Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin 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 an ...

to treat

leprosy Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...

. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum, and its discovery greatly improved the overall efficiency of the treatment. 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 together with a

macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...

and

ethambutol Ethambutol (EMB, E) is a medication primarily used to treat tuberculosis. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. It may also be used to treat ''Mycobacterium avi ...

, as well as the drugs

amikacin Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of ...

and

clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...

. However, in the United States, clofazimine is currently considered an

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

. 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 Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

, 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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. Clofazimine was discovered in the 1950s at

Trinity College, Dublin Trinity College Dublin (), officially titled The College of the Holy and Undivided Trinity of Queen Elizabeth near Dublin, and legally incorporated as Trinity College, the University of Dublin (TCD), is the sole constituent college of the Univ ...

, and approved for medical use in the United States in 1986. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. 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 ''Mycobacterium avium ''complex is a group of mycobacteria comprising ''Mycobacterium intracellulare'' and ''Mycobacterium avium'' that are commonly grouped because they infect humans together; this group, in turn, is part of the group of nontu ...

'' infections in people with

HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

and '' Mycobacterium avium paratuberculosis''. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction,

erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...

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

for leprosy.Clinical Microbiology Made Ridiculously Simple Early research suggested clofazimine inhibits the replication of

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...

''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

ichthyosis Ichthyosis is a family of genetic disorder, genetic skin disorders characterized by Xeroderma, dry, Scleroderma, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cau ...

and skin dryness are also reported in response to this drug (8%-28%), as well as rash and itchiness (1-5%).

Mechanism

Clofazimine works by binding to the

guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

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).

Metabolism

Clofazimine has a biological half life of about 70 days.

Autopsies An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death; ...

performed on those who have died while on clofazimine show

crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

-like aggregates in the intestinal mucosa,

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

, and

lymph nodes A lymph node, or lymph gland, is a kidney-shaped Organ (anatomy), organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphoc ...

History

Clofazimine, initially known as B663, was first synthesised in 1954 by a team of scientists at

: Frank Winder, J.G. Belton, Stanley McElhinney, M.L. Conalty, Seán O'Sullivan, and Dermot Twomey, led by

Vincent Barry Vincent Christopher Barry (17 May 1908 – 4 September 1975) was an Irish scientist and researcher. He is known for leading the team which developed the anti-leprosy drug clofazimine. Early life and education Vincent Christoper Barry was bo ...

. 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 Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...

launched the product in 1969 under the brand name Lamprene. Novartis was granted FDA approval of clofazimine in December 1986 as an

. The drug is currently no longer commercially available in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

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.

Society and culture

Clofazimine is marketed under the trade name Lamprene by

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 India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...

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 proliferation and complement-mediated solubilization of pre-formed immune complexes in vitro. A mechanistic studying of clofazimine in human

T cells T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

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 f ...

) channel blocker. This indicates that clofazimine will be potentially used for treatment of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

and type 1 diabetes. Because the Kv1.3-high effector memory T cells (T_EM) are actively involved in the development of these diseases, and Kv1.3 activity is essential for stimulation and proliferation of T_EM 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, formally called 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. Common ...

. Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

, Miescher's granulomatous cheilitis.

References

External links

* {{portal bar, Medicine Antileprotic drugs Orphan drugs World Health Organization essential medicines Phenazines 4-Chlorophenyl compounds Irish inventions Wikipedia medicine articles ready to translate