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 Pamaquine

Pamaquine is a synthetic agent belonging to the 8-aminoquinoline class of drugs. It shares structural similarity with Primaquine, another well-known antimalarial agent. Though Pamaquine is no longer widely used, it played a significant role in the early management of relapsing malaria.

Pamaquine is a lipophilic compound, structurally based on the quinoline nucleus, which is key to its antimalarial activity. The molecular weight of Pamaquine is 315.5g/mol. Warfarin is also marketed under several brand names and synonyms, including Plasmoquine, Pamaquin, Praequine, Plasmochin, Plasmocide, Rhodoquine, Aminoquine, and Beprochin.

Chemical structure of Pamaquine:

• The molecular formula of Pamaquine is [C19H29N3O].

• The IUPAC name of Pamaquine is 1-N, 1-N-diethyl-4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine.

Mechanism of action of Pamaquine:

The Mechanism of Action of pamaquine, an 8-aminoquinoline derivative, is not fully understood but is believed to involve multiple pathways that interfere with the survival of the Plasmodium parasite. Like other drugs in its class (Such as Primaquine and Tafenoquine), Primaquine acts primarily on the exo-erythrocytic (Liver) stages and gametocytes of the malarial parasite. Here's a more in-depth look at the possible ways Pamaquine exerts its antimalarial effects:

1. Generation of Reactive Oxygen Species (ROS): One of the most widely accepted theories is that pamaquine induces the production of reactive oxygen species (ROS) and free radicals within the parasite. These oxygen-based molecules generate oxidative stress by damaging cellular components, including lipids, proteins, and nucleic acids. The Plasmodium species, particularly in their liver stages (hypnozoites), have limited antioxidant defenses, making them especially susceptible to ROS-induced damage.
2. Disruption of Mitochondrial Function: Another proposed mechanism involves the inhibition of mitochondrial electron transport chain activity within the malaria parasite. By disrupting mitochondrial respiration, Pamaquine impairs ATP Synthesis, leading to an energy crisis and eventual cell death.
3. DNA Interaction and Damage: Pamaquine may also interact with the DNA of plasmodium parasites, causing strand breaks, cross-linking, or base modification. These changes can hinder DNA replication and transcription, ultimately leading to cell cycle arrest or apoptosis (Programmed cell death) of the parasite.
4. Immunomodulatory Effects (Hypothetical): Some studies suggest that 8-aminoquinoline-like Pamaquine might enhance the host immune response against the malarial parasite. By increasing phagocytic activity or altering cytokine levels, the drug could indirectly aid in parasite clearance.

Therapeutic Uses of Pamaquine:

Pamaquine was primarily used for its antimalarial activity. Key uses include,

• Treatment of hyponozoites: Effective against dormant liver stages of Plasmodium vivax and Plasmodium ovale, which are responsible for relapses.
• Erythrocytic stage activity: Active against blood stage parasites of all four human malarial species (Plasmodium vivax, Plasmodium ovale, Plasmodium falciparum, and Plasmodium malariae).

Due to the development of safer alternatives like Primaquine and Tafenoquine, Pamaquine is now largely of historical significance

Common side effects of Pamaquine:

Pamaquine is associated with several adverse effects, especially in patients with G6PD deficiency:

• It causes haemolytic anaemia in patients with G6PD deficiency. 
• Vomiting. 
• Nausea. 
• Epigastric distress.
• Abdominal cramps. 

Conclusion:

Pamaquine, an early 8-aminoquinoline antimalarial, played a key role in treating relapsing malaria by targeting dormant liver-stage hypnozoites. Although no longer widely used due to toxicity risk in G6PD-deficient patients, its historical significance and unique mechanism of action remain important in malaria research and pharmacology education.