Mepacrine

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Mepacrine
Quinacrine.svg
Clinical data
Trade names Atabrine, Atebrin
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ATC code
Pharmacokinetic data
Protein binding 80–90%
Elimination half-life 5–14 days
Identifiers
  • (RS)-N′-(6-Chloro-2-methoxy-acridin-9-yl)-N,N-diethylpentane-1,4-diamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.371 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H30ClN3O
Molar mass 399.96 g·mol−1
3D model (JSmol)
  • CCN(CC)CCCC(C)Nc1c2ccc(cc2nc3c1cc(cc3)OC)Cl
  • InChI=1S/C23H30ClN3O/c1-5-27(6-2)13-7-8-16(3)25-23-19-11-9-17(24)14-22(19)26-21-12-10-18(28-4)15-20(21)23/h9-12,14-16H,5-8,13H2,1-4H3,(H,25,26) Yes check.svgY
  • Key:GPKJTRJOBQGKQK-UHFFFAOYSA-N Yes check.svgY
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Mepacrine, also called quinacrine or by the trade names Atabrine or Atebrin (german), is a medication with several uses. It is related to chloroquine and mefloquine. Although formerly available from compounding pharmacies, as of August 2020 it is unavailable in the United States. [1]

Contents

Medical uses

These men didn't take their Atabrine (as an anti-malaria drug); this sign was posted at the 363rd Station Hospital on Papua New Guinea during World War II Atabrine advertisement in Guinea during WW2.jpg
These men didn't take their Atabrine (as an anti-malaria drug); this sign was posted at the 363rd Station Hospital on Papua New Guinea during World War II

The main uses of mepacrine are as an antiprotozoal, antirheumatic, and an intrapleural sclerosing agent. [2]

Antiprotozoal use include targeting giardiasis, where mepacrine is indicated as a primary agent for patients with metronidazole-resistant giardiasis and patients who should not receive or cannot tolerate metronidazole. Giardiasis that is very resistant may even require a combination of mepacrine and metronidazole. [2]

Mepacrine is also used off-label for the treatment of systemic lupus erythematosus, [3] indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take chloroquine derivatives. [2]

As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients. [2]

Mepacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. See mefloquine for more information.

In addition to medical applications, mepacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Mepacrine is a green fluorescent dye taken up by most cells. Platelets store mepacrine in dense granules. [4]

Mechanism

Its mechanism of action against protozoa is uncertain, but it is thought to act against the protozoan's cell membrane.

It is known to act as a histamine N-methyltransferase inhibitor.

It also inhibits NF-κB and activates p53.

History

Antiprotozoal

Atabrine and mosquito poster Atabrine and mosquito poster - "Don't be a jerk" (MAMAS D44-170-1), National Museum of Health and Medicine (302828613) (cropped).jpg
Atabrine and mosquito poster

Mepacrine was initially approved in the 1930s as an antimalarial drug. It was used extensively during the second World War by Allied forces fighting in North Africa and the Far East to prevent malaria. [5]

This antiprotozoal is also approved for the treatment of giardiasis (an intestinal parasite), [6] and has been researched as an inhibitor of phospholipase A2.

Scientists at Bayer in Germany first synthesised mepacrine in 1931. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.

Anthelmintics

In addition it has been used for treating tapeworm infections. [7]

Creutzfeldt–Jakob disease

Mepacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro , [8] and full clinical trials of its use as a treatment for Creutzfeldt–Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease, [9] although other reports have shown no significant effect, [10] and treatment of scrapie in mice and sheep has also shown no effect. [11] [12] Possible reasons for the lack of an in vivo effect include inefficient penetration of the blood–brain barrier, as well as the existence of drug-resistant prion proteins that increase in number when selected for by treatment with mepacrine. [13]

Non-surgical sterilization for women

The use of mepacrine for non-surgical sterilization for women has also been studied. The first report of this method claimed a first year failure rate of 3.1%. [14] However, despite a multitude of clinical studies on the use of mepacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use. [2]

Pellets of mepacrine are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The procedure is undertaken twice, first in the proliferative phase, 6 to 12 days following the first day of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a six-week interval to close off the tubes permanently.

In the United States, this method has undergone Phase I clinical testing. The FDA has waived the necessity for Phase II clinical trials because of the extensive data pertaining to other uses of mepacrine. The next step in the FDA approval process in the United States is a Phase III large multi-center clinical trial. The method is currently used off-label.

Many peer reviewed studies suggest that [15] mepacrine sterilization (QS) is potentially safer than surgical sterilization. [16] [17] Nevertheless, in 1998 the Supreme Court of India banned the import or use of the drug, allegedly based on reports that it could cause cancer or ectopic pregnancies. [18]

Skin dye

During the Second Sino-Japanese War, American Sino-American Cooperative Organization operatives yellowed their skin using mepacrine tablets in order to more closely match the skin color of their Chinese peers. [19]

See also

Related Research Articles

<span class="mw-page-title-main">Creutzfeldt–Jakob disease</span> Degenerative neurological disorder

Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later symptoms include dementia, involuntary movements, blindness, weakness, and coma. About 70% of people die within a year of diagnosis. The name Creutzfeldt–Jakob disease was introduced by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.

