Yellow fever

WHO, FDA Registered Antimalarial, Pyramax Approved For Coronavirus Clinical Trials

The World Health Organisation prequalified and Ghana Food and Drugs Authority registered Antimalarial Pyramax (Artesunate-Pyronaridine), a fixed-dose combination medication for the treatment of malaria, has been approved for clinical trials for Covid-19 in South Korea.

Also, it is being tried in South Africa, Kenya and Burkina Faso to pick African efficacy data.

The study, which is being led by the Liverpool School of Hygiene and Tropical Medicine, has the primary purpose to compare and evaluate Pyramax efficacy and safety in treating patients infected with the coronavirus, especially mild to moderate covid-19 infection and viral clearance (negative nasal swab) on Day 7.

Despite various drug development efforts, only vaccines led by AstraZeneca, Pfizer-BioNTech, Moderna, and more recently Sputnik V have been approved for the management of COVID-19.

Efforts towards drug treatment of COVID-19 is still ongoing. That notwithstanding, several drug molecules including drugs already approved for other diseases are emerging as providing benefits for the treatment of COVID-19 patients.

Between October 2020 to date, Sars-CoV-2 has manifested in three different variants from the original virus for which some vaccines were produced.

These mutations include the B.1.1351(501Y.V2) from South Africa, 501Y.V3 in Brazil and B.1.1.7 (501Y.V1) from the United Kingdom.

Following the higher transmissible nature of N501Y mutation familiar to all these variants from South Africa, Brazil and the UK, the projected impact of vaccines needs revision since highly transmissible variants lead to exponential growth in the number of infections.

This calls for consideration of alternative drug development avenues aside from vaccines.

Some drug molecules such as Pyronaridine, synthesized in 1970 at the Institute of Chinese Parasitic Disease has been used in China for over 30 years for the treatment of malaria.

Pyronaridine was approved as an orphan drug for the management of Ebola in different parts of the world and is showing promise in the fight against COVID-19 due to its antiviral properties.

In vitro studies comparing pyronaridine, artesunate and hydroxychloroquine against SARS-COV-2 show that pyronaridine-artesunate is more potent than hydroxychloroquine in the human lung epithelial cell line.

Artesunate, on the other hand, has similar antiviral properties and offers anti-inflammatory effects which suggest its potential usefulness in the treatment of COVID-19. The Estimated Study Completion date is September 30, 2021.

In 2017, Pyramax an oral drug produced as a result of a collaboration between Medicines for Malaria Venture (MMV), University of Iowa and Shin Poong Pharm, a South Korean pharmaceutical firm specializing in neglected tropical diseases were included in both the pediatric and adult Essential Medicines Lists of WHO for the treatment of uncomplicated malaria.

To enhance accessibility in Low- and Middle-Income Countries, the Global Fund has also included Pyramax in its list of drugs.

Internationally, Pyramax is registered in twenty-six countries with high malaria burden and locally registered by the Ghana Food and Drugs Authority since March 2020 for the management of uncomplicated malaria.

Source: GNA

New Antimalarial Prevents Malaria More Effectively Than Current Treatments But Does Not Improve Birth Outcomes

A large LSTM-led trial confirms new antimalarial, dihydroartemisinin-piperaquine, is more effective at preventing malaria than current WHO recommended treatment but does not improve adverse birth outcomes.

A large multi-country trial of 4680 women in sub-Sahara Africa, looking at new antimalarial treatment for pregnant women in Africa, led by Prof. Feiko ter Kuile, Professor of Tropical Epidemiology, Liverpool School of Tropical Medicine, publishes outcomes in The Lancet this week.

The trial, known as the IMPROVE trial, was jointly funded by the EDCTP-2 programme (supported by the European Union) and the UK Joint Global Health Trials. It confirms the new antimalarial, dihydroartemisinin-piperaquine, is better tolerated, safer, and prevents malaria more effectively than current WHO recommended treatment but does not improve birth outcomes.

