. 2018 Apr 20;12(4):e0006422. doi: 10.1371/journal.pntd.0006422

Table 3. Characteristics of synthetic compounds for the treatment of human cystic and alveolar echinococcosis based on the published literature.

Compound	Disease	Assay setting			Dosage	Treatment		Efficacy assessment		Toxicity	References
Compound	Disease	In vitro	In vivo	In patients (n)	Dosage	Initiation (p.i.)	Duration	Activity against	Success^a (%)	Toxicity	References
ANTIVIRALS AND ANTIBIOTICS
Benzoic acid thioureides	AE	Yes	—	—	2–20 μM	N/A	1 week	Cysts	Yes (30-˃50)	N/A	[20]
Cetrimide	CE	Yes	Yes^c^,^d	—	1.5% (cetrimide) + 0.5% (chlorhexidine) (in vitro)	N/A	10 min (in vitro)	PSC	Yes (93, in vitro)	No	[15,73]
Cetrimide	CE	Yes	Yes^c^,^d	—	0.1–5% (in vivo)^f	N/A	1 min (in vivo)	PSC	Yes (100, in vivo)	No	[15,73]
Chlorhexidine gluconate	CE	—	Yes^b	Yes (30)	0.04% (in vivo)^f	N/S	5 min	PSC	Yes (100, in vivo)	N/S	[16,17]
Fluoride	CE	Yes	—	—	20%	N/A	16 h	PSC	Yes (100)	N/A	[140]
Glucose 50%	CE	Yes	—	—	50%	N/A	5 min	PSC	Yes (95)	N/A	[134]
H₂O₂	CE	Yes	—	See text	4%	N/A	10 min	PSC	Yes (96)	N/A	[73]
Isoprinosine	AE	Yes	Yes^b	—	2 mM (in vitro)	N/A (in vitro)	48 h (in vitro)	PSC, Cysts	Yes (95, in vitro)	N/S	[146,147]
	AE	Yes	Yes^b	—	0.5 g·kg^-1·day^-1 (in vivo)^e	3 moths (in vivo)	2 weeks (in vivo)	PSC, Cysts	Yes (42, in vivo)	N/S	[146,147]
	CE	—	Yes^b	—	1–2 g·kg^-1·day^-1,^e	10 months	2 weeks to 2 months	Cysts	Yes (80–90)	N/S	[143]
Monensin	CE	Yes	—	—	10 μM	N/A	3 days	PSC	Yes (100)	N/A	[137]
Nitrite and peroxynitrite	CE	Yes	—	—	80–320 μM	N/A	1–2 days	PSC	Yes (100)	N/A	[138]
Povidone-iodine	CE	Yes	—	See text	10%	N/A	N/S	PSC	Yes (100)	N/A	[90]
Rifampicin	AE	Yes	—	—	10 μg·mL^-1	N/A	6 weeks	Cysts	No	N/A	[144,145]
Rifampicin	CE	—	Yes	—	9 mg·kg^-1,^e	3 months	2 weeks	Cysts	No	N/S	[142]
Saline 20%	CE	Yes	—	See text	20%	N/A	10 min	PSC	Yes (99–100)	N/A	[73,90]
Sodium arsenite	CE	Yes	—	—	20 M	N/A	6 days	PSC	Yes (100)	N/A	[141]
Taurolidine	CE	Yes	Yes^b	—	5 mg·mL^-1 (in vitro)	N/A (in vitro)	1.5 h (in vitro)	PSC	Yes (100, in vitro)	No	[139]
Taurolidine	CE	Yes	Yes^b	—	400 mg·kg^-1 (in vivo)^g^,^h	0–3 months (in vivo)	Single dose (in vivo)	PSC	Yes (prophylaxis) No (therapy)	No	[139]
Trimetoprim-sulfametoxazole	AE	Yes	—	—	0.02 mg·mL^-1	N/A	4 weeks	Cysts	No	N/A	[144]
ANTIPROTOZOA
Artemisinin and synthetic ozonide derivates	CE	Yes	—	—	40 μM	N/A	4 days	PSC	Yes (90)	N/A	[95]
	AE	Yes	Yes^b	—	20–40 μM (in vitro)	N/A (in vitro)	4–5 days (in vitro)	Cysts	Yes (100, in vitro)	Yes	[95,149]
	AE	Yes	Yes^b	—	200 mg·kg^-1·day^-1 (in vivo)^e	2 months (in vivo	6 weeks (in vivo)	Cysts	Yes (75–100, in vivo)	Yes	[95,149]
