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Table 1 Summary of included studies assessing methylene blue (MB) in the treatment of malaria

From: Efficacy and safety of methylene blue in the treatment of malaria: a systematic review

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
  1. ACPR adequate clinical and parasitological response, AQ amodiaquine, AS artesunate, CQ chloroquine, IQ isopentaquine, MB methylene blue, SAE serious adverse event
  2. aControlled phase II study
  3. bPhase II dose-finding study