Administration Of Quinine Research Articles

Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.

The effect of rifampicin and isoniazid pretreatment on the pharmacokinetics of quinine after a single oral dose (600 mg quinine sulphate) was studied in nine healthy young Thai male volunteers using a three-way randomized crossover design. Subjects were studied over three 2 day periods, during which they received no pretreatment, or pretreatment with daily 600 mg p.o. rifampicin for 2 weeks, or isoniazid 300 mg p.o. daily for 1 week, prior to quinine administration. The mean (+/- s.d.) clearance (CL/F) of quinine coadministered with rifampicin (0.87 +/- 0.35 1 h-1 kg-1) was significantly greater than that of quinine alone (0.14 +/- 0.05 1 h-1 kg-1). The mean difference in clearance from the control treatment was 0.73 1 h-1 kg-1, with 95% confidence interval (C.I.) of 0.48 to 0.98. The unbound clearance (CLu/F) of quinine, which reflects the activity of the drug-metabolizing enzymes, was considerably greater (6.9-fold) in subjects when rifampicin was coadministered with quinine than that of quinine alone (6.9 +/- 3.6 vs 1.0 +/- 0.5 1 h-1 kg-1; the 95% C.I. for the mean difference was 3.3 to 8.5). The mean elimination half-life of quinine when coadministered with rifampicin (5.5 +/- 3.0 h) was significantly shorter than when quinine was given alone (11.1 +/- 3.0 h; the 95% C.I. for the mean difference was -8.6 to -2.6). In contrast to rifampicin, pretreatment for 1 week with 300 mg oral isoniazid had no significant effects on the pharmacokinetics of quinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrarectal Quinimax ® (an association of Cinchona alkaloids) for the treatment of Plasmodium falciparum malaria in children in Niger: efficacy and pharmacokinetics

In an attempt to avoid the complications associated with intramuscular quinine administration, we assessed the intrarectal route. Sixty-six children aged from 2 to 10 years with Plasmodium falciparum malaria were included in the study, which took place in Niamey, Niger. Fifty-five children were given 20 mg/kg of the diluted injectable form of Quinimax ® (a quinine, quinidine, cinchonine, cinchonidine association) intrarectally. A further 11 children with malaria were treated with 12·5 mg/kg of the same Quinimax ® solution by the intramuscular route. All the children were treated twice a day for 3 d. Blood samples were drawn from 20 children (15 treated intrarectally and 5 intramuscularly) for a kinetic study. Both modes of administration were well tolerated. Mean fever clearance times (±standard errors) were 48·6 ± 2·7 h and 35·9 ± 2·2 h in the intrarectal and intramuscular groups, respectively ( P = 0·05). Mean parasite clearance times (± standard errors) and mean times to achieve 50% reduction in parasitaemia (±standard errors) were similar after intrarectal (46·5 ± 5·7 h and 7·8 ± 0·9 h respectively) and intramuscular administration (27·4 ± 3·6 h and 8·7 ± 1·7 h, respectively). T max. after intrarectal administration (2·7 ± 0·4 h) did not differ significantly from the value after intramuscular administration (1·1 ± 0·6 h), but C max. and the area under the concentration-time curve from 0 to 48 h were lower (4·9 ± 0·6 mg/L and 230·0 ± 9·6 mg/L.h, respectively) than after intramuscular administration (9·1 ± 1·2 mg/L and 356·0 ± 4·2 mg/L.h, respectively) ( P < 0.001). Compared to the intramuscular route, intrarectal Quinimax ® bioavailability was 40%. The tolerability and efficacy of this alkaloids association administered by the intrarectal route were satisfactory, while bioavailability should be improved by the use of a formulation specifically adapted to this route.

