Old Stain in a New Combination
New combinations of agents based on the oldest synthetic malaria drug, the methylene blue stain, can curb the spread of malaria parasites and make a significant contribution to the long-term eradication called for by the international “Roll Back Malaria Initiative.” In a study on 160 children with malaria in Burkina Faso, specialists in tropical medicine from the Heidelberg University Hospital have shown that in combination with newer malaria drugs, methylene blue prevents the malaria pathogen in infected persons from being re-ingested by mosquitoes and then transmitted to others and is thus twice as effective as the standard therapy. The results of the study were published in May 2009 in the online journal PLoS One.
Malaria is still one of the deadliest tropical diseases. Every year, 300 million people are infected with malaria and more than one million of them die or suffer severe brain damage. Children under five years are particularly susceptible.
Malaria pathogens need humans and mosquitoes
When the Anopheles mosquito bites, the malaria parasites (plasmodia) in the saliva of the mosquito enter the human body, reproduce in liver cells and then attack the red blood cells. This causes severe symptoms such as high fever or anemia; children in particular can even fall into a coma. During reproduction in the human body, some parasites develop into special reproductive cells, gametocytes. If they are ingested by an Anopheles mosquito, they continue to reproduce in the mosquito. The cycle is complete.
The gametocytes are the key for the spread of malaria by the Anopheles mosquito. Common malaria drugs known as artemisinins block reproduction of the parasites in the human body and reduce the number of gametocytes in blood by half. This makes the transmission of the parasite to the mosquito more difficult but does not completely prevent it. “We urgently need alternative therapies that are effective against the gametocytes and thus improve the control of malaria,” states Professor Dr. Olaf Müller, Project Head in the Department of Tropical Medicine and Public Health of the Hygiene Institute at the University of Heidelberg.
Methylene blue prevents transmission to mosquitoes
The appropriate component for such an alternative is a proven agent – the methylene blue stain which has been given to malaria patients since the end of the 19th century has proven to be safe, well tolerated, and effective in combination with various malaria medications.
In the current study in Burkina Faso with 160 malaria patients between the ages of six and ten the Heidelberg scientists tested the effect of combination therapies with artemisinins and methylene blue on gametocytes in the blood. One group of the children received the standard treatment, consisting of a combination of artesunate and amodiaquine. Two other groups received methylene blue combined with one of the two drugs respectively. The physicians checked the number of gametocytes in blood samples three, seven, and fourteen days after the start of therapy.
Combination therapy is twice as effective as standard therapy
It was shown that both combination therapies are twice as effective against gametocytes as the standard therapy – these parasites had almost completely disappeared in the first few days. “Methylene blue not only inhibits the formation of the reproductive forms, but also destroys already existing cells,” explains Professor Müller. “In this way, the profiles of methylene blue and artemisinins, which quickly and effectively eliminate the parasites in the red blood cells, complement each other.” Since the study group from Heidelberg has used methylene blue in Western Africa for years, it has already been adequately clinically tested – severe or frequent side effects did not occur. Especially important is that the combination makes it more difficult for resistance to artemisinins to develop.
The study is a project in the special research area SFB 544 “Control of Tropical Infectious Diseases” of the German Research Association, to which scientists and physicians from the university hospital and other Heidelberg research centers belong.
Boubacar Coulibaly, Augustin Zoungrana, Frank P. Mockenhaupt, R. Heiner Schirmer, Christina Klose, Ulrich Mansmann, Peter E. Meissner, and Olaf Müller. Strong Gametocytocidal Effect of Methylene Blue-Based Combination Therapy against Falciparum Malaria: A Randomised Controlled Trial. PLoS ONE. 2009; 4(5): e5318. Published online 2009 May 5. DOI: 10.1371/journal.pone.0005318.
Prof. Dr. med. Olaf Müller, MPH
Department of Tropical Hygiene and Public Health
Heidelberg University Hospital
Im Neuenheimer Feld 324
phone: +49 6221 / 56 50 35
Heidelberg University Hospital and Medical Faculty:
Internationally recognized patient care, research, and teaching
Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 7,000 employees, training and qualification is an important issue. Every year, around 500,000 patients are treated on an inpatient or outpatient basis in more than 40 clinics and departments with 1,600 beds. Currently, about 3,100 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany.
Requests by journalists:
Dr. Annette Tuffs
Head of Public Relations and Press Department
University Hospital of Heidelberg and
Medical Faculty of Heidelberg
Im Neuenheimer Feld 672
phone: +49 6221 / 56 45 36
fax: +49 6221 / 56 45 44