Melarsoprol

Last updated
Melarsoprol
Melarsoprol2DCSD.svg
Melarsoprol-3D-spacefill.png
Clinical data
Trade names Arsobal [1]
Other namesMel B, Melarsen Oxide-BAL [2]
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration 		IV
ATC code
Pharmacokinetic data
Elimination half-life 35 hours
Excretion Kidney
Identifiers
  • (2-{4-[(4,6-Diamino-1,3,5-triazin-2-yl)amino]phenyl}-1,3,2-dithiarsolan-4-yl)methanol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.007.086 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H15AsN6OS2
Molar mass 398.33 g·mol−1
3D model (JSmol)
  • OCC1S[As](SC1)c3ccc(Nc2nc(nc(n2)N)N)cc3
  • 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) Yes check.svgY
  • Key:JCYZMTMYPZHVBF-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Melarsoprol is an arsenic-containing medication used for the treatment of sleeping sickness (African trypanosomiasis). [1] It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved. [1] For Trypanosoma brucei gambiense , eflornithine or fexinidazole is usually preferred. [1] It is effective in about 95% of people. [3] It is given by injection into a vein. [2]

Contents

Melarsoprol has a high number of side effects. [4] Common side effects include brain 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 with glucose-6-phosphate dehydrogenase (G6PD) deficiency, red blood cell breakdown may occur. [2] It has not been studied in pregnancy. [2] It works by blocking pyruvate kinase, an enzyme required for aerobic metabolism by the parasite. [2]

Melarsoprol has been used medically since 1949. [1] It is on the World Health Organization's List of Essential Medicines. [5] In regions of the world where the disease is common, melarsoprol is provided for free by the World Health Organization. [4] It is not commercially available in Canada or the United States. [2] In the United States, it may be obtained from the Centers for Disease Control and Prevention, while in Canada it is available from Health Canada. [1] [2]

Medical uses

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 or T. 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. [6]

The following are considerable treatment options: [6]

Melarsoprol is a treatment used during the second stage of the disease. So far, it is the only treatment available for late-stage T. b. rhodesiense. [7]

Due to high toxicity, melarsoprol is reserved only for the most dangerous cases. Other agents associated with lower toxicity levels are used during stage 1 of the disease. [8] The approval of the nifurtimox-eflornithine combination therapy (NECT) in 2009 for the treatment of T. b. gambiense limited the use of melarsoprol to the treatment of second-stage T. b. rhodesiense. [9]

Failure rates of 27% in certain African countries have been reported. [10] This was caused by both drug 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 this transporter. [11] Resistance has been present since the 1970s. [12]

Mechanism of action

Melarsoprol is a prodrug, a complex of melarsen oxide (a melamine derivative of phenylarsonous acid) with dimercaprol (also known as British anti-Lewisite, or BAL). It is metabolized to melarsen oxide in the body, which then acts by irreversibly binding to sulfhydryl groups on the enzyme pyruvate kinase, thus disrupting energy production in the parasite. The inability to distinguish between the host's and the parasite's pyruvate kinase renders this drug highly toxic, with many side effects.[ citation needed ]

Melarsen oxide also reacts with trypanothione (a spermidine-glutathione adduct that replaces glutathione in trypanosomes). It forms a melarsen oxide-trypanothione adduct (Mel T) that competitively inhibits trypanothione reductase, effectively killing the protist. [11]

Pharmacokinetics

The half-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. [13]

Dosage

Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. Since melarsoprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection. [11] To avoid the risk of injection site reactions, melarsoprol must be given slowly.[ citation needed ]

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. [6] To monitor for relapse, follow-up is recommended every six months for at least two years. [3]

Side effects

Although melarsoprol cures about 96% of people with late stage disease, its toxicity limits its use. [7] 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". [14] 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 causes encephalopathy. Of those, about 50% die due to encephalopathy-related adverse reactions. [6] 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]

