IHD.10

Market Overview

• Global Market for Antiparasitic Drugs:

  • Estimated at USD 21 billion in 2024.

  • Projected to increase to USD 28 billion by 2030.

Characteristics of Ideal Anti-malarial Drug

• Desirable Features:

  • Potent against all Plasmodium species

  • High oral bioavailability

  • Rapid action

  • Robust safety profile (including use in children and pregnant women)

  • Affordable pricing

  • Exoerythrocytic activity (affecting both gametocyte and liver stages) for transmission-blocking and prophylaxis.

Targets of Anti-Malarial Drugs

• Key Targets:

  • Tissue schizonticides

  • Blood schizonticides

  • Intra-erythrocytic targets:

    • Gametocytocides

    • Sporontocides

Quinine

• Historical Use:

  • Used since the 1600s as a crude drug; isolated in 1820.

  • A type of 4-quinoline methanol with significant activity but notable side effects:

    • Curare effect

    • Myocardial depression

    • Vasodilation

    • Hemolytic anemia

  • Still utilized for severe malaria despite the superiority of parenteral artesunate.

4-Aminoquinolines and Derivatives

• Development: Explores drugs developed from quinine prototype:

  • Hydroxychloroquine (similar to chloroquine)

  • Chloroquine (analogue of quinine)

  • Mefloquine

  • Amodiaquine (derived from chloroquine)

  • Piperaquine.

Structure-Activity Relationships of 4-Aminoquinolines

• Key Characteristics:

  • Optimal chain length: 2-5 carbons.

  • Terminal nitrogen must be trisubstituted (usually with ethyl groups).

  • The best substituent for R1 is Chlorine.

  • Chirality at X is not significant.

Proposed Mechanisms of Action of 4-Aminoquinolines

• Hypotheses:

  • Potential DNA intercalation, but concentration needed to inhibit DNA synthesis exceeds that needed to inhibit parasite growth.

  • Weak base hypothesis; aminoquinolines accumulate in lysosomes (pH 4.8-5.2), raising pH may impede hemoglobin digestion.

  • FPIX hypothesis: Plasmodium's digestion of host hemoglobin creates toxic Ferriprotoporphyrin IX (FPIX); drug-FPIX complex retains toxicity, inducing cell death.

FPIX Hypothesis

• Overview:

  • Interactions between anti-malarial drugs and hemozoin from hemoglobin digestion are crucial for understanding mechanisms of action.

8-Aminoquinolines

• Prototype Drug: Pamaquine (1926), followed by Primaquine.

• Effectiveness: Active against tissue and hepatic stages.

• Gametocidal: Can be combined with chloroquine for comprehensive malaria eradication.

• Caution: Not to be used long-term due to toxicity risk and potential for resistance.

Mechanism of Action of 8-Aminoquinolines

• Action Pathway:

  • Interfere with cell redox systems, inducing oxidative stress leading to cell death.

Structure-Activity Relationships of 8-Aminoquinolines

• Chemical Structure Variability:

  • Chain length from C2 to C6.

  • R2 and R3 can be H or any alkyl group.

  • R1 variations include H, OCH3, OH, or O-alkyl.

  • Additional substituents enhance activity, especially second OCH3 on C4 or C5.

Tafenoquine

• Purpose: Create a longer-acting, potent, and less toxic alternative to primaquine.

• Effectiveness: Highly effective for radical cure of relapsing malaria (both P. vivax and P. falciparum) with protective efficacy of ≥ 90%.

• Approval: First approved in 2018 as a single-dose treatment. Currently approved in 8 countries and undergoing review in over 30.

Pyrimethamine-Sulfadoxine (Fansidar®)

• Mechanism:

  • Pyrimethamine inhibits plasmodial dihydrofolate reductase.

  • Sulfadoxine inhibits dihydropteroate synthase.

• Uses: Developed to treat chloroquine-resistant malaria; also used for intermittent preventive treatment (IPT) in vulnerable populations.

Artemisinins

• Background:

  • Parent compound artemisinin derived from TCM (Traditional Chinese Medicine) Qinghaosu (Artemisia annua).

• Characteristics: Contains a reactive endoperoxide moiety; mechanism unclear, possibly involving free radical damage.

• Significance: Active against resistant and cerebral malaria; fundamental to ACTs (Artemisinin Combination Therapies).

Development of Semisynthetic Artemisinins

• Current Focus: Understanding active metabolites to enhance treatment effectiveness.

WHO Recommendations for Malaria Treatment

• Recommended Combinations for Uncomplicated P. falciparum:

  • Artemether & Lumefantrine

  • Artesunate & Amodiaquine

  • Artesunate & Mefloquine

  • Dihydroartemisinin & Piperaquine

  • Artesunate & Sulfadoxine/Pyrimethamine.

Lumefantrine

• Description:

  • Aryl amino alcohol characterized by lipophilic substituents.

• Uses: Combines with artemether to treat falciparum malaria, acting over a longer period to eliminate residual parasites post-artemether clearance.

Malaria and Pregnancy

• Risks in Low and High Transmission Areas:

  • Higher risk of severe malaria in low transmission.

  • Most women in high transmission areas have adequate immunity, often with no symptoms.

• Drug Treatment Options:

  • Quinine (especially during the first trimester)

  • Clindamycin

  • Artemisinins (trimesters II & III)

• Prophylaxis: Mefloquine, depending on local transmission levels.

Malarial Prophylaxis

• Guidelines for Travelers:

  • Begin regimens one week before travel and continue four weeks post-travel.

  • Protection against mosquito bites is essential.

• Common Regimens:

  • Malarone® (atovaquone-proguanil)

  • Doxycycline

  • Mefloquine.

Atovaquone & Proguanil (Malarone®)

• Atovaquone:

  • Lipophilic hydroxynaphthoquinone that inhibits mitochondrial electron transport and pyrimidine synthesis.

• Proguanil:

  • Metabolizes to inhibit dihydrofolate reductase; works synergistically with atovaquone.

Tetracyclines

• Mechanism of Action:

  • Effective against malaria due to a plastid-like organelle (apicoplast).

• Notable Attributes:

  • Slow-acting; doxycycline is effective due to fat solubility and good tissue distribution.

  • Used for prophylaxis especially in cases of mefloquine intolerance.

Mosquito Bite Prevention

• Preventive Measures:

  • Wear protective clothing during peak hours (dusk to dawn).

  • Apply insect repellents with 30-50% DEET, safe for use in pregnancy and with children over 2 months.

  • Utilize insecticide-treated bed nets (ITNs).

  • Resistance to pyrethroids reported in 41 countries.

Need for New Therapies

• Current Situation: WHO reports indications that ACT is failing in certain regions.

• Possible Future Options:

  • Triple ACTs

  • Novel drug classes.

Pyronaridine

• Features:

  • Fixed-dose combination with artesunate for once daily, 3-day treatment of uncomplicated malaria in adults and children over 20 kg.

• Registration: Being introduced in areas with reported artemisinin resistance.

Vaccines for Malaria

• Effectiveness of RTS,S (Mosquirix):

  • 50.4% effective against falciparum malaria in children aged 5-17 months.

  • 45.1% effective against severe malaria.

• Limitations: Partially protective, thus affirming the ongoing need for antimalarial drugs.

Counterfeit Medicines

• Global Health Issue: Refers to the presence of counterfeit medications, significantly impacting treatment efficacy and public health.