MALAKANT DISPERSIBLE TABLETS

Indications

• Malaria caused by Plasmodium species
• Toxoplasmosis, particularly in immunocompromised patients
• Adjunct treatment of autoimmunity-related conditions

Dosage

Adults: For the treatment of toxoplasmosis in adults, the recommended dosage is 50 mg once daily until delivery, usually in combination with sulfadiazine and

Mechanism of action

Pyrimethamine inhibits the dihydrofolate reductase enzyme in plasmodia, blocking the biosynthesis of purines and pyrimidines necessary for DNA synthesis and cell multiplication. This inhibition leads to failure in nuclear division during the formation of schizonts in erythrocytes and liver. Additionally, it has immunomodulatory effects by increasing oxidative stress, which may aid in the elimination of parasites.

Pharmacodynamics

As an antiparasitic compound, pyrimethamine is particularly effective against uncomplicated, chloroquine-resistant Plasmodium falciparum malaria and Toxoplasma gondii. It exhibits blood schizonticidal activity and some tissue schizonticidal effects, though it does not affect gametocytes. The selective toxicity towards parasites, contrasted with minimal effects on human cells, is due to differences in nucleic acid precursor requirements. Its effectiveness is notably enhanced when used in combination with sulfonamides.

Pharmacokinetics

Pyrimethamine is absorbed well after oral administration and undergoes hepatic metabolism. Its elimination half-life is variable but can be prolonged in cases of renal impairment. The drug is primarily excreted in urine, both as unchanged drug and metabolites. Caution is advised in patients with liver and renal impairment, and monitoring of blood counts is recommended during prolonged therapy due to the risk of haematological toxicity.

Contra-indications

• G6PD deficiency
• Severe renal impairment
• Severe hepatic impairment
• History of seizures
• Heart block (requires ECG monitoring during parenteral treatment)

Adverse effects

• Abdominal pain
• Agitation
• Agranulocytosis
• Anaemia
• Angioedema
• Asthma
• Diarrhoea
• Dizziness
• Fever
• Flushing
• Headache
• Hearing impairment
• Hypersensitivity reactions
• Loss of consciousness
• Muscle weakness
• Nausea
• Skin reactions
• Thrombocytopenia
• Tinnitus
• Vertigo
• Vomiting

Interactions

• Antiepileptics (increases risk of haematological toxicity)
• Fosphenytoin (increases risk of haematological toxicity)
• Phenytoin (increases risk of haematological toxicity)
• Phenobarbital (increases risk of haematological toxicity)
• Primidone (increases risk of haematological toxicity)
• Methotrexate (increases risk of adverse effects)
• Pemetrexed (increases risk of adverse effects)

Precautions

• Monitor blood counts during prolonged treatment
• Consider dose reduction in renal and hepatic impairment
• Caution in patients predisposed to folate deficiency
• Avoid large loading doses in patients with a history of seizures
• Use with caution in pregnancy (theoretical teratogenic risk in the first trimester)

Pregnancy

High doses are teratogenic in the first trimester; however, in malaria, the benefit of treatment may outweigh the risks.

Breast-feeding

Present in milk but not known to be harmful; adequate folate supplements should be given to the mother. Avoid breastfeeding during treatment of toxoplasmosis.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Daraprim 25 mg tablets
• Oral suspension

Indications

• Treatment of malaria caused by Plasmodium falciparum
• Prevention of malaria in individuals traveling to endemic areas

Dosage

Children: Refer to BNF for Children for specific dosing information.

Adults: Refer to BNF for specific dosing information.

Mechanism of action

Sulfadoxine acts as an antimetabolite by competitively inhibiting the enzyme dihydropteroate synthase, which is crucial for the synthesis of folic acid from para-aminobenzoic acid (PABA). This inhibition disrupts the folic acid production necessary for DNA synthesis and cellular growth in the Plasmodium species, particularly P. falciparum, thereby impairing its ability to reproduce.

Pharmacodynamics

Sulfadoxine's inhibition of dihydropteroate synthetase leads to a decrease in folic acid levels within the parasite. Folic acid is essential for the synthesis, repair, and methylation of DNA, and its deficiency hampers the growth and replication of Plasmodium falciparum, thereby aiding in the treatment of malaria.

Pharmacokinetics

Sulfadoxine is well-absorbed after oral administration, with peak plasma concentrations typically reached within 4 to 6 hours. It has a long half-life, allowing for once-daily dosing in many cases. The drug is metabolized in the liver and excreted primarily via the kidneys. Its pharmacokinetic profile supports its use in combination therapies for malaria, as it maintains therapeutic levels over extended periods.