<span class="mw-page-title-main">Prion</span> Pathogenic type of misfolded protein

A prion is a misfolded protein that can transmit its misfoldedness to normal variants of the same protein and trigger cellular death. Prions cause prion diseases known as transmissible spongiform encephalopathies (TSEs) that are transmissible, fatal neurodegenerative diseases in humans and animals. The proteins may misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein. The consequent abnormal three-dimensional structure confers on them the ability to cause misfolding of other proteins.

<span class="mw-page-title-main">Mefloquine</span> Pharmaceutical drug

Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It can be used to treat mild or moderate malaria but is not recommended for severe malaria. It is taken by mouth.

Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young children and pregnant women. As of 2018, modern treatments, including for severe malaria, continued to depend on therapies deriving historically from quinine and artesunate, both parenteral (injectable) drugs, expanding from there into the many classes of available modern drugs. Incidence and distribution of the disease is expected to remain high, globally, for many years to come; moreover, known antimalarial drugs have repeatedly been observed to elicit resistance in the malaria parasite—including for combination therapies featuring artemisinin, a drug of last resort, where resistance has now been observed in Southeast Asia. As such, the needs for new antimalarial agents and new strategies of treatment remain important priorities in tropical medicine. As well, despite very positive outcomes from many modern treatments, serious side effects can impact some individuals taking standard doses.

<span class="mw-page-title-main">Scrapie</span> Degenerative disease that affects sheep and goats

Scrapie is a fatal, degenerative disease affecting the nervous systems of sheep and goats. It is one of several transmissible spongiform encephalopathies (TSEs), and as such it is thought to be caused by a prion. Scrapie has been known since at least 1732 and does not appear to be transmissible to humans. However, it has been found to be experimentally transmissible to humanised transgenic mice and non-human primates.

Transmissible spongiform encephalopathies (TSEs) also known as prion diseases, are a group of progressive, incurable, and fatal conditions that are associated with prions and affect the brain and nervous system of many animals, including humans, cattle, and sheep. According to the most widespread hypothesis, they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection. Mental and physical abilities deteriorate and many tiny holes appear in the cortex causing it to appear like a sponge when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen chronically.

<span class="mw-page-title-main">Metronidazole</span> Antibiotic and antiprotozoal medication

Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is effective for dracunculiasis, giardiasis, trichomoniasis, and amebiasis. It is an option for a first episode of mild-to-moderate Clostridium difficile colitis if vancomycin or fidaxomicin is unavailable. Metronidazole is available orally, as a cream or gel, and by slow intravenous infusion.

<span class="mw-page-title-main">Giardiasis</span> Parasitic disease that results in diarrhea

Giardiasis is a parasitic disease caused by Giardia duodenalis. Infected individuals who experience symptoms may have diarrhea, abdominal pain, and weight loss. Less common symptoms include vomiting and blood in the stool. Symptoms usually begin one to three weeks after exposure and, without treatment, may last two to six weeks or longer.

<span class="mw-page-title-main">Chloroquine</span> Medication used to treat malaria

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.

<span class="mw-page-title-main">Pentosan polysulfate</span> Chemical compound

Pentosan polysulfate, sold under the brand name Elmiron among others, is a medication used for the treatment of interstitial cystitis. It was approved for medical use in the United States in 1996.

<span class="mw-page-title-main">Hydroxychloroquine</span> Antimalarial medication

Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth, often in the form of hydroxychloroquine sulfate.

<span class="mw-page-title-main">Leflunomide</span> Chemical compound

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

Antiprotozoal agents is a class of pharmaceuticals used in treatment of protozoan infection.

<span class="mw-page-title-main">Nitazoxanide</span> Chemical compound

Nitazoxanide, sold under the brand name Alinia among others, is a broad-spectrum antiparasitic and broad-spectrum antiviral medication that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; evidence as of 2014 suggested that it possesses efficacy in treating a number of viral infections as well.

<span class="mw-page-title-main">Kuru (disease)</span> Rare neurodegenerative disease caused by prions

Kuru is a rare, incurable, and fatal neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea. Kuru is a form of transmissible spongiform encephalopathy (TSE) caused by the transmission of abnormally folded proteins (prions), which leads to symptoms such as tremors and loss of coordination from neurodegeneration.

<span class="mw-page-title-main">Dehydroemetine</span> Chemical compound

Dehydroemetine is a synthetically produced antiprotozoal agent similar to emetine in its anti-amoebic properties and structure, but it produces fewer side effects. In the United States, it is manufactured by Roche.

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.

<span class="mw-page-title-main">Disulfiram-like drug</span> Drug that causes an adverse reaction to alcohol

A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.

Real-time quaking-induced conversion (RT-QuIC) is a highly sensitive assay for prion detection.

<span class="mw-page-title-main">Chloroquine and hydroxychloroquine during the COVID-19 pandemic</span> Early experimental treatment efforts during the start of COVID-19 pandemic

Chloroquine and hydroxychloroquine are anti-malarial medications also used against some auto-immune diseases. Chloroquine, along with hydroxychloroquine, was an early experimental treatment for COVID-19. Neither drug prevents SARS-CoV-2 infection.

References

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  19. "How naked World War II sailors ended up riding Mongolian ponies in the Gobi Desert to shoot bazookas at the Japanese". 2019-01-26.