Malaria in pregnancy can have devasting consequences for the mother and developing foetus, resulting in severe anaemia in the mother, maternal death, or the mother losing the pregnancy or the baby being born too early or too small. These premature and low birth weight babies have a four times higher risk of dying during their first year.

The WHO currently recommends using a form of malaria prophylaxis called intermittent preventive therapy during pregnancy, or IPTp for short. IPTp is used in 35 countries in sub-Saharan Africa but the malaria parasite has become increasingly resistant to the only drug currently recommended by the WHO for IPTp: sulfadoxine-pyrimethamine (SP), which threatens its efficacy in east and southern Africa.

In 2003, investigators began a worldwide series of clinical trials to find other antimalarials as suitable alternatives to SP. Out of five candidates evaluated, the antimalarial dihydroartemisinin-piperaquine (DP) was the only candidate tolerated well enough to be considered for further trials. By 2015 it was shown that DP was much more effective than SP in killing malaria parasites or preventing new infections and reducing severe anaemia in the mother. However, these earlier trials were not large enough to determine if this also reduced the risk of babies being born too early or too small. WHO recommended that more research was needed to evaluate the effect of IPTp with dihydroartemisinin-piperaquine on adverse pregnancy outcomes.

In response to this, the LSTM IMPROVE study took place in 12 hospitals in highly malarious areas in western Kenya, northern Tanzania, and southern Malawi, in a multi-country collaboration.

The trial confirmed that the new antimalarial DP was well tolerated, safe, and much more effective than SP. However, the results on birth outcomes were surprising. Despite the apparent superior effect of DP on malaria infections, the risk of adverse pregnancy outcomes was lower, rather than higher, in the SP arm, the arm which has much more malaria during pregnancy. Successive ultrasound scans revealed that babies showed better foetal growth during pregnancy; the chance of being born with low birthweight was 30% lower in the SP arm. There were no differences in the number of babies born too early, pregnancy loss or early infant deaths. The study also revealed that mothers in the SP arm had better weight gain during pregnancy and better nutritional status at delivery. The results were seen in all three countries, including northern Tanzania, which had the highest rates of SP resistance in sub-Saharan Africa.

A third arm, which included the addition of a single dose of the broad-spectrum antibiotic azithromycin at enrolment to monthly IPTp with DP, did not result in better pregnancy outcomes but increased the incidence of nausea in the mother.

Another surprising finding was that monthly SP was better at reducing the risk of chlamydia, one of the sexually transmitted diseases we investigated, when compared to azithromycin, which is the standard of care recommended by the WHO."

Dr Matthew Chico, Associate Professor at the London School of Hygiene & Tropical Medicine, and Co-Author

Dr Mwayiwawo Madanitsa, Senior Lecturer and Head of Department, Clinical Sciences, Academy of Medical Sciences, Malawi University of Science and Technology, and first author, said: "These results suggest that despite the waning antimalarial activity of SP, IPTp-SP continues to provide some benefits, even in areas with very high SP resistance. Our study also shows the importance of well-conducted trials before making policy recommendations."

Feiko ter Kuile, who was the senior author, said: "These results were unexpected as they showed that the new antimalarial was much more effective in treating and preventing malaria infections in pregnancy. However, the babies in the standard of care arm with SP did much better in terms of birthweights, even though the newborns in this arm were born to mothers with double the rate of malaria infections during pregnancy compared to those in the DP arm.

"This is surprising because malaria is one of the most important causes of low birth weight. We now hypothesize that SP has potent non-malarial effects on foetal growth. It does not mean DP had no beneficial effect on birth outcomes, but the non-malarial effects of SP on birthweight may outweigh any improvements in birthweight associated with better prevention from malaria in the DP arm, masking the beneficial effects of DP. We don't yet fully understand how SP promotes maternal gestational weight gain and foetal growth, independent of its antimalarial effects. More research is needed to explore the mechanism."

Whether WHO and countries in East and southern Africa update their recommendation for preventing malaria in pregnancy, in line with the findings, remains to be seen. Feiko ter Kuile continues: "DP is clearly the more effective drug in reducing malaria in pregnancy. So, if the main goal is to prevent severe malaria and malaria-associated deaths in the mother, DP is the better option. However, another option currently being explored is combining the potent non-malarial effects of SP on fetal growth with the superior antimalarial effects of DP, rather than replacing SP with DP in areas of high SP resistance."

An accompanying commentary in The Lancet suggests that studies that combine DP and SP are ongoing in Uganda and Papua New Guinea, and the first results may be available by 2025.

Researchers Use A 'Trojan Horse' Approach To Develop New Antimalarial Drugs

Antimalarial drug resistance is a pressing issue in combating the spread of malaria worldwide. In a new study, researchers from Children's Hospital of Philadelphia (CHOP) discovered a key process where malarial parasites take up a human blood cell enzyme, which could provide a new approach for antimalarial treatment. The findings, published today in the journal Proceedings of the National Academy of Sciences, provide new insights into how to design drugs that more effectively treat patients affected by this devastating infectious disease.

Despite many drugs and preventive strategies used to treat or halt the spread of malaria, the life-threatening disease continues to infect more than 250 million people each year, resulting in more than 600,000 deaths, the majority of which occur in children under the age of 5. Compounding this challenge, malarial parasites have become resistant to nearly every available antimalarial treatment. While a class of drugs known as artemisinin-based combination therapies (ACT) has helped save millions of lives that would have otherwise been claimed by malaria, ACT-resistant strains of malaria have been found in Southeast Asia and Africa. New treatment strategies are urgently needed to combat this disease.

Many potential drugs fail in development because they are poorly absorbed in the gastrointestinal tract or absorbed and removed from the body too rapidly. However, one promising strategy for drug development is the use of prodrugs, which are used to improve a drug's ability to be absorbed or reach its target. Prodrugs work like a Trojan horse in that they are able to offer a more targeted attack against infections and diseases once they break through and reach the appropriate tissues or cells. However, prodrugs are inactive and must be activated, typically by an enzyme, to achieve their desired effect. Researchers at CHOP set out to understand how antimalarial prodrugs are activated, in the hopes of identifying a way to more effectively treat malaria.

"Prodrugging is an enticing strategy because these drugs have methods for getting through the layers of protection offered by membranes of the parasite and host cells, as well as a drug 'warhead' that effectively kills the parasite," said senior study author Audrey R. Odom-John, MD, PhD, chief of the Division of Infectious Diseases at CHOP. "We've been working on prodrugs that might be effective for treating malaria, but in doing so, we've also needed to learn what kinds of enzymes within the parasite are capable of activating the prodrug, as that information is critical to understanding the nature of the target for future antimalarial strategies."

In this study, researchers found that a human enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme of multiple antimalarial prodrugs known as lipophilic ester prodrugs. The APEH enzyme is normally found in red blood cells. However, in the case of malaria, the enzyme is taken into the parasite's cytoplasm where APEH retains its activity. The researchers' findings suggest that APEH activates antimalarial prodrugs within the parasite, greatly increasing the potency of the lipophilic ester prodrugs.

While this finding was unexpected, the researchers note that it could help design "resistance-proof" prodrugs. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance. However, the parasite would be unable to mutate a host enzyme, decreasing the likelihood that drug resistance could develop by this mechanism.

"Based on our findings, we believe that leveraging an internalized host enzyme would circumvent these issues and enabling the design of prodrugs with higher barriers to drug resistance," said first study author Sesh A. Sundararaman, MD, PhD, an attending physician with the Division of Infectious Diseases at CHOP. "This might eventually lead to the development of parasite- or bacteria-specific prodrugs that are less reliant on specific enzymes."

This study was supported by the PIDS-St. Jude Children's Research Hospital Fellowship Award in Basic and Translational Science, the National Institutes of Health grants R01AI171514, R01AI123433, T32AI141393, the Doris Duke Foundation Paragon of Research Excellence Award, the Indiana Academy of Sciences Senior Research Grant and CHOP.

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