Magnitude Changes in Transient Evoked Otoacoustic Emissions and High-level 2f1-f2Distortion Products in Man During Quinine Administration

Quinine reversibly affects the outer hair cells (OHC). It is therefore an ideal drug for studying OHC-related phenomena, such as transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs). Pure-tone thresholds (PTTs), 1,000-4,000 Hz, TEOAEs, and DPOAEs were measured monaurally in 5 normal-hearing volunteers during quinine administration. DPOAE was evoked at 75 dB SPL (f2/f1 = 1.22) and analysed at 2f1-f2 with f2 at 6 frequencies (700-4,000 Hz), while TEOAE was obtained at 79 dB SPLp and analysed at the f2 frequencies (1/3 octave). The PTT-shift was flat, 10 dB, whereas the TEOAE-power and the global mean of the DPOAEs decreased 4.5 dB and 1.4 dB, respectively. No correlation was found between the intra-individual emission shifts. It is concluded that TEOAE is more sensitive than high-level DPOAE for identifying minor cochlear hearing losses. Support is given to the hypothesis that different sources are involved in generating DPOAEs at different evoking levels.

Magnitude Changes in Transient Evoked Otoacoustic Emissions and High-level 2f1-f2Distortion Products in Man During Quinine Administration

Magnitude Changes in Transient Evoked Otoacoustic Emissions and High-level 2f₁-f₂Distortion Products in Man During Quinine Administration

Otoacoustic emissions and quinine sulfate

A moderate dose of quinine sulfate, administered to three young adult males, reduced or eliminated various forms of otoacoustic emission (OAE). The individual differences in response to the drug were substantial, but a number of generalizations did emerge. The time courses of onset and recovery were considerably more rapid than for the parallel effects produced by aspirin. Most spontaneous otoacoustic emissions (SOAEs) were eliminated within 7 h of the first 325-mg dose (about 3 h after the second dose). Most SOAEs showed partial or complete recovery about 24 h after the last dose, although considerable instability often remained. The functions relating the magnitude of a distortion-product OAE (DPOAE) to the sound-pressure level (SPL) of the primary tones producing it were displaced toward higher primary levels and became lower sloped following quinine administration. The magnitudes of SOAEs, DPOAEs, and nonlinear peaks in the click-evoked spectra declined and recovered with grossly similar time courses, but there were some partial dissociations. The ability of a DPOAE to suppress an SOAE lying about 50 Hz below it either increased slightly or remained about constant through the drug episode, even though the magnitudes of both DPOAE and SOAE were changing. On several occasions, increases in SOAE magnitude of as much as 10-20 dB were observed during the first 15-30 min of an SOAE measurement period (an initializing effect). Psychophysical measures revealed hearing losses of as much as 20 dB at some frequencies in some subjects. Several short-lived "enhancements" of OAEs are discussed relative to similar quinine-induced effects reported in an animal model.

Falciparum malaria: Acute liver disease never contra-indicates quinine administration in travellers with fever after returning from areas endemic for malaria

Falciparum malaria: Acute liver disease never contra-indicates quinine administration in travellers with fever after returning from areas endemic for malaria

Cigarette smoking enhances the elimination of quinine

The pharmacokinetics of a single dose (600 mg) of quinine sulphate were examined in a group of non-smokers (n = 10) and in heavy cigarette smokers (n = 10). The mean (+/- s.d.) oral clearance of quinine in smokers (0.189 +/- 0.075 1 h(-1) kg(-1)) was significantly greater than in non-smokers (0.107 +/- 0.045 1 h(-1) kg(-1) , P < 0.01). The unbound clearance of quinine which reflects activity of the drug-metabolizing enzyme, was considerably greater (1.5-fold) in the smokers than in the non-smoker subjects. The mean elimination half-life of quinine in smokers was 7.5 +/- 1.4 (s.d.) h, significantly shorter (P < 0.005) than the mean value in non-smokers (12.0 +/- 3.1 h). These results suggest that cigarette smoking enhances the elimination of quinine. The clinical significance of these findings is unknown but they indicate the need for caution in the administration of quinine to patients who are heavy cigarette smokers.