Cautions

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 or arrhythmias, any damage to the heart muscles and potential signs of heart failure), preexisting nervous system disorders, and any signs of leprosy.[ citation needed ]

Routine laboratory testing is needed before and after melarsoprol initiation. Laboratory parameters for both therapeutic effects and toxic effects need to be evaluated.[ citation needed ]

Blood analysis is used to detect the presence of trypanosomes. An evaluation of the cerebrospinal fluid via a lumbar 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.[ citation needed ]

To assess potential concerns related to toxicity, the following should be completed: a complete blood count, an assessment of electrolyte levels, liver and kidney function tests, and a urinalysis to detect the appearance, concentration and content of the urine.[ citation needed ]

Melarsoprol should be given using glass syringes (if they can be reliably sterilized). The propylene glycol it contains is capable of dissolving plastic. [15]

Pregnancy and breastfeeding

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.[ citation needed ]

Society and culture

Melarsoprol is produced by Sanofi-Aventis and under an agreement with the WHO, they donate melarsoprol to countries where the disease is common. [16]

Melarsoprol was used to treat a patient with second-stage African trypanosomiasis on season 1 episode 7 "Fidelity" of the medical drama House MD . [17]

Resistance

Drug resistance evolution is encouraged by the use of diminazene for nagana. [18]

Related Research Articles

<span class="mw-page-title-main">African trypanosomiasis</span> Parasitic disease also known as sleeping sickness

African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 92% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.

<span class="mw-page-title-main">Tsetse fly</span> Genus of disease-spreading insects

Tsetse are large, biting flies that inhabit much of tropical Africa. Tsetse flies include all the species in the genus Glossina, which are placed in their own family, Glossinidae. The tsetse is an obligate parasite, which lives by feeding on the blood of vertebrate animals. Tsetse has been extensively studied because of their role in transmitting disease. They have a pronounced economic impact in sub-Saharan Africa as the biological vectors of trypanosomes, causing human and animal trypanosomiasis.

<span class="mw-page-title-main">Pentamidine</span> Medical antimicrobial drug

Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin. It is an option for both visceral leishmaniasis and cutaneous leishmaniasis. Pentamidine can be given by injection into a vein or muscle or by inhalation.

<span class="mw-page-title-main">Trypanosomiasis</span> Medical condition

Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and Chagas disease. A number of other diseases occur in other animals.

<span class="mw-page-title-main">Suramin</span> Medical drug

Suramin is a medication used to treat African sleeping sickness and river blindness. It is the treatment of choice for sleeping sickness without central nervous system involvement. It is given by injection into a vein.

<i>Trypanosoma</i> Genus of parasitic flagellate protist in the Kinetoplastea class

Trypanosoma is a genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Euglenozoa. The name is derived from the Greek trypano- (borer) and soma (body) because of their corkscrew-like motion. Most trypanosomes are heteroxenous and most are transmitted via a vector. The majority of species are transmitted by blood-feeding invertebrates, but there are different mechanisms among the varying species. Trypanosoma equiperdum is spread between horses and other equine species by sexual contact. They are generally found in the intestine of their invertebrate host, but normally occupy the bloodstream or an intracellular environment in the vertebrate host.

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

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis and excessive hair growth on the face in women. Specifically it is used for the second stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is taken intravenously or topically. It is an ornithine decarboxylase inhibitor.

<i>Trypanosoma brucei</i> Species of protozoan parasite

Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases: African trypanosomiasis or sleeping sickness in humans, and animal trypanosomiasis or nagana in cattle and horses. It is a species complex grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. The first is a parasite of non-human mammals and causes nagana, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.

Winterbottom's sign is a swelling of lymph nodes (lymphadenopathy) along the posterior cervical lymph node chain, associated with the early phase of African trypanosomiasis, a disease caused by the parasites Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It may be suggestive of cerebral infection. Winterbottom reported about the slave traders who, apparently aware of the ominous sign of swollen cervical lymph glands, used to palpate the necks of the slaves before buying them.