Mefloquine	AE	Yes	Yes^b	—	60 μM (in vitro)	N/A (in vitro)	2–5 days (in vitro)	Cysts	Yes (100, in vitro)	Yes (see [152])	[97,152]
					60 μM (in vitro)	N/A (in vitro)	8 weeks (in vivo)^g		Yes (100, in vitro)
					25 mg·kg^-1·day^-1 (in vivo)^g	1.5 months (in vivo)^e^{. g}	12 weeks (in vivo)^e		Yes (100^g, 78^e, in vivo)
					100 mg·kg^-1 3 days^-1 (in vivo)^e	1.5 months (in vivo)^e^{. g}	12 weeks (in vivo)^e		Yes (100^g, 78^e, in vivo)
Mefloquine enantiomer DB1127	AE	Yes	Yes^b	—	20 μM (in vitro)	N/A (in vitro)	5 days (in vitro)	Cysts	Yes (100, in vitro)	Yes	[98,153]
					50 mg·kg^-1·day^-1 (in vivo)^e	N/A (in vitro)	4 weeks (in vivo)^e		No (in vivo)^e
					2 mg·kg^-1·day^-1 (in vivo)^g	1.5 months (in vivo)	6 weeks (in vivo)^g		Yes (70, in vivo)^g
Miltefosine	AE	Yes	—	—	7.5 μg·mL^-1	N/A	6 weeks	Cysts	No	N/A	[144,145]
Nitazoxanide	AE	Yes	Yes^b	Yes (6)	10 μg to 5 mg·mL^-1 (in vitro)	N/A (in vitro)	10 days-6 weeks (in vitro)	Cysts	Yes (variable, in vitro and in vivo)	Yes	[5] [6] [22] [145] [150] [154]
					3 mg·day^-1 (in vivo)^e	0–2 months (in vivo)	35 days (in vivo)
					N/S (in patients)	15 months (in patients)	15 months (in patients)		No (in patients)
	CE	—	Yes^c	See text	15 mg·kg^-1·week^-1 or 30 mg·kg^-1·day^-1 (in vivo)^e	N/A	5 days to 5 weeks	Cysts	No	No	[26]
Nitazoxanide derivates RM4807 and RM4841	AE	Yes	—	—	5 mg·mL^-1	N/A	5 days	Cysts	Yes (N/S)	N/A	[22]
ANTIHELMINTHIC
Clorsulon	AE	Yes	—	—	15 μg·mL^-1	N/A	20 days	Cysts	No	N/A	[120]
Ivermectin	AE	Yes	—	—	1.75 mg·mL^-1	N/A	6 weeks	Cysts	No	N/A	[144,145]
	CE	Yes	Yes^b	—	0.1 mg·mL^-1 (in vitro)	N/A (in vitro)	50–72 h (in vitro)	PSC, Cysts	Yes (100, in vitro)	N/S	[160] [161] [162] [163]
	CE	Yes	Yes^b	—	4 mg·kg^-1·day^-1 (in vivo)^e	48 h or 4 months (in vivo)	4 months (in vivo)	PSC, Cysts	No (in vivo)	N/S	[160] [161] [162] [163]
Levamisole	CE	Yes	—	—	0.1 mg·mL^-1	N/A	6 days	PSC	Yes (100)	N/A	[160]
Praziquantel	CE	Yes	—	See text	0.1 mg·mL^-1	N/A	48 h	PSC	Yes (100)	N/A	[14]
	AE	Yes	Yes^b	See text	10 μg·mL^-1 (in vitro)	N/A (in vitro)	N/S (in vivo)	PSC, Cysts	Yes (100, in vitro)	N/S	[164,165]
	AE	Yes	Yes^b	See text	300 mg·kg^-1·day^-1 (in vivo)^e	1 month (in vivo)	69 days (in vivo)	PSC, Cysts	No (in vivo)	N/S	[164,165]
ANTIARTHROPODA
Lufenuron	CE	—	Yes^b	—	100 mg·kg^-1·day^-1,ⁱ	4 months	4 months	Cysts	No	N/S	[28]
ANTIMYCOTIC
Caspofungin	AE	Yes	—	—	0.07 mg·mL^-1	N/A	1.5 months	Cysts	No	N/A	[144]
Itraconazole	AE	Yes	—	—	0.7 mg·mL^-1	N/A	5 weeks	Cysts	No	N/A	[144,145]
IMMUNOMODULATORS
Cyclosporin A	AE	—	Yes^b	—	40 mg·kg^-1·day^-1,ⁱ	1.5 months	80 days	Cysts	No	N/A	[170]
	CE	Yes	Yes^b	—	50 μg·mL^-1 (in vitro)	N/A (in vitro)	15 days (in vitro)	PSC, Cysts	Yes (100, in vitro)	N/S	[168,169]
