• 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

  • 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.

    • 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

          • 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.

    • 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

    •  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.

Primary Reference: Goldsmith, R. S., Antiprotozoal Drugs in Basic and Clinical Pharmacology (Katzung, B. G., ed) Appleton-Lange, 1998, pp. 838-861.