ARTEQUIN PAEDIATRIC

Indications

• Severe malaria caused by _Plasmodium falciparum_
• Uncomplicated malaria in combination with other antimalarial agents

Dosage

Adults: For adults, the typical dosing regimen is an initial dose of 2.4 mg/kg intravenously, followed by 1.2 mg/kg at 12 and 24 hours, with subsequent doses depending on clinical response

Mechanism of action

Artesunate is metabolized to dihydroartemisinin (DHA), which reacts with heme, generating free radicals that inhibit protein and nucleic acid synthesis in _Plasmodium_ parasites during all erythrocytic stages. This interaction with free radicals can lead to the alkylation of essential parasitic proteins, disrupting their normal function. Two primary theories explain its action: one suggests that artemisinins are activated by interaction with ferrous iron or reduced heme, producing reactive radicals that alkylate biomolecules; the other posits that the intact artemisinin binds to vital proteins in the parasite, leading to the formation of reactive oxygen species.

Pharmacodynamics

As an artemisinin derivative, artesunate is metabolized to dihydroartemisinin, which generates free radicals that inhibit the function of _Plasmodium_ parasites. It has a short duration of action due to its short half-life, and while it possesses a moderate therapeutic index, patients should be informed about potential post-treatment hemolytic anemia and hypersensitivity reactions.

Pharmacokinetics

Artesunate is rapidly absorbed and converted to DHA, which has a short half-life. The pharmacokinetics of artesunate can be influenced by factors such as the presence of food and other medications. It is primarily metabolized in the liver and excreted in urine, with a rapid onset of action that makes it suitable for emergency treatment of severe malaria.

Adverse effects

• Hypersensitivity reactions
• Hemolytic anemia
• Gastrointestinal disturbances
• Headache
• Dizziness
• Fatigue

Precautions

• Caution in patients with a history of hypersensitivity to artemisinin derivatives
• Monitor for signs of hemolytic anemia
• Use with caution in patients with liver impairment

Pregnancy

Artesunate is classified as category C. The risks versus benefits should be assessed before use in pregnant women.

Breast-feeding

It is not known if artesunate is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store at room temperature (15-30 degrees Celsius) in a tightly closed container, protected from light and moisture.

Formulations

• Injectable solution
• Oral tablets

Indications

• Treatment of malaria
• Prophylaxis of malaria

Dosage

Children: For children, dosing varies by body weight: 62.5 mg once weekly for 5-15 kg, 125 mg for 16-24 kg, 187.5 mg for 25-44 kg, and 250 mg for 45 kg and above, starting 2-3 weeks before entering an endemic area and continuing

Adults: For adults, 250 mg once weekly for prophylaxis, starting 2-3 weeks before entering an endemic area and continuing for 4 weeks after leaving.

Mechanism of action

Mefloquine's mechanism of action is not completely understood but is believed to involve inhibition of protein synthesis in the Plasmodium falciparum by targeting the 80S ribosome. It interferes with the parasite's ability to metabolize hemoglobin, leading to schizonticidal effects. Additionally, mefloquine may inhibit calcium release in certain cellular contexts, which contributes to its antimalarial activity.

Pharmacodynamics

Mefloquine acts as a blood schizonticide, targeting the intraerythrocytic stages of malaria parasites. It prevents the maturation of parasites within red blood cells, thereby reducing the severity of malaria. The drug's effectiveness is evident in reducing the parasitemia associated with malaria infection.

Pharmacokinetics

Mefloquine is well-absorbed after oral administration, with peak plasma concentrations achieved within 24 hours. It has a long half-life, allowing for once-weekly dosing in prophylaxis. The drug is extensively metabolized in the liver, with only a small portion excreted unchanged in urine. Caution is advised in patients with hepatic or renal impairment, though dose adjustments are typically unnecessary for prophylaxis in mild to moderate cases.

Contra-indications

• History of psychiatric disorders (including depression)
• History of convulsions
• History of blackwater fever

Adverse effects

• Anxiety
• Depression
• Insomnia
• Abnormal dreams
• Psychosis
• Suicidal ideation
• Dizziness
• Nausea
• Headache
• Gastrointestinal discomfort
• Arrhythmias
• Mood alterations
• Memory loss
• Hearing impairment
• Visual disturbances

Interactions

• Increased exposure with ketoconazole
• Increased exposure with fluconazole
• Increased exposure with itraconazole
• Increased exposure with voriconazole
• Increased risk of bradycardia with non-selective beta-blockers
• Increased risk of bradycardia with selective beta-blockers
• Increased risk of bradycardia with calcium channel blockers
• Increased risk of bradycardia with digoxin
• Decreased exposure with rifampicin

Precautions

• Caution in hepatic impairment, especially in cirrhosis
• Caution in renal impairment, as only partially excreted by the kidneys
• Long-term use may necessitate regular ophthalmic examinations

Pregnancy

Use in pregnancy should be avoided if the disease is well controlled.

Breast-feeding

Present in breast milk; breastfeeding should be avoided when used to treat rheumatic disease. Amount in milk probably too small to be harmful when used for malaria.

Storage

Store below 25°C, protected from light.

