Intramuscular Amopyroquin for Acute Malaria

Clavier

et al. 1989

The disposition of amopyroquin was investigated in 10 healthy volunteers after a single 2-mg/kg (body weight) intramuscular dose of amopyroquin base. The major form of the drug in plasma and in whole blood was nonmetabolized amopyroquin, and only very low levels of its primary amine derivative were detected. After a rapid absorption phase (15 min), levels in plasma declined, following a tri-exponential model with a terminal elimination half-life of 129.6 + 92.5 h. The apparent volume of distribution (V/F) and the systemic clearance (CL/F) were 238 + 75 liters/kg and 2,063 ± 1,159 ml/min, respectively. The renal clearance, calculated by using urine excreted during the first 48 h, was 119 + 99 ml/min and represented about 6% of the systemic clearance. About 1.2 and 0.2% of the amopyroquin dose was excreted in the urine during the first 48 h as nonmetabolized amopyroquin and its primary amine metabolite, respectively. Twenty-two Plasmodium falciparum malaria patients were studied after treatment with one of the following regimens of intramuscularly injected amopyroquin base: 3 mg/kg (body weight), 6 mg/kg, or 6 mg/kg followed by 3 mg/kg 24 h later. Parasitemia was cleared at day 7 in one of six, four of seven, and seven of nine patients, respectively. On the basis of this study, a regimen of 12 mg/kg (body weight) administered in two or three injections is suggested.The 4-amino quinoline amopyroquin was proposed for antimalarial therapy nearly 30 years ago. It has been effective in the treatment of acute Plasmodium falciparum and Plasmodium vivax malaria (10,11,17). Moreover, amopyroquin seems more active in vitro than the other 4-amino quinolines (chloroquine or monodesethyl amodiaquine) against resistant strains of P. falciparum (15).Amopyroquin is metabolized more extensively in rats than in rabbits to three metabolites, one of which is probably the primary amine derivative (15). In rats, amopyroquin is widely distributed in tissues and in plasma the drug concentrations are decreased, with a terminal half-life of 14 h (15,18). But during the 8 h after a single 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally, this half-life has been estimated as 2 h (6). In rabbits, a similar bioavailability, about 70%, was observed after oral and intramuscular (i.m.) administration, and terminal elimination half-lives were 18, 24, and 26 h for intravenous (i.v.), i.m., and oral routes, respectively (15). No study has described the metabolism and the pharmacokinetic behavior of amopyroquin in humans.The aims of the present study were as follows: (i) to investigate the metabolism and the pharmacokinetic parameters of amopyroquin in healthy subjects after i.m. administration of amopyroquin base at 2 mg/kg (body weight) and (ii) to compare the following three i.m. therapeutic regimens in P. falciparum malaria patients on the basis of drug concentrations in the blood and in vivo efficacy: 3 mg/kg (body weight) (group 1), 6 mg/kg (group 2), and 6 mg/kg followed by 3 mg/kg 24 h later (group 3). * Corresponding...

Section: Discussioncontrasting

confidence: 57%

“…It has been effective in the treatment of acute Plasmodium falciparum and Plasmodium vivax malaria (10,11,17). Moreover, amopyroquin seems more active in vitro than the other 4-amino quinolines (chloroquine or monodesethyl amodiaquine) against resistant strains of P. falciparum (15).…”

mentioning

confidence: 99%

Pharmacokinetics of intramuscular amopyroquin in healthy subjects and determination of a therapeutic regimen for Plasmodium falciparum malaria

Verdier

Clavier

et al. 1989

“…injection has been demonstrated in more than 700 patients suffering from acute Plasmodium falciparum or Plasmodium vivax malaria (8,9,16). Moreover, amopyroquin seems more active than other 4-aminoquinolines in monkeys infected with chloroquine-resistant strains of P. falciparum (18).…”

mentioning

confidence: 99%

Disposition of amopyroquin in rats and rabbits and in vitro activity against Plasmodium falciparum

