| 毒性の概要 | IDENTIFICATION: Primaquine phosphate is used to treat malaria caused by Plasmodium virax. Primaquine is an orange-red, odorless crystalline powder which has a bitter taste It is soluble in water and it is practically insoluble in alcohol, chloroform and ether. For elimination of primary and secondary exoerythrocytic stages of Plasmodium vivax, Plasmodium malariae and Plasmodium ovale and the primary exoerythrocytic forms only of Plasmodium falciparum. Primaquine must always be given in conjunction with full doses of a 4-aminoquinoline. HUMAN EXPOSURE: Main risks and target organs: Target organs are: cardiovascular, hematological system, and gastrointestinal. Acute, dose-dependent methemoglobinemia and hemolytic anemia occurs in persons with a deficiency of glucose-6-phosphate dehydrogenase (G6PD)leucopenia or agranulocytosis may also occur. Adverse effects with therapeutic doses are usually mild. Summary of clinical effects: Toxic manifestations include cardiovascular disturbances, especially ventricular dysrhythmias, abdominal cramps, vomiting, burning epigastric distress, headache, confusion, cyanosis, methemoglobinemia, leucocytosis or leucopenia, and anemia. Granulocytopenia, acute hemolytic anemia and acute hemolysis may occur in individuals who are hypersensitive to primaquine. Contraindications: The balance of risk and benefit should be considered when primaquine is administered under the following conditions: in acutely ill patients suffering from systemic disease characterized by a tendency to granulocytopenia (for example, patients with arthritis or lupus erythematosus). Agents capable of depressing the myeloid elements of the bone marrow (antineoplastic agents, colchicine, gold salts, penicillamine, phenylbutazone, quinacrine). Individuals who have shown previous idiosyncratic reaction to primaquine, individuals with a history of favism or acute haemolytic anaemia. Individuals with G6PD deficiency or NADH methemoglobin reductase deficiencyprimaquine should be discontinued immediately if hemolysis occurs. Routes of entry: Oral: Oral absorption is the only common cause of intoxication. Absorption by route of exposure: Primaquine is readily absorbed from the gastrointestinal tract. The plasma concentration peaks within 1 to 3 hr after ingestion but is negligibly low after 24 hr Considerable inter-individual variation in peak plasma concentrations of primaquine has been reported with the same dose of the drug. Distribution by route of exposure: Primaquine is extensively distributed into body tissues. About 75% of primaquine in plasma is bound to proteins and high concentrations occur in erythrocytes. Primaquine crosses the placenta but it is uncertain whether significant amounts occur in breast milk. Biological half-life by route of exposure: Primaquine has a plasma elimination half-life of 3.7 to 9.6 hr in healthy adults. Metabolism: Primaquine is not subject to extensive first pass metabolism. However, it is readily metabolized in the liver to three metabolites: 8-(3-carboxyl-1-methyl-propylamino)-6-methoxy-quinoline, 5-hydroxy primaquine and 5-hydroxy-6-desmethyl-primaquine. The carboxyl derivative is the major metabolite found in plasmait accumulates during repeated administration, when the plasma concentration greatly exceeds that of unchanged primaquine. These metabolites have appreciably less antimalarial activity than primaquine but their haemolytic activity, as assessed by formation of methemoglobin in vitro, is greater than that of the parent compound. Elimination by route of exposure: Only 3.6% of the dose of primaquine is excreted as unchanged drug. The principal metabolite is carboxyprimaquine. Mode of action: Toxicodynamics: Primaquine may cause hemolysis and methemoglobinemia. Certain ethnic groups, especially those arising in the Mediterranean basin, are more susceptible to these effects and primaquine sensitivity occurs in persons with G6PD deficiency. G6PD deficiency is genetically acquiredthere are a large number of variants in which the extent of the deficiency differs. The sensitivity of individuals to primaquine therefore varies. G6PD is an enzyme which protects the erythrocyte from the direct oxidative effects of some drugs and chemicals by maintaining intracellular stores of reduced glutathione. In people who are G6PD deficient, oxidation of hemoglobin leads to precipitation within the cell, producing characteristic inclusions called Heinz bodiesincreased oxidation of hemoglobin also produces methemoglobinemia. There is an increase in the generation of free radicals which also contribute to cellular damage. These effects ultimately cause hemolysis. Pharmacodynamics: The exact mechanism of anti-malarial activity of primaquine has not been determined, but the drug appears to bind to plasmodial DNA and interfere with its function. Human data: Adults: The toxicity of primaquine phosphate is dose-dependentweekly administration (in combination with chloroquine) is less toxic than daily administration. Serious hematologic reactions may occur in some people with a G6PD deficiency even at the low weekly doses of primaquine used in combination with chloroquine for the prophylaxis of malaria. This occurs primarily in patients with a family or personal history of favism. Methemoglobinemia is more common in individuals with nicotinamide adenine dinucleotide methemoglobin reductase deficiency. About 10% of the black population with G6PD deficiency develop anaemia due to intravascular