<span class="mw-page-title-main">Nifurtimox</span> Anti-parasitic medical drug

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease it is a second-line option to benznidazole. It is given by mouth.

<span class="mw-page-title-main">Alan Fairlamb</span> British biochemist

Alan Hutchinson Fairlamb, CBE, FRSE, FLS, FMedSci, FRSB is a Wellcome Trust Principal Research Fellow and Professor of Biochemistry in the Division of Biological Chemistry and Drug Discovery at the School of Life Sciences, University of Dundee, Scotland. From 2006-2011 he was a member of the Scientific and Technical Advisory Committee of the Special Programme for Research and Training in Tropical Diseases (TDR) -- an independent global programme of scientific collaboration co-sponsored by UNICEF, UNDP, the World Bank and WHO. Currently he is a member of the governing board of the Tres Cantos Open Lab Foundation, whose aim is to accelerate the discovery and development of medicines to tackle diseases of the developing world in an open collaborative manner.

<span class="mw-page-title-main">Trypanothione synthase</span> Class of enzymes

In enzymology, a trypanothione synthase (EC 6.3.1.9) is an enzyme that catalyzes the chemical reaction

Wendy Gibson is Professor of Protozoology at University of Bristol, specialising in trypanosomes and molecular parasitology.

Fexinidazole is a medication used to treat African trypanosomiasis caused by Trypanosoma brucei gambiense. It is effective against both first and second stage disease. Also a potential new treatment for Chagas disease, a neglected tropical disease that affects millions of people worldwide. It is taken by mouth.

<span class="mw-page-title-main">Louise Pearce</span> American pathologist (1885–1959)

Louise Pearce was an American pathologist at the Rockefeller Institute who helped develop a treatment for African sleeping sickness (trypanosomiasis). Sleeping sickness was a fatal epidemic which had devastated areas of Africa, killing two-thirds of the population of the Uganda protectorate between 1900 and 1906 alone. With chemists Walter Abraham Jacobs and Michael Heidelberger and pathologist Wade Hampton Brown, Pearce worked to develop and test arsenic-based drugs for its treatment. In 1920, Louise Pearce traveled to the Belgian Congo where she designed and carried out a drug testing protocol for human trials to establish tryparsamide's safety, effectiveness, and optimum dosage. Tryparsamide proved successful in combating the fatal epidemic, curing 80% of cases.

<span class="mw-page-title-main">John William Watson Stephens</span> British parasitologist (1865–1946)

John William Watson Stephens FRS (1865–1946) was a British parasitologist and expert on tropical diseases.

<span class="mw-page-title-main">Acoziborole</span> Antiprotozoal drug to treat sleeping sickness

Acoziborole (SCYX-7158) is an antiprotozoal drug invented by Anacor Pharmaceuticals in 2009, and now under development by the Drugs for Neglected Diseases Initiative for the treatment of African trypanosomiasis.

Nifurtimox/eflornithine is a combination of two antiparasitic drugs, nifurtimox and eflornithine, used in the treatment of African trypanosomiasis. It is included in the World Health Organization's Model List of Essential Medicines.

Victor Kande Betu Kumeso is a Congolese physician who is an expert in African trypanosomiasis. He works at the Programme National de Lutte contre la Trypanosomiase Humaine Africaine at the University of Kinshasa.

<span class="mw-page-title-main">Robert Michael Forde</span>

Robert Michael Forde was Colonial Surgeon in The Gambia when in 1901, he made the first definitive observation of trypanosomes in a human being when he found them in the blood of a steamboat master on the Gambia River. In 1907 he became principal medical officer of Sierra Leone.

