Quinine Dosage Research Articles

Molecular dynamics simulations of quinine encapsulation into biodegradable nanoparticles: A possible new strategy against Sars-CoV-2

A new coronavirus disease, SARS-CoV-2, has spread into a global pandemic in December 2019. Since no specific therapeutic drugs for treating COVID‐19 have been approved by FDA, recent studies suggest that the known antimalarial quinine and its derivatives (chloroquine and hydroxychloroquine) inhibit receptor binding of the viral particles and inhibits the strong “cytokine storm”, which is the main cause of death among infected patients. In particular, the natural alkaloid quinine has shown to possess a better safety profile and greater tolerability compared to its derivatives. Dosage optimization of quinine is still necessary as the currently available dosage forms have controversial pharmacokinetics and safety profiles. Therefore, repurposing quinine dosage forms to improve its pharmacokinetics and safety profile may be necessary to support its use against SARS-CoV-2. In this context, biodegradable/biocompatible polymeric nanoparticles may provide a safe site-specific and controlled quinine delivery, reducing the frequency of drug administration and the dose.In this study, a full atomistic molecular dynamics simulation approach has been used to investigate the use of poly-(glycolic acid) and poly-(lactic acid) and their copolymer poly-(lactic-co-glycolic acid) as potential delivery systems for lipophilic quinine to get insights into the mechanism of quinine encapsulation and release at the atomic/molecular level.

Application of NIR handheld transmission spectroscopy and chemometrics to assess the quality of locally produced antimalarial medicines in the Democratic Republic of Congo

In recent decades, more than 15% of the antimalarials marketed in low- and middle-income countries have been of poor quality, in which quinoline derivatives and quinine-based formulations account for 21%.Near infrared spectroscopy (NIR) was chosen for its fast and inexpensive test properties as well as the ability of using handheld devices to monitor drugs directly on the field. Data driven - soft independent modeling of class analogy (DD-SIMCA) and partial least squares (PLS) regression models were developed for qualitative and quantitative purpose, respectively. The specificity and selectivity tests were performed using the DD-SIMCA models on the placebo, the quinidine and cinchonine standard samples. Then, PLS regression methods have been developed and validated for the quality control of quinine dosage forms manufactured by a major local manufacturer in the Democratic Republic of Congo (DRC).Calibration and validation samples were prepared by dissolving quinine sulfate / quinine hydrochloride in the presence of excipients in HCl 1 M. The opportunity to work with dissolved quinine with a cheap and readily available medium in low- and middle-income countries allowed analysis of different pharmaceutical forms (oral drops, solutions for injection and tablets) with the same regression model. DD-SIMCA models have demonstrated, for both equipment, perfect authentication of quinine and good discrimination of the two alkaloids close to quinine namely cinchonine and quinidine.The NIR PLS regression models were successfully validated using the total error approach with acceptance limits set at ± 10% with a risk level of 5%. The predictive performance of the methods developed was tested in terms of robustness.

Quinine for muscle cramps.

Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014. To assess the efficacy and safety of quinine-based agents in treating muscle cramps. On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014. Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives. Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine-theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events. There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine-vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long-term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine.

PO.16 Is quinine useful in muscle cramps? A Cochrane meta-analysis

BackgroundGlobal controversy on the efficacy and safety of quinine for muscle cramps (banned in USA, widely prescribed in UK), led us to conduct a meta-analysis of all trials comparing quinine...

Disposition of quinine and its major metabolite, 3-hydroxyquinine in patients with liver diseases

Quinine, extensively metabolized by CYP 3A4, has 3-hydroxyquinine as the major metabolite which also contributes to its antimalarial activity. This study assessed the impact of various liver diseases on the disposition of quinine and 3-hydroxyquinine. Ten adult patients with liver diseases ranging from cirrhosis, primary liver carcinoma, hepatitis, ascites, and amoebic liver disease as well as six healthy subjects received single oral dose of 600 mg quinine sulphate tablets. Venous blood and urine were collected over 48 h. Quinine and 3-hydroxyquinine were determined from the matrices by a validated high performance liquid chromatography (HPLC) method. Wide inter-individual variations were observed in the subjects especially those with liver diseases. Cmax (4.47 vs 2.41mcg/ml) and AUC (73 vs 51mcg.h/ml) values were significantly increased in liver disease patients. Clearance was reduced by 30% from 3.27 to 2.31 (p = 0.009). Metabolic ratio of quinine/3-hydroxyquinine in plasma decreased from 5.5 to 1.42 over 4 to 48 h. Cumulative amount of quinine and 3-hydroxyquinine produced in urine were 38 mg (8%) and 32 mg (7%) respectively. Compromised metabolism of quinine in liver disease patients suggests the necessity of reviewing the dosage of quinine in liver disease patients who come up with malaria, a situation that further reduces liver function.

