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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