Clofazamine
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Clofazimine, sold under the brand name Lamprene, is a medication used together with
rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...
and
dapsone Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...
to treat leprosy. It is specifically used for multibacillary (MB) leprosy and
erythema nodosum leprosum Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of ''Mycobacterium avium'' complex (MAC) when administered with a macrolide and ethambutol, as well as the drugs amikacin and clarithromycin. However, in the United States, clofazimine is considered an
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...
, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally. Common side effects include abdominal pain, diarrhea, itchiness, dry skin, and change in skin color. It can also cause swelling of the lining of the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
, increased blood sugar, and sensitivity to the sun. It is unclear if use during pregnancy is safe. Clofazimine is a phenazine dye and is believed to work by interfering with DNA. Clofazimine was discovered in the 1950s at
Trinity College, Dublin , name_Latin = Collegium Sanctae et Individuae Trinitatis Reginae Elizabethae juxta Dublin , motto = ''Perpetuis futuris temporibus duraturam'' (Latin) , motto_lang = la , motto_English = It will last i ...
, and approved for medical use in the United States in 1986. It is on the World Health Organization's List of Essential Medicines. In the United States it is not available commercially but can be obtained from the US Department of Health and Human Services.


Medical uses

The primary use of clofazimine is for the treatment of leprosy. Other uses have not been proven to be safe or effective. It has been studied in combination with other antimycobacterial drugs to treat '' Mycobacterium avium'' infections in people with HIV/AIDS and ''
Mycobacterium avium paratuberculosis ''Mycobacterium avium'' subspecies ''paratuberculosis'' (MAP) is an obligate pathogenic bacterium in the genus '' Mycobacterium''. It is often abbreviated ''M. paratuberculosis'' or ''M. avium'' ssp. ''paratuberculosis''. It is the causative ag ...
''. 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 Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...
for leprosy.Clinical Microbiology Made Ridiculously Simple 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


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. 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. It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids, which are toxic and inhibit bacterial proliferation. Clofazimine is also a FIASMA (functional inhibitor of
acid sphingomyelinase Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase de ...
).


Metabolism

Clofazimine has a biological half life of about 70 days. Autopsies performed on those who have died while on clofazimine show crystal-like
aggregate Aggregate or aggregates may refer to: Computing and mathematics * collection of objects that are bound together by a root entity, otherwise known as an aggregate root. The aggregate root guarantees the consistency of changes being made within the ...
s in the intestinal mucosa, liver, spleen, and lymph nodes.


History

Clofazimine, initially known as B663, was first synthesised in 1954 by a team of scientists at
Trinity College, Dublin , name_Latin = Collegium Sanctae et Individuae Trinitatis Reginae Elizabethae juxta Dublin , motto = ''Perpetuis futuris temporibus duraturam'' (Latin) , motto_lang = la , motto_English = It will last i ...
:
Frank Winder Frank Winder (Francis Gerard Augustine Winder; 14 April 1928 – 30 December 2007, in Dublin) was an Irish professor of biochemistry, a naturalist, and one of Ireland's leading rock climbing, rock climbers in the 1950s and 1960s. Scientific car ...
, J.G. Belton, Stanley McElhinney, M.L. Conalty, Seán O'Sullivan, and Dermot Twomey, led by
Vincent Barry Vincent Christopher Barry (1908–1975) was a scientist and researcher from Ireland. He is known for leading the team which developed the anti-leprosy drug clofazimine. Early life and education Barry was born in Sunday's Well, Cork. He was ...
. 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. Novartis was granted FDA approval of clofazimine in December 1986 as an
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...
. The drug is currently no longer commercially available in the United States.


Society and culture

Clofazimine is marketed under the trade name Lamprene by Novartis. One producer of the clofazimine molecule is Sangrose Laboratories, located in Mavelikara, India.


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. Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation, mitogen-induced
PBMC A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neu ...
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 Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the ''KCNA3'' gene. Potassium channels represent the most complex class of voltage-gated ion channels fro ...
) channel blocker. This indicates that clofazimine will be potentially used for treatment of
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, 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 Discoid lupus erythematosus is the most common type of chronic cutaneous lupus (CCLE), an autoimmune skin condition on the lupus erythematosus spectrum of illnesses. It presents with red, painful, inflamed and coin-shaped patches of skin with a sc ...
with 17 out of 26 patients got remission. But later another group found it was ineffective in treating diffuse, photosensitive,
systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
. Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis, Miescher's granulomatous cheilitis.


References


External links

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