Table 1.
Summary of included studies assessing methylene blue (MB) in the treatment of malaria
| Study: First Author Place of study (Year) |
Patient information | Malaria type | Malaria diagnosis | MB treatment | Follow-up | Efficacy outcome | Safety outcome | Other Information |
|---|---|---|---|---|---|---|---|---|
| Randomised controlled trials | ||||||||
| Coulibaly et al. Burkina Faso (2015) [55] |
n = 193 (6–59-month-old children) |
P. falciparum | By microscope | Arm 1: AS-AQ-MB (n = 92) (MB: 15 mg/kg per day for 3 days) Arm 2: AS-AQ (n = 101) Formulation: mini-tablets |
28 days | ACPR was 80% in arm 1, and 85% in arm 2. Significant lower gametocyte prevalence on day 7 in arm 1 compared to arm 2 (both microscopically and molecular biologically) Clearance of P. falciparum asexual parasites in AS-AQ-MB took 1.82 days compared to 1.96 days in the AS-AQ group |
MB regimen was associated with more vomiting. Haemoglobin values were significantly lower in arm 1 than in arm 2 at day 2 and day 7 (difference 0.5–1.0 mg/dl) | (1) There were no differences in parents and caregivers self-reported acceptance rate between groups (2) The MB mini-tablets were provided on a spoon with local food to improve the acceptability for children |
| Zoungrana et al. Burkina Faso (2008) [56, 57] |
n = 180 (6–10-year-old children) |
P. falciparum | By microscope | Arm 1: MB-AS (n = 61) Arm 2: MB-AQ (n = 58) (MB: 20 mg/kg per day for 3 days) Arm 3: AS-AQ (n = 61) Formulation: taste-masked tablets |
28 days | ACPR was 62% in arm 1, 95% in arm 2 and 82% in arm 3 MB regimens were associated with a more rapid parasite clearance and significantly reduced gametocyte prevalence during follow-up |
MB regimen was associated with vomiting and dysuria | Vomiting was shown to be much reduced by administering MB together with food |
| Meissner et al. Burkina Faso (2005) [58] |
n = 226 (6–59-month-old children) |
P. falciparum | By microscope | Arm 1: CQ-MB (n = 181) (MB: 4 mg/kg per day for 3 days) Arm 2: CQ (n = 45) Formulation: 0.5% MB solution |
14 days | ACPR was 56% (93/166) in arm 1 compared to 46% (19/41) in arm 2 | No differences in SAEs, and no cases of severe haemolysis No differences in haemoglobin over time in both the G6PD-deficient and G6PD-sufficient subgroups |
Administration of the bitter-tasting MB solution was sometimes difficult, especially in younger children |
| Non-randomised control trials | ||||||||
| Bountogo et al. Burkina Faso (2010)a [59] |
n = 60 (age range: 18–55 years, median 25) |
P. falciparum | By microscope | Arm 1: MB for 7 days (n = 20) Arm 2: MB for 5 days (n = 20) Arm 3: MB for 3 days (n = 20) MB: 780 mg per day Formulation: taste-masked tablets |
28 days | Arm 1: 0/20 recrudescence Arm 2: 4/19 recrudescence Arm 3: 2/20 recrudescence |
Dysuria (47/60). Gastrointestinal symptoms (13/60). No significant differences in adverse events between groups |
MB was given at a dose of 390 mg twice daily after breakfast and supper |
| Meissner et al. Burkina Faso (2006)b [60] |
n = 435 (6–59-month-old children) |
P. falciparum | By microscope | Arm 1: CQ-MB (n = 156) (MB: 12 mg/kg per day for 3 days) Arm 2: CQ-MB (n = 155) (MB: 18 mg/kg per day for 3 days) Arm 3: CQ-MB (n = 123) (MB: 24 mg/kg per day for 3 days) Formulation: 2.3% MB solution |
14 days | Overall clinical and parasitological cure rate on day 14 was 90% (326/364) and 77% (278/364) respectively, without differences between groups | There were three SAEs, one probably associated with MB Haemoglobin development was not associated with G6PD deficiency |
MB was given with fruit flavouring and honey supplement to mask the bitter taste |
| Alving (1949) Cited by Baird et al. USA (2012)a [61] |
n = 37 | P. vivax | Clinical | Arm 1: IQ (n = 10) Arm 2: IQ-quinine (n = 15) Arm 3: IQ-MB (n = 9) (MB: 500 mg per day) Arm 4: IQ-MB-quinine (n = 3) (MB: 500 mg per day) All treatments were for 14 days |
14 days | Arm 1: 9/10 relapsed Arm 2: 5/15 relapsed Arm 3: 3/9 relapsed Arm 4: 0/3 relapsed |
1/10 in arm 1 experienced severe haemolysis; after being treated again with IQ plus MB for 14 days, no haemolysis | – |
| Case series | ||||||||
| Mayer Russia (1919) [62] |
n = 3 | P. malariae | By microscope | 1000 mg per day over 30 days (16 days MB and 14 days breaks); MB divided into five doses of 200 mg per day | 52–72 days | 2/3: cure 1/3: relapsed after 4 months |
Mild urogenital symptoms despite daily nutmeg application | – |
| Panse Africa (1902) [63] |
n = 2 | P. malariae | By microscope | Case 1: 400–1000 mg per day for 14 days Case 2: 600–1000 mg per day for 32 days |
14–32 days | Case 1: cure Case 2: failure | No safety information | Both patients were pretreated with quinine |
| Glogner Indonesia (1901) [64] |
