Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

White, Nicholas J.; Chanthavanich, Pornthep; Edwards, Geoffrey; Nicholl, Deborah D.; Bunch, C; Warrell, D. A.

doi:10.1111/j.1365-2125.1986.tb02876.x

Cited by 88 publications

(56 citation statements)

References 17 publications

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“…It remains the most widely used antimalarial agent although there is considerable concern surrounding its safety when given parenterally (WHO, 1984). Preliminary studies in volunteers (Gustafsson et al, 1983;Looareesuwan et al, 1986) showed that intravenous injection of chloroquine was potentially dangerous because of transient but very high, plasma chloroquine concentrations. It seemed likely that slow intravenous infusion of chloroquine would be safer.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

Edwards¹,

Davies²,

Wattanagoon³

et al. 1988

Brit J Clinical Pharma

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1 Chloroquine diphosphate (15 mg base kg-") was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2 Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals.3 Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-' in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-'.Values for terminal elimination rate constant, (X,) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were X, = 0.062 ± 0.030 day-1, CL = 597 ± 238 ml min-, V1 = 0.66 ± 0.71 1 kg-" and Vss = 132 ± 50 1 kg-1For the group of malaria patients, the corresponding values were A, = 0.055 ± 0.032 day-1, CL = 535 ± 246 ml min-1, V1 = 0.74 ± 0.75 1 kg-1 and Vss = 136 ± 64 1 kg-1There was no statistically significant difference in the estimates for any parameter between groups (P -0.05). 4 Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group. Peak red-cell concentrations were significantly higher than the equivalent plasma concentration in both groups. In the malaria patients the range of concentration was 1829-11052 ng ml-'. In the healthy volunteers, the range was 2410-4570 ng ml-'. were not statistically significant. There was no significant difference in the area under the sacked red-cell concentration vs time curve between the malaria patients (151637 + 85737 ng m-1' h) and healthy volunteers (100053 ± 42536 ng ml-1 h), when measured to infinite time.5 Various subjective side effects were reported in all participants. A small but significant fall from baseline systolic blood pressure 105 ± 6 mmHg was recorded, 2 h into the infusion (99 ± 9 mmHg), but baseline values had been regained by the end of the infusion (101 ± 10 mmHg). There was no significant rise in heart rate. However the minimum measured blood pressure and maximum recorded pulse in each subject were significantly different from the resting values. 6 Coincident with changes in blood pressure, there was, in both groups, a significant prolongation of the PR interval, QRS interval (88 ± 13 ms to 101 ± 17 ms) and an increase in T wave height (44 ± 13%). 7 These findings suggest that there are no major differences in the pharmacokinetics of chloroquine between the group of patients with vivax malaria studied here and a matched group of healthy volunteers. The cardiovascular effects of the drug are common to both groups, suggesting that the relationships between the pharmacokinetics of chloroquine are governed principally by the ...

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

Edwards¹,

Davies²,

Wattanagoon³

et al. 1988

Brit J Clinical Pharma

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“…Due to its extensive tissue distribution throughout the body, the total volume of distribution is extremely large (100 to 1,000 l/kg body weight) compared with the volume of central compartment (0.2 l/kg body weight) (Krishna and White, 1996). This explains the transiently high blood concentrations and wide peak to trough fluctuation after parenteral administration (Looareesuwan et al, 1986). Approximately 50 to 70% of CQ is bound to plasma protein mainly to alpha 1 -acid glycoprotein.…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 98%

“…In another two published articles (Na-Bangchang et al, 1994a;Hoglund et al, 2016), the relationship between clinical efficacy of the standard three-day CQ and the pharmacokinetics of CQ and DECQ were examined in patients with P. vivax infection to explain the cause of treatment failure in the light of accumulating evidence for the declining of in vitro sensitivity of P. vivax isolates in Thailand to CQ. Looareesuwan et al (1986) reported a transient but markedly high plasma CQ concentration in a preliminary study in healthy Thai subjects. Edwards et al (1987) further carried out a detailed study to confirm whether the change in CQ pharmacokinetics during P. falciparum infection was also a significant contributing factor to the severe cardiovascular adverse effects following treatment with intravenous administration of CQ.…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

“…The first two studies investigated the relationship between CQ blood concentrations and cardiovascular adverse effects, as well as the possibility of enhancement of toxicity during acute phase malaria infection due to alteration of pharmacokinetics of CQ/DECQ (Looareesuwan et al, 1986;Edwards et al, 1988). The report on significant impact of acute phase malaria infection on quinine pharmacokienetics (White et al, 1982) stimulated great concern for clinical use of CQ in patients with malaria.…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

“…Slow, rate-controlled intravenous infusion, is an acceptable mode of CQ administration in seriously illpatients or where oral therapy is not possible (Looareesuwan et al, 1986;Edwards et al,1987). CQ is generally well tolerated (Ducharme et al, 1996).…”

Section: Chloroquinementioning

confidence: 99%

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A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

Chukanchitipat¹,

Na‐Bangchang²

2017

Afr. J. Pharm. Pharmacol.

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The blood schizontocidal chloroquine (CQ) and the tissue schizontocidal and gametocytocidal primaquine (PQ) remain the mainstay treatment of Plasmodium vivax and Plasmodium ovale infections for more than six decades. The review focuses on the clinical pharmacokinetic studies of both drugs in Thai population that have provided useful information for clinical application in the treatment of malaria. There appears to be no major differences in the pharmacokinetics of both drugs with respect to the influences of ethinicity, acute phase malaria infection, and G6PD status. The increase in systemic exposure of CQ and/or its metabolite mono-desethylchlorooquine (DECQ) following oral administration could be due to change in the absorption kinetics during acute phase infection. The high clinical efficacy of CQ for treatment of P. vivax infection in Thailand supports this benefitial pharmacokinetic change. Transiently high and toxic plasma/whole blood concentrations of CQ following intravenous infusion at high rate is explained by the pharmacokinetic characteristics of CQ. Pharmacokinetics of PQ following repeated dosing in most studies appears to be similar to that following a single dosing. This suggests that auto-inhibition of PQ metabolism during multiple dosing is unlikely. Coadministration of CQ, dihydroartemisinin-piperaquine (DHA-PIP), and pyronaridine-artesunate (PYR-ARS) significantly altered the pharmacokinetics of PQ. In the presence of these drugs, PQ exposure was significantly increased. The apparent volume of distribution of PQ was reduced when coadministered with PYR-ARS. In addition, plasma concentrations of CPQ were significantly increased in the presence of CQ. Clinical relevance of these interactions needs to be confirmed.

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Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study

Vicente

Zusterzeel

Johannesen

et al. 2019

Clin Pharma and Therapeutics

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Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐T peak (J‐T peak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐T peak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT peak ‐T end . Absence of J‐T peak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.

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Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

Cited by 88 publications

References 17 publications

Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

Assessment of Multi‐Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study

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