• Pyrimethamine-proguanil (Chloroguanide)
  • Overview:pyrimethamine-proguanil (Chloroguanide)
    •  pyrimethamine (Daraprim) & proguanil (Paludrine): dihydrofolate reductase inhibitors {folic acid antagonists: antifols}
    •  pyrimethamine (Daraprim): related to trimethoprim (generic)
    •  proguanil (Paludrine) -- biguanide primitive
  • Pharmacokinetics: pyrimethamine-proguanil (Chloroguanide)
    •  slow, but complete absorption from the gastrointestinal tract
    •  differences in elimination kinetics require that proguanil (Paludrine) be administered daily, although pyrimethamine (Daraprim) can be given once per week
    •  pyrimethamine (Daraprim): extensively metabolize prior to excretion
    •  Proguanil (Paludrine): prodrug-triazine metabolite cycloguanil is the active form

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  • Antimalarial-Characteristics: pyrimethamine-proguanil (Chloroguanide)
    • Antimalarial activity:
      •  slow-acting blood schizonticides
      •  active against all four malarial species affecting humans (assuming susceptible strains)
      •  Proguanil (Paludrine): significant effect on primary tissue stage of P falciparum {possible prophylactic action; possibly effective even when blood schizonts are resistant}
      •  Neither proguanil (Paludrine) or pyrimethamine (Daraprim) are sufficiently gametocidal or effective against liver stages of P vivax or P ovale
      •  Pyrimethamine (Daraprim) & cycloguanil {active form of proguanil (Paludrine)} and are more effective inhibitors of plasmodial dihydrofolate reductase-compared to the human form.
    • Resistance:pyrimethamine-proguanil (Chloroguanide)
      •  Widespread pyrimethamine (Daraprim) & proguanil (Paludrine) resistance for P falciparum {less common resistance for P vivax}
        •  Prophylaxis against P falciparum is not recommended using these drugs alone.

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    • Clinical Uses: (Chloroguanide), pyrimethamine (Daraprim)
      • Chemoprophylaxis:
        •  The combination pyrimethamine-proguanil (Chloroguanide) is used as an alternative to mefloquine (Lariam) in areas of the world without widespread chloroquine (Aralen) resistance
          • note: proguanil (Paludrine) is not available in United States
      • Treatment of Chloroquine (Aralen)-resistant falciparum malaria
        •  Pyrimethamine-sulfadoxine (Fansidar)
      • Toxoplasmosis Treatment:pyrimethamine (Daraprim)
        • "Toxoplasma gondii is a protozoan parasite that infects most species of warm blooded animals, including humans, causing the disease toxoplasmosis."-CDC (http://www.dpd.cdc.gov/DPDx/HTML/Toxoplasmosis.htm)
          • Life Cycle
          • Clinical Features
          • Laboratory Diagnosis
            • Preferred Method: Serologic Testing
          • Microscopic Features
          •  Treatment:
            • "Generally, an asymptomatic healthy, but infected, person does not require treatment. For pregnant women or persons who have weakened immune systems, spiramycin or pyrimethamine plus sulfadiazine may be used in specific cases."-CDC
        •  Treatment of choice: pyrimethamine (Daraprim) + either trisulfapyrimidines or sulfadiazine
          • Leucovorin calcium (folinic acid) is used avoid hematological consequences of pyrimethamine (Daraprim)-caused folate deficiency.
        •  For management of toxoplasmal encephalitis (associated with AIDS): higher doses are required
        •  With ocular Toxoplasmosis, systemic corticosteroids are administered to reduce increased intracranial pressure.

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    • Adverse Effects:pyrimethamine-proguanil (Chloroguanide)
      • For malarial treatment: pyrimethamine (Daraprim) & proguanil (Paludrine) are generally well tolerated
        •  Rare: skin rashes, itching, gastrointestinal disturbances
        •  Rare: mouth ulcers & alopecia (proguanil)
      • For management of Toxoplasmosis, higher dosages are required:
        •  Side effects related to folic acid deficiency-common (unless leucovorin calcium is concurrently used), including:
          •  megaloblastic anemia
          •  agranulocytosis
          •  thrombocytopenia
          •  atrophic glossitis
        •  Gastrointestinal irritation
        •  Neurological symptoms:
          •  headache
          •  tremors
          •  respiratory depression
          •  seizures
          •  ataxia

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    •  Contraindications/Cautions:pyrimethamine (Daraprim)
      • cautious use in the presence of renal/hepatic dysfunction
      • pyrimethamine (Daraprim) avoidance during first trimester pregnancy-consider risk vs. benefit
      • When high doses are required for Toxoplasmosis treatment:
        • white blood cell/platelet counts-2 Times/week
        • Discontinuation if:
          • sore throat
          • purpura
          • glossitis
          • rash
      • Proguanil (Paludrine)-considered safe and pregnancy; leucovorin should be administered.

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