Melarsoprol

Melarsoprol

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250px
Systematic (IUPAC) name
(2-(4-(4,6-diamino-1,3,5-triazin-2-ylamino)phenyl)- 1,3,2-dithiarsolan-4-yl)methanol
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy category	?
Legal status	?
Routes of administration	IV
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Biological half-life	35 hours
Excretion	Renal
Identifiers
CAS Number	494-79-1 N
ATC code	P01CD01 (WHO) QP51AD04 (WHO)
PubChem	CID: 10311
ChemSpider	9889 Y
UNII	ZF3786Q2E8 Y
KEGG	D00832 Y
ChEMBL	CHEMBL166 Y
Chemical data
Formula	C12H15AsN6OS2
Molecular mass	398.341 g/mol
SMILES OCC1S[As](SC1)c3ccc(Nc2nc(nc(n2)N)N)cc3
InChI InChI=1S/C12H15AsN6OS2/c14-10-17-11(15)19-12(18-10)16-8-3-1-7(2-4-8)13-21-6-9(5-20)22-13/h1-4,9,20H,5-6H2,(H5,14,15,16,17,18,19) Y Key:JCYZMTMYPZHVBF-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Melarsoprol (INN) is a prodrug used in the treatment of East African (rhodesiense) human African trypanosomiasis. It is produced by Sanofi-Aventis and is on the World Health Organization's List of Essential Medicines.

Freidheim demonstrated in 1949 the effects of melarsoprol against late-state trypanosomiasis. Melarsoprol is the dimercaptopropanol derivative of melarsen oxide (Mel Ox), whose structure is shown below:

The main drug prescribed is Mel B, however, an alarming number of side effects occur from treatment. The active metabolite of Mel B is Mel Ox, which is taken up by the TbAT1 adenosine transporter in T. brucei brucei. Due to side effects similar to arsenic poisoning, other pharmacological agents have become first-line treatments for stage one of the disease and for certain trypanosomes.

Medical uses

All people with confirmed trypanosome-caused disease must be treated. Treatment differs based on whether disease levels are considered stage 1 or stage 2 and based on which specific trypanosome has infected a patient. Below are treatment options (all adapted from ).

Melasarprol is used in the treatment of the second stage of the disease, and is the only treatment available for late-stage T. b. rhodesiense treatment.

Due to high toxicity, melarsarprol is reserved only for the most dangerous of cases - stage 2 infection. Other agents with lower toxicity are used in stage 1. The 2009 approval of nifurtimoxeflornithine combination therapy (NECT) for the treatment of T. b. gambiense served to limit merlarsoprol to the treatment of second-stage T. b. rhodesiense solely.

Failure rates of 20-27% in certain African countries have been reported. These are linked to both drug resistance and other mechanisms which 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 this transporter.

Side effects

Being a toxic organic compound of arsenic, melarsoprol is a highly dangerous treatment which is only administered by injection under the supervision of a physician, as it can produce similar effects as arsenic poisoning. Among clinicians, it is colloquially referred to as "arsenic in antifreeze". It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea, and vomiting. It causes encephalopathy in 5–10% of cases, of which 40% die.

Mechanism of action

Melarsoprol is a prodrug, which is metabolized to melarsen oxide (Mel Ox) as its active form. Mel Ox is an arsen-oxide which irreversibly binds to vicinal sulfhydryl groups causing the inactivation of enzymes. The inability to distinguish between host and parasites renders this drug highly toxic with many side effects.

Mel Ox reacts with trypanothione (a spermidine-glutathione adduct which replaces glutathione in trypanosomes). Binding to this adduct forms a melarsen oxide-trypanothione adduct (Mel T) which competitively inhibits trypanothione reductase, effectively killing the parasitic cell.

Dosage

Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. As melarsarprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection.

Pharmacokinetics

The half-life of melarsoprol is less than 1 hour, but bioassays indicate a 35-hour half-life. This is indicative of pharmacologic agents with active metabolites. One such metabolite, Mel Ox, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Clearance is at 21.5 ml/min/kg and Mel Ox half-life is 3.9 hours.