Artemisinins & Malaria Treatment

Learning Aims and Objectives

• The development of Artemisinin Combination Therapies (ACTs) are first-line therapies in malaria
• Structural features and the mode of action of artemisinins
• How the structure of artemisinin has been modified to produce semisynthetic derivatives with optimised activity and use
• The treatment of malaria in pregnancy
• The prophylaxis of malaria in travellers and preventative strategies

Artemisinins

• Artemisinin is isolated from the leafy portions of the herb Artemisia annua L., (0.01 - 1.4% plant dry weight)
• It is used to treat fever in traditional Chinese medicine (TCM)
• Artemisinin is the most effective antimalarial drug in terms of promptness and low toxicity
• It is also active in resistant and cerebral malaria
• Discovered by Prof. You-you Tu in 1972
• They were awarded the 2015 Joint Nobel Prize for Medicine

Artemisinin & Derivatives

• Artemisinin and derivatives are Sesquiterpene trioxanes with an endoperoxide bridge
• The reactive endoperoxide moiety is key to activity
• The mechanism of action is via a free radical
• Which causes oxidative damage to the parasite membrane

Postulated Modes of Action

• Open peroxide model and reductive scission model
• The activated artemisinin is free radical-mediated oxidative stress
• As well as covalent interactions with plasmodial vital biomolecules
• This causes inhibition of PfATP6 and parasite membrane damage
• As well as interference with plasmodial mitochondrial functions and with the heme detoxification pathway
• Leading to Alkylation of heme and other proteins and Inhibition of Proteins (HRP II & HDP)

WHO Recommendations for Treatment of Malaria: ACT

• ACT is needed because Artemisinins have short in vivo half-lives and low bioavailability
• 3 days ACT, with: Artemether & Lumefantrine
• Artesunate & Amodiaquine
• Artesunate & Mefloquine
• Dihydroartemisinin & Piperaquine
• Artesunate & Sulfadoxine/Pyrimethamine
• Artesunate-pyronaridine (2022)
• Additional info for special risk groups: http://www.who.int/malaria/

Artemisinins Beyond Malaria

• Other potential uses: antitumour, antibacterial, antiviral, antileishmanial, antischistosomiatic, herbicidal

Lumefantrine

• Synthesised in the 1970s in China and used in the 80s but rarely as monotherapy
• Now used in combination with artemether in falciparum malaria
• Chemically, an arylamino alcohol - inspired by quinine
• Note lipophilic substituents: N-dealkylation in vivo to a metabolite which is active

Malaria and Pregnancy

• In areas of low transmission there is a 2-3 fold higher risk of severe disease than non-pregnant adults in the same area
• In areas of high and stable malaria transmission most women have enough immunity so infection does not usually result in clinical symptoms
• Fe supplements are important
• For prophylaxis mefloquine is used
• Drug options include: Quinine (esp. I)
• Clindamycin
• And Artemisinins (II & III)

Malarial Prophylaxis

• Around 125 million travellers visit malaria-endemic areas annually
• ALL need to take steps to prevent infection with malaria
• Each year 10,000-30,000 cases of malaria are reported in returned travellers, but the real figure is likely to be higher
• The individual risk of acquiring malaria is determined by: Host immune status
• Area travelled to
• Duration of travel and season
• Use of prevention measures
• Pregnant women, young children and non-immune travellers are particularly vulnerable to severe disease if infected
• In Europe, the incidence of malaria is higher in people who travel to their country of origin to visit friends and relatives than in tourists, but mortality is higher in tourists

Malarial Prophylaxis

• Drug options for prophylaxis depend on the area being travelled to: travellers entering endemic areas need cover, expert advice is essential
• Treatment may be suppressive or causal
• Various drug regimes are utilised, most commonly: Mefloquine (Lariam®)
• Atovaquone / Proguanil (Malarone®)
• Doxycycline
• Dosing schedules of each regimen are different but are generally 1 + weeks before and up to 4 after and adherence to therapy critical
• NO drug is 100% effective
• Protection against bites is also vital
• Post travel illness must mean consideration of possibility of malaria

Prophylactic Mefloquine

• A suppressive prophylactic that acts in the blood stream as the schizonts invade erythrocytes
• Given as a weekly dose of 250 mg when used for prophylaxis in adults
• Typically taken for two to three weeks before travel and continued for four weeks following return
• Safe in pregnancy (esp II & III), and in children
• Limited by neurological and psychological side effects which range from mild headaches and dizziness to reports of suicide and psychosis

Atovaquone-Proguanil

• A lipophilic hydroxynaphthoquinone
• Developed from the natural product lapachol
• Inhibits electron transport in mitochondria
• Impairs pyrimidine synthesis
• Synergistic with Proguanil (Malarone®)

Mode of Action: Atovaquone

• Malaria parasites rely almost solely on glycolysis to satisfy their energy requirements during the blood stages of the life cycle
• The primary purpose of the mitochondrial ETC in blood stage parasites is the provision of reducing power for DHODH function in the synthesis of pyrimidines

Doxycycline

• Some antibiotics are effective in malaria due to the presence of a plastid-like organelle, the so-called apicoplast
• Tetracyclines are active but slow-acting
• Inhibition of the prokaryote-like RNA
• Doxycycline best due to fat solubility
• Good tissue distribution
• Potential for further structural modification
• Used in malaria prophylaxis, especially if there is mefloquine intolerance

Avoidance & Preventing Mosquito Bites

• Wear trousers, socks, and long sleeved shirts when outside between dusk and dawn
• Apply insect repellents to exposed skin such as 30-50% diethyltoluamide (DEET)
• Consider the use of this repellent in pregnancy and in children >2 months
• Use bed nets (ITN) impregnated with insecticide
• Tuck in under mattress
• Re-treat with pyrethroids every 6 months
• Resistance to pyrethroids reported in 41 countries
• Other classes: organochlorines, carbamates, organophosphates

Need for New Therapies

• Recent results suggest that ACT is beginning to fail in GMS
• In November 2009, there was the First Phase III trial for malaria vaccine
• With 5,000+ African children
• Using the Vaccine candidate RTS,S (Mosquirix)
• 2021 - widespread roll-out

Need for New Therapies

• In 2012: Pyronaridine, fixed-dose combination with artesunate
• Once daily, 3-day treatment of acute, uncomplicated P. falciparum and blood-stage P. vivax malaria in adults and children over 20kg
• Pyramax® will be registered in areas of low malaria transmission where there is reported artemisinin resistance and diminished efficacy of other ACTs
• Repurposing of an old drug: pyronaridine around since the 1970s!

GSK Candidate Vaccine: Phase III Preliminary Results

• Directed against sporozoites
• 50.4% effective vs. falciparum malaria in 6000 African children aged 5-17 months
• 45.1% effective vs. severe malaria
• As only partially protective, so will not obliterate need for antimalarial drugs
• 2023: Expansion of vaccine programme & second vaccine (R21/Matrix-M)

Fake Medicines and Malaria

• Each year approximately 627,000 people die from malaria (uncertainty interval, 473,000-789,000), a preventable and treatable disease
• Most cases and deaths occur in Africa
• Children under 5 years are the most affected: Every minute 1 child dies of malaria
• In sub-Saharan Africa - where the burden of malaria is the greatest- the prevalence of fake medicines can be even higher where up to 64% are fake

Reccomendations for medicines

• Always buy WHO prequalified antimalarial medicines from a reputable source where medicines are stored properly.
• Always check the packaging carefully: - Check the expiry date and if the dosage is correct, check if the patient information leaflet is in the correct language.
• Closely examine the appearance of your medicines like checking if the pills are cracked or chipped.

After the lecture, become familiar with:

• The need for ACT as a first-line treatment of malaria
• How artemisinin may be derivatised
• Management of malaria in vulnerable populations: children, pregnancy
• Prophylactic treatment in malaria