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Primaquin
PRIMAQUIN · primaquine · Primaquine USP/EP/BP · 8-(4-Amino-1-methylbutylamino) · n4-(6-methoxy-8-quinolinyl)-4-pentanediamine · N-(6-Methoxyquinolin-8-yl)pentane-1,4-diamine · N'-(6-Methoxy-8-quinolinyl)pentane-1,4-diamine · N4-(6-Methoxy-8-quinolinyl)-1,4-pentanediaMine
Identifikatoren & physikalische Daten
| CAS No. | 90-34-6 |
|---|---|
| Summenformel | C15H21N3O |
| Durchschnittliche Molmasse | 259,35 g/mol |
| Monoisotopische Masse | 259,16846229 g/mol |
| SMILES | COc1cc(NC(C)CCCN)c2ncccc2c1 |
| InChIKey | INDBQLZJXZLFIT-UHFFFAOYSA-N |
| PubChem CID | 4908 |
| ChEMBL | CHEMBL506 |
| ChEBI | CHEBI:8405 |
| EC No. | 201-987-2 |
| DTXSID | DTXSID8023509 |
| Lokaler Name | Primaquin |
Chemische & physikalische Eigenschaften
| XLogP | 2,2 |
|---|---|
| Polarare Oberfläche (TPSA) | 60,2 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 6 |
| Schwere Atome | 19 |
| Formalladung | 0 |
| Komplexität | 262 |
| LogP (Verteilungskoeffizient) | 2.1 |
| Color/Form | Viscous liquid |
| Löslichkeit | 5.64e-02 g/LChloroform (Slightly), Methanol (Slightly)718.4g/L(25 ºC) |
| Human Drugs | Breast FeedingLactationMilk, HumanAnti-infective AgentsAntiparasitic AgentsAntimalarialsAntiprotozoal AgentsAntimalarial medicines > For curative treatment |
| Siedepunkt | 175-179 °Cbp0.2 175-179° |
| Schmelzpunkt | < 25 °C25°C |
| Physical Description | Solid |
| Stability/Shelf Life | Primaquine phosphate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40 °C, preferably between 15-30 °C. |
| Dissociation Constants | 10.03 |
| Other Experimental Properties | Upon decomposition emits NOxYellow crystals from 90% ethanol. mp 197-198 °C. Moderately soluble in water /Phosphate/Yellow crystals from 80% ethanol. mp 182-185 °C /Oxalate/ |
| Dichte | 1.0313 (rough estimate) |
| Brechungsindex | 1.5600 (estimate) |
| Lagerbedingungen | Refrigerator |
| pKa (Säurekonstante) | pKa 3.74/9.99(H2O,t =25) (Uncertain) |
| Aggregatzustand | Oil |
| Farbe | Dark Yellow to Dark Orange |
| InChI | 1S/C15H21N3O/c1-11(5-3-7-16)18-14-10-13(19-2)9-12-6-4-8-17-15(12)14/h4,6,8-11,18H,3,5,7,16H2,1-2H3 |
| InChIKey | INDBQLZJXZLFIT-UHFFFAOYSA-N |
| SMILES | N(C(CCCN)C)c1c2ncccc2cc(c1)OC |
| CAS Datenbank | 90-34-6 |
| NIST chemische Informationen | 1,4-Pentanediamine, n(4)-(6-methoxy-8-quinolinyl)-(90-34-6) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]P203, P264, P270, P280, P301+P316, P318, P321, P330, P405, and P501 (click each P-code to see the statement)The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory. |
|---|---|
| Weitere Sicherheitsinformationen | IMAP assessments - 1,4-Pentanediamine, N4-(6-methoxy-8-quinolinyl)-: Environment tier I assessment |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl primaquine phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Primaquine phosphate/ |
| Hazard Classes and Categories | Acute Tox. 3 (100%) |
| Entsorgungsverfahren | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Wechselwirkungen | Because quinacrine appears to potentiate the toxicity of antimalarial agents that are structurally related to primaquine, concomitant administration of quinacrine and primaquine is contraindicated and primaquine should not be administered to patients who have recently received quinacrine.Aluminum and magnesium salts decrease the GI absoption of /primaquine/.Concurrent use of primaquine with bone marrow depressants may increase the leukopenic effectif concurrent use is require, close observation for myelotoxic effects should be considered.Concurrent use of primaquine with other hemolytics may increase the potential for toxic side effects. |
| Hepatotoxicity | Despite use for more than 50 years, primaquine has not been linked to significant serum aminotransferase elevations or to clinically apparent acute liver injury. Primaquine can cause hemolysis in patients with G6PD deficiency, which can result in mild jaundice. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5X10+4(SRC), determined from a structure estimation method(2), indicates that primaquine is expected to be immobile in soil(SRC). The pKa of primaquinex is 9.9(3), indicating that this compound will primarily exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Cations do not volatilize from moist soil surfaces(SRC). Primaquine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-6 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(2005, SRC).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5X10+4(SRC), determined from a structure estimation method(2), indicates that primaquine is expected to adsorb to suspended solids and sediment(SRC). The pKa of primaquine is 9.9(3), indicating that this compound will primarily exist in the cation form at pH values of 5 to 9 and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Cations do not volatilize from water surfaces. According to a classification scheme(5), an estimated BCF of 53(SRC), from an estimated log Kow of 3.15(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate, assuming the compound is not metabolized by the organism(SRC). Biodegradation data were not available(SRC, 2005).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), primaquine, which has an estimated vapor pressure of 9.9X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase primaquine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 1.5 hours(SRC), calculated from its rate constant of 2.5X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase primaquine may be removed from the air by wet and dry deposition(SRC). Primaquine contains chromophores that may absorb at wavelengths >290 nm and therefore it may be susceptible to direct photolysis by sunlighthowever, the exact rate of this reaction is not known(SRC). |
