Primaquine Chemical Properties

Melting point:

25°C

Boiling point:

bp0.2 175-179°

Density 

1.0313 (rough estimate)

refractive index 

1.5600 (estimate)

storage temp. 

Refrigerator

solubility 

Chloroform (Slightly), Methanol (Slightly)

pka

pKa 3.74/9.99(H2O,t =25) (Uncertain)

form 

Oil

color 

Dark Yellow to Dark Orange

Water Solubility 

718.4g/L(25 ºC)

CAS DataBase Reference

90-34-6

NIST Chemistry Reference

1,4-Pentanediamine, n(4)-(6-methoxy-8-quinolinyl)-(90-34-6)

Safety Information

Hazardous Substances Data

90-34-6(Hazardous Substances Data)

Toxicity

LD50 oral in mouse: 100mg/kg

Primaquine Usage And Synthesis

Pharmacology and mechanism of action

Primaquine is active against primary exoerythrocytic stages of all malaria parasites. Primaquine is also effective against latent exoerythrocytic stages of P. vivax and P. ovale responsible for relapse. It possesses gametocytocidal activity against all four species of plasmodia which infect man and could theoretically be used to block malaria transmission. Primaquine has no effect on the erythrocytic stages of plasmodia unless toxic concentrations are achieved^【1】. The mechanism of action of primaquine is unknown.

Indications

Primaquine is used for the radical treatment of P. vivax and P. ovale infections. It has also been used in large populations to avoid spread of chloroquine-resistant strains of falciparum malaria (through its gametocytocidal action).
 

Side effects

Primaquine is usually well tolerated in the therapeutic dosage of 15 mg base/day for 14 days, but abdominal pain and gastric distress are common if administered on an empty stomach ^[2] The severity of the gastrointestinal side effects are dose-related, and with larger doses, nausea and vomiting occurs. Rare effects include hypertension and cardiac arrhythmia ^[2]. The principal toxic effect of primaquine is haemolytic anaemia especially in patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD)^[1]It is estimated that 200–300 million people have G6PD deficiency^[3]. The acute haemolysis is seen after a latent phase of 1–3 days. Drug administration should be discontinued when a darkening of the urine (if possible check urine urobilinogen after 1–3 days) or a sudden decrease in haemoglobin levels occurs. The prognosis of this condition is good and specific treatment usually not needed ^[1]. In addition to haemolytic anaemia, primaquine can also cause methaemoglobinaemia and may rarely suppress bone marrow activity leading to leucopenia ^{[2, 3]}.

Contraindications and precautions

It is recommended not to use primaquine in patients with conditions affecting bone marrow function or on myelosuppressive medication ^[3].
 

Interactions

In one study, the effect of primaquine has been studied on the metabolism of antipyrine. Primaquine (45 mg) given 2 hours before antipyrine (300 mg orally), increased antipyrinehalf-life (calculated from 0 to 24 hours) from a mean of 13 to 25 hours and decreased clearance from 3 to 1 l/h ^[4].
 

Preparations

Available as primaquine phosphate: 26.3 mg phosphate equals 15 mg base.
 
• Primaquine® (Zeneca) Tablets 13.2 mg.
 

References

1. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Primaquine. In: Chemotherapy of Malaria, 2nd edn, edited by L.Bruce-Chwatt. Geneva: World Health Organization, pp. 61–63.
2. Primaquine. Martindale: The Extra Pharmacopoeia, 28th edn (1982). (London: Pharmaceutical Press), p. 404.
3. Primaquine. Therapeutic Drugs, edited by Sir Colin Dollery (1991). (London: Churchill Livingstone), pp. P209–P213.
4. Back DJ, Purba HS, Park BK, Ward SA, Orme ML’E (1983). Effect of chloroquine and primaquine on antipyrine metabolism. Br J Clin Pharmacol, 16, 497–502.

Uses

Antimalarial .

Uses

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.

Uses

Primaquine is an intermediate in the synthesis of Primaquine-d3 Diphosphate (P733502). Primaquine-d3 Diphosphate is an isotope labelled Primaquine (P733500), which is an antimalarial.

Indications

Primaquine is the least toxic and most effective of the 8- aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline–quinone metabolite that inhibits the coenzyme Q–mediated respiratory chain of the exoerythrocytic parasite.

Definition

ChEBI: A N-substituted diamine that is pentane-1,4-diamine substituted by a 6-methoxyquinolin-8-yl group at N4 position. It is a drug used in the treatment of malaria and Pneumocystis pneumonia.

brand name

Primaquine (Sanofi Aventis).

Antimicrobial activity

Primaquine is highly active against the hepatic stages of the malaria life cycle, including the latent hypnozoite stage of P. vivax. It has poor activity against erythrocytic stages of malaria parasites, other than gametocytes. The isomers have similar antiplasmodial activity but differ in toxicity. It exhibits activity against Pneumocystis jirovecii and, in experimental models, against Babesia spp. and the intracellular stages of Leishmania spp. and Trypanosoma cruzi.

Acquired resistance

Failure rates of up to 35% have been reported in South East Asia in patients treated with a standard course for P. vivax infections.

Pharmaceutical Applications

A synthetic 8-aminoquinoline, formulated as the diphosphate for oral administration.

