90-34-6 Usage
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
Different sources of media describe the Indications of 90-34-6 differently. You can refer to the following data:
1. 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).
2. 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.
Side effects
Different sources of media describe the Side effects of 90-34-6 differently. You can refer to the following data:
1. 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].
2. 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.
3. 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.
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
Different sources of media describe the Uses of 90-34-6 differently. You can refer to the following data:
1. Antimalarial
.
2. 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.
3. 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.
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.
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%
Cmax 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
Different sources of media describe the Clinical Use of 90-34-6 differently. You can refer to the following data:
1. 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.
2. 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.
3. 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.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 90-34-6 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 9 and 0 respectively; the second part has 2 digits, 3 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 90-34:
(4*9)+(3*0)+(2*3)+(1*4)=46
46 % 10 = 6
So 90-34-6 is a valid CAS Registry Number.
InChI:InChI=1/2C16H23N3O/c2*1-11(17)6-7-12(2)19-15-10-14(20-3)9-13-5-4-8-18-16(13)15/h2*4-5,8-12,19H,6-7,17H2,1-3H3/t2*11?,12-/m10/s1
90-34-6Relevant articles and documents
Repurposing primaquine as a polyamine conjugate to become an antibiotic adjuvant
Bourguet-Kondracki, Marie-Lise,Brunel, Jean Michel,Cadelis, Melissa M.,Chen, Dan,Copp, Brent R.,Edmeades, Liam R.,Pearce, A. Norrie,Troudi, Azza
, (2021/04/12)
In our search for new antibiotic adjuvants as a novel strategy to deal with the emergence of multi-drug resistant (MDR) bacteria, a series of succinylprimaquine-polyamine (SPQ-PA) conjugates and derivatives of a cationic amphiphilic nature have been prepared. Evaluation of these primaquine conjugates for intrinsic antimicrobial properties and the ability to restore the antibiotic activity of doxycycline identified two derivatives, SPQ-PA3-8-3 and SPQ-PA3-10-3 that exhibited intrinsic activity against the Gram-positive bacteria Staphylococcus aureus and the yeast Cryptococcus neoformans. None of the analogues were active against the Gram-negative bacterium Pseudomonas aeruginosa. However, in the presence of a sub-therapeutic amount of doxycycline (4.5 μM), both SPQ-PA3-4-3 and SPQ-PA3-10-3 compounds displayed potent antibiotic adjuvant properties against P. aeruginosa, with MIC's of 6.25 μM. A series of derivatives were prepared to investigate the structure-activity relationship that explored the influence of both a simplified aryl lipophilic substituent and variation of the length of the polyamine scaffold on observed intrinsic antimicrobial properties and the ability to potentiate the action of doxycycline against P. aeruginosa.
Synthesis of primaquine glyco-conjugates as potential tissue schizontocidal antimalarial agents
Azad, Chandra S.,Saxena, Mridula,Siddiqui, Arif J.,Bhardwaj, Jyoti,Puri, Sunil K.,Dutta, Guru P.,Anand, Nitya,Saxena, Anil K.
, p. 254 - 261 (2017/07/13)
Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side-effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco-conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92?mmol/kg) than the standard drug PQ diphosphate (3.861?mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.
Targeting the erythrocytic and liver stages of malaria parasites with s-triazine-based hybrids
Rodrigues, Catarina A. B.,Frade, Raquel F. M.,Albuquerque, Inês S.,Perry, Maria J.,Gut, Jiri,Machado, Marta,Rosenthal, Philip J.,Prudêncio, Miguel,Afonso, Carlos A. M.,Moreira, Rui
supporting information, p. 883 - 890 (2015/05/05)
A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.