Verdier

Faurisson

et al. 1988

The disposition of amopyroquin was studied in rats after a single 50-mg/kg (body weight) oral dose of amopyroquin base. After a rapid absorption phase, the drug concentrations decreased in the plasma, with a terminal half-life of 14.5 h. The drug was widely distributed in the liver and lungs and, to a lesser extent, in the kidneys and spleen. In rabbits, the kinetic parameters were compared after a single 10-mg/kg dose of amopyroquin base through intravenous, intramuscular (i.m.), and oral routes. The similar bioavailability values (0.67 and 0.69) suggested that the drug could be used through i.m. or oral administration. Clearance and distribution volume did not differ significantly among the three modes of administration, and the terminal half-lives were 18.1 3.3, 23.9 + 6.7, and 25.7 5.4 h for intravenous, i.m., and oral routes, respectively. The ratio of concentrations in erythrocytes and plasma was about 5 in rats and rabbits. Three metabolites were detected in both animal species (one was tentatively identified as the primary amine derivative). The amopyroquin in vitro activity was tested against four chloroquine-susceptible and 11 chloroquine-resistant African Plasmodium falciparum strains. For all isolates, the 50% inhibitory concentrations of amopyroquin were much lower than those of chloroquine and monodesethylamodiaquine.Amopyroquin, a compound similar in structure to amodiaquine, has been used since about 1957, and its antimalarial clinical efficacy after a single intramuscular (i.m.) injection has been demonstrated in more than 700 patients suffering from acute Plasmodium falciparum or Plasmodium vivax malaria (8, 9, 16). Moreover, amopyroquin seems more active than other 4-aminoquinolines in monkeys infected with chloroquine-resistant strains of P. falciparum (18).Because suitable analytical methods were not available, little is known about the metabolism and pharmacokinetic behavior of this drug. Recently, a high-performance liquid chromatographic method for analyzing amopyroquin has been applied to the determination of its half-life (t1/2) in rats during the 8 h after a 60-or 120-mg/kg (body weight) dose of amopyroquin given intraperitoneally (5). However, the purpose of this study was not to describe drug metabolism. Recent studies in humans have demonstrated that the chemical analog amodiaquine is rapidly converted after oral administration to a monodesethyl derivative responsible for the pharmacologic activity of the drug (4, 14). It was thus necessary to determine the metabolism of amopyroquin and its kinetic parameters.The present study was undertaken (i) to describe the disposition of amopyroquin in rats after oral administration, MATERIALS AND METHODSAnimal studies. (i) Rats. A total of 72 male SpragueDawley rats weighing 194 ± 15 g, fed on standard rat food VAR AQ4, and housed in conventional cages with controlled lighting were separated into 12 groups. All were given 50 mg of amopyroquin base (Substantia-Parke Davis, Courbevoie, France) per kg by an esophageal tube. Each group was sacrif...

“…Amopyroquin (ApQ) is a 4-aminoquinoline which is structurally related to amodiaquine (Aq) and which was demonstrated nearly 30 years ago to be effective in the treatment of Plasmodium falciparum and Plasmodium vivax malaria when given as a single 3-mg/kg (of body weight) intramuscular injection (7,8,14). After being abandoned in favor of chloroquine (Cq) and then Aq, interest in ApQ is now renewed following the extensive development of resistance to Cq and the appearance of severe side effects with Aq after prolonged prophylaxis (2,6).…”

mentioning

confidence: 99%

Efficacy of intramuscular amopyroquin for treatment of Plasmodium falciparum malaria in the Gabon Republic

Gaudebout

Clavier

et al. 1993

The efficacy of a 12-mg/kg (of body weight) intramuscular amopyroquin (ApQ) regimen (two successive 6-mg/kg injections at a 24-h interval), previously established from kinetic studies on healthy volunteers and multicenter studies on patients with malaria, was investigated in 152 patients (children and adults) in Gabon with Plasmodium faciparum malaria. All children in the present study ( Amopyroquin (ApQ) is a 4-aminoquinoline which is structurally related to amodiaquine (Aq) and which was demonstrated nearly 30 years ago to be effective in the treatment of Plasmodium falciparum and Plasmodium vivax malaria when given as a single 3-mg/kg (of body weight) intramuscular injection (7,8,14). After being abandoned in favor of chloroquine (Cq) and then Aq, interest in ApQ is now renewed following the extensive development of resistance to Cq and the appearance of severe side effects with Aq after prolonged prophylaxis (2, 6). Since no pharmacokinetic studies of ApQ were available, we initially studied its metabolism and kinetics in the rat and rabbit (13) and then in healthy human volunteers (16), using the dosage of 3 mg/kg, which was initially effective. At clinical resistance to Cq in Gabon was supposed to be intermediate.MATERUILS AND METHODS Study patients. One hundred seventy-five patients attending out-patient clinics in a hospital in Mounana, Gabon, were recruited for the study from May to November 1989, after receiving approval for the study from the Ethical Committee of the Health Ministry of Gabon and informed consent from the patients or the parents or guardians of the children. The patients enrolled in the present study fulfilled the following criteria: age of over 1 year, a history of fever or rectal temperature of >38°C, and more than 1,000 asexual P. falciparum parasites detected per ,ul of blood. Exclusion criteria were clinical evidence of severe malaria, as follows: impaired consciousness, prostration or convulsions, acute dehydration, and suspicion of pregnancy and previous adverse reactions to 4-aminoquinolines. On admission, the presence of other 4-aminoquinolines self-prescribed by the patients was evaluated by a urine test with a detection limit of 10 ,umol/liter (1). Of the 175 patients initially recruited for the study, 6 were eliminated because no follow-up of drug levels on day 2 was possible and 17 others were eliminated because their parasite count was not available on day 7. The total number of patients in the study group was thus 152.Study design.