n = 6 (2 adults, 4 children) |
P. vivax/ovale | By microscope | Adults: 1000 mg every 2 days; 1000 mg per day Children: 300 mg per day every 5 days; 300 mg per day every 2 days |
2–7 months | 6/6 relapsed | No safety information | All patients were pretreated with quinine |
| Ollwig (1899) Africa [65] |
n = 10 |
P. vivax/ovale (3/10) P. falciparum (4/10) P. malariae (1/10) P. vivax/ovale and P. falciparum (1/10) Unspecified (1/10) |
By microscope | 300 mg per day to 1000 mg per day for 3 days to 14 days, followed by breaks of 5–8 days. The regimen was cycled up to 3 months | 8 days to 3 months | 7/10: cured 3/10: failure |
Urogenital symptoms (n = 2) Vomiting after MB intake (n = 3) Diarrhoea (n = 1) |
Frequent vomiting of MB reported in 2/3 failure cases 6/10 cases were pretreated with quinine Nutmeg was taken together with MB against urogenital symptoms |
| Cardamatis Greece (1898) [66] |
n = 275 (157/118 male/female); 129 children, 91 youths, 55 adults |
P. vivax/ovale (72/275) P. falciparum (178/275) P. malariae (21/275) Unspecified (4/275) |
Clinical | In 245/275 MB monotherapy Adults: 400–500 mg per day Youth: 300 mg per day Children: 200 mg per day Infants: 20–40 mg per day Regimens given in four doses per day (every 2 hours) initially for 6–12 days and for a total of 22–60 days (with variable pauses) In 30/275 MB in combination with quinine or arsenic |
Up to 1 year | 257/275 cured 18/275 failure |
Urogenital symptoms observed only with very high MB doses Colouring properties in particular in association with vomiting of children |
Good efficacy in quinine non-responders Nutmeg was taken together with MB against urogenital symptoms |
| Röttger Germany (1895) [67] |
n = 7 | No specific information |
Clinical | 600–800 mg per day for 8–33 days | 8–33 days | 6/7 cured 1/7 failure |
1/7 vomiting after MB1/7 urogenital symptoms | Nutmeg helped to reduce the urogenital side effects |
| Ferreira Brazil (1893) [68] |
n = 21 (2–180-month-old children, median 18 months) |
No specific information |
Clinical | 200–600 mg per day, usually in divided doses, for 3–30 days | 3–30 days (median 9 days) | 21/21 cured | 1/21 reported urogenital symptoms | 5/21 initial treatment with quinine failed |
| Parenski and Blatteis Europe (1893) [69] |
n = 35 | No specific information |
By microscope | 800–1500 mg per day | 7 days to 4 months | 33/35 cases cured after 7 days 2/35 failure |
Divided small doses (0.1–0.2 g) of MB rarely produced side effectsDivided higher doses (0.4–0.6 g) of MB produced more side effects, in particular vomiting and urogenital symptoms | Medicinale MB Merck free of chlorinated zinc, lead and arsenic was used |
| Thayer USA (1892) [70] |
n = 7 (age range: 17–58 years, median 33) |
P. vivax/ovale (3/7) P. malariae (1/7) Unspecified (3/7) |
Clinical | 400–1000 mg per day for 7–23 days | 7–23 days |
4/7 cured 3/7 failure |
Urogenital symptoms (3/7) Dizziness (1/7) |
Nutmeg was taken together with MB to reduce urogenital symptoms |
| Guttmann and Ehrlich Germany (1891) [29] |
n = 2 | P. vivax/ovale | By microscope | 500 mg per day for 12–24 days | 1–2 months | 2/2 cured | Urogenital symptoms (n = 1) | Nutmeg was taken together with MB to reduce urogenital symptoms |
| Case reports | ||||||||
| Mühlens and Kirschbaum Germany (1921) [71] |
n = 1 | P. vivax/ovale | By microscope | 1000 mg per day for 7 days followed by alternating 5-day breaks and 3-day treatments with 1000 mg per day for 3 months | 3 months | Cured | No safety information | Nutmeg was taken together with MB to reduce urogenital symptoms |
| Atkinson China (1903) [72] |
n = 1 (male child) |
Unspecified | By microscope | 300 mg per day | 11 days | Cured | Gastrointestinal disorder | Initial treatment with quinine failed |
| Sivers Germany (1901) cited by Merck (1922) [73, 74] |
n = 1 (15-year-old girl) |
P. vivax/ovale | By microscope | 500 mg per day | 3 days | Cured | Vomiting | – |
| Anonymous Germany (1893) [75] |
n = 1 (32-year-old man) |
P. vivax/ovale | By microscope | 1000 mg on day 1, 500 mg on day 2, then 300 mg for 14 days, then continued treatment for 6 weeks |
2 months | Parasite-free on day 7, relapse on day 14, and cured without relapse on day 60 | Urogenital symptoms | MB dose for treatment after relapse not specified Nutmeg helped to reduce urogenital side effects |
| Trintignan India (1882) cited by Röttger (1895) [67] |
n = 1 | P. falciparum | Clinical | 2000 mg per day during acute attack, followed by 500 mg per day until day 20 | 20 days | Cured | None | – |
ACPR adequate clinical and parasitological response, AQ amodiaquine, AS artesunate, CQ chloroquine, IQ isopentaquine, MB methylene blue, SAE serious adverse event
aControlled phase II study
bPhase II dose-finding study