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==Overview==
==Overview==
Medical treatment of [[African trypanosomiasis]] should begin as soon as possible and is based on the [[infected]] person’s symptoms and laboratory results. [[Pentamidine isethionate]] and [[suramin]] (under an investigational New Drug Protocol from the [[Centers for Disease Control and Prevention|CDC]] Drug Service) are the drugs of choice to treat the hemolymphatic stages of West and [[African trypanosomiasis|East African Trypanosomiasis]], respectively. [[Melarsoprol]] is the drug of choice for late disease with [[central nervous system]] involvement (infections by ''[[Trypanosoma brucei gambiense|T.b. gambiense]]'' or ''[[Trypanosoma brucei rhodesiense|T. b. rhodiense]]''). Hospitalization for treatment is necessary. Periodic follow-up exams including a [[spinal tap]] are required for 2 years. If a person fails to receive medical treatment for [[African trypanosomiasis]], death will occur within several weeks to months.<ref name="pmid23260189">{{cite journal |vauthors=Kennedy PG |title=Clinical features, diagnosis, and treatment of human African trypanosomiasis (African trypanosomiasis|sleeping sickness) |journal=Lancet Neurol |volume=12 |issue=2 |pages=186–94 |year=2013 |pmid=23260189 |doi=10.1016/S1474-4422(12)70296-X |url=}}</ref><ref name="pmid27072715">{{cite journal |vauthors=Singh Grewal A, Pandita D, Bhardwaj S, Lather V |title=Recent Updates on Development of Drug Molecules for Human African Trypanosomiasis |journal=Curr Top Med Chem |volume=16 |issue=20 |pages=2245–65 |year=2016 |pmid=27072715 |doi= |url=}}</ref><ref name="pmid17160135">{{cite journal |vauthors=Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, Checchi F, Ghabri S, Piola P |title=Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda |journal=PLoS Clin Trials |volume=1 |issue=8 |pages=e39 |year=2006 |pmid=17160135 |pmc=1687208 |doi=10.1371/journal.pctr.0010039 |url=}}</ref><ref name="pmid16080099">{{cite journal |vauthors=Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA |title=Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis |journal=Clin. Infect. Dis. |volume=41 |issue=5 |pages=748–51 |year=2005 |pmid=16080099 |doi=10.1086/432576 |url=}}</ref>


==Medical Therapy==
==Medical Therapy==
*Medical treatment of East African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Medication for the treatment of East African trypanosomiasis is available through the CDC. Hospitalization for treatment is necessary. Periodic follow-up exams that include a spinal tap are required for 2 years. If a person fails to receive medical treatment for East African trypanosomiasis, death will occur within several weeks to months.
===Antimicrobial Regimen===
 
:* ''' Sleeping sickness'''<ref>{{cite web|title=African Trypanosomiasis| url=  http://www.cdc.gov/parasites/sleepingsickness/health_professionals/index.html}}</ref> 
*Medication for the treatment of West African trypanosomiasis is available. Hospitalized treatment of West African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Hospitalization for treatment is necessary.  Periodic follow-up exams that include a spinal tap are required for 2 years. West African trypanosomiasis is fatal if it is not treated.
::* 1. '''East African trypanosomiasis'''
 
:::* 1.1 '''''T. b. rhodesiense'', hemolymphatic stage'''
===Pharmacotherapy===
::::* 1.1.1 '''Adult '''
Pentamidine isethionate and suramin (under an investigational New Drug Protocol from the CDC Drug Service) are the drugs of choice to treat the hemolymphatic stage of West and East African Trypanosomiasis, respectively.  Melarsoprol is the drug of choice for late disease with central nervous system involvement (infections by T.b. gambiense or T. b. rhodiense).
:::::* Preferred regimen: [[Suramin]] 1 gm IV on days 1, 3, 5, 14, and 21
The current standard treatment for first stage disease is:
:::::* Alternate regimen: Fexinidazole po od
* Intravenous [[pentamidine]] (for ''T.b. gambiense''); or
::::* 1.1.2 '''Pediatric'''  
* Intravenous [[suramin]] (for ''T.b. rhodesiense'')
:::::* Preferred regimen: [[Suramin]] 20 mg/kg IV on days 1, 3, 5, 14, and 21
 
