Scientists In Singapore Discover New Drug Against Malaria

Scientists from the Singapore Immunology Network (SIgN) of Singapore’s Agency of Science, Technology and Research’s (A*STAR) led by Dr Laurent Renia have made a breakthrough concerning a drug that is effective against malaria.

Their work, carried out with industry leader Novartis, the Swiss Tropical and Public Health Institute, and The Scripps Research Institute, was published in top scientific journal Science.

The discovery and validation of the new drug, spiroindolone NITD609, is timely as many strains of drug-resistant malaria are emerging.

Dr Renia and his team of scientists from SIgN played a significant role in the testing and validation of the drug. With the help of a pioneering technology, Dr Renia tested spiroindolone NITD609 against field isolates – samples of the parasite isolated directly from patients.

This enabled researchers to obtain a clearer picture of how the drug would perform in a real life situation. In addition, Dr Renia’s team also tested the drug against a strain of malaria, P. vivax, that cannot be cultured in a lab, showing that the drug was also effective against another important species of malaria parasites.

Said Dr Renia, “We are excited to be able to contribute to the fight against malaria with our expertise and know-how. Our technology enabled Novartis to obtain a clearer picture of how their drug might perform in the field, giving them a better idea of the effectiveness of their spiroindolone NITD609. Moving forward, we will continue to collaborate with Novartis in the necessary steps to bring the drug closer to a medical reality. ”

Prof Paola Castagnoli, Scientific Director of SIgN, commented, “Malaria is a threat that kills approximately one child every 45 seconds. This kind of collaboration between SIgN and Novartis represents how the talent and know-how of our researchers can be applied to problems as pressing and urgent as malaria. SIgN will continue to explore ways in which we can work together with the private sector (biotech and pharma companies) to fight against human infectious diseases.”

Dr Renia and his team plan to continue the fight against malaria by assisting Novartis in the further testing of other possible drug candidates against field isolates.

They are also planning to further develop SIgN’s expertise in technologies that can be used in the fight against malaria by developing a new, fast, and robust assay using portable flow cytometer to test drugs in field conditions

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New malaria pill matches Novartis drug in study

A new drug for malaria proved as effective as Novartis's leading treatment Coartem in a clinical trial, researchers said on Friday, although an outside expert said the findings had limitations.
Coartem is the current "gold standard" for people infected with the mosquito-borne disease. The two-in-one Novartis drug needs to be taken twice a day and requires a fatty diet for optimum absorption.

Pyramax from South Korean drugmaker Shin Poong Pharmaceuticals is taken just once daily.

A randomized Phase III study of Pyramax -- a fixed-dose combination of pyronaridine and artesunate -- showed a treatment response of 99.5 percent compared to 99.2 percent among patients on Coartem, which combines artemether and lumefantrine.

Researchers involved in the study wrote in the Lancet medical journal that a three-day course of Pyramax should be considered for inclusion in malaria treatment programs, especially given its low cost of less than $1 for adults and 50 cents for children.

In an accompanying comment, however, Dr Francois Henri Nosten of the Mahidol-Oxford University Tropical Medicine Research Programme said a limitation of the study was that it consisted of many older African children and adults who had probably acquired some malaria immunity.

He also raised concerns about patients on Pyramax having raised liver enzymes, a possible signal of liver toxicity.

The Pyramax study was sponsored by Shin Poong and the non-profit Medicines for Malaria Venture (MMV).

MMV argues it is vital to have multiple anti-malaria drugs available to ensure innovation and guarantee competition in the marketplace, thereby driving down prices for life-saving medicines in poor countries.

Pyramax was submitted to the European Medicines Agency for regulatory approval earlier this year.

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Threat of resistance to artemisinin-based anti-malarial drugs highlighted by new study

Malaria parasites in western Cambodia have become resistant to artemisinin-based therapies, the first-line treatment for malaria, according to a study published in the New England Journal of Medicine today. Resistance to the drugs makes them less effective and could eventually render them obsolete, putting millions of lives at risk.

Signs of artemisinin resistance have been reported in the region already, but this new research is the first detailed study of the problem. The study was funded by the Wellcome Trust, the Li Ka Shing Foundation, and the Global Malaria Programme of the World Health Organisation (through grants from the Bill and Melinda Gates Foundation and the Western Pacific Regional Office).

Malaria is a potentially deadly disease that kills more than a million people each year, mainly young children and pregnant women. It is caused by malaria parasites, which are injected into the bloodstream by infected mosquitoes. The most deadly form, Plasmodium falciparum, is responsible for nine out of ten deaths from malaria.