The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse—3. Quinine

It has been shown that caesium, which shares properties with quinine as a K +-channel blocker, enhanced 5-HT-mediated behaviour in both rats and mice. It was therefore of interest to investigate the effects of quinine on 5-HT-mediated behaviour in the rat and mouse. Quinine, dose-dependently (ED 50 = 5 mg/kg), produced the 5-HT behavioural syndrome in rats pre-treated with tranylcypromine (TCP) (15 mg/kg, i.p.). p-Chlorophenylalanine (i.p., 300 mg/kg × 2) or ( − )-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.), all prevented the behavioural syndrome induced by quinine (72 mg/kg, i.p.) plus TCP. The administration of quinine (72 mg/kg, i.p.) enhanced the 5-HT syndrome elicited by p-chloroarnphetamine (4 mg/kg, i.p.) and the 5-HT agonists, 8-OH-DPAT (0.5 mg/kg, s.c.), 5-MeODMT (2 mg/kg, i.p.), DOI (8 mg/kg, s.c.) and quipazine (25 mg/kg, i.p.) in rats. Pretreatment with quinine also potentiated the 5-HT 2-mediated head-twitch in the mouse but had no effect on the hypothermia in the mouse, induced by 8-OH-DPAT (0.5 mg/kg, s.c.). Quinine also enhanced the rate of synthesis of 5-HT in the brain of the rat. On the basis of these findings, together with those in the preceding two papers, it is suggested that the effects of rubidium, caesium and quinine, to enhance differentially various aspects of 5-HT function are mediated by actions on 5-HT-modulated K +-channels. This conclusion is also discussed in relation to the actions of lithium and electroconvulsive shock on 5-HT function in brain and the treatment of manic-depressive disease.

Quinine-Induced Tinnitus in Rats

Quinine ingestion reportedly induces tinnitus in humans. To expand our salicylate-based animal model of tinnitus, a series of conditioned suppression experiments was performed on 54 male-pigmented rats using quinine injections to induce tinnitus. Quinine induced changes in both the extent of suppression and recovery of licking, which followed a pattern that paralleled those produced after salicylate injections, and which may be interpreted as the result of tinnitus perception in animals. These changes depended on the dose and time schedule of quinine administration. Additionally, the calcium channel blocker, nimodipine, abolished the quinine-induced effect in a dose-dependent manner.

Disposition of oral quinine in acute falciparum malaria

Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg.l-1 compared to 5.7 mg.l-1 in convalescence. There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml.kg-1.min-1, which was significantly lower than in convalescence--2.67 ml.kg-1.min-1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml.kg-1.min-1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of alpha 1 acid glycoprotein (r = 0.5), which was significantly higher in the acute phase; 1.48 g.l-1 compared to 1.05 g.l-1 during convalescence. Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.

Comparative effects of the diastereoisomers, quinine and quinidine in producing phenocopy debrisoquine poor metabolisers (PMs) in healthy volunteers

1. A single oral dose (50 mg) of quinidine significantly increased the debrisoquine metabolic ratio in six healthy volunteers. For four of the volunteers the metabolic ratio changed to that typical of the poor metaboliser (PM) phenotype. 2. The effect of quinidine in producing debrisoquine oxidation "poor metaboliser" phenocopies persisted for at least 3 days but had disappeared by 1 week. 3. The debrisoquine metabolic ratios for the same six subjects were not significantly altered by the oral administration of quinine (200 or 400 mg), the diastereoisomer of quinidine. 4. The plasma pharmacokinetic parameters of both nortriptyline and desipramine in healthy volunteers were all changed to those more typical of the debrisoquine PM phenotype following the concomitant administration of quinidine (50 mg). 5. It is concluded that quinidine, but not its diastereoisomer quinine, is a potent selective inhibitor of the in vivo oxidation of debrisoquine and can produce an artifactual PM phenocopy in persons who are phenotypically extensive metaboliser (EM) phenotype status. The clinical implications of this observation are discussed.

