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Abstract: The bioavailability of orally administered drugs can be influenced by interactions with food components and by physico-chemical conditions in the upper gastrointestinal tract. Normally, bile salts enhance the transport of lipophilic drugs across mucosal membranes. Bile salts are able to form stable mixed micelles consisting of fatty acids and phospholipids. Conventional micellar systems are known to solubilize lipophilic drugs having a low bioavailability. The influence of bile salts and mixed micelles on the pharmacokinetics of the lipophilic drug quinine was investigated in rabbits. Female rabbits were given intraduadenally quinine (5mg/kg body weight) without and with incorporation into the micellar or mixed micellar systems. Blood was collected every 30min for 6h. In plasma, concentration of quinine was measured using HPLC. The plasma concentration–time profiles of quinine were significantly lower within the first 2h after administration in presence of both the sodium salt of glycodeoxycholic acid (above the critical micellar concentration) as well as of mixed micellar systems consisting of glycodeoxycholic acid and palmitic acid and/or lecithin. The pharmacokinetic parameters AUC (relative bioavailability) and c max of quinine were significantly decreased by micellar systems in rabbits. These mixed micellar systems lower and not as expected, increase the absorption of quinine in vivo. Therefore, quinine should be orally administered at least 1h before food intake, particularly before fat intake. [Copyright &y& Elsevier]

The main objective of this work was to develop and evaluate rectal quinine paediatric formulations to treat acute uncomplicated malaria attack in some African countries. Developed dosage forms must be able to assure a prolonged release in the rectum but not too much so as to avoid product expulsion by the child anus. Two quinine rectal gels, namely mucoadhesive (MA) gel and thermosensitive (TS) gel, containing 20 mg quinine base/g were developed and evaluated in vitro and in vivo in the rabbit. The MA and the TS gels contained hydroxypropyl methylcellulose 4000 (HPMC) and poloxamer 407, respectively. The calculated in vitro release exponent (n) values suggested that drug was released from both gels by non-Fickian diffusion. Both gels exhibit practically similar efficient of dissolution (ED%) which was not reflected in the plasma and, therefore, quinine bioavailability from MA gel was found to be higher than that obtained from TS gel and their AUC0–∞ were statistically different (P = 0.0006). The t1/2 values of quinine were significantly higher for Hydrogels than for IV and rectal solutions. MRT values displayed by TS gel and MA gel were not statistically different but were about 3.8- and 1.3-fold, respectively, larger than those obtained for IV solution and rectal solution, respectively. These results confirm the sustained-release behaviour of both hydrogels in the rabbit. Tolerability study of hydrogels didn’t show any damage on the rectal mucosa of the rabbit. [Copyright &y& Elsevier]

The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism)., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: The surface charge of nanoparticles, such as nanospheres (NS) and nanocapsules (NC), has been studied with the purpose of improving the in vivo performance of drugs. The aim of this study was to develop, characterize, and evaluate the in vitro antimalarial efficacy of NCP80 and NSP80 (polysorbate coated) or NCEUD and NSEUD (prepared with Eudragit RS 100) loading quinine (QN)., Methods: Formulations were prepared by the nanoprecipitation method, followed by wide physicochemical characterization. Antimalarial activity in Plasmodium berghei- infected mice and populational pharmacokinetics (PopPK) in rats were evaluated., Results: The formulations showed a nanometric range (between 138 ± 3.8 to 201 ± 23.0 nm), zeta potential (mV) of -33.1 ± 0.7 (NCP80), -30.5 ± 1 (UNCP80), -25.5 ± 1 (NSP80), -20 ± 0.3 (UNSP80), 4.61 ± 1 (NCEUD), 14.1 ± 0.9 (UNCEUD), 2.86 ± 0.3 (NSEUD) and 2.84 ± 0.6 (UNSEUD), content close to 100%, and good QN protection against UVA light. There was a twofold increase in the penetration of QN into infected erythrocytes with NC compared to that with NS. There was a significant increase in t 1/2 for all NC evaluated compared to that of Free-QN, due to changes in Vdss. PopPK analysis showed that NCP80 acted as a covariate to Q (intercompartmental clearance) and V2 (volume of distribution in the peripheral compartment). For NCEUD, V1 and Q were modified after QN nanoencapsulation. Regarding in vivo efficacy, NCEUD increased the survival of mice unlike Free-QN., Conclusion: Cationic nanocapsules modified the pharmacology of QN, presenting a potential alternative for malaria treatment., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Michels et al.)

Previous reports assessing morphine effects in two bottle choice (TBC) paradigms often use taste adulterants such as sweeteners (e.g., saccharin) and/or bitterants (e.g., quinine) to demonstrate morphine preference with C57BL6 mice. The effect of these additional components on the morphine preference of C57BL6 remains poorly understood. Thus, we sought to elucidate the interrelationship of morphine and quinine in the TBC paradigm. As expected, when morphine was included in the opposite bottle from quinine, a preference for the morphine solution was observed. Conversely, when quinine was included in each bottle, or when fentanyl without quinine was used, no preference was observed. All opioid-drinking mice displayed withdrawal signs, and morphine was detectable in plasma and brain. When these results were compared to previous results via conversion to quinine preference scores, quinine was revealed to determine largely the measured morphine preference. Thus, quinine is effective to drive morphine consumption and engender dependence but may confound the ability to measure oral abuse liability of morphine. Together, these results suggest future TBC procedures should consider the effect of quinine upon measured preference for compounds in the opposite bottle, and that excessively high quinine concentrations appear to influence preference more so than the opposite solute when using C57BL6 mice. Alternative conditions to assess oral abuse liability may be necessary to complement and confirm results from TBC experiments utilizing morphine or other opioids., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Recent studies indicate that inflammation may also affect CYP3A4 activity. Associations of CYP3A4-mediated metabolism of quinine, with inflammatory biomarkers were investigated in patients undergoing maintenance hemodialysis (HD)., Methods: A single dose of 100 mg quinine was given to 44 HD patients and the plasma concentration of quinine and its metabolite 3-OH-quinine were measured 12 h after drug intake. The ratios of quinine/3-OH-quinine and 4β-OH-cholesterol/cholesterol were used as markers of CYP3A4 activity. Inflammatory biomarkers, high-sensitive CRP (hsCRP), pentraxin 3 (PTX3) and orosomucoid were followed during 4 weeks prior to quinine administration., Results: The quinine/3-OH-quinine ratio correlated with median concentrations of hsCRP (Rho = 0.48; p = 0.001) and orosomucoid (Rho = 0.44; p = 0.003), and also with interleukin-6 at 12 h after drug intake (Rho = 0.43; P = 0.004) but not PTX3. In multivariate regression analysis, the correlation between CYP3A4 activity and median hsCRP remained borderline significant (p = 0.05). 4β-OH-cholesterol/cholesterol ratio correlated with quinine/3-OH-quinine (p = 0.008), but not with any of the inflammation markers., Conclusions: The association between CYP3A4 activity and inflammatory biomarkers suggest that the activity of CYP3A4 is reduced by inflammation in HD patients. Further studies are needed to confirm this finding and to assess to what extent magnitude and duration of inflammation as well as the microbiota affect drug metabolism.