| Toxizitätsübersicht | 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/ |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of primaquine can be estimated to be 5X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that primaquine is expected to be immobile in soil. The estimated pKa of primaquine is 9.9(3), indicating that this compound will primarily exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ The most important adverse effects are hemolytic anemia in patients with G6PD deficiency, other defects of the erythrocytic pentose phosphate pathway of glucose metabolism, or some other types of hemoglobinopathy. In patients with the African variant of G6PD deficiency, the standard course of primaquine generally produces a benign self-limiting anemia. In the Mediterranean and Asian variants, hemolysis may be much more severe. Therapeutic doses may also cause abdominal pain if administered on an empty stomach. Larger doses can cause nausea and vomiting. Methemoglobinaemia may occur. Other uncommon effects include mild anemia and leukocytosis. Overdosage may result in leukopenia, agranulocytosis, gastrointestinal symptoms, hemolytic anemia and methemoglobinaemia with cyanosis./SIGNS AND SYMPTOMS/ Symptoms of overdosage of primaquine include abdominal cramps, vomiting, burning epigastric distress, CNS and cardiovascular disturbances, cyanosis, methemoglobinemia, moderate leukocytosis or leukopenia, and anemia. The most striking symptoms are granulocytopenia and acute hemolytic anemia in sensitive individuals. Acute hemolysis occurs, but patients recover completely if the drug is discontinued./SIGNS AND SYMPTOMS/ ... The oxidized, denatured hemoglobin species /by primaquine/ comprise what has been designated sulfhemoglobin. The denatured hemoglobin can form aggregates that bind to the cell membrane to form inclusions called Heinz bodies, a hallmark of oxidative injury to erythrocytes. Heinz bodies can be visualized by use of phase-contrast microscopy or supravital stains such as crystal violet. These membrane-associated inclusions impair the deformability of the erythrocyte membrane and thus impede movement of erythrocytes through the microcirculation and the spleen. Heinz bodies are effectively removed from the erythrocyte by the spleen, so they are not often observed in peripheral blood samples from patients despite ongoing oxidative injury. However, the culling of Heinz bodies can alter the morphology of the affected cells, giving rise to what are called "bite" cells and "blister" cells ... /which/ look as though a portion of the cytoplasm had been cut away ... /Oxidative hemolysis/ |
| Artificial Pollution Sources | Primaquine's production and use as an antimalarial(1) may result in its release to the environment through various waste streams(SRC). |
| Drug Induced Liver Injury | Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)primaquineAntiprotozoalsNot Applicableno-DILI-concern |
| Environmental Bioconcentration | An estimated BCF of 53 was calculated for primaquine(SRC), using an estimated log Kow of 3.15(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC), provided the compound is not metabolized by the organism(SRC). |
| Volatilization from Water/Soil | An estimated pKa of 9.9(1) indicates primaquine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore, volatilization from moist soil and water surfaces is not expected to be an important fate process. Primaquine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-6 mm Hg(SRC), determined from a fragment constant method(2). |
| Populations at Special Risk | Methemoglobinemia can occur even with usual doses of primaquine ... and can be severe in individuals with congenital deficiency of nicotinamide adenine dinucleotide (NADH) methemoglobin reductase.Therapeutic or higher doses of primaquine, via its oxidative metabolites, may cause acute hemolysis and hemolytic anemia in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency ... About 11% of African Americans have the A- variant ... which makes them vulnerable to hemolysis caused by prooxidant drugs such as primaquine. Sensitivity of erythrocytes to primaquine can be even more severe in some darker-hued Caucasian ethnic groups, including Sardinians, Sephardic Jews, Greeks, and Iranians. Because primaquine sensitivity is inherited by a gene on the X chromosome, hemolysis often is of intermediate severity in heterozygous females who have 2 populations of red cells, one normal and the other deficient in G6PD. Due to "variable penetrance," such females may be less frequently affected than predicted. |
| Environmental Abiotic Degradation | The rate constant for the vapor-phase reaction of primaquine with photochemically-produced hydroxyl radicals has been estimated as 2.5X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Primaquine is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Primaquine contains chromophores that may absorb at wavelengths >290 nm and therefore it may be susceptible to direct photolysis by sunlighthowever, the exact rate of this reaction is not known(SRC). |
| Wassergefährdungsklasse (WGK) | WGK 3 |
| Toxizität | LD50 oral in mouse: 100mg/kg |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 90-34-6(Hazardous Substances Data) |
| Gefahrenklasse | Acute Tox. 3 OralRepr. 2 |
Anwendungen & Verwendung
Verwenden
Primaquine is the most effective and most toxic drug from the whole series of known 8-aminoquinolines. It is generally used for treating exoerythrocyte forms of malaria caused by P. vivax and P. ovale. It also acts on the sexual forms of the plasmodia, which die in the human body upon using this drug. Primaquine is used for treating and preventing late relapses of 3- and 4-day malaria as well as tropic malaria. Synonyms of this drug are avlon and others.