Clofazimine
Encyclopedia
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.
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.
. 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
.
performed on clofazimine patients have found crystal
lized clofazimine in the intestinal mucosa, liver
, spleen
, and lymph nodes.
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 suicide
s.
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.
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.
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
and dapsone
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
as multidrug therapy (MDT) for the treatment of leprosy
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients and Mycobacterium avium paratuberculosis infection in Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
patients. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
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
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci 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, DublinTrinity College, Dublin
Trinity College, Dublin , formally known as the College of the Holy and Undivided Trinity of Queen Elizabeth near Dublin, was founded in 1592 by letters patent from Queen Elizabeth I as the "mother of a university", Extracts from Letters Patent of Elizabeth I, 1592: "...we...found and...
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
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
group of drug producers), the product was launched in 1969 as Lamprene.
The U.S. government named clofazimine an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
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 NovartisNovartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
. 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
Kerala
or Keralam is an Indian state located on the Malabar coast of south-west India. It was created on 1 November 1956 by the States Reorganisation Act by combining various Malayalam speaking regions....
.
Metabolism
Clofazimine has a very long half life of about 70 days. AutopsiesAutopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
performed on clofazimine patients have found crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...
lized clofazimine in the intestinal mucosa, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, 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
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
as a result of this chronic skin discoloration, resulting in two suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
s.
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 PBMCPBMC
A peripheral blood mononuclear cell is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells , B cells...
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
KCNA3
Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein which in humans is encoded by the KCNA3 gene....
) channel blocker. This indicates that clofazimine will be potentially used for treatment of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
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.