hemolysis at daily dose levels of 15 mg (base) and higher. Some darker-skinned Mediterranean populations are more sensitive than blacks. Teratogenicity: No reports are available to associate primaquine with congenital defects. Interactions: Primaquine should not be administered concurrently with any other drug that is likely to induce hemolysis or bone marrow depression (see section 4.3) as this may increase the risk of toxicity. Concurrent use of primaquine with bone marrow depressants may increase the risk of leukopenia. If concurrent use is essential, close observation for myelotoxicity should be considered. The toxicity of primaquine appears to be potentiated by antimalarial agents that are structurally similar (for example, quinacrine). Primaquine should not be administered to patients who have received quinacrine within the previous 3 months. Although primaquine inhibits the elimination of drugs which undergo oxidative metabolism (for example, antipyrine), therapeutic doses have no effect on paracetamol metabolism. The combination of chloroquine and primaquine with dapsone may prevent hemolysis in G6PD deficient subjects. The antimalarial effects of quinacrine and primaquine in various test organisms are synergistic with many antibiotics. After administration of primaquine, the metabolism of antipyrine (calculated from 0 to 24 h) to its 3 main metabolites, 3 hydroxymethyl-antipyrine, 4 hydroxy-antipyrine and norantipyrine, is significantly reduced. There is no selective effect on a particular metabolic pathway. Main adverse effects: Gastrointestinal tract: Dose-related gastrointestinal symptoms include anorexia, nausea, vomiting, epigastric distress, and abdominal cramps. Hematological system: Acute hemolytic anemia occurs most frequently in G6P Ddeficient individuals. It is usually self-limiting but in severe cases blood transfusion may be necessary. Methemoglobinemia, agranulocytosis, granulocytopenia and leucopenia are also reported. Methemoglobinemia can be severe in people who are nicotinamide dinucleotide (NADH) methemoglobin reductase deficient. Cardiovascular system: Hypertension and arrhythmias have been reported. Other: Headache, interference with visual accommodation and pruritus have been reported with primaquine. Adverse CNS effects, including depression and confusion, can also occur. Clinical effects: Acute poisoning: Ingestion: Toxic manifestations such as methemoglobinemia and cyanosis occur in most subjectsadverse gastrointestinal effects occur at higher doses. These doses also cause severe hematologic reactions such as leucopenia, anemia and intravascular hemolysis. Chronic poisoning: Ingestion: The adverse effects associated with chronic administration are similar to those which occur in acute poisoning. Course, prognosis, cause of death: Course: Commonly, symptoms of overdoses are nausea, abdominal pain, sometimes vomiting and jaundice. Hemolytic anemia may occur in G6PD deficiency but is usually self-limiting. Prognosis: If patient survives for 48 h recovery is likely. Death: Cardio-circulatory arrest may occur within 1 to 2 h of ingestion due to ventricular dysrhythmia or asystole. Hypotension is common and may progress rapidly to cardiogenic shock with increased central venous pressure. Hypertension and cardiac arrhythmias have been reported on rare occasions. Systematic description of clinical effects Cardiovascular: Based on its anti-arrhythmic activity in mice, primaquine is predicted to have quinidine like cardiotoxicity. Hypertension and cardiac arrhythmias have been reported on rare occasions. Respiratory: Respiratory arrest secondary to circulatory arrest or severe shock may occur within 1 to 2 hr following overdose. Neurological: CNS: In severe cases, headache, mental depression and confusion occur, especially in persons with prior exposure to chloroquine. Gastrointestinal: Abdominal cramps and epigastric distress have been reported. Hepatic: Hepatic function is unaffected. Dermatological: Pruritus and urticaria. Eye, ear, nose, throat: local effects: Diplopiavisual disturbancesblurred visionirreversible changes to the cornea and retinaoptic neuritis. Hematological: Toxic doses of primaquine induce marked bone marrow depression, methemoglobinemia, agranulocytosis and hemolytic anemia. Hemolytic anemia is commonest in persons with G6PD deficiency. The effects are more pronounced in the B-type G6PD deficiency (the Mediterranean type) than in the A-type (the type mainly present among black American and African populations) Immunological: Primaquine may also cause immunosuppression Metabolic: Fluid and electrolyte disturbances: Hypokalemia is common in severe intoxication. Others: Hypo- or hyperthermia and hypo- or hyperglycemia have been reported. Special risks: Pregnancy: Primaquine should be withheld from women with G6PD deficiency who are pregnant. If prophylaxis or treatment is essential, the possible benefits should outweigh the potential risks. Transplacental transfer of primaquine to a fetus with G6PD deficiency may result in life-threatening anemia and methemoglobinemia in utero. Breast-feeding: It is not known whether primaquine is excreted in breast milk. However, problems in man have not been documented. Enzyme deficiency: Primaquine should be used with caution in patients with G6PD deficiency who are receiving other drugs likely to induce hemolysis, (for example, nitrites, sulfonamides). /Primaquine phosphate/ |
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