Mechanism of action

Moving the side chain from the fourth position of the quinoline ring to the eighth position completely changes the compound’s spectrum of activity. Unlike the 4-substituted aminoquinolines, primaquine has practically no effect on erythrocyte forms of the malaria parasite. Its activity is limited to tissue forms of the parasite in mammals and in the mosquitoes themselves. This makes primaquine an especially valuable drug, allowing radical recovery and simultaneous prevention, which is usually not achieved by using erythrocyte drugs. The place of action of primaquine is the mitochondria of the malarial parasite. It seems likely that primaquine interferes in the process of electron transfer, causing damage to mitochondrial enzymatic systems. This is expressed in the swelling and vacuolization of the parasite’s mitochondria. Host mitochondria are not affected.

Pharmacokinetics

Oral absorption: >75%
C_max 45 mg oral: 0.2 mg/L after 2–3 h
Plasma half-life: 4–10 h
Volume of distribution: 2 L/kg
Plasma protein binding: Extensive
Bioavailability is variable after oral administration. There is extensive tissue distribution. About 60% of the dose is metabolized to carboxyprimaquine, which can reach levels 50 times that of the parent drug; this metabolite has a half-life of 16 h, a low tissue distribution and is detectable at 120 h. Methoxy and hydroxy metabolites are also detectable. Less than 4% of the original dose is excreted unchanged in urine.

Clinical Use

Primaquine is the only 8-aminoquinolinecurrently in use for the treatment of malaria. It is not usedfor prophylaxis. Its spectrum of activity is one of the narrowestof the currently used antimalarial drugs being indicatedonly for exoerythrocytic P. vivax malaria. To treat endoerythrocytic P. vivax, chloroquineor a drug indicated for chloroquine-resistant P. vivax isused with primaquine. In addition to its approved indication,it is also active against the exoerythrocytic stages ofP. ovale and primary exoerythrocytic stages of P. falciparum.Primaquine also inhibits the gameocyte stage that eliminates the form required to infect themosquito carrier. In vitro and in vivo studies indicate thatthe stereochemistry at the asymmetric is not important forantimalarial activity. There appears to be less toxicity withthe levorotatory isomer, but this is dose dependent andmay not be that important at the doses used to treatexoerythrocytic P. vivax malaria.
Although structurally related to the cinchona alkaloids,the 8-aminoquinolines act by a different mechanism of action.Primaquine appears to disrupt the parasite’s mitochondria.The result is disruption of several processes includingmaturation into the subsequent forms. An advantage is destroyingexoerythrocytic forms before the parasite can infecterythrocytes. It is the latter step in the infectious process thatmakes malaria so debilitating.

Clinical Use

Radical cure of malaria caused by P. vivax or P. ovale
Mild or moderately severe infections with Pn. jirovecii (in combination with clindamycin).
Because of its gametocytocidal properties, primaquine has been used rarely in a single dose to prevent the spread of chloroquine- resistant P. falciparum.

Clinical Use

Primaquine is an important antimalarial because it is essentially the only drug effective against the liver (exoerythrocytic) forms of the malarial parasite. The drug also kills the gametocytes in all four species of human malaria. Primaquine is relatively ineffective against the asexual erythrocyte forms. Primaquine finds its greatest use in providing a radical cure for P. vivax and P. ovale malaria.

Side effects

Primaquine is readily absorbed from the gastrointestinal tract, and in contrast to chloroquine, it is not bound extensively by tissues. It is rapidly metabolized, and the metabolites are reported to be as active as the parent drug itself. Peak plasma levels are reached in 4 to 6 hours after an oral dose, with almost total drug elimination occurring by 24 hours. The half-life is short, and daily administration is usually required for radical cure and prevention of relapses.
Although primaquine has a good therapeutic index, a number of important side effects are associated with its administration. In individuals with a genetically determined glucose 6-phosphate dehydrogenase deficiency, primaquine can cause lethal hemolysis of red cells.This genetic deficiency occurs in 5 to 10% of black males, in Asians, and in some Mediterranean peoples. With higher dosages or prolonged drug use, gastrointestinal distress, nausea, headache, pruritus, and leukopenia can occur. Occasionally, agranulocytosis also has been observed.

Side effects

At standard doses side effects are mild: abdominal cramps, anemia, leukocytosis and methemoglobinemia. However, primaquine is often associated with serious adverse effects due to the toxic metabolites 5-hydroxyprimaquine or 6-methoxy- 8-aminoquinoline which are considered to be directly responsible for complications such as hemolytic anemia. Toxicity is worse in people deficient of glucose-6-phosphate dehydrogenase (G6PD) or glutathione synthetase. Adverse effects can be further increased by the repeated administration of high doses, due to its limited oral bioavailability.

Synthesis

Primaquine, 8-[(4-amino-1-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.4), is made from 6-methoxy-8-nitroquinoline (37.1.2.1), which is synthesized in a Skraup reaction from 4-methoxy-2-nitroaniline and glycerol in the presence of sulfuric acid. The nitro group in this compound is reduced to make 6-methoxy-8-aminoquinoline (37.1.2.2). Alkylating the amino group with 4-bromo-1-phthalimidopentane gives 8-[(4-phthalimido-1-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.3), the hydrazinolysis of which removes the phthalimide protection, giving primaquine.

Veterinary Drugs and Treatments

Primaquine is considered the drug of choice for treating Babesia felis in cats. Primaquine does not apparently “cure” the infection; repeated courses of therapy may be necessary. It may be useful in treating Hepatazoon canis in dogs or Plasmodium spp. in birds. In humans, primaquine is used for treatment and prophylaxis for malaria and treating Pneumocystis pneumonia.

Primaquine(90-34-6)Related Product Information

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