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

This review has the purpose to summarize concentration-effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine-induced increase in hearing threshold and its recovery can be analysed according to 'the psychophysical power function'. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half-maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self-attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Quinine monitoring should be based on unbound concentration due to variable unbound fraction in malaria patients., (Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: The co-existence of malaria with bacterial infections is common in the tropics, hence the concurrent use of antimalarials and antibiotics., Objective: This study aimed to investigate the effect on pharmacokinetics and antimicrobial activity of co-administration of quinine and combined ampicillin-cloxacillin., Methods: In total, 14 healthy adults received single oral doses of ampicillin-cloxacillin combination alone and with quinine in a randomized crossover manner. Urine samples collected at predetermined intervals over 48 h were analysed. The effect of quinine on minimum inhibitory concentrations (MICs) of ampicillin and cloxacillin were determined against Staphylococcus aureus by agar diffusion, agar dilution, and broth dilution., Results: Quinine significantly reduced the rate and extent of excretion of ampicillin and cloxacillin (p < 0.0002). The total amounts of ampicillin and cloxacillin excreted unchanged (Du(∞)) alone were 217.10 ± 53.82 and 199.0 ± 64.29 mg versus 126.40 ± 50.63 and 135.20 ± 52.24 mg, respectively, with quinine. Respective maximum excretion rates (dDu/dt max) for ampicillin and cloxacillin were 43.55 ± 19.41 and 77.64 ± 29.65 mg/h alone versus 18.01 ± 8.52 and 53.16 ± 20.72 mg/h with quinine. This indicates a significant reduction in Du(∞)and dDu/dt max by 41.78 and 58.65 % for ampicillin and 32.06 and 31.53 % for cloxacillin. Conversely, the disposition of quinine was unaffected by ampicillin-cloxacillin (p > 0.1). The MIC of antibiotics alone versus with quinine, respectively, were 0.11 ± 0.04 and 0.78 ± 0.1 µg/ml for ampicillin, and 0.18 ± 0.1 and 0.92 ± 0.4 µg/ml for cloxacillin, with a five- to sevenfold increase (p > 0.01); indicating a decrease in antimicrobial activity by quinine., Conclusions: Quinine therefore, reduced the bioavailability and the antimicrobial activity of ampicillin-cloxacillin upon co-administration, which may have therapeutic implications. Caution is required with the co-administration of these medicines.

This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0-∞, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0-∞, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted., (© The American Society of Tropical Medicine and Hygiene.)

Effective strategies to monitor pharmacotherapy adherence are necessary, and sensitive biological markers are lacking. This study examined a subtherapeutic dose of quinine as a potential adherence tracer. Primary aims included examination of the plasma and urinary pharmacokinetic profile of once-daily quinine; secondary aims assessed pharmacokinetic/pharmacodynamic interactions with oxycodone (a CYP3A and CYP2D substrate). Healthy, nondependent opioid users (n = 9) were enrolled in this within-subject, double-blind, placebo-controlled inpatient study. Participants received the following oral doses: day 1, oxycodone (30 mg); days 2-4, quinine (80 mg); day 5, quinine and oxycodone (2 hours postquinine). Blood and 24-hour urine samples were collected throughout the study, and pharmacodynamic outcomes were assessed during experimental sessions (days 1, 4, 5). Quinine displayed a plasma Tmax ∼2 hours and t1/2 ∼10 hours. Oxycodone and noroxycodone parameters (Tmax , Cmax , t1/2 ) were similar with or without quinine present, although drug exposure (AUC) was slightly greater when combined with quinine. No pharmacodynamic interactions were detected, and doses were safely tolerated. During washout, quinine urinary concentrations steadily declined (elimination t1/2 ∼16 hours), with a 94% decrease observed 72 hours postdose. Overall, low-dose quinine appears to be a good candidate for a medication additive to monitor adherence for detection of missed medication., (© 2015, The American College of Clinical Pharmacology.)

We investigated the effect of concurrent ingestion of Garcinia kola seed on the pharmacokinetics of quinine. In a randomized crossover study, 24 healthy Nigerian volunteers were assigned into 2 groups (A and B; n = 12 per group) on the basis of G. kola dose orally ingested. Each subject received 600 mg quinine sulfate before and after ingesting 12.5 g of G. kola once daily for 7 days (group A) or 12.5 g twice daily for 6 days and once on the seventh day (group B). Blood samples were collected and analyzed for plasma quinine and its metabolite (3-hydroxyquinine) using a validated high performance liquid chromatography method. Concurrent administration of quinine with G. kola reduced quinine tmax by 48% (group A), mean Cmax by 19% and 26% in groups A and B, respectively, and slight reduction in mean AUC0- ∞ of quinine in both groups. 3-hydroxyquinine Cmax also reduced by 29% and 32%; AUC0-∞ by 13% and 9%, respectively. The point estimates of the T/R ratio of the geometric means for all Cmax obtained and only the AUC0-∞ at a higher dose of G. kola were outside the 80%-125% bioequivalence range. In conclusion, an herb-drug interaction was noted with concurrent quinine and G. kola administration., (© 2014, The American College of Clinical Pharmacology.)