Contra-indications

• Hypersensitivity to sulfadoxine or other sulfonamides
• Severe liver or kidney impairment
• Pregnancy at term
• Infants under 2 months of age

Adverse effects

• Nausea
• Vomiting
• Rash
• Fever
• Anemia
• Leukopenia
• Thrombocytopenia
• Hepatotoxicity
• Stevens-Johnson syndrome

Interactions

• May enhance the effects of anticoagulants such as warfarin
• May interact with methotrexate, increasing its toxicity
• May reduce the effectiveness of certain oral contraceptives

Precautions

• Monitor for signs of hypersensitivity reactions
• Use cautiously in patients with G6PD deficiency
• Assess renal function prior to and during therapy

Pregnancy

Use is contraindicated at term due to the risk of kernicterus in the neonate. Caution is advised during the first and second trimesters.

Breast-feeding

Sulfadoxine is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Sulfadoxine 500 mg tablets
• Sulfadoxine/pyrimethamine combination tablets

Mechanism of action

Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver. Pyrimethamine is an antimalarial drug that has also been used successfully to treat autoimmune diseases such as lymphoproliferative syndrome. In this work, the effect of pyrimethamine (PYR) on the production of free radicals in malaria-infected mice was studied to better understand the drug's immunomodulatory properties. BALB/c and CBA/Ca mice were infected with Plasmodium yoelii 17XL. Seven days after infection, mice were treated with PYR or vehicle and sacrificed 24h later. Treatment with PYR increased superoxide dismutase and glutathione peroxidase activities in erythrocytes and the liver, augmented the levels of nitric oxide in the serum, and upregulated mRNA levels of superoxide dismutase, glutathione peroxidase, catalase, and iNOS in the spleen. In addition, PYR increased lipoperoxidation and protein carbonylation in infected mice. Our results indicate that P. yoelii 17XL reduces oxidative stress in infected cells, while PYR induces it, which is associated with increased parasite elimination. Thus, it is possible that oxidative stress generated by pyrimethamine is also involved in its immunomodulatory mechanism of action. Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of pyrimethamine (PYR) and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIV(NL4.3) strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 uM CQ and ART inhibited HIV-1 replication by 76% and 60% in PBMCs, respectively, but not in MT-2 cells. In contrast, 10 uM PYR enhanced HIV-1 replication in MT-2 cells by >10-fold. A series of molecular mechanism studies revealed that PYR increased intracellular HIV gag proteins without affecting the promoter or the reverse transcriptase activity. The effect of PYR was independent of HTLV-1 produced by MT-2 cells. Of interest, PYR treatment led to S-phase accumulation and increased AZT and d4T antiviral activity by ~ 4-fold. Taken together, we show that PYR significantly enhances HIV-1 replication by affecting the cellular machinery. Our results could be relevant for the management of malaria and HIV particularly in regions where HIV-1 and malaria epidemics overlap. Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD. The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the de

Pharmacodynamics

Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. Pyrimethamine is a folic acid antagonist and the rationale for its therapeutic action is based on the differential requirement between host and parasite for nucleic acid precursors involved in growth. This activity is highly selective against plasmodia and Toxoplasma gondii. Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.

Mechanism of action

Sulfadoxine is a sulfa drug, often used in combination with pyrimethamine to treat malaria. This medicine may also be used to prevent malaria in people who are living in, or will be traveling to, an area where there is a chance of getting malaria. Sulfadoxine targets Plasmodium dihydropteroate synthase and dihydrofolate reductase. Sulfa drugs or Sulfonamides are antimetabolites. They compete with para-aminobenzoic acid (PABA) for incorporation into folic acid. The action of sulfonamides exploits the difference between mammal cells and other kinds of cells in their folic acid metabolism. All cells require folic acid for growth. Folic acid (as a vitamin) diffuses or is transported into human cells. However, folic acid cannot cross bacterial (and certain protozoan) cell walls by diffusion or active transport. For this reason bacteria must synthesize folic acid from p-aminobenzoic acid.

Pharmacodynamics

Sulfadoxine helps inhibit the enzyme dihydropteroate synthetase which is an enzyme necessary in the conversion of PABA to folic acid. As folic acid is vital to the synthesis, repair, and methylation of DNA which is vital to cell growth in Plasmodium falciparum. With this vital nutrient lacking, the parasite has difficulty in reproducing.