:::* 1.2 '''''T. b. rhodesiense'', CNS involvement'''
<ref>http://www.cdc.gov/ncidod/dpd/parasites/trypanosomiasis/factsht_ea_trypanosomiasis.htm#what
::::* 1.2.1 '''Adult'''
http://www.cdc.gov/ncidod/dpd/parasites/trypanosomiasis/factsht_wa_trypanosomiasis.htm#Top
:::::* Preferred regimen: [[Melarsoprol]] 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days
http://www.dpd.cdc.gov/dpdx/HTML/TrypanosomiasisAfrican.htm</ref>
::::* 1.2.2 '''Pediatric'''
 
:::::* Preferred regimen: [[Melarsoprol]] 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days  
The current standard treatment for second stage (late stage) disease is:
::* 2. '''West African trypanosomiasis'''
* Intravenous [[melarsoprol]] 2.2 [[Wiktionary:milligram|mg]]/[[Wiktionary:kilogram|kg]] daily for 10 consecutive days.<ref>{{cite journal | Burri C, Nkunku S, Merolle A, ''et al.'' | title=Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial | journal=Lancet | year=2000 | volume=355 | issue=9213 | pages=1419&ndash;25 | id=PMID 10791526 }}</ref>
:::* 2.1 '''''T. b. gambiense'', hemolymphatic stage'''
Alternative first line therapies include:
::::* 2.1.1 '''Adult'''
* Intravenous melarsoprol 0.6 mg/kg on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3 to 10;<ref name="Bisser2007">{{cite journal | author=Bisser S, N'Siesi F-X, Lejon V, ''et al.'' | journal=J Infect Dis | year=2007 | volume=195 | pages=322&ndash;29 | url=http://www.journals.uchicago.edu/JID/journal/issues/v195n3/36827/36827.html }}</ref> or
:::::* Preferred regimen: [[Pentamidine]] 4 mg/kg/day IM/IV for 7-10 days
* Intravenous [[eflornithine]] 50 mg/kd every six hours for 14 days.<ref>{{cite journal | author=van Nieuwenhove S, Schechter PJ, Declercq J, ''et al.'' | title=Treatment of gambiense sleeping sickness in the Sudan with oral DFMO (DL-alfa-difluoromethyl ornithine) an inhibitor of ornithine decarboxylase: first field trial | journal=Trans R Soc Trop Med Hyg | year=1985 | volume=79 | issue=5 | pages=692&ndash;8 }}</ref>
::::* 2.1.2 '''Pediatric'''
 
:::::* Preferred regimen: [[Pentamidine]] 4 mg/kg/day IM/IV for 7-10 days
In areas with melarsoprol resistance or in patients who have relapsed after melarsoprol monotherapy, the treatment should be:
:::::* Note (1): [[Pentamidine]] should only be used during [[pregnancy]] and [[lactation]] if the potential benefit justifies the potential risk
* melarsoprol and nifurtimox, or
:::::* Note (2): IM/IV [[Pentamidine]] have a similar safety profile in children age 4 months and older as in [[Adult|adults]]. [[Pentamidine]] is listed as a medicine for the treatment of 1st stage African trypanosomiasis infection (''[[Trypanosoma brucei gambiense]]'') on the '''[[World Health Organization|WHO]] Model List of Essential Medicines for Children''', intended for use in children up to 12 years of age
* eflornithine
:::* 2.2  '''''T. b. gambiense'', CNS involvement'''
 
::::* 2.2.1 '''Adult'''
The following traditional regimens should no longer be used:
:::::* Preferred regimen: [[Eflornithine]] 400 mg/kg/day  IV qid for 14 days
* (old "standard" 26-day melarsoprol therapy) Intravenous melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously for 3 days, with 7-day breaks between the series) (this regimen is less convenient and patients are less likely to complete therapy)<ref name="Pepin2006">{{cite journal | author=Pepin J, Mpia B | title=Randomized controlled trial of three regimens of melarsoprol in the treatment of ''Trypanosoma brucei gambiense'' trypanosomiasis | journal=Trans R Soc Trop Med Hyg | year=2006 | volume=100 | pages=437&ndash;41 | id=PMID 16483622 }}</ref>;
::::* 2.2.2 '''Pediatric'''
* (incremental melarsoprol therapy) 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3–10) (previously thought to reduce the risk of treatment-induced encephalopathy, but now known to be associated with an increased risk of relapse and a higher incidence of encephalopathy)<ref name="Bisser2007"/><ref name="Pepin2006"/>;
:::::* Preferred regimen: [[Eflornithine]] 400 mg/kg/day IV  qid for 14 days
 