Materials which undergo self-assembly to form supramolecular structures can provide alternative strategies to drug loading problems in controlled release application. RADA 16 is a simple and versatile self-assembling peptide with a designed structure formed of two distinct surfaces, one hydrophilic and one hydrophobic that are positioned in such a well-ordered fashion allowing precise assembly into a predetermined organization. A "smart" architecture in nanostructures can represent a good opportunity to use RADA16 as a carrier system for hydrophobic drugs solving problems of drugs delivery. In this work, we have investigated the diffusion properties of Pindolol, Quinine and Timolol maleate from RADA16 in PBS and in BSS-PLUS at 37°C. A sustained, controlled, reproducible and efficient drug release has been detected for all the systems, which allows to understand the dependence of release kinetics on the physicochemical characteristics of RADA16 structural and chemical properties of the selected drugs and the nature of solvents used. For the analysis various physicochemical characterization techniques were used in order to investigate the state of the peptide before and after the drugs were added. Not only does RADA16 optimise drug performance, but it can also provide a solution for drug delivery issues associated with lipophilic drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pregnant women bear the greatest burden of malaria-human immunodeficiency virus co-infection. Previous studies suggest that interaction with antiretroviral drugs may compromise antimalarial pharmacokinetics and treatment outcomes. We conducted a preliminary clinical study to assess quinine pharmacokinetics in Malian pregnant women with acute malaria who reported taking nevirapine-based antiretroviral therapy. Of seven women, six had stable concentrations of nevirapine in the plasma and one had none. Quinine concentrations were lower, and its metabolite 3-hydroxyquinine higher, in the six women with nevirapine than in the one without, and quinine concentrations were below the recommended therapeutic range in 50% of the women. This preliminary observation warrants further research to understand the impact of long-term antiretroviral therapy on the treatment of acute malaria.

Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.

Malaria continues to be a major global public health problem with 3.3 billion people at risk in 106 endemic countries. Globally, over 1000 plants have been used as potential antimalarials in resource-poor settings due to fragile health-care systems and lack of accessibility and affordability of artemisinin-based combination therapies (ACTs). Although many believe that the use of medicinal plants that have folklore reputations for antimalarial properties is relatively safe, many herbs may be potentially toxic due to their intrinsic adverse side effects. Therefore, herbal-derived remedies require powerful and deep assessment of their pharmacological qualities to establish their mode of action, safety, quality, and efficacy. In addition, the evolution of drug resistance also demands new antimalarial agents. This can be achieved by forming a vibrant antimalarial discovery pipeline among all stakeholders, including traditional healers, ethnobotanists, scientists, entomologists, pharmacists, and research institutions, for the isolation and characterization of the bioactive compounds with the ultimate objective of finding novel modes of action antimalarial compounds that can be used to fight against drug-resistant malarial parasites.

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).

The centuries-old antimalarial drug, quinine, continues to play a critical role in the treatment of severe falciparum malaria and uncomplicated malaria in pregnant women. It shares cytochrome P450 (CYP )-mediated metabolic pathways with several commonly used antiretroviral drugs, raising the potential for clinically important drug–drug interactions. A phase I pharmacokinetic study was conducted to assess the impact of long-term use of ritonavir-boosted lopinavir (LPV/r) on quinine pharmacokinetics in healthy volunteers. LP V/r significantly decreased the exposure of quinine and its major active metabolite, 3-hydroxyquinine, in both total and free (unbound) forms. These findings highlight the complex nature of the influence exerted by LPV/r on several of the drug-metabolizing enzymes involved in quinine disposition,including CYP 3A4, UDP-glucuronosyltransferase (UG T), and P-glycoprotein (P-gp). A decline in quinine exposure may compromise clinical efficacy. Further studies are warranted to assess changes in quinine pharmacokinetics and treatment outcomes in patients with acute malaria receiving antiretroviral therapy that includes LPV/r.

The biowaiver approach permits evaluation of bioequivalence (BE) using a set of laboratory tests, obviating the need for expensive and time-consuming pharmacokinetic BE studies provided that both the active pharmaceutical ingredient and the formulations can meet the specified criteria. In the present monograph, the biowaiver-relevant data including solubility and permeability data, therapeutic use and therapeutic index, pharmacokinetic properties, reported excipient interactions, and BE/bioavailability studies of quinine sulfate are itemized and discussed. Quinine sulfate has borderline solubility characteristics and, on the whole, is highly permeable. Thus, depending on the jurisdiction, it is assigned to Biopharmaceutics Classification System class I or II. Although these characteristics would suggest a low risk of bioinequivalence among oral quinine products, a recent pharmacokinetic study showed bioinequivalence of two products. Even though quinine does not, strictly speaking, fit the definition of a narrow therapeutic index drug, it shows dose-related and, in some cases, irreversible side effects and toxicities at concentrations not far above the therapeutic concentration range. Taking all relevant aspects into consideration, a biowaiver cannot be recommended for new quinine immediate-release multisource products or major post-approval changes of already marketed quinine products, and in such cases, BE should be evaluated using an in vivo BE study., (Copyright © 2011 Wiley Periodicals, Inc.)

Quinine is an antimalarial agent whose main mechanism of action on Plasmodium is to inhibit the transformation of toxic haem to polymeric non-toxic haemozoin. After oral and intramuscular administration, quinine is well absorbed, with peak plasma concentration reached in 1 to 3 hours. The pharmacokinetic of quinine differs depending on the severity of the disease: the volume of distribution and the clearance decrease proportionally to the infection, while the half-life increases. Plasma concentrations are approximately 50% higher in patients in the acute phase than in convalescence. Quinine is metabolized primarily by CYP3A4, implying changing the dosage when combined with inhibitors or inducers of CYP. The efficacy of quinine has been proved for residual concentrations above 5 mg/L (15 μmol/L) throughout the duration of treatment. Some side effects are concentration-dependent and a concentration of 20 mg/L (60 μmol/L) is considered as the threshold for toxicity. The 2007 consensus conference of the French Language Infectious Diseases Society calls for daily monitoring of plasma concentrations during the first 3 days of treatment targeting a trough concentration between 10 and 12 mg/L (30-36 μmol/L). For this compound, the level of evidence of the interest of therapeutic drug monitoring has been evaluated and the latter is recommended., (© 2011 Société Française de Pharmacologie et de Thérapeutique.)

