Add time:09/25/2019         Source:infona.pl

Oral formulation of quinine is of great potential interest in uncomplicated malaria, especially in chloroquine-resistant strains. As a preliminary step to efficacy and safety studies in children, 3 studies were undertaken with a new formulation of quinine in white young healthy adults at the therapeutic dose of 25 mg/kg/d divided in 3 doses.Methods. In 2 randomised cross-over design trials, the pharmacokinetics and the bioavailability of single and multiple syrup oral doses of quinine were assessed with reference to i.v. infusion. In the first study (n=12), one single oral dose of quinine formate (equivalent to 8.3 mg kg quinine base) was compared with i.v. infusion (8.3 mg kg - 1 quinine base). The second study (n=8, 16 scheduled) investigated a 4-day oral regimen (8.3 mg.kg - 1 , 8h, 16h, 24h on Day 1 to Day 3 and 8h on Day 4) vs the same single i.v. dose. The third study (n=18) was a biocquivalence study comparing quinine formate tablets and ace arsolate and quinine formate tablets. Quinine was assayed by HPLC with fluorometric detection. Extended ECG monitoring was performed.Results. From study I. The medial Tmax was 1.6h (0.6-5) and the mean fraction available (F± s.d.) was 0.97 (0.18) after single oral dose. There was no significant difference in the t12 between the 2 routes of administration (oral: 10.6 ± 2.4 h vs i.v: 11.5 ± 3.3). The clearance ranged from 0.09 to 0.56 1 kg - 1 h - 1 with a mean (s.d.) of 0.23 ± 0.12 1 kg - 1 h - 1 . In study II, quinine was absorbed with a median Tmax of 1.3h (0.5-4). The F ranged from 0.50 to 0.80. The t12 after oral administration (11.8 ± 1.7 h) were in the same range than those following the infusion (10.6 ± 1.2 h), and not different from the first study. Adverse effects were ear disorders as tinnitus in all the subjects (described as cinchonism). Three subjects experienced partial or total subjective reversible hearing loss, so the trial was interrupted. The study III showed bioequivalence between the 2 tablets formulations of quinine. The modifications of the QT intervals appeared to be concentration-dependent, they all remained within the normal range over the 3 studies.In conclusion. on a pharmacokinetic point of view, quinine formate orally administered might be, when suitable, an alternative to the parenteral administration.

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