamp FM. |title=The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals. |journal=Lepr Rev. |volume=53 |issue=2 |pages=85-90 |year=1982 |month=Jun |pmid=7098757 |doi= |url=}}</ref>, mitogen-induced PBMC proliferation <ref name="pmid7049077">{{cite journal |author=van Rensburg CE, Gatner EM, Imkamp FM, Anderson R. |title=Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy. |journal=Antimicrob Agents Chemother. |volume=21 |issue=5 |pages=693-7 |year=1982 |month=May |pmid=7049077 |doi= |url=}}</ref> and complement-mediated solubilization of pre-formed immune complexes in vitro <ref name="pmid1624226">{{cite journal |author=Kashyap A, Sehgal VN, Sahu A, Saha K. |title=Anti-leprosy drugs inhibit the complement-mediated solubilization of pre-formed immune complexes in vitro. |journal=Int J Immunopharmacol. |volume=14 |issue=2 |pages=269-73 |year=1992 |month=Feb |pmid=1624226 |doi= |url=}}</ref>. A sysmatic mechanistic studying of clofazimine in human T cells revealed that this drug actually is a Kv1.3 (KCNA3)channel blocker <ref name="pmid19104661">{{cite journal |author=Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J, Dang Y, Zhang J, Jiang H, Penner R, Liu JO. |title=Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. |journal=PLoS ONE. |volume=3 |issue=12 |pages=e4009 |year=2008 |month=Dec |pmid=19104661 |doi= |url=}}</ref>. This indicated that clofazimine will be potentially used for treatment of multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Because the Kv1.3-high expressing effector memory T cells (T<sub>EM</sub>) are actively involved in development of these diseases <ref name="pmid17088564">{{cite journal |author=Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, S Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus HG, Nepom GT, Gutman GA, Calabresi PA, Chandy KG. |title=Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. |journal=Proc Natl Acad Sci U S A. |volume=103 |issue=46 |pages=17414-9 |year=2006 |month=Nov |pmid=17088564 |doi= |url=}}</ref>, and Kv1.3 activity is essential for stimulation and proliferation of (T<sub>EM</sub>) by regulating calcium influx in the T cells <ref name="pmid12782673">{{cite journal |author=Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG. |title=The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. |journal=J Clin Invest. |volume=111 |issue=11 |pages=1703-13 |year=2003 |month=Jun |pmid=17088564 |doi= |url=}}</ref>.
Several clinical trials were also conducted looking for its immunosuppressive activity even before it was approved for leprosy by FDA. Barnes first reported it was effective in treating chronic discoid lupus erythematosus with 17 out of 26 patients got remission <ref name="pmid4851057">{{cite journal |author=Mackey JP, Barnes J. |title=Clofazimine in the treatment of discoid lupus erythematosus. |journal=Br J Dermatol. |volume=91 |issue=1 |pages=93-6 |year=1974 |month=Jul |pmid=4851057 |doi= |url=}}</ref>. But later aother group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus <ref name="pmid7137755">{{cite journal |author=Jakes JT, Dubois EL, Quismorio FP Jr. |title=Antileprosy drugs and lupus erythematosus. |journal=Ann Intern Med. |volume=97 |issue=5 |pages=788 |year=1982 |month=Nov |pmid=7137755 |doi= |url=}}</ref>. Clofazimine also has been sporadically reported with some success in a limited number of autoimmune diseases such as psoriasis <ref name="pmid708598">{{cite journal |author=Chuaprapaisilp T, Piamphongsant T. |title=Treatment of pustular psoriasis with clofazimine. |journal=Br J Dermatol. |volume=99 |issue=3 |pages=303-5 |year=1978 |month=Sep |pmid=708598 |doi= |url=}}</ref>, Miescher’s granulomatous cheilitis <ref name="pmid3720016">{{cite journal |author=Podmore P, Burrows D. |title=Clofazimine--an effective treatment for Melkersson-Rosenthal syndrome or Miescher's cheilitis. |journal=Clin Exp Dermatol. |volume=11 |issue=2 |pages=173-8 |year=1986 |month=Mar |pmid=3720016 |doi= |url=}}</ref>, Crohn’s disease and ulcerative colitis [http://gut.bmj.com/cgi/reprint/23/5/A432]. Antin's group did most systematic immuno-clinical study of clofazimine in post-bone marrow transplantation patients <ref name="pmid9116272">{{cite journal |author=Lee SJ, Wegner SA, McGarigle CJ, Bierer BE, Antin JH. |title=Treatment of chronic graft-versus-host disease with clofazimine. |journal=Blood. |volume=89 |issue=7 |pages=2298-302 |year=1997 |month=Apr |pmid=9116272 |doi= |url=}}</ref> 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.


==References==
==References==

Revision as of 19:56, 6 January 2009

Clofazimine
Clinical data
Other namesN,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine
ATC code
Pharmacokinetic data
Elimination half-life70 days
Identifiers
  • N,5-bis(4-chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.016.347 Edit this at Wikidata
Chemical and physical data
FormulaC27H22Cl2N4
Molar mass473.396 g/mol g·mol−1

Clofazimine is a fat-soluble riminophenazine 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).

