Table 2.

Approved drugs for the treatment of human trypanosomiasis.

Drug class	Drug name	Molecular targets	Disease form	Disease stage	Drug form	Dosage	Major limitations and side effects	Year of discovery	References
Human African trypanosomiasis (HAT)
Diamidine	Pentamidine	Binds to parasite DNA, inhibits type II topoisomerase, and disrupts mitochondrial DNA	Effective against T. b. gambiense infection; most used drug for early HAT	First stage	Colorless powder	4 mg/kg/day IM or IV (diluted in saline in 2-h infusions) × 7 d (67–69)	Hypoglycemia, hypotension, drug resistance, reasonably tolerable, yet do not permeate through the BBB (therefore only used for treating stage 1 HAT), highly polar and these drugs are available in powder form for parenteral use during treatment of the early stage of disease	1940	(4, 70, 71)
Polysulfonated naphthyl amine	Suramin	Non-specifically binds to L-α-glycerophosphate oxidase	T. b. rhodesiense	First stage	Powder and ready-to-use solution	IM or intravenous (IV) route Test dose of 4–5 mg/kg (Day 0) slowly IV, then 20 mg/kg IV (max 1 gm/injection) over several hours on Days 1, 3, 7, 14, and 21 For children, 10–20 mg/kg of Suramin is given, and maximum of 1 g at times considered. In situations of renal toxicity, daily dose and the interval between doses should be adjusted accordingly (67, 68)	Toxicity, e.g., nephrotoxicity, allergic reaction, although reasonably tolerable, but unable to cross BBB (therefore only used for treating stage 1 of the disease), highly polar, has a short half-life, and is available in ready-to-use solution or powder form for parenteral use during treatment of the early phase of the disease	1920	(72–77)
Melaminophenyl arsenical (MPA)	Melarsoprol	Inhibition of trypanothine reductase	Both gambiense and rhodesiense infections (T. b. gambiense and T. b. rhodesiense infections); currently recommended as first-line treatment for the rhodesiense form, rarely used in the gambiense form	Second stage	Ready-to-use solution in propylene glycol	IV route 2.2 mg/kg per day (max 180–200 mg/day) IV × 10 d Likely chance of developing encephalopathic reaction to melarsoprol can be avoided by considering pretreatment with corticosteroid drugs (67, 68, 78–80)	Narrow therapeutic index, highly toxic, reactive encephalopathy Can cross the BBB, has a long half-life of 35 hours, therefore is widely used during treatment of late stages of the disease, but the associated encephalopathy and drug resistance limit its use	1949	(71, 72, 81–86)
Ornithine analog	Eflornithine	Inhibits ornithine decarboxylase	This drug is much less toxic than melarsoprol but is only effective against T. b. gambiense; it is generally used in combination with nifurtimox (as part of the nifurtimox-eflornithine combination therapy, NECT) but can also be used as monotherapy	Second stage	IV infusion	IV route	Large doses (400 mg/kg), the regimen is complex and cumbersome to apply, has a short half-life, and these drugs are available in ready-to-use solution for parenteral use during treatment of the early stage of disease	Registered in 1990	(81, 82, 84, 87–91)
NECT	Nifurtimox-eflornithine combination therapy	Synergistic effect of individual drugs	Effective replacement of toxic melarsoprol in stage 2 T. b. gambiense infection; simplifies the use of eflornithine by reducing the duration of treatment and the number of IV perfusions	Second stage	Nifurtimox tablets and eflornithine IV infusion	Oral route (nifurtimox) and IV route (eflornithine) Nifurtimox 15 mg/kg per day orally in 3 doses for 10 d, and eflornithine 400 mg/kg/day IV in two 2-h infusions (each dose diluted in 250 mL of water for injection) × 7 d For children weighing below 10 kg, eflornithine should be diluted in 50 mL of water for injection while those with body weights of 10–25 kg, this drug should be diluted in 100 mL of water for injection. If water for injection is unavailable, eflornithine can be diluted in 5% dextrose or saline (67–69) Eflornithine might not be effective in immunosuppressed patients because it is trypanostatic and not trypanocidal	Less effective against T. b. rhodesiense	Introduced in 2009
Nitroimidazole	Fexinidazole	The precise mechanism of action of this drug remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins (metabolic activation by a bacteria-like nitroreductase)	T. brucei, i.e., T. b. gambiense and T. b. rhodesiense	First and second stage; it is indicated as the first line for the first stage and non-severe second stage.	Oral tablets	Oral route	There is decreased efficacy in patients with severe stage 2 HAT), therefore it should be used in case of no other available treatment options	It is a new oral nitroimidazole drug candidate entering clinical trials for the treatment of sleeping sickness, has recently been identified as a promising new drug for HAT; delivered in 2018; is included in 2019 in the WHO essential medicines list and WHO HAT treatment guidelines.	(71, 87, 92–95)