Hypoglycaemia in severe malaria, clinical associations and relationship to quinine dosage

BackgroundHypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence.MethodsRetrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded.Results954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01.ConclusionThere was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.

Malaria Treatment in Enugu Urban Nigeria: Physicians\' Compliance with the National Treatment Guidelines

Incorrect use of antimalarial drugs undermines therapeutic effectiveness and promotes emergence and spread of drug-resistant malaria. Strategies for improving compliance require accurate information about current practices. This is a survey of the attitude and practices in the treatment of malaria among doctors practicing in Enugu urban, Nigeria. Standard questionnaire technique was used among 300 doctors practicing in Enugu urban. Chloronquine and sulfadoxine – pyrimethamine were the commonest drugs used for treating uncomplicated malaria, while quinine was the commonest drug used for treating severe malaria. More than 60% of the doctors prescribe intramuscular chloroquine in the dosage of 5ml (~200mg) daily for 3 days for adults and 5mg/kg/daily for 3 days for children. Recommended dosage of quinine was used by 41.8% of the doctors in treating children, and 50% of doctors in treating in treating children, and 50% of doctors in treating adults. Only 40% of the doctors utilized the National guidelines for treatment of malaria. Comparison between duration of practice, or area of intramuscular chloroquine and intravenous quinines showed no significant difference with P values > 0.05. It was concluded that incorrect use of parental antimalarial drugs occurs at all levels and specialties of medical doctors practicing in Enugu. NQJHM Vol. 14 (3&4) 2004: pp. 227-232

Clinical pharmacokinetics in the treatment of tropical diseases. Some applications and limitations.

In recent years major advances have been made in the clinical pharmacology of many drugs used for the treatment of tropical diseases, particularly in the design and development of dosage regimens for the treatment of severe malaria. For example, by careful manipulation of its rate of administration, chloroquine has been shown to be well tolerated when used for treatment of severe disease caused by susceptible parasites. Similarly, important advances have been made in the rational design of quinine dosage regimens for patients in South East Asia and Africa. Investigation of the pharmacokinetics of mefloquine has drawn attention to the problems associated with its administration as combination therapy with pyrimethamine and sulfadoxine in Thailand. Similarly, evaluation of the pharmacokinetic properties of halofantrine has led to the demonstration that poor and erratic absorption could be just as likely to explain therapeutic failure as resistance of the parasite to effects of this drug. Disposition of the antimalarial biguanides has highlighted the role of host-related effects in the determination of drug response. For example, a small percentage of individuals are unable to convert proguanil (chloroguanide) to its active triazine metabolite, cycloguanil. Finally, agents that reverse chloroquine resistance are currently under development for the treatment of malaria. The importance of assessing the clinical pharmacokinetic properties of potential resistance reversers must be recognised. While limited success has been achieved in antifilarial chemotherapy, other parasitic diseases have been largely neglected with advances in the laboratory still awaiting full recognition of their clinical application. For example, clinical pharmacokinetic concepts may be used to improve the therapy of human hydatid disease. We believe that clinical management of tropical diseases can be improved by the application of clinical pharmacokinetic principles. However, this may not be universally advantageous. For example, the artemisinin (qinghaosu) derivatives are among the most recently developed antimalarials that have great therapeutic promise. Recent evidence suggests that pharmacokinetic data would be of limited value in the design and optimisation of dosage regimens because of its chemical reactivity and the unusual mechanism by which these drugs kill parasites. Similar limitations may apply to the microfilaricidal drug, ivermectin.

Disposition of quinine in rats with induced renal failure.

Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (elimination t1/2, CLp, V, CLR AUC0-infinity) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease in V and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage.

