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| Clinical data | |
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| Trade names | Arsobal[1] |
| Other names | Mel B, Melarsen Oxide-BAL[2] |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| Routes of administration | IV |
| ATC code | |
| Pharmacokinetic data | |
| Eliminationhalf-life | 35 hours |
| Excretion | Kidney |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.007.086 |
| Chemical and physical data | |
| Formula | C12H15AsN6OS2 |
| Molar mass | 398.33 g·mol−1 |
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Melarsoprol is anarsenic-containing medication used for the treatment ofsleeping sickness (African trypanosomiasis).[1] It is specifically used for second-stage disease caused byTrypanosoma brucei rhodesiense when thecentral nervous system is involved.[1] ForTrypanosoma brucei gambiense,eflornithine orfexinidazole is usually preferred.[1] It is effective in about 95% of people.[3] It is given byinjection[2] and is known by patients as "fire in the veins".[4]
Melarsoprol has a high number of side effects.[5] Common side effects includebrain dysfunction, numbness, rashes, and kidney and liver problems.[2] About 1–5% of people die during treatment, although this is tolerated due to sleeping sickness itself having a practically 100% mortality rate when untreated.[3] In those withglucose-6-phosphate dehydrogenase (G6PD) deficiency,red blood cell breakdown may occur.[2] It has not been studied inpregnancy.[2] While its mechanism of action is not fully understood, its covalent binding totrypanothione to form the toxic Mel T complex is thought to play a large role.[6]
Melarsoprol has been used medically since 1949.[1] It is on theWorld Health Organization's List of Essential Medicines.[7] In regions of the world where the disease is common, melarsoprol is provided for free by theWorld Health Organization.[5] It is not commercially available in Canada or the United States.[2] In the United States, it may be obtained from theCenters for Disease Control and Prevention, while in Canada it is available fromHealth Canada.[1][2]
People diagnosed with trypanosome-caused disease should be treated with an anti-trypanosomal. Treatment is based on stage, 1 or 2, and parasite,T. b. rhodesiense orT. b. gambiense. In stage 1 disease, trypanosomes are present only in the peripheral circulation. In stage 2 disease, trypanosomes have crossed the blood-brain barrier and are present in the central nervous system.[8]
The following are considerable treatment options:[8]
Melarsoprol is a treatment used during the second stage of the disease. So far, it is the only treatment available for late-stageT. b. rhodesiense.[9]
Due to high toxicity, melarsoprol is reserved only for the most dangerous cases. Other agents associated with lowertoxicity levels are used during stage 1 of the disease.[10] The approval of thenifurtimox-eflornithine combination therapy (NECT) in 2009 for the treatment ofT. b. gambiense limited the use of melarsoprol to the treatment of second-stageT. b. rhodesiense.[11]
Failure rates of 27% in certain African countries have been reported.[12] This was caused by bothdrug resistance and additional mechanisms that have not yet been elucidated. Resistance is likely due to transport problems associated with the P2 transporter, an adenine-adenosine transporter. Resistance can occur with point mutations within thistransporter.[13] Resistance has been present since the 1970s.[14]
In August 2024, the World Health Organization recommendedfexinidazole, developed by the Drugs for Neglected Diseases initiative and partners[15] to replace melarsoprol as the first-line treatment for sleeping sickness caused byT. b. rhodesiense.[16]
Two arsenic-containingstereoisomers exist in a 3:1 molar ratio. Since melarsoprol is insoluble in water, dosage occurs via a 3.6%propylene glycol intravenous injection.[13] To avoid the risk of injection site reactions, melarsoprol must be given slowly.[17]
Melarsoprol used for the treatment of African trypanosomiasis with CNS involvement is given under a complicated dosing schedule. The dosing schedule for children and adults is 2–3.6 mg/kg/day intravenously for three days, then repeated every seven days for a total of three series.[8] To monitor for relapse, follow-up is recommended every six months for at least two years.[3]
Currently, melarsoprol is not recommended for use in pregnant women. The World Health Organization suggests that treatment be deferred until immediately after delivery since the effects of the medication on the developing fetus have not yet been established.[3]
Lactation guidelines associated with melarsoprol have not yet been established.[18]
Numerous warnings must be examined before melarsoprol treatment can be initiated. Prior to initiation, the following must be noted:glucose-6-phosphate dehydrogenase deficiency, kidney or liver disease, cardiac problems (high blood pressure, irregular beating of the heart orarrhythmias, any damage to the heart muscles and potential signs ofheart failure), preexisting nervous system disorders, and any signs of leprosy.[6]
Routine laboratory testing is needed before and after melarsoprol initiation. Laboratory parameters for both therapeutic effects and toxic effects need to be evaluated.[19]
Blood analysis is used to detect the presence of trypanosomes. An evaluation of thecerebrospinal fluid via alumbar puncture is also used to determine an individual's white blood count and level of protein. These are diagnostic criteria such that the presence of trypanosomes, an elevated white blood count greater than five per microliter, or a protein content greater than 40 mg are considered abnormal and initiation should be considered. Continuous cerebrospinal fluid evaluation should be repeated every six months for at least three years in individuals that have undergone melarsoprol treatment.[19][20]
To assess potential concerns related to toxicity, the following should be completed: a complete blood count, an assessment ofelectrolyte levels, liver and kidney function tests, and aurinalysis to detect the appearance, concentration and content of the urine.[19][21]
Melarsoprol should be given using glass syringes (if they can be reliably sterilized). Thepropylene glycol it contains is capable of dissolving plastic.[22]
Although melarsoprol cures about 96% of people with late stage disease, its toxicity limits its use.[9] About 1–5% of people die during treatment.[3] As a toxic organic compound of arsenic, melarsoprol is a dangerous treatment that is typically only administered by injection under the supervision of a licensed physician. Notable side effects are similar to arsenic poisoning. Among clinicians, it is colloquially referred to as "arsenic in antifreeze".[23] Severe and life-threatening adverse reactions are associated with melarsoprol. It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea and vomiting. In approximately 5–10% of cases, it causesencephalopathy. Of those, about 50% die due to encephalopathy-related adverse reactions.[8] Additional potentially serious side effects of melarsoprol include damage to the heart, presence of albumin in the urine that could be associated with kidney damage, and an increase in blood pressure.[3]
Drug resistance evolution is encouraged by the use ofdiminazene fornagana.[24]
Melarsoprol is aprodrug, a complex of melarsen oxide (amelamine derivative of phenylarsonous acid) withdimercaprol (also known as British anti-Lewisite, or BAL). It is metabolized to melarsen oxide in the body, which then forms a toxic compound known as Mel T, through binding with trypanothione, (aspermidine-glutathione adduct that replaces glutathione in trypanosomes).[6] While Mel T is a competitive inhibitor of trypanothione reductase, research suggests this is not sufficient to explain the rapid cell death of the trypanosome parasites.[25] Some research has also discredited the theory that the disruption of glycolysis is essential to its mechanism of action.[26]
While the exact mechanism of action of melarsoprol has not been determined beyond the formation of Mel T, it has been suggested that this complex is implicated in several cytotoxic processes, including inhibition of DNA synthesis and increasing susceptibility tooxidative stress.[27] This follows from the fact that trypanothione itself plays a role in the proper function of a variety of biochemical pathways.
Thehalf-life of melarsoprol is less than one hour, but bioassays indicate a 35-hour half-life. This is commonly associated with pharmacologic agents that have active metabolites. One such metabolite, melarsen oxide, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Melarsoprol clearance is 21.5 ml/min/kg and the half-life of melarsen oxide is approximately 3.9 hours.[28]
Melarsoprol is produced bySanofi and under an agreement with the WHO, it donates melarsoprol to countries where the disease is common.[29]
Melarsoprol was used to treat a patient with second-stageAfrican trypanosomiasis on season 1 episode 7 "Fidelity" of the medical dramaHouse MD.[30]