Pharmacokinetics of quinine in young and elderly subjects

The effect of age on the pharmacokinetics of quinine was investigated by comparing its kinetic behaviour in 12 young healthy adults and 8 healthy elderly subjects after a single 600 mg oral dose of quinine sulphate. Peak plasma quinine concentration and the time of peak concentration were similar in the young and elderly subjects. The mean oral clearance of quinine was found to be significantly decreased in the elderly ( P < 0·05, 0·062 litre/h/kg vs 0·084 litre/h/kg) as compared to the young. This was accompanied by a significant increase in the mean elimination half-life of quinine in the elderly group (18·4 ± 5·7 [standard deviation] h vs 10·5 ± 1·6 h, P < 0·05). There was no significant difference in the renal clearance of quinine between the young and the elderly ( P > 0·05). However, elderly subjects excreted 16·6 ± 3·7% of the dose as unchanged quinine in the urine and this was significantly greater ( P < 0·005) than the amount excreted by the young (11·2 ± 2·5%). The results of this study indicate that the elimination processes for quinine are impaired in normal elderly subjects. The clinical significance of these findings is unknown, but they indicate the need for caution in the administration of quinine to elderly patients.

Altered flecainide disposition in healthy volunteers taking quinine

The pharmacokinetics of flecainide and its two sequential metabolites, both free and conjugated, its pharmacodynamics, and the influence of simultaneously administered quinine, have been studied in 10 healthy subjects. The study comprised two, 48-h open phases at an interval of 1 week. Flecainide acetate 150 mg was given as a 30-min i.v. infusion and quinine sulphate orally 500 mg x 3 over 24 h. Quinine administration did not change the apparent volume of distribution or the renal clearance of flecainide, but it significantly reduced its systemic clearance (9.1 vs 7.6 ml.kg-1.min-1), thus increasing the elimination half-life (9.6 vs 11.5 h). The amount of flecainide transformed to its first, meta-O-dealkylated metabolite (MODF) fell with no change in the renal excretion of the latter, either in its free or conjugated forms. This finding, in association with a fall in amount of the second, meta-O-dealkylated lactam metabolite (MODLF) recovered in its conjugated forms in the urine, suggests that quinine inhibits both the first and the second steps of the sequential metabolism of flecainide. When the subjects received quinine in addition to flecainide, the PR interval in the ECG was slightly more prolonged than with flecainide alone. Due to the study design, an effect of quinine per se and the consequence of increased serum flecainide levels could not be distinguished.

Interactions in the renal and biliary elimination of digoxin: Stereoselective difference between quinine and quinidine

The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady-state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within-subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady-state biliary clearance of digoxin from control value 134 +/- 57 ml/min (mean +/- SD) to 87 +/- 39 ml/min during treatment with quinine (p less than 0.05) and from 95 +/- 24 to 55 +/- 27 ml/min during treatment with quinidine (p less than 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 +/- 26 versus 110 +/- 21 ml/min) (p less than 0.05; n = 4), whereas quinine had no such effect (177 +/- 40 versus 185 +/- 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.

Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria.

Hypoglycemia may develop in patients with severe untreated malaria and can complicate the course of treatment with parenteral quinine as a result of quinine-induced hyperinsulinemia. Intravenous quinine is used increasingly as the therapy of choice in patients with severe malaria, most of whom are children. To assess the importance of both pretreatment and quinine-related hypoglycemia in children in an area in which the disease is endemic, we prospectively studied 95 Malawian children with falciparum malaria and altered consciousness who were treated with intravenous quinine. Nineteen patients had hypoglycemia before treatment. Seven (37 percent) died, and five of the survivors (26 percent) had neurologic sequelae. The corresponding values for patients who were initially normoglycemic were 4 percent and 4 percent, respectively (P less than 0.0001). Hypoglycemia was associated with low plasma insulin concentrations and with elevated plasma concentrations of lactate, alanine, and 5'-nucleotidase--a finding that suggests that impaired hepatic gluconeogenesis but not hyperinsulinemia contributes to the pathogenesis of pretreatment hypoglycemia. All patients were given quinine dihydrochloride in a 5 percent dextrose infusion, and those with hypoglycemia received 50 percent dextrose. Hypoglycemia recurred in seven of the patients with pretreatment hypoglycemia, but these episodes were also not associated with hyperinsulinemia. Of the 76 children who were initially normoglycemic, none became hypoglycemic during the course of treatment with intravenous quinine. We conclude that hypoglycemia is a frequent complication of falciparum malaria in children and that it reflects severe disease and is associated with a poor prognosis. We did not find it to be a complication of quinine treatment.