Malaria is a serious parasitic infection, which affects millions of people worldwide. As pregnancy has been shown to alter the pharmacokinetics of many medications, the efficacy and safety of antimalarial drug regimens may be compromised in pregnant women. The objective of this review is to systematically review published literature on the pharmacokinetics of antimalarial agents in pregnant women. A search of MEDLINE (1948-May 2011), EMBASE (1980-May 2011), International Pharmaceutical Abstracts (1970-May 2011), Google and Google Scholar was conducted for articles describing the pharmacokinetics of antimalarials in pregnancy (and supplemented by a bibliographic review of all relevant articles); all identified studies were summarized and evaluated according to the level of evidence, based on the classification system developed by the US Preventive Services Task Force. Identified articles were included in the review if the study had at least one group that reported at least one pharmacokinetic parameter of interest in pregnant women. Articles were excluded from the review if no pharmacokinetic information was reported or if both pregnant and non-pregnant women were analysed within the same group. For quinine and its metabolites, there were three articles (one level II-1 and two level III); for artemisinin compounds, two articles (both level III); for lumefantrine, two articles (both level III); for atovaquone, two articles (both level III); for proguanil, three articles (one level II-1 and two level III); for sulfadoxine, three articles (all level II-1); for pyrimethamine, three articles (all level II-1); for chloroquine and its metabolite, four articles (three level II-1 and one level II-3); for mefloquine, two articles (one level II-1 and one level III); and for azithromycin, two articles (one level II-1 and one level III). Although comparative trials were identified, most of these studies were descriptive and classified as level III evidence. The main findings showed that pharmacokinetic parameters are commonly altered in pregnancy for the majority of recommended agents. Importantly, first-line regimens of artemisinin-based compounds, lumefantrine, chloroquine and pyrimethamine/sulfadoxine may undergo significant changes that could decrease therapeutic efficacy. These changes are usually due to increases in the apparent oral clearance and volume of distribution that commonly occur in pregnant women, and may result in decreased exposure and increased therapeutic failure. In order to assess the clinical implications of these changes and to provide safe and effective dosage regimens, there is an immediate need for dose-optimization studies of all recommended first- and second-line agents used in pregnant women with malaria.

To determine if quinine has a metabolic effect during treatment of severe or complicated malaria, we studied its effects on plasma glucose and plasma insulin levels in 150 pregnant women with malaria referred to Madani maternity teaching hospital, Gezira state and 50 healthy pregnant controls. Levels were determined at baseline (day 0) before the start of quinine treatment, after 2 days of treatment (2 hours after the 4th dose) and after 7 days of treatment (day 8). There was a statistically significant increase in plasma insulin concentrations during the quinine infusion and fall in plasma glucose concentration (P < 0.001). Quinine administered at the recommended dose and rate can disrupt plasma glucose homeostasis although it is still the drug of choice for severe and complicated malaria in Sudan.

Background: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns., Methods: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans., Results: The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies., Conclusions: Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Background: The relatively little resistance to quinine globally has led to an increase in its use in P. falciparum malaria especially in multi-drug resistant strains., Objective: To evaluate the physicochemical and equivalency of three brands of quinine sulphate tablets available in South Western region of Nigeria., Methods: The pharmaceutical and chemical equivalence of three brands of quinine sulphate tablets were assessed through the evaluation of some biopharmaceutical parameters and active drug content., Results: All the brands complied with the official specification for uniformity of weight. Two of the brands (A & B) gave similar crushing strengths while the third brand (C) gave a much lower value. Similarly all the brands complied with the official specification of disintegration test but the obtained values were statistically different (p<0.05). The T(70) obtained from the dissolution rate profile was less than 45 minutes for the three brands, although A and B were not statistically different but C was statistically from A and B. The quinine content of brands B and C are within the official specification however brand A with percentage content of 110±1.3%w/w, is above the specification while it is statistically different from the other brands., Conclusion: Brands B and C could be regarded as chemical equivalent, but they are not biopharmaceutical equivalents, on the other hand, brands A and B may be regarded as biopharmaceutical equivalents but not chemical equivalent.

Purpose: The study aimed to investigate the effects of Plasmodium falciparum infection on the pharmacokinetics of quinine and its metabolites in pregnant and non-pregnant Sudanese women., Methods: In a case-control study, nine pregnant and eight non-pregnant Sudanese women infected with P. falciparum were treated with intramuscular artemether. Before being given artemether, they received a single dose of quinine hydrochloride as intravenous infusion. Blood samples were collected frequently and analysed for quinine and its metabolites (phase I). One week later (after clearance of parasitaemia) the quinine part of the protocol was repeated (phase II)., Results: During phase I, the AUCs (mean ± SD) of quinine and its major metaboplite, 3-hydroxyquinine, in pregnant women were 428.2 ± 132.4 and 27.8 ± 14.1 μmol l(-1) h(-1) respectively. In non-pregnant women the AUCs of quinine and 3-hydroxyquinine were 517.8 ± 100.0 and 32.3 ± 15.3 μmol l(-1) h(-1). In pregnant women the mean (90% confidence interval) AUC ratios of phase I to phase II of quinine and 3-hydroxyquinine were 1.6 (0.61, 4.22) and 1.01 (0.18, 5.60). In non-pregnant women, the AUC ratios of phase I to phase II of quinine and 3-hydroxyquinine were 1.93 (1.74, 2.15) and 1.19 (0.95, 1.47)., Conclusions: Plasmodium falciparum infection significantly increased plasma concentration of quinine in non-pregnant women and showed the same trend in pregnant women.

