Clofazimine

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). Drug is given as an alternative to patients who can not tolerate the effects of dapsone for tuberculosis.

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 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.

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

Supply
Clofazimine is marketed under the trade name Lamprene by Novartis. One of the only suppliers of clofazimine's 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
Eosinophilic enteritis, GI irritation, and discoloration of the skin upon exposure to the sun are the major reported 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 gastrointestinal 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. Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation, mitogen-induced PBMC proliferation and complement-mediated solubilization of pre-formed immune complexes in vitro. A mechanistic studying of clofazimine in human T cells revealed that this drug is a Kv1.3 (KCNA3) channel blocker. 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, and Kv1.3 activity is essential for stimulation and proliferation of TEM by regulating calcium influx in the T cells.

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. But later another group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus. Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis, Miescher’s granulomatous cheilitis, Crohn’s disease and ulcerative colitis. A recent clinical study of clofazimine was done in post-bone marrow transplantation patients 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.