:::::* Note (1): [[Eflornithine]] should only be used during [[pregnancy]] and [[lactation]] if the potential benefit outweighs the potential risk
According to a treatment study of Trypanosoma gambiense caused human African trypanosomiasis, use of eflornithine (DMFO) resulted in fewer adverse events than treatment with melaroprol. <ref>{{cite journal |author=Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA |title=Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis |journal=Clin. Infect. Dis. |volume=41 |issue=5 |pages=748-51 |year=2005 |pmid=16080099 |doi=10.1086/432576}}</ref>
:::::* Note (2): The safety of [[eflornithine]] in children has not been established. [[Eflornithine]] is not approved by the [[Food and Drug Administration]] ([[Food and Drug Administration|FDA]]) for use in [[pediatric]] patients. [[Eflornithine]] is listed for the treatment of 1st stage African trypanosomiasis in ''[[Trypanosoma brucei gambiense]]'' infection on the '''[[WHO]] model List of Essential Medicines for Children''', intended for use in children up to 12 years of age
 
All patients should be followed up for two years with lumbar punctures every six months to look for relapse.
 
===Historical perspective of treatment for sleeping sickness===
[[Suramin]] was introduced in 1920 to treat the first stage of the disease.  By 1922, Suramin was generally combined with Tryparsamide (another pentavalent organo-arsenic drug) in the treatment of the second stage of the gambiense form. It was used during the grand epidemic in West and Central Africa in millions of people and was the mainstay of therapy until 1969.  
 
[[Pentamidine]], a highly effective drug for the first stage of the disease, has been used since 1939. During the fifties, it was widely used as a [[prophylactic]] agent in Western Africa, leading to a sharp decline in infection rates. At the time, it was thought that eradication of the disease was at hand.
 
The organo-arsenical [[melarsoprol]] (Arsobal) was developed in the 1940s, and is effective for patients with second stage sleeping sickness. However, 3 - 10% of those injected have reactive [[encephalopathy]] (convulsions, progressive coma, or psychotic reactions), and 10 - 70% die; it can cause [[brain damage]] in those that survive the encephalopathy. However, due to its effectiveness, [[melarsoprol]] is still used today.  Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under research.
 
[[Eflornithine]] (difluoromethylornithine or DFMO), the most modern treatment, was developed in the 1970s by Albert Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was approved by the United States [[Food and Drug Administration]] in 1990, but [[Aventis]], the company responsible for its manufacture, halted production in 1999.  In 2001, however, Aventis, in association with [[Médecins Sans Frontières]] and the [[World Health Organization]], signed a long-term agreement to manufacture and donate the drug.
 
The genome of the parasite has been decoded and several proteins have been identified as potential targets for drug treatment. The decoded DNA also revealed the reason why generating a vaccine for this disease has been so difficult. ''T. brucei'' has over 800 genes that manufacture proteins that the disease mixes and matches to evade immune system detection.<ref>{{cite journal |author=Berriman M, Ghedin E, Hertz-Fowler C, ''et al'' |title=The genome of the African trypanosome Trypanosoma brucei |journal=Science |volume=309 |issue=5733 |pages=416-22 |year=2005 |pmid=16020726 |doi=10.1126/science.1112642 |url=http://www.sciencemag.org/cgi/content/full/309/5733/416}}</ref>
 
An international research team working in the Democratic Republic of the Congo, Southern Sudan and Angola involving Immtech International and University of North Carolina at Chapel Hill have completed a [[Phase IIb]] clinical trial and commenced a [[Phase III]] trial in 2005 testing the efficacy of the first oral treatment for Sleeping Sickness, known at this point as "DB289".
<ref>{{cite news
  |first=David
  |last=Williamson
  |title=Compound might defeat African sleeping sickness, clinical trial beginning this month
  |date=August 25, 2005
  |publisher=University of North Carolina
  |url=http://usinfo.state.gov/xarchives/display.html?p=washfile-english&y=2005&m=August&x=20050826160501cmretrop0.7327387&t=livefeeds/wf-latest.html
}}</ref>
<ref>{{cite news
  |author=Staff
  |page=5
  |title=Clinical Trials Update
  |date=September 15, 2005
  |publisher=[[Genetic Engineering News]]
}}</ref>
 