Unlabelled: Children with uncomplicated malaria are generally treated with oral medication, except those unable to take oral drugs. Even though quinine has shown to be effective in treatment of African children with uncomplicated malaria its high bitterness limited the paediatric use. This study aimed to develop taste-masked quinine tablets suitable for children and offering dosing flexibility to adjust the quinine dose in function of body weight., Methods: Insoluble quinine pamoate was used to formulate fast-disintegrating tablets, using a specific tablet design (rectangular tablet which can be divided into 8 subunits) to allow dosing flexibility. The physical properties of tablets were evaluated in vitro, as well as the quinine bioavailability in healthy adults (n=18) and the efficacy for treatment of children with uncomplicated Plasmodium falciparum malaria (n=56) using a 7-day regimen of 8 mg quinine/kg., Results: Quinine pamoate tablets complied with the pharmacopoeial requirements for mass uniformity, friability, content uniformity, breakability, disintegration and dissolution. The quinine pharmacokinetic parameters after single administration of a quinine pamoate tablet were similar to a commercially available quinine sulfate tablet. The fast decline in parasitemia (28.6%/24h), the reduction rate of fever (all children were apyretic after 72 h) and the steady state quinine plasma concentration (5.7-15.8 microg/ml) proved the efficacy of the quinine pamoate tablets against P. falciparum., Conclusion: Fast-dispersible and taste-masked quinine pamoate tablets improved dosing accuracy, allowed easy administration and resulted in a high efficacy during the treatment of children with uncomplicated malaria., (Copyright 2010. Published by Elsevier B.V.)

The aims of this work were to develop quinine (QN)-loaded nanocapsules, to evaluate their efficacy in vivo and to determine their pharmacokinetics and erythrocyte partition coefficient. Plasmodium berghei-infected Wistar rats were used to evaluate the efficacy of QN-loaded nanocapsules using different dosing regimens. Pharmacokinetics was evaluated after intravenous administration of free or nanoencapsulated QN (25 mg/kg) to infected rats. The QN partition coefficient into P. berghei-infected erythrocytes was evaluated. QN-loaded nanocapsules presented an adequate particle size (176 nm), narrow particle distribution (0.19), negative zeta potential (-18 mV) and high drug content and encapsulation efficiency. Intravenous administration of QN-loaded nanocapsules at 75 mg/kg/day to infected rats resulted in 100% survival, representing an almost 30% reduction compared with the free QN effective dose (105 mg/kg/day). The pharmacokinetic parameters of nanoencapsulated QN were not significantly different from those determined for free drug (alpha=0.05). The QN partition coefficient into infected erythrocytes doubled (6.25+/-0.25) when the drug was nanoencapsulated compared with the free drug (3.03+/-0.07). Therefore, nanoencapsulation increased the interaction between QN and the erythrocyte and this mechanism is responsible for the drug's increased efficacy when nanoencapsulated.

Objectives: Nevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine., Methods: Quinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3-hydroxquinine, using a validated HPLC method., Key Findings: Administration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration-time curve (AUC(T)), maximum plasma concentration (C(max)) and terminal elimination half-life (T((1/2)beta)) of quinine compared with values with quinine dosing alone (AUC: 53.29 +/- 4.01 vs 35.48 +/- 2.01 h mg/l; C(max): 2.83 +/- 0.16 vs 1.81 +/- 0.06 mg/l; T((1/2)beta): 11.35 +/- 0.72 vs 8.54 +/- 0.76 h), while the oral plasma clearance markedly increased (11.32 +/- 0.84 vs 16.97 +/- 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in C(max) and AUC of the metabolite (P < 0.01)., Conclusions: Nevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.

Quinine is the first line treatment in severe P. falciparum malaria and nocturnal leg cramps and a fast, convenient delivery method of this drug quinine is needed. The purpose of this study was to investigate in vitro the sublingual route for the delivery of quinine. Permeation studies were carried out with Franz diffusion cells containing sublingual mucosa membranes with PBS receptor phase and dosed with solutions of quinine hydrochloride or quinine/2-hydroxypropyl-beta-cyclodextrin complexes. Receptor phase samples were taken 2 hourly over a 12h period and quinine was determined by reverse-phase HPLC analysis. The ventral surface of the tongue was significantly more permeable than porcine floor of the mouth (p<0.05) and there was no significant effect of freezing on the ventral surface of the tongue (p 0.2444). The presence of saliva caused a decrease in the permeation of quinine across the ventral surface of the tongue by up to 68%. Inclusion complexation between quinine and 2-HP-beta-CD was supported by (1)H NMR spectral data, and an ethanol vehicle provided the highest quinine flux from the inclusion complex solutions compared to deionised water and PEG. Overall, the data support further investigations into the clinical use of sublingual quinine, particularly for children with falciparum malaria or patients with nocturnal leg cramps. Use of quinine/cyclodextrin inclusion complexes may circumvent compliance issues due to bitter taste.

The selection and spread of antimalarial drug resistance pose enormous challenges to the health of people living in tropical countries. Most antimalarial drugs are slowly eliminated and so, following treatment in areas of endemicity, provide a gradient of concentrations to which newly acquired parasites are exposed. There is a variable period during which a new blood-stage infection with resistant malaria parasites can emerge from the liver and subsequently produce gametocyte densities sufficient for transmission while reinfection by sensitive parasites is still suppressed. This "window of selection" drives the spread of resistance. We have examined the factors which determine the duration of this window and, thus, the resistance selection pressure. The duration ranges from zero to several months and is dependent on the degree of parasite resistance, the slope of the concentration-effect relationship, and the elimination kinetics of the antimalarial drug. The time at which the window opens and the duration of opening are both linear functions of the terminal elimination half-life. Because of competition from sibling susceptible parasites, the greater risks of extinction with low starting numbers, and opening of the window only when blood concentrations have fallen below the MIC, the window of selection for de novo resistance is narrower than that for resistance acquired elsewhere. The windows were examined for the currently available antimalarials. Drugs with elimination half-lives of less than 1 day, such as the artemisinins and quinine, do not select for resistance during the elimination phase.

Predicting drug-drug interactions requires an assessment of the drug concentration available to the enzyme active site, both in vivo, and within an in vitro incubation. These predictions are confounded when the inhibitor accumulates within the liver, either as a result of active transport processes or intracellular binding (including lysosomal trapping). In theory, hepatocytes should provide a more accurate estimation of inhibitory potency compared with microsomes for those compounds that undergo hepatic accumulation. However, they are not routinely used for Ki determination and there is limited comparative information available. Therefore, the aims of this study were to compare Ki values determined in rat microsomes and freshly isolated hepatocytes using six cytochrome P450 inhibitors (miconazole, fluconazole, ketoconazole, quinine, fluoxetine, and fluvoxamine) with a range of uptake properties (cell-to-medium concentration ratios 4.2-6000). Inhibition studies were performed using four probe substrates for CYP2C, CYP2D, and CYP3A enzymes (tolbutamide and phenytoin, dextromethorphan and midazolam, respectively). Comparison of unbound Ki values (range 0.05-30 microM) showed good agreement between microsomes and hepatocytes for inhibition of 18 pathways of metabolism. In addition to this, there was no relationship between the cell-to-medium concentration ratios (covering over 3 orders of magnitude) and the microsomal to hepatocyte Ki ratio of these inhibitors. These data suggest that the hepatic accumulation of these inhibitors results from intracellular binding rather than the involvement of uptake transporters and indicate that microsomes and hepatocytes appear to be equivalent for determining the inhibitory potency of the six inhibitors investigated in the present study.

The impact of P-glycoprotein (P-gp) on the distribution of quinine between brain and plasma was studied experimentally in mice. Administration of quinine (20mg/kg, i.v.) to mdrla knockout mice resulted in enhanced brain concentrations of quinine as compared to the wild-type mice (7.9+/-1.4 microg/g versus 1.6+/-0.8 microg/g, respectively). Quinine concentrations and quinine-to-3-hydroxyquinine ratio in plasma were similar in normal and P-gp-deficient mice. The effect of intravenously administered drugs before quinine (20mg/kg, i.v.) was evaluated on brain uptake and biotransformation of quinine in mice. Cyclosporine A (50 mg/kg), erythromycine (40 mg/kg), verapamil (5mg/kg) or mefloquine (20 mg/kg) increased the brain-to-plasma quinine concentration ratio (by factors of 3.8-, 1.8-, 1.9- and 2.5-fold, respectively) and the quinine-to-3-hydroxyquinine ratio in plasma (by factors 2.1-, 3.7-, 1.8- and 2.0-fold, respectively). After cinchonine (40 mg/kg) and halofantrine (40 mg/kg) pre-treatment, the brain-to-plasma ratio for quinine increased by factor of 2.3 and 1.8, respectively without changes of quinine or metabolite concentrations in plasma. Doxycycline (20 mg/kg), artesunate (50 mg/kg) or artemether (50 mg/kg) did not alter quinine disposition. These results confirm in vivo that quinine is a substrate for mdr1a P-gp. Drug associations led not only to metabolic interactions but also increased quinine uptake by tissues protected by P-gp. Such interactions may have implications for the improvement of chemotherapy but should be also taken into account for potential enhancement of adverse effects.

The hepatic uptake of quinine, fluvoxamine, and fluoxetine (0.1-10 microM) was investigated with freshly isolated rat hepatocytes. The cell-to-medium concentration ratios (K(p)) were concentration-dependent: the mean maximum K(p) values (at 0.1 microM) were 150 (quinine), 500 (fluvoxamine), and 2000 (fluoxetine). There was also a large capacity site that was not saturable over the concentration range used (possibly partition into the phospholipid component of membranes); representing this site, the mean minimum K(p) values (at 10 microM) were 30 (quinine), 200 (fluvoxamine), and 500 (fluoxetine). To eliminate concomitant metabolism, cells were pretreated with the irreversible P450 inhibitor, aminobenzotriazole. The saturable uptake was substantially eliminated after exposure to carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (ATP inhibitor). The difference between the maximum and minimum K(p) for these three amine drugs, as well as for dextromethorphan, propranolol, and imipramine, was within a limited range of 3-fold, indicating a common magnitude of saturable uptake. Basic, permeable drugs are expected to be sequestered into lysosomes, which actively maintain their low internal pH (approximately 5) using ATP, and this process is predictable from the combined effects of pH-driven ion accumulation and unsaturable binding representing partition into membranes. The resultant predicted maximum K(p) correlated strongly with the observed maximum K(p). Thus, at low substrate concentrations, the fraction of drug unbound in the hepatocyte incubation (critical for assessing drug clearance and drug-drug interaction potential) may be dependent upon saturable as well as unsaturable binding, and for lipophilic, basic drugs, this can be readily estimated assuming a common degree of uptake into lysosomes.

Previously, we reported minimal opioid receptor occupancy following a clinical dose of the micro-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [(11)C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (micro- and kappa-receptor agonist), morphine (micro-receptor agonist), and buprenorphine (partial agonist at the micro-receptor and antagonist at the delta- and kappa-receptors), each given at antinociceptive doses. In vivo binding of [(11)C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by approximately 90% by buprenorphine. In addition, given that [(11)C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [(11)C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies.

Transferrin (Tf)-conjugated solid lipid nanoparticles (SLNs) were investigated for their ability to deliver quinine dihydrochloride to the brain, for the management of cerebral malaria. SLNs were prepared by an ethanol injection method using hydrogenated soya phosphatidyl choline (HSPC), triolein, cholesterol and distearylphosphatidylethanolamine (DSPE). Coupling of SLNs with Tf was achieved by incubation of Tf with quinine-loaded SLNs in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) hydrochloride in phosphate buffered saline (pH 7.4) as a cross-linker. SLNs were characterized for shape, particle size, polydispersity and percentage drug entrapment. The SLNs were 108-126 nm in size, and maximum drug entrapment was 38.4-42.7%. Average size increased on coupling with Tf but percentage drug entrapment was reduced. The in-vitro release profile was determined using a dialysis technique; non-conjugated SLNs released comparatively more drug than Tf-SLNs. Fluorescence studies revealed enhanced uptake of Tf-SLNs in brain tissue compared with unconjugated SLNs. In in-vivo performance studies, quinine plasma level and tissue distribution after intravenous administration of drug-loaded Tf-SLNs and unconjugated SLNs was compared with that of free drug. Intravenous administration of quinine dihydrochloride solution resulted in much higher concentrations of drug in the serum than with SLNs. Conjugation of SLNs with Tf significantly enhanced the brain uptake of quinine which was shown by the recovery of a higher percentage of the dose from the brain following administration of Tf-coupled SLNs compared with unconjugated SLNs or drug solution.

Objectives: The study was conducted in New Halfa teaching hospital, eastern Sudan to investigate the pharmacokinetics of quinine in pregnant Sudanese women., Methods: Sixteen (eight pregnant and eight non-pregnant) Sudanese women infected with Plasmodium falciparum malaria were given a single dose of quinine hydrochloride (10 mg/kg body weight) as intravenous infusion over 2 h. The women were treated with intramuscular artemether. Plasma was collected before quinine administration and up to 72 h thereafter. These were analysed for quinine and its metabolites, 3-hydroxyquinine, (10R)-10,11-dihydroxyquinine and (10S)-10,11-dihydroxyquinine using high-performance liquid chromatography., Results: The two groups were well matched in their basic characteristics. There was no significant difference in the mean maximum plasma concentration attained (C(max)), the mean time at which C(max) was attained, the elimination half-life (t(1/2)) and the total area under the plasma concentration vs. time curve (AUC) of quinine and its metabolites between the pregnant in non-pregnant women., Conclusion: There was no significant difference in quinine metabolism between pregnant and non-pregnant women and there is no need to adjust quinine dose when treating pregnant women.

Objective: Intravenous artesunate is commonly used in the emergency treatment of patients with severe falciparum malaria in Asia. The choice of doses used has been empirical. To inform dosage recommendations we assessed the pharmacokinetics of intravenous artesunate after the first dose., Methods: As part of a clinical trial of artesunate in adults with severe falciparum malaria in western Thailand, we assayed plasma concentrations of artesunate and the principal biologically active metabolite dihydroartemisinin (DHA) in 17 patients given an initial dose of 2.4 mg/kg body weight of intravenous artesunate. Drug levels were measured using high performance liquid chromatography with mass spectroscopy-electrospray ionisation detection., Results: Median (range) observed DHA Cmax was 2128 (513-5789) nmol/L, elimination half-life was 0.34 (0.14-0.87) h, and the time to the last detectable DHA was 2 h., Conclusion: The large inter-individual variability (10 fold) in DHA Cmax and AUC in patients with potentially lethal, severe malaria, suggests that 2.4 mg/kg should be the minimum daily dose in severe malaria.

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

The objective of the study was to investigate the relationship between transdermal iontophoretic flux--specifically, the electromigratory component--and electrophoretic mobility as determined by capillary zone electrophoresis (CZE). First, the steady-state iontophoretic transport rates of a series of dipeptides across porcine skin were determined in vitro. Co-iontophoresis of acetaminophen was used to quantify the respective contributions of electroosmosis (EO) and electromigration (EM). Second, the electrophoretic mobilities of the dipeptides and three other cationic drugs (lidocaine, propranolol, and quinine) were determined, under equivalent experimental conditions, using CZE. Analysis of the transport data using the results of the CZE experiments revealed a linear dependence (r2 > 0.9) between EM flux and electrophoretic mobility. The CZE measurements also provided insight into the charge state of "zwitterionic" dipeptides, H-Glu-epsilon-Lys-OH and H-Tyr-Gln-OH, revealing that these molecules had partial net negative charges under the formulation conditions, accounting for the absence of anodal iontophoretic delivery. The results suggest that CZE might (i) enable identification of ionization states of complex molecules, (ii) serve as a preliminary screen to identify electrically mobile compounds suitable for iontophoretic delivery, and (iii) prove useful for predicting the EM contribution to transdermal iontophoretic flux., ((c) 2005 Wiley-Liss, Inc.)

The aim of the present study was to assess the pharmacokinetics and the efficacy of a shorter than usual 5-day quinine treatment given orally to children in Cameroon with malaria caused by Plasmodium falciparum. Quinine (8.3 mg of base per kg of body weight every 8 h) was administered as a 2% formiate salt syrup for 5 days to 30 children (age range, 0.55 to 6.7 years) with uncomplicated falciparum malaria (initial parasitemia, 1.4 x 10(3) to 1.8 x 10(5)/microl). Quinine concentrations in plasma samples (five to nine per patient) were measured by liquid chromatography on days 1 to 3. Parasitemia was counted on days 0, 1, 2, 3, 4, 7, and 14. Pharmacokinetic and pharmacodynamic data were analyzed by population approaches by using NONMEM and WinBugs, respectively. The kinetics of quinine were best described by a one-compartment model with time-varying protein binding. Clearance and the volume of distribution were positively correlated with body weight and increased over time. Parasitemia was undetectable from day 3 to 14 in all children. The time to a 4-log reduction of the initial level of parasitemia (Ter) was related to the average quinine concentration from 0 to 72 h (Cav) as Ter = Tmin [1 + (C50/Cav)s], where sigmoidicity (s) is equal to 2, Tmin is the time to eradication at infinite Cav, and C50 is the value of Cav for which Ter is twice Tmin. The C50 distribution was unimodal, and all C50 values were less than 8 mg/liter, while Cav ranged from 5.9 to 18.3 mg/liter. The median (10th to 90th percentile) Ter was 47 h (range, 39 to 76 h). The efficacy of a 5-day treatment course should be evaluated in a larger clinical trial.

Chloroquine resistance in Plasmodium falciparum malaria results from mutations in PfCRT, a member of a unique family of transporters present in apicomplexan parasites and Dictyostelium discoideum. Mechanisms that have been proposed to explain chloroquine resistance are difficult to evaluate within malaria parasites. Here we report on the targeted expression of wild-type and mutant forms of PfCRT to acidic vesicles in D. discoideum. We show that wild-type PfCRT has minimal effect on the accumulation of chloroquine by D. discoideum, whereas forms of PfCRT carrying a key charge-loss mutation of lysine 76 (e.g. K76T) enable D. discoideum to expel chloroquine. As in P. falciparum, the chloroquine resistance phenotype conferred on transformed D. discoideum can be reversed by the channel-blocking agent verapamil. Although intravesicular pH levels in D. discoideum show small acidic changes with the expression of different forms of PfCRT, these changes would tend to promote intravesicular trapping of chloroquine (a weak base) and do not account for reduced drug accumulation in transformed D. discoideum. Our results instead support outward-directed chloroquine efflux for the mechanism of chloroquine resistance by mutant PfCRT. This mechanism shows structural specificity as D. discoideum transformants that expel chloroquine do not expel piperaquine, a bisquinoline analog of chloroquine used frequently against chloroquine-resistant parasites in Southeast Asia. PfCRT, nevertheless, may have some ability to act on quinine and quinidine. Transformed D. discoideum will be useful for further studies of the chloroquine resistance mechanism and may assist in the development and evaluation of new antimalarial drugs.

In a previous paper by the authors on RS-8359, a new selective and reversible monoamine oxidase A (MAO-A) inhibitor, it was reported that the (S)-enantiomer of RS-8359 is rapidly eliminated from rats, monkeys and humans as a result of the formation of a 2-oxidative metabolite. The present study investigates the properties of the enzyme responsible for the 2-oxidation of RS-8359. Subcellular localization, cofactor requirement and the inhibitory effects of typical compounds were studied using rat liver preparations. In addition, the enzyme was purified from rat liver cytosol for further characterization. The enzyme activity was localized in the cytosolic fraction without the need for any cofactor and was extensively inhibited by menadione, chlorpromazine and quinacrine. The purified enzyme was also a homodimer with a monomeric molecular weight of 140 kDa and it had an A280/A450 ratio of 5.1 in the absorption spectrum. The results suggest that the enzyme responsible for the biotransformation of RS-8359 to give the 2-keto derivative is aldehyde oxidase (EC 1.2.3.1). The reaction of aldehyde oxidase is highly stereoselective for the (S)-configuration of RS-8359 and the (9R)-configuration of cinchona alkaloids.

The current study examined the ability of antimalarials chloroquine (CQ), primaquine (PQ), and quinine (Q) to inhibit human erythrocyte membrane acetylcholinesterase (AChE) and the mechanisms underlying their inhibitory action. CQ was found to be the most effective inhibitor of the enzyme followed by PQ and Q. The concentrations required to obtain 33% inhibition (IC(33)) for CQ and PQ were 22 and 38 microM, respectively, whereas that for Q was 3.2 mM. The concentrations required to obtain 67% inhibition (IC(67)) were about 9 and 7 times higher for CQ and PQ, whereas that for Q was only about 2.5 times higher. Hill plot analysis revealed that CQ shows de-binding above 40 microM. The two kinetic components of AChE were inhibited by the three antimalarials, and the inhibition was of mixed type. Increasing concentrations of antimalarials caused progressive decrease in the V(max) of both components. IC(33) concentrations resulted in 1.6- to 6-fold increase in K(m) of both the components while IC(67) concentration caused 2.8- to 13-fold increases in K(m) with maximum effect being seen with Q. The K(i) values were lowest for CQ suggesting that it was the most potent inhibitor; these values were 3.3 and 60 times higher for PQ and Q. Antimalarials represent the bifunctional compounds that possess anti-inflammatory properties and also inhibit cholinesterases. The results of our studies suggest that 4-aminoquinoline-based antimalarials like CQ and hydroxychloroquine, which are both potent anti-inflammatory agents and inhibitors of cholinesterases, may have potential use as the most effective neuroprotective agents against amyloid-beta-peptide (Abeta) neurotoxicity in Alzheimer's disease.

The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.

This study compared the absolute bioavailability of quinine sulphate as capsule and as tablet against the intravenous (i.v.) infusion of the drug in twelve male volunteers. Six of the volunteers received intravenous infusion over 4 h as well as the capsule formulation of the drug in a cross-over manner, while the other six received the tablet formulation. Blood samples were taken at predetermined time intervals and plasma analysed for quinine (QN) using reversed-phase HPLC method. QN was rapidly absorbed after the two oral formulations with average t(max) of 2.67 h for both capsule and tablet. The mean elimination half-life of QN from the i.v. and oral dosage forms varied between 10 and 13.5 hr and were not statistically different (P > 0.05). On the contrary, the maximum plasma concentration (C(max)) and area under the curve (AUC) from capsule were comparable to those from i.v. (P > 0.05), while these values were markedly higher than values from tablet formulation (P < 0.05). The therapeutic QN plasma levels were not achieved with the tablet formulation. The absolute bioavailability (F) were 73% (C.l., 53.3 - 92.4%) and 39 % (C.I., 21.7 - 56.6%) for the capsule and tablet respectively and the difference was significant (P < 0.05). The subtherapeutic levels obtained from the tablet form used in this study may cause treatment failure during malaria and caution should be taken when predictions are made from results obtained from different formulations of QN.

The aim of the study was to test the efficacy of 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate as a blood-brain barrier (BBB) permeator by examining its effect on quinine uptake into the central nervous system in rats, analgesic action of morphine, and on the sleeping time induced by pentobarbital. The obtained results indicate that sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate can be considered as modifier of BBB permeability, as it exhibited a promoting effect in all three tests. In the test of quinine uptake, methyl ester of 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanoic acid (included in the study for comparison) did not show a promoting effect, which can suggest its specific action.

The resistance of Plasmodium falciparum to antimalarial drugs is one of the most worrisome problems in tropical medicine, but few clinical studies or observations have described confirmed cases of therapeutic failure. We report two cases of in vivo P. falciparum resistance (RIII response) to quinine in French Guiana, an Amazonian focal zone in which multi-resistant malaria is endemic. Both patients presented with uncomplicated malaria and were initially treated with intravenous quinine. Although absorption was normal, the treatment was not effective and the patients still had fever and significant parasitemia three days after the onset of treatment (day 3). The addition of intravenous tetracycline completely resolved the parasitemia within approximately 96 hours. These clinical reports confirm the necessity to combine quinine with tetracycline in this area, as recommended by the recent French regional antimalarial policy.