	CE	Yes	Yes^b	—	50 mg·kg^-1·day^-1 (in vivo)ⁱ	4.5 months (in vivo)	5 days (in vivo)	PSC, Cysts	Yes (42, in vivo)	N/S	[168,169]
ANTINEOPLASTIC
Bortezomib	AE	Yes	Yes^b	—	0.5 μM (in vitro)	N/A (in vitro)	5 days (in vitro)	Cysts	Yes (100, in vitro)	N/S	[177]
Bortezomib	AE	Yes	Yes^b	—	0.7 mg or 0.5 kg^-1·week^-1 (in vivo)^g	6 weeks (in vivo)	3 weeks (in vivo)	Cysts	No (in vivo)	N/S	[177]
Doxorubicin (nanoparticles)	AE	—	Yes^b	—	5 mg·kg^-1,^h	70–80 days	2 doses	Cysts	Yes (60)	N/S	[179]
Genistein and derivates	AE, CE	Yes	—	—	10 μg·mL^-1	N/A	4 to 14 days	PSC, Cysts	Yes (60–100 for PSC, N/S for cysts in vitro)	N/A	[173]
Imatinib	AE	Yes	—	—	50 μM	N/A	1–3 weeks	Cells, PSC, Cysts	Yes (100)	N/A	[174]
5-fluorouracil, Paclitaxel	CE	Yes	—	—	10 μg·mL^-1	N/A	7–72 days	Cells, PSC, Cysts	Yes (100, for 5-fluorouracil)	N/A	[175]
Methotrexate, Navelbine, Vincristine	AE	Yes	—	—	2.4–60 nM	N/A	5 days	Cysts	No	N/A	[171]
2-Methoxyestradiol	CE	Yes	—	—	10 μM	N/A	1 week	Cysts	Yes (100)	N/A	[172]
	AE	Yes	Yes^b	—	10 μM (in vitro)	N/A (in vitro)	1 week (in vitro)	Cysts	Yes (100, in vitro)	N/A	[172]
	AE	Yes	Yes^b	—	200 mg·kg^-1·day^-1 (in vivo)^e	2 months (in vivo)	6 weeks (in vivo)	Cysts	No (in vivo)	N/A	[172]
Mitomycin C	AE	—	Yes^b	—	0.1 mg·week^-1,^g	1 day or 1 month	3 weeks	Cysts	Yes (76)	N/A	[180]
η(6)-Areneruthenium (II) phosphite	AE	Yes	—	—	20 μM	N/A	5 days	Cysts	Yes (100)	N/A	[176]
Tamoxifen	CE	Yes	Yes^b	—	20 μM (in vitro)	N/A (in vitro)	2–7 days (in vitro)	PSC, Cysts	Yes (100, in vitro	N/S	[25]
Tamoxifen	CE	Yes	Yes^b	—	20–200 mg·kg^-1·day^-1 (in vivo)^e	3–6 months (in vivo)	32–80 days (in vivo)	PSC, Cysts	Yes (61–83, in vivo)	N/S	[25]
GENOME-BASED
Kinase inhibitor BI2536	AE	Yes	—	—	50 nM	N/A	2–3 weeks	Cells, Cysts	Yes (100 for cysts; 98 for cells)	N/A	[182]
Kinase inhibitors ML3403 and SB202190	AE	Yes	—	—	5 μM	N/A	4 days (cysts), 4 weeks (cells)	Cells, Cysts	Yes (100 for cells, 50 for cysts)	N/A	[183]
Kinase inhibitor SB202190	CE	Yes	—	—	80 μM	N/A	1 day	PSC	Yes (70)	N/A	[184]
OTHERS
Chenodeoxycholic acid	CE	Yes	—	—	2 M	N/A	10 days	PSC	Yes (100)	N/A	[188]
Selenium nanoparticles	CE	Yes	—	—	500 μg·mL^-1	N/A	10 min	PSC	Yes (100)	N/A	[186]

N/A: Not applicable; N/S: Not specified; PSC: Protoscoleces.

^a Defined as a significant reduction of the parasite burden or the viability of the any form of the larval stage of the parasite, including protoscoleces or cysts.

^b Experimental infection in mice.

^c Natural infection in sheep.

^d Natural infection in cattle.

^e Oral or intra-gastric administration.

^f Intracystic injection administration.

^g Intraperitoneal administration.

^h Intravenous administration.

ⁱ Subcutaneous administration.