Recent findings indicate that the parasite is unable to survive in the bloodstream without its [[flagellum]]. This insight gives researchers a new angle with which to attack the parasite.<ref>{{cite web | title=African Sleeping Sickness Breakthrough | url=http://domino.lancs.ac.uk/info/LUNews.nsf/I/448E635736B6B25A8025714700317FD1 | accessdate=April 7 | accessyear=2006 }}</ref>
 
A new treatment based on a truncated version of the apolipoprotein L-1 of [[high density lipoprotein]] and a nanobody has recently been found to work in mice, but has not been tested in humans.<ref>
[[New Scientist]], [http://www.newscientist.com/channel/health/mg19526181.400-cholesterol-secret-of-our-killer-blood.html 25 Aug. 2007, pp. 35-7]
</ref>


==References==
==References==
{{reflist|2}}
{{reflist|2}}


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Latest revision as of 20:19, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Pilar Almonacid

Overview

Medical treatment of African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Pentamidine isethionate and suramin (under an investigational New Drug Protocol from the CDC Drug Service) are the drugs of choice to treat the hemolymphatic stages of West and East African Trypanosomiasis, respectively. Melarsoprol is the drug of choice for late disease with central nervous system involvement (infections by T.b. gambiense or T. b. rhodiense). Hospitalization for treatment is necessary. Periodic follow-up exams including a spinal tap are required for 2 years. If a person fails to receive medical treatment for African trypanosomiasis, death will occur within several weeks to months.[1][2][3][4]

Medical Therapy

Antimicrobial Regimen

  • Sleeping sickness[5]
  • 1. East African trypanosomiasis
  • 1.1 T. b. rhodesiense, hemolymphatic stage
  • 1.1.1 Adult
  • Preferred regimen: Suramin 1 gm IV on days 1, 3, 5, 14, and 21
  • Alternate regimen: Fexinidazole po od
  • 1.1.2 Pediatric
  • Preferred regimen: Suramin 20 mg/kg IV on days 1, 3, 5, 14, and 21
  • 1.2 T. b. rhodesiense, CNS involvement
  • 1.2.1 Adult
  • Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days
  • 1.2.2 Pediatric
  • Preferred regimen: Melarsoprol 2-3.6 mg/kg/day IV for 3 days. After 7 days, 3.6 mg/kg/day for 3 days. Give a 3rd series of 3.6 mg/kg/d after 7 days
  • 2. West African trypanosomiasis
  • 2.1 T. b. gambiense, hemolymphatic stage
  • 2.1.1 Adult
  • Preferred regimen: Pentamidine 4 mg/kg/day IM/IV for 7-10 days
  • 2.1.2 Pediatric
  • Preferred regimen: Pentamidine 4 mg/kg/day IM/IV for 7-10 days
  • Note (1): Pentamidine should only be used during pregnancy and lactation if the potential benefit justifies the potential risk
  • Note (2): IM/IV Pentamidine have a similar safety profile in children age 4 months and older as in adults. Pentamidine is listed as a medicine for the treatment of 1st stage African trypanosomiasis infection (Trypanosoma brucei gambiense) on the WHO Model List of Essential Medicines for Children, intended for use in children up to 12 years of age
  • 2.2 T. b. gambiense, CNS involvement
  • 2.2.1 Adult
  • Preferred regimen: Eflornithine 400 mg/kg/day IV qid for 14 days
  • 2.2.2 Pediatric

References

  1. ↑ Kennedy PG (2013). "Clinical features, diagnosis, and treatment of human African trypanosomiasis (African trypanosomiasis". Lancet Neurol. 12 (2): 186–94. doi:10.1016/S1474-4422(12)70296-X. PMID 23260189. Text "sleeping sickness) " ignored (help)
  2. ↑ Singh Grewal A, Pandita D, Bhardwaj S, Lather V (2016). "Recent Updates on Development of Drug Molecules for Human African Trypanosomiasis". Curr Top Med Chem. 16 (20): 2245–65. PMID 27072715.
  3. ↑ Priotto G, Fogg C, Balasegaram M, Erphas O, Louga A, Checchi F, Ghabri S, Piola P (2006). "Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda". PLoS Clin Trials. 1 (8): e39. doi:10.1371/journal.pctr.0010039. PMC 1687208. PMID 17160135.
  4. ↑ Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA (2005). "Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis". Clin. Infect. Dis. 41 (5): 748–51. doi:10.1086/432576. PMID 16080099.
  5. ↑ "African Trypanosomiasis".
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