Disposition of the Diastereoisomers Quinine and Quinidine in the Ovine Fetus

The disposition of the diastereoisomers quinine and quinidine was investigated in the near-term pregnant ewe. Five sheep were administered quinine and quinidine separately in random order by a combination of bolus and 30-h iv infusion. On a subsequent occasion, four of the five sheep were also administered the two drugs simultaneously. After separate dosage, systemic clearance of quinine tended to be greater than that of quinidine (714 ± 299 versus 422 ± 146 mL/min, p = 0.08). Maternal renal clearance exhibited no stereoselectivity and represented <2% of total clearance. Simultaneous administration did not alter the disposition of either drug in the mother. After separate dosage, fetal total concentrations (C,) of quinine and quinidine were substantially lower than maternal total concentrations, as reflected in C,:Cm ratios of 0.15 ± 0.06 versus 0.10 ± 0.08, respectively. Similarly, fetal unbound concentrations (Ctu) were substantially lower than maternal unbound concentrations (Cmu; CJCmu = 0.46 ± 0.09 for quinine and 0.23 ± 0.09 for quinidine). This indicates the presence of fetal elimination of both isomers. Fetal renal clearances of quinine and quinidine were similar (0.34 ± 0.24 mL/min versus 0.38 ± 0.24 mL/min) and less than that of endogenous creatinine, indicating the absence of net renal tubular secretion. After simultaneous dosage of quinine and quinidine, C,:Cm (0.48 ± 0.24 and 0.31 ±0.19, respectively) and C,u:Cmu (0.73 ± 0.14 and 0.52 ± 0.20, respectively) were greater than for separate dosages. Fetal renal clearance of both drugs was unchanged, suggesting that the higher C(u:Cmu ratios after simultaneous dosage were due to mutual inhibition of the fetal metabolism of these drugs.

The treatment of severe falciparum malaria

In severe falciparum malaria there is a pathophysiological cascade beginning with changes in the parasitized red blood cells which induce intermediate effects, in turn contributing to dysfunction of several organs. A low serum albumin is a common but often unrecognized finding which may contribute to oedema especially in the lung and brain. The only irreversible complication in falciparum malaria is the acute respiratory distress syndrome, manifested by cyanosis and rapid breathing, basically distinct from acute pulmonary oedema caused by therapeutic overhydration. The pathophysiology of falciparum malaria may be complex but the treatment is simple. Drugs, other than antimalarials, are rarely needed. Guidelines for cholorquine or quinine dosage in severe disease are proposed; each drug is given at a dose of 5 to 10 mg/kg in 10 ml/kg of fluid as an intravenous infusion in four hours at a frequency of dosing every 12 to 24 hours. When the disease has been brought under control the treatment should be changed from the intravenous to the oral route.

Quinine disposition during malaria and during induced fever.

Quinine disposition was studied in 5 subjects before and during an experimentally induced infection with a chloroquine-resistant strain of Plasmodium falciparum and in 2 individuals before and during artificially induced fever. Plasma quinine levels were determined by both a benzene extraction method (QB), which measures principally unmetabolized quinine, and a metaphosphoric acid precipitation method (QMPA), which measures quinine and quinine metabolites. The ratio QB/QMPA in plasma was used to estimate the extent of metabolism of quinine. In all individuals plasma levels of quinien and QB/QMPA ratios were increased during malaria, suggesting impaired hepatic metabolism of quinine. The changes observed during malaria were not due to altered renal excretion of quinine. In 2 subjects in whom fever was artificially induced there were similar changes in quinine metabolism. These observations suggest that quinine dosage should be modified during the initial period of treatment, when symptoms and fever are greatest, in acute falciparum malaria.

QUININE THERAPY AND PERITONEAL DIALYSIS IN ACUTE RENAL FAILURE COMPLICATING MALARIAL HÆMOGLOBINURIA

Quinine dosage and peritoneal clearance of urea, creatinine, and quinine were studied in four patients undergoing treatment for acute renal failure complicating chloroquine-resistant Plasmodium falciparum malaria with blackwater fever (malarial hæmoglobinuria). Quinine dihydrochloride was administered by constant intravenous infusion to each patient. Peritoneal dialysis was effective in treating the acute renal failure component of the disease process. The clearance of urea and creatinine across the peritoneal membrane was reduced during the early phase of malaria, but increased as the patients' malaria improved clinically. The total concentrations of quinine removed by dialysis were trivial, and this procedure did not alