Clinical data | |
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Trade names | Lamprene |
Other names | N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682128 |
Routes of administration | By mouth |
ATC code | |
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Pharmacokinetic data | |
Elimination half-life | 70 days |
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CAS Number | |
PubChem CID | |
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ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.016.347 |
Chemical and physical data | |
Formula | C27H22Cl2N4 |
Molar mass | 473.40 g·mol−1 |
3D model (JSmol) | |
Melting point | 210 to 212 °C (410 to 414 °F) |
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Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. [1] It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. [2] Evidence is insufficient to support its use in other conditions [1] though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol, [3] as well as the drugs amikacin and clarithromycin. [4] However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. [5] It is taken orally. [1]
Common side effects include abdominal pain, diarrhea, itchiness, dry skin, and change in skin color. [1] It can also cause swelling of the lining of the gastrointestinal tract, increased blood sugar, and sensitivity to the sun. [2] It is unclear if use during pregnancy is safe. [1] Clofazimine is a phenazine dye and is believed to work by interfering with DNA. [1]
Clofazimine was discovered in the 1950s at Trinity College, Dublin, [6] and approved for medical use in the United States in 1986. [1] It is on the World Health Organization's List of Essential Medicines. [7] In the United States it is not available commercially but can be obtained from the US Department of Health and Human Services. [1]
The primary use of clofazimine is for the treatment of leprosy. [1] Other uses have not been proven to be safe or effective. [1]
It has been studied in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in people with HIV/AIDS and Mycobacterium avium paratuberculosis . 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 for leprosy. [8]
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 [9]
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. [10]
Cases of ichthyosis and skin dryness are also reported in response to this drug (8%-28%), as well as rash and itchiness (1-5%).[ medical citation needed ]
Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation. [11] [12] It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids, [11] [12] which are toxic and inhibit bacterial proliferation. [13] [14]
Clofazimine is also a FIASMA (functional inhibitor of acid sphingomyelinase). [15]
Clofazimine has a biological half life of about 70 days. Autopsies performed on those who have died while on clofazimine show crystal-like aggregates in the intestinal mucosa, liver, spleen, and lymph nodes. [16]
Clofazimine, initially known as B663, was first synthesised in 1954 by a team of scientists at Trinity College, Dublin: Frank Winder, J.G. Belton, Stanley McElhinney, M.L. Conalty, Seán O'Sullivan, and Dermot Twomey, led by Vincent Barry. 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.[ citation needed ]
Novartis was granted FDA approval of clofazimine in December 1986 as an orphan drug. The drug is currently no longer commercially available in the United States 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. [17]
Clofazimine is marketed under the trade name Lamprene by Novartis 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.[ citation needed ]
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. [18] Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation, [19] mitogen-induced PBMC proliferation [20] and complement-mediated solubilization of pre-formed immune complexes in vitro. [21] A mechanistic studying of clofazimine in human T cells revealed that this drug is a Kv1.3 (KCNA3) channel blocker. [22] 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, [23] and Kv1.3 activity is essential for stimulation and proliferation of TEM by regulating calcium influx in the T cells. [24] 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. [25] But later another group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus. [26] Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis, [27] Miescher's granulomatous cheilitis. [28]
Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as some occurring in certain forms of pneumonia. It is generally less preferred than the tetracycline doxycycline. Minocycline is also used for the treatment of acne and rheumatoid arthritis. It is taken by mouth or applied to the skin.
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Mycobacterium is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy in humans. The Greek prefix myco- means 'fungus', alluding to this genus' mold-like colony surfaces. Since this genus has cell walls with a waxy lipid-rich outer layer containing high concentrations of mycolic acid, acid-fast staining is used to emphasize their resistance to acids, compared to other cell types.
Mycobacterium leprae is one of the two species of bacteria that cause Hansen's disease (leprosy), a chronic but curable infectious disease that damages the peripheral nerves and targets the skin, eyes, nose, and muscles.
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 and prevention of pneumocystis pneumonia and for the prevention of toxoplasmosis in those who have poor immune function. Additionally, it has been used for acne, dermatitis herpetiformis, and various other skin conditions. Dapsone is available both topically and by mouth.
Pimecrolimus is an immunosuppressant drug of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema).
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.
Mepacrine, also called quinacrine or by the trade names Atabrine or Atebrin, is a medication with several uses. It is related to chloroquine and mefloquine. Although available from compounding pharmacies, as of August 2020 approved formulations are not available in the United States.
Penicillamine, sold under the brand name of Cuprimine among others, is a medication primarily used for the treatment of Wilson's disease. It is also used for people with kidney stones who have high urine cystine levels, rheumatoid arthritis, and various heavy metal poisonings. It is taken by mouth.
Lupus vulgaris are painful cutaneous tuberculosis skin lesions with nodular appearance, most often on the face around the nose, eyelids, lips, cheeks, ears and neck. It is the most common Mycobacterium tuberculosis skin infection. The lesions may ultimately develop into disfiguring skin ulcers if left untreated.
Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex (MAC), which is made of two Mycobacterium species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS, it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.
Belimumab, sold under the brand name Benlysta, is a human monoclonal antibody that inhibits B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS). It is approved in the United States and Canada, and the European Union to treat systemic lupus erythematosus and lupus nephritis.
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.
Lupus erythematosus is a collection of autoimmune diseases in which the human immune system becomes hyperactive and attacks healthy tissues. Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs. The most common and most severe form is systemic lupus erythematosus.
A leprostatic agent is a drug that interferes with proliferation of the bacterium that causes leprosy.
Tumid lupus erythematosus is a rare, but distinctive entity in which patients present with edematous erythematous plaque.
Palisaded neutrophilic and granulomatous dermatitis (PNGS) is usually associated with a well-defined connective tissue disease, lupus erythematosus or rheumatoid arthritis most commonly, and often presents with eroded or ulcerated symmetrically distributed umbilicated papules or nodules on the elbows.
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 symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms. Children up to 18 years old develop a more severe form of SLE termed childhood-onset systemic lupus erythematosus.
Blisibimod is a selective antagonist of B-cell activating factor, being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus. It is currently under active investigation in clinical trials.
Promin, or sodium glucosulfone is a sulfone drug that was investigated for the treatment of malaria, tuberculosis and leprosy. It is broken down in the body to dapsone, which is the therapeutic form.
By 1954 related molecules known as iminophenazines were being investigated... one of the first ones to be made, originally given the laboratory code B663 ... B663—subsequently called clofazimine