History

Clofazimine, initially known as B663, was first synthesised in 1954 by a team 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 Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, some sponsored by the Swiss pharmaceutical company Geigy (today member of the Novartis group of drug producers), the product was launched in 1969 as Lamprene.

The U.S. government named Clofazimine an orphan drug in June 1986. Geigy gained FDA approval for the drug in December 1986.

Supply

Clofazimine is marketed under the trade name Lamprene by Novartis. One of the only suppliers of Clofazimine Active Pharmaceutical Ingredient in the world is Sangrose Laboratories, located at Mavelikara in the southern Indian state of Kerala.

Metabolism

Clofazimine has a very long half life of about 70 days. Autopsies performed on clofazimine patients have found crystallized clofazimine in the intestinal mucosa, liver, spleen, and lymph nodes.

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. The prescribing information indicates that several patients have developed depression as a result of this chronic skin discoloration, resulting in two suicides.

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 gastrointestial intolerance. Rarely, patients have died from bowel obstructions and intestinal bleeding, or required abdominal surgery to correct the same.

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.[1] Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation [2], mitogen-induced PBMC proliferation [3] and complement-mediated solubilization of pre-formed immune complexes in vitro [4]. A sysmatic mechanistic studying of clofazimine in human T cells revealed that this drug actually is a Kv1.3 (KCNA3)channel blocker [5]. This indicated that clofazimine will be potentially used for treatment of multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Because the Kv1.3-high expressing effector memory T cells (TEM) are actively involved in development of these diseases [6], and Kv1.3 activity is essential for stimulation and proliferation of (TEM) by regulating calcium influx in the T cells [7]. Several clinical trials were also conducted looking for its immunosuppressive activity even before it was approved for leprosy by FDA. Barnes first reported it was effective in treating chronic discoid lupus erythematosus with 17 out of 26 patients got remission [8]. But later aother group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus [9]. Clofazimine also has been sporadically reported with some success in a limited number of autoimmune diseases such as psoriasis [10], Miescher’s granulomatous cheilitis [11], Crohn’s disease and ulcerative colitis [1]. Antin's group did most systematic immuno-clinical study of clofazimine in post-bone marrow transplantation patients [12] 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.

References

  1. ^ Conalty ML, Barry VC, Jina A (1971). "The antileprosy agent B.663 (Clofazimine) and the reticuloendothelial system". Int J Lepr Other Mycobact Dis. 39 (2): 479–92. PMID 4948088. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Gatner EM, Anderson R, van Remsburg CE, Imkamp FM. (1982). "The in vitro and in vivo effects of clofazimine on the motility of neutrophils and transformation of lymphocytes from normal individuals". Lepr Rev. 53 (2): 85–90. PMID 7098757. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ van Rensburg CE, Gatner EM, Imkamp FM, Anderson R. (1982). "Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy". Antimicrob Agents Chemother. 21 (5): 693–7. PMID 7049077. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Kashyap A, Sehgal VN, Sahu A, Saha K. (1992). "Anti-leprosy drugs inhibit the complement-mediated solubilization of pre-formed immune complexes in vitro". Int J Immunopharmacol. 14 (2): 269–73. PMID 1624226. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Ren YR, Pan F, Parvez S, Fleig A, Chong CR, Xu J, Dang Y, Zhang J, Jiang H, Penner R, Liu JO. (2008). "Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes". PLoS ONE. 3 (12): e4009. PMID 19104661. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, S Andrews B, Sankaranarayanan A, Homerick D, Roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus HG, Nepom GT, Gutman GA, Calabresi PA, Chandy KG. (2006). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proc Natl Acad Sci U S A. 103 (46): 17414–9. PMID 17088564. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG. (2003). "The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS". J Clin Invest. 111 (11): 1703–13. PMID 17088564. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Mackey JP, Barnes J. (1974). "Clofazimine in the treatment of discoid lupus erythematosus". Br J Dermatol. 91 (1): 93–6. PMID 4851057. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Jakes JT, Dubois EL, Quismorio FP Jr. (1982). "Antileprosy drugs and lupus erythematosus". Ann Intern Med. 97 (5): 788. PMID 7137755. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Chuaprapaisilp T, Piamphongsant T. (1978). "Treatment of pustular psoriasis with clofazimine". Br J Dermatol. 99 (3): 303–5. PMID 708598. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Podmore P, Burrows D. (1986). "Clofazimine--an effective treatment for Melkersson-Rosenthal syndrome or Miescher's cheilitis". Clin Exp Dermatol. 11 (2): 173–8. PMID 3720016. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Lee SJ, Wegner SA, McGarigle CJ, Bierer BE, Antin JH. (1997). "Treatment of chronic graft-versus-host disease with clofazimine". Blood. 89 (7): 2298–302. PMID 9116272. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

Stub icon

This systemic antibiotic-related article is a stub. You can help Wikipedia by expanding it.

References

Retrieved from "https://en.wikipedia.org/w/index.php?title=Clofazimine&oldid=262365889"