Quinine pharmacokinetics in cerebral malaria: predicted plasma concentrations after rapid intravenous loading using a two-compartment model

To investigate the toxic potential of rapid intravenous quinine administration in severe malaria, the pharmacokinetic properties of low-dose quinine dihydrochloride injection (4 mg/kg body weight, equivalent to 3 · 3 mg base/kg) followed one hour later by infusion of 16 mg/kg over 3 h were studied in 7 patients with cerebral malaria. Plasma quinine concentrations closely followed a bi-exponential decline. Both the volumes of the central compartment (mean ± SD: 0 · 17 ± 0 · 10 litre/kg) and total volumes of distribution (0 · 74 ± 0 · 30 litre/kg) were significantly smaller than those previously reported for healthy subjects. Based on the derived pharmacokinetic parameters, predicted plasma quinine concentrations following intravenous injection of the standard therapeutic dose (10 mg salt/kg) over 10–20 min are potentially toxic in severe malaria. Further reductions in administration time would produce disproportionately higher plasma quinine concentrations, especially as the distribution half-time (2 · 3 ± 3 · 2 min) is approached. A theoretical regimen designed to achieve therapeutic, non-toxic plasma quinine concentrations promptly would be 7·0 mg quinine dihydrochloride/kg over 30 min. A subsequent maintenance infusion of 10 mg/kg over 4 h would allow for drug elimination and acute changes in pharmacokinetic parameters due to rescucitation and rehydration.

Quinine induced photosensitivity: clinical and experimental studies.

Quinine induced photosensitivity, an infrequently described adverse effect, is reported in four patients. The clinical presentation and distribution was that of a light exposed site eruption characterized by oedema and erythema in three patients, and by lichen planus in the fourth. Monochromator phototesting demonstrated abnormal delayed erythema responses in the UVB, UVA and visible wavebands. The clinical features suggested a phototoxic effect but laboratory studies indicated that the molecular mechanisms involved are unusual. Clinical and phototest evidence of abnormal photosensitivity persisted for some months after stopping quinine. Broad spectrum sunscreens are advised for the management of such patients and, where possible, cessation of quinine administration.

Glucose homeostasis in rats treated acutely and chronically with quinine

Glucose homeostasis in normal rats was studied after chronic or acute administration of quinine. Male rats received a daily dose of 10–30 mg/kg of quinine in the drinking water for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. Though basal plasma insulin levels were increased in treated rats, their plasma glucose levels were only slightly and not consistently decreased. After oral or intravenous administration of glucose, the plasma insulin levels were higher and the disappearance rate of glucose was greater in rats receiving quinine than in the controls. The insulin content of the pancreas was not affected by quinine treatment. Intraperitoneal injection of a high dose of quinine (30 mg/kg) transiently increased plasma glucose and insulin levels. The insulin response was increased during a subsequent administration of glucose but the glucose levels were not modified. This study shows that chronic administration of quinine increases plasma insulin levels, accelerates disposal of oral or intravenous glucose but does not cause hypoglycaemia in normal rats.

Decrease of potassium permeability by intracellular application of sodium ions in snail neurons

In the identified neurons B1, B2 and B3 of Helix pomatia an intracellular injection of Na + induced an outward current in 10% and an inward current in 90% of the experiments. The outward current was associated with an increase and the inward current with a decrease of the membrane conductance. Both currents reversed at membrane potentials of between −60 and −70 mV. Inward currents were also elicited by intracellular Li + or tris-[hydroxymethyl]-aminomethane (Tris +) injection. All inward currents were reduced by extracellular administration of tetraethylammonium or quinine. It is suggested that the outward current represents a calcium-activated potassium current and that the inward current is due to a blockade of potassium channels from the intracellular side.

Effect of quinine on digoxin kinetics.

Six subjects were evaluated for the effect of quinine, the l-isomer of quinidine, on digoxin pharmokinetics. A 1.0-mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half-life (t 1/2) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x = 628. 29 micrograms to x = 772.52 micrograms (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quamtitatively different, from quinidine.