References

  1. 1 2 3 4 5 6 "Our Formulary". Infectious Diseases Laboratories. CDC. 22 September 2016. Archived from the original on 16 December 2016. Retrieved 7 December 2016.
  2. 1 2 3 4 5 6 7 8 "Melarsoprol Drug Information, Professional". Drugs.com. 20 December 1994. Archived from the original on 30 December 2016. Retrieved 7 December 2016.
  3. 1 2 3 4 5 6 "WHO Model Prescribing Information: Drugs Used in Parasitic Diseases - Second Edition: Protozoa: African trypanosomiasis: Melarsoprol". WHO. 1995. Archived from the original on 2016-11-10. Retrieved 2016-11-09.
  4. 1 2 "Trypanosomiasis, human African (sleeping sickness)". World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. 1 2 3 4 CDC (2013). "Disease Control and Prevention: Parasites – African Trypanosomiasis". Archived from the original on 2017-06-19.
  7. 1 2 Pepin J (2014). "Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African Trypanosomiasis) - Infectious Disease and Antimicrobial Agents". antimicrobe.org. Archived from the original on 2016-11-28. Retrieved 2016-11-17.
  8. ↑ Bisser S, N'Siesi FX, Lejon V, Preux PM, Van Nieuwenhove S, Miaka Mia Bilenge C, Būscher P (February 2007). "Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness". The Journal of Infectious Diseases. 195 (3): 322–329. doi:10.1086/510534. PMID   17205469. S2CID   10175400.
  9. ↑ Manson's tropical diseases: expertconsult. Vol. 23 (23rd ed.). Edinburgh: Elsevier Saunders. 2014. p. 616. ISBN   978-0-7020-5306-1.
  10. ↑ Kioy D, Jannin J, Mattock N (March 2004). "Human African trypanosomiasis". Nature Reviews. Microbiology. 2 (3): 186–187. doi: 10.1038/nrmicro848 . PMID   15751187. S2CID   36525641.
  11. 1 2 3 Brunton L (2011). Goodman & Gillman's The Pharmacological Basis of Therapeutics. McGraw Hill Medical. pp. 1427–28.
  12. ↑ Brun R, Schumacher R, Schmid C, Kunz C, Burri C (November 2001). "The phenomenon of treatment failures in Human African Trypanosomiasis". Tropical Medicine & International Health. 6 (11): 906–914. doi: 10.1046/j.1365-3156.2001.00775.x . PMID   11703845. S2CID   21542129.
  13. ↑ Keiser J, Ericsson O, Burri C (May 2000). "Investigations of the metabolites of the trypanocidal drug melarsoprol". Clinical Pharmacology and Therapeutics. 67 (5): 478–488. doi:10.1067/mcp.2000.105990. PMID   10824626. S2CID   24326873.
  14. ↑ Hollingham R (2005). "Curing diseases modern medicine has left behind". New Scientist. 2005 (2482): 40–41. Archived from the original on 2015-05-11.
  15. ↑ "MELARSOPROL injectable - Essential drugs". medicalguidelines.msf.org. Retrieved 6 December 2019.
  16. ↑ "WHO renews agreement with sanofi-aventis". who.int. Retrieved 15 February 2022.
  17. ↑ Holtz A (2006). The Medical Science of House, M.D. Penguin. p. 272. ISBN   1440628734 . Retrieved 25 March 2020.
  18. ↑ Maudlin I (December 2006). "African trypanosomiasis". Annals of Tropical Medicine and Parasitology. Taylor & Francis. 100 (8): 679–701. doi:10.1179/136485906x112211. PMID   17227648. S2CID   19567898. ...cites this study: Fèvre EM, Coleman PG, Odiit M, Magona JW, Welburn SC, Woolhouse ME (August 2001). "The origins of a new Trypanosoma brucei rhodesiense sleeping sickness outbreak in eastern Uganda". Lancet. Elsevier BV. 358 (9282): 625–628. doi:10.1016/s0140-6736(01)05778-6. PMID   11530149. S2CID   205937568.
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