The most effective anti-malarial drug is artemisinin, derived from Artemisia annua, also known as sweet wormwood, which had been used in Chinese medicine for centuries under the name Qinghaosu. It was rediscovered in the 1970s, evaluated first in South-East Asia, and eventually accepted as an essential component of antimalarial treatment in the past few years. The artemisinin derivatives have the advantage over other anti-malarial drugs, such as chloroquine and mefloquine, in having few side effects and – until now – malaria parasites have no resistance against it.

Although the drugs – most commonly in the form of the derivative artesunate – can be used on their own as a monotherapy, fears over the possible development of resistance mean that they are usually given in conjunction with one or more other drugs as artemisinin-based combination therapies (ACTs), now recommended by the WHO as the first-line treatment for uncomplicated falciparum malaria in all endemic countries.

Following increasing reports that the efficacy of artemisinin monotherapies and combination therapies were declining in western Cambodia, researchers at the Wellcome Trust-Mahidol University Oxford Tropical Medicine Research Programme, based in Bangkok, studied the susceptibility of P. falciparum parasites to the drugs. The Research Programme is a collaboration between Mahidol University, Bangkok, and the University of Oxford, supported by the Wellcome Trust.

The researchers studied forty patients in each of Pailin, western Cambodia, and Wang Pha, north-western Thailand. In two open-label, randomised trials, each was given the relevant dosage appropriate to their body weight of either artesunate or a combination of artesunate and mefloquine.

On average, patients in Thailand were clear of parasites in 48 hours; in western Cambodia this took 84 hours – in other words, it took almost twice as long to clear the parasites in Cambodia as it did in Thailand.

During the treatment period, as the number of parasites in the blood falls, so the infection should clear. Its recurrence can be a sign that the drug treatment is not working effectively.

In this study, out of the twenty patients treated with the monotherapy in each country, there were recurrences of the infection in six patients in western Cambodia compared to just one person in Thailand. Of the twenty patients treated with the combination therapy, infection recurred in two patients in Cambodia compared to one in Thailand. These results again suggest that artemisinin was less effective on the Cambodian parasites.

"Our study suggests that malaria parasites in Cambodia are less susceptible to artemisinin than those in Thailand," says Dr Arjen Dondorp, lead author of the study. "This means that it takes longer to kill the parasites. Artemisinin should clear the parasites at an early stage, preventing them further maturing and reproducing. When the drug's action is impaired, it becomes more difficult to eliminate the parasites from the body.

"With artesunate losing its potency, ACTs rely much more on the weaker partner drug, increasing the risk that resistance also evolves towards the partner drug. This has very important consequences for the lifespan of ACTs. Losing ACTs would be a disaster for malaria control."

Artemisinin-based drugs have been in use in western Cambodia for around thirty years and the country was one of the earliest to switch to ACTs in 2001. However, the majority of patients in the region receive their medication from the private sector, which is less well regulated. Patients in the private sector are frequently provided with monotherapies or incomplete treatment courses. Added to this is the problem of substandard or counterfeit drugs with sub-clinical doses of artemisinin. This extended period of sub-optimal use of artemisinin-based drugs may have contributed to the emergence of resistance.

With signs of artemisinin-resistance occurring in other areas of Cambodia and Thailand, Dr Dondorp says swift action is required to contain the spread.

"Preventing the spread of resistant parasites when they emerge is crucial," he says. "The use of combination therapies is very important for this. I would like to see a ban on artesunate monotherapy except for specific cases."

Professor Nick White, co-author of the study and Chair of the Wellcome Trust South-East Asia Programme, believes the implications of the findings are potentially huge.
"Artemisinins are essential weapons in our war against malaria," he says. "If they become ineffective, we have no immediate replacement. The consequences could be devastating. Elimination of malaria will not be possible and millions of lives could be lost."

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New Lead On Malaria Treatment

Approximately 350 million to 500 million cases of malaria are diagnosed each year mostly in sub-Saharan Africa. While medications to prevent and treat malaria do exist, the demand for new treatments is on the rise, in part, because malaria parasites have developed a resistance to existing medications. Now, researchers at the Johns Hopkins University School of Medicine have discovered one way to stop malaria parasite growth, and this new finding could guide the development of new malaria treatments.

“Our research on malaria is in line with Johns Hopkins’ mission to address health problems on a global level,” says Jun O. Liu, Ph.D., a professor of pharmacology and molecular sciences. “Our findings offer both a new potential molecular target for treating malaria and a compound that interacts at that target. These are important steps in discovering drugs that could help to treat malaria.” The results of the research were published in the February 27 issue of Chemistry & Biology.

Liu’s research team has for many years studied MetAP2 proteins, which are found in all organisms — from humans to single-celled bacteria — and essential for cell survival. They reasoned that if the malaria parasite has its own MetAP2, finding a chemical that disrupts MetAP2 function may lead to a new drug to stop parasite growth and malaria spread. So they searched a computer database of the sequence of the malaria parasite genome and found one protein very similar to human MetAP2, which they named PfMetAP2 for plasmodium falciparum, the parasite that causes malaria.

Recently other researchers reported that the natural antibiotic fumagillin can stop malaria parasites from growing, possibly by interfering with MetAP2. But the man-made version of fumagillin causes brain cells to die, so Liu’s team made several compounds chemically related to fumagillin in hopes of finding one less toxic but still effective in interfering with PfMetAP2. They chose to further study one of these compounds, fumarranol, because it interacts with human MetAP2 and is less toxic to mice.

The team first tested whether fumarranol can stick to and interfere with PfMetAP2 by treating mouse cells containing PfMetAP2 with different amounts of fumarranol and fumagillin and comparing them to untreated cells. In treated cells, fumarranol stuck to PfMetAP2 and stopped it from working.

They next asked whether fumarranol could stop malaria parasites from growing in a culture dish. They treated both drug-resistant and multidrug-resistant strains of Plasmodium falciparum and found that fumarranol could stop the parasite from multiplying.

The team then gave mice infected with malaria fumarranol for four days after infection and measured the parasite load in the blood. They found that after four days, fumarranol worked as well as fumagillin to slow infection. After another 26 days they again measured parasites in the blood, found that some mice carried no observable level of parasites and considered these animals cured.

“The next step for establishing a new treatment for malaria would be to test whether fumarranol is the most optimal treatment or if new compounds that are similar to fumarranol might be even more specific to malaria parasites,” Liu says.

This research was funded by a pilot grant from the Malaria Research Institute of Johns Hopkins Bloomberg School of Public Health and the Department of Pharmacology, Johns Hopkins School of Medicine and the Keck Foundation.

Authors on the paper are X. Chen, S. Xie, S. Bhat, T.A. Shapiro, and J.O. Liu of the Johns Hopkins University School of Medicine, and N. Kumar of the Johns Hopkins Bloomberg School of Public Health.

Source : www.hopkinsmedicine.org

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Novel ”double whammy” drug may treat malaria

Researchers from Portland State University have developed what they call a ‘double whammy’ drug that not only kills malaria parasite but also reverses resistance to other drugs.

The drug called acridone derivative has been developed by Jane Kelly and colleagues, and it contains a chemical, which prevents the malaria parasite getting rid of a toxic by-product of feeding on red blood cells.

By combining the new drug with existing ones such as chloroquine and quinine, it inhibits the genetic defence mechanism thus allowing them to do their job.

When the parasite enters the body it attacks red blood cells and take away the haemoglobin, from which they take amino acids as their food.

The by-product of this process called haem is toxic to the malaria parasites, carried by mosquitoes, however they convert it into the non-toxic form called haemozoin.

The new drug thwarts the conversion process.

“What we wanted was to design a molecule that would be of itself an antimalarial drug, but that would have the power to work together with drugs like chloroquine and quinine, even against parasites that were resistant to those drugs,” The BBC quoted Dr Mike Riscoe from Portland State University as saying.

“We would hope to make existing drugs like chloroquine and quinine useful again, so combining those with this new one could help to combat the rising tide of drug resistance in this neglected disease,” he added.

While the researchers have successfully tested the new compound in mouse models, they need to conduct further experiments to understand its effectiveness before moving on to human studies.

The team says it could be at least 10 years before the drug is available.

Source : www.duniyalive.com

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New malaria drug fights resistance

U.S. researchers said on Wednesday they had designed a new kind of malaria drug that kills the parasite that causes the disease and keeps it from becoming resistant to the drug.

Tests in mice show the compound also helps other malaria drugs work better, the researchers reported in the journal Nature.

Now they are looking for funding to step up development, Jane Kelly and colleagues at the Veteran Affairs Medical Center and Oregon Health and Science University in Portland said.

Malaria is a mosquito-borne disease that kills 880,000 people a year, most of them in Africa and most under the age of 5. There is no vaccine against the parasite that causes the illness and it quickly evolves resistance against drugs.

Kelly and colleagues set out to design a drug that could stop the parasite.

"When the parasite invades the human body, it takes up the red blood cells," Kelly said in a telephone interview. "They take the hemoglobin from our red blood cells and they chew it up."

The iron-containing heme in these cells is toxic to the parasites but they can convert it to a nontoxic form.

Chloroquine and other drugs stop this process but the parasite can develop the ability to pump these drugs out of its stomach.

"We engineered a new scaffold with both features incorporated into one molecule," the researchers wrote in Nature. It is called by its chemical name for now, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)- acridone).

The new drug works in the same way as the older drugs by keeping heme toxic to the parasite, plus it stops them from pumping it out of their bodies, Kelly said.

"On its own it is intrinsically potent, and in combination with other antimalarials it is synergistic," Kelly said. "It helps the other antimalarials."

Source : www.reuters.com

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