Pyrimethamine-proguanil (Chloroguanide)

• Overview:  pyrimethamine-proguanil (Chloroguanide)

  •  Pyrimethamine (Daraprim) and 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) and 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) and 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

    • 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

          "Members of the cat family (Felidae) are the only known definitive hosts for the sexual stages of T. gondii and thus are the main reservoirs of infection.  Cats become infected with T. gondii by carnivorism.  After tissue cysts or oocysts are ingested by the cat, viable organisms are released and invade epithelial cells of the small intestine where they undergo an asexual followed by a sexual cycle and then form oocysts, which are then excreted.  The unsporulated oocyst takes 1 to 5 days after excretion to sporulate (become infective).  Although cats shed oocysts for only 1 to 2 weeks, large numbers may be shed.  Oocysts can survive in the environment for several months and are remarkably resistant to disinfectants, freezing, and drying, but are killed by heating to 70oC for 10 minutes. Human infection may be acquired in several ways: 1) ingestion of undercooked infected meat containing Toxoplasma cysts; 2) ingestion of the oocyst from fecally contaminated hands or food; 3) organ transplantation or blood transfusion; 4) transplacental transmission; 5) accidental inoculation of tachyzoites.  The parasites form tissue cysts, most commonly in skeletal muscle, myocardium, and brain; these cysts may remain throughout the life of the host."- CDC (used with permission, public domain)

        • Clinical Features

          • "Acquired infection with Toxoplasma in immunocompetent individuals is generally an asymptomatic infection. 

            • However, 10% to 20% of patients with acute infection may develop cervical lymphadenopathy and/or a flu-like illness. 

            • The clinical course is benign and self-limited; symptoms usually resolve within a few months to a year.

          • Immunodeficient patients often have central nervous system (CNS) disease but may have myocarditis, or pneumonitis. 

            •  In patients with AIDS, toxoplasmic encephalitis is the most common cause of intracerebral mass lesions and is thought to be due to reactivation of chronic infection. 

            •  Toxoplasmosis in patients being treated with immunosuppressive drugs may be due to either newly acquired or reactivated latent infection.

          • Congenital toxoplasmosis results from an acute primary infection acquired by the mother during pregnancy. 

            • The incidence and severity of congenital toxoplasmosis vary with the trimester during which infection was acquired. 

            • Because treatment of the mother reduces the incidence of congenital infection, prompt and accurate diagnosis is extremely important. 

            • Most infants with subclinical infection at birth will subsequently develop signs or symptoms of congenital toxoplasmosis unless the infection is treated.

          •  Ocular Toxoplasma infection, an important cause of chorioretinitis in the United States, is usually a result of congenital infection.  Patients are often asymptomatic until the second or third decade of life, when lesions develop in the eye." source: CDC-public domain

        • Laboratory Diagnosis

          • "The diagnosis of toxoplasmosis may be documented by:

            •  Observation of parasites in patient specimens, such as bronchoalveolar lavage material from immunocompromised patients, or lymph node biopsy.

            •  Isolation of parasites from blood or other body fluids, by intraperitoneal inoculation into mice or tissue culture. The mice should be tested for the presence of Toxoplasma organisms in the peritoneal fluid 6 to 10 days post inoculation; if no organisms are found, serology can be performed on the animals 4 to 6 weeks post inoculation.

            •  Detection of parasite genetic material by PCR, especially in detecting congenital infections in utero.

            •  Serologic testing is the routine method of diagnosis, because the techniques described above are technically complex and generally not rewarding. "-CDC (used with permission, public domain)

           

          • Preferred Method: Serologic Testing

            "Antibody Detection: Serologic examination is used initially to indicate the presence of the infection by detecting Toxoplasma-specific antibodies. Serum, plasma, cerebrospinal fluid (CSF), and eye fluid specimens may all be tested for antibodies. If determination of immune status is the reason for testing, a single specimen is satisfactory. If determining the time of infection is important, two specimens drawn at least 3 weeks apart may or may not be useful. In most cases, detection of a rising IgG or IgM titer is not possible because the titers have already reached a plateau by the time the initial sample is drawn. The above algorithm may be used to determine the appropriate sequence of serological testing." CDC (used with permission, public domain)

        •  

          Microscopic Features

          "Toxoplasma gondii in the bronchoalveolar lavage (BAL) material from an HIV infected patient.  Numerous trophozoites (tachyzoites) can be seen, which are typically crescent shaped with a prominent, centrally placed nucleus.   Most of the tachyzoites are free, some are still associated with bronchopulmonary cells."-CDC (used with permission,public domain) http://www.dpd.cdc.gov/DPDx/HTML/Toxoplasmosis.htm

      •  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) and proguanil (Paludrine) are generally well tolerated

      •  Rare: skin rashes, itching, gastrointestinal disturbances

      •  Rare: mouth ulcers and 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

        •  Rremors

        •  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.