Formulations

• Mefloquine tablets
• Malarivon syrup (80mg/5ml)

Mechanism of action

Artesunate is metabolized to the active DHA. the endoperoxide bridge of DHA reacts with heme, generating free radicals which inhibit protein and nucleic acid synthesis of the _Plasmodium_ parasites during all erythrocytic stages. Reactions with these free radicals can also lead to alkylation of parasitic proteins such as a calcium adenosine triphosphatase and EXP1, a glutathione S-transferase. Two theories have been put forward for the mode of antimalarial action of the artemisinin antimalarials, in accodance with the known properties of peroxides with medicinal activity. The first assumes that the artemisinins must be activated by contact with either reduced haem (ferrous haem, Fe(ll)PPIX) or non-haem ferrous iron (exogenous iron), causing cleavage of the peroxide to generate oxygen-centered radicals (alkoxy radicals') which are the presumed to be converted into carbon-centered radicals by transfer of proximate hydrogen atoms from the periphery of the peroxide molecule. These carbon-centered radicals are then thought to alkylate sensitive, yet unspecified, biomolecules in the parasite. A second theory argues for a process in which the intact artemisinin binds to a site within a vital protein in the parasite. The act of binding causes the peroxide to be converted to hydroperoxide or similar open peroxide, which in accordance with known properties of such compounds, generates one or more active chemical entities, either oxidizing agents or oxygen transfer agents per se, or oxygen-centered free radicals. This would be associated with the binding process. In such a way, the artemisinins might act as (irreversibile) inhibitors. Iron may, or may not, be associated with the activation process. No specific biological target in the parasite has yet been identified in support of this theory, but it may be membrane-bound proteins. Artesunate is a water soluble derivative of artemisinin, an antimalarial compound isolated from the Chinese herb Qinghao (Artemisia annua). Artesunate is rapidly metabolized to dihydroartemisinin (DHA) in the body. Chemically, artesunate, and its active metabolite, DHA, are sesquiterpene lactones with a trioxane ring containing a peroxide bridge. The peroxide bridge appears to be essential for the antimalarial activity of artesunate. Structure-activity relationship studies show that the deoxy derivative of DHA (that lack the peroxide bridge) was 277-fold less active than DHA. The activity of deoxyartesunate was not measured. Deoxy derivatives of other artemisinin analogs were 10- to 1000-fold less active compared to the parent compounds. Artesunate increases superoxide anion production and lipid peroxidation in falciparum-infected erythrocytes in vitro. However, artesunate does not suppress the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase) in infected or uninfected erythrocytes. Erythrocytes infected with the ring or trophozoite forms in vitro accumulate 100- and 180- fold higher concentrations of DHA (12 nM ie, 3.40 ng/mL), respectively, compared to uninfected erythrocytes. These experiments were performed in a medium containing 10% human serum. The relevance of these findings to the uptake in vivo is unclear. The precise mechanism by which artesunate exhibits antiplasmodial activity is not understood. A 2025 systematic review notes Artesunate's pharmacological activities (antimalarial, antiparasite,antitumor, antivirus, antiinflammation, and antibacterial),and that it is a highly effective antimalarial agent with the potential to induce organ toxicity under certain conditions. The authors note that mechanisms of Artesunate-induced toxicity include oxidative stress, inflammation, and apoptotic signaling patthhways.They also note that Artesunate ameliorates MASH (Metabolic Dysfunction-Associated Steatohepatitis) by reducing inflammation and lipid accumulation by regulating NLRP3 inflammasome and reducing lipid accumulation (SREBP-1c, FAS).

Pharmacodynamics

Artesunate is an artemisinin derivative that is metabolized to DHA, which generates free radicals to inhibit normal function of _Plasmodium_ parasites. It has a short duration of action due to its short half life, and a moderate therapeutic index. Patients should be counselled regarding the risk of post treatment hemolytic anemia and hypersenstivity.

Mechanism of action

The mechanism of action of mefloquine is not completely understood. Some studies suggest that mefloquine specifically targets the 80S ribosome of the Plasmodium falciparum, inhibiting protein synthesis and causing subsequent schizonticidal effects. There are other studies in the literature with limited in vitro data on mefloquine's mechanism of action. Mefloquine, like chloroquine and quinine, is a blood schizonticidal agent and is active against the intraerythrocytic stages of parasite development. Similar to chloroquine and quinine, mefloquine appears to interfere with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. The antimalarial activity of mefloquine may depend on the ability of the drug to form hydrogen bonds with cellular constituents; results of structure-activity studies indicate that the orientation of the hydroxyl and amine groups with respect to each other in the mefloquine molecule may be essential for antimalarial activity. While the precise mechanism of action of mefloquine is unknown, it may involve mechanisms that differ from those proposed for chloroquine. The effects of the antimalarial drug, mefloquine, on the uptake and release of Ca2+ by crude microsomes from dog brain were investigated using a spectrophotometric method. Mefloquine inhibited the inositol-1,4,5-phosphate (IP3)-induced Ca2+ release with an IC50 of 42 uM, but was a weaker inhibitor of the uptake of Ca2+ into the vesicles (IC50: 272 uM). These effects of mefloquine are in contrast to its actions on Ca2+ uptake and release by skeletal muscle microsomes, where its predominant effect was seen to be the inhibition of Ca2+ uptake into the vesicles. Mefloquine was found to be more potent than quinine as a specific inhibitor of Ca2+ release from IP3-sensitive stores in dog brain microsomes. The possibility of the drug affecting cellular IP3-linked signal transduction processes should be considered.

Pharmacodynamics

Sporozoites located in the salivary glands of mosquitoes infected with malaria parasites are introduced into the bloodstream of a human host during mosquito feeding. These sporozoites rapidly invade the liver, where they mature into liver-stage schizonts, rupturing and releasing 2,000 - 40,000 merozoites that invade red blood cells. Mefloquine is an antimalarial drug acting as a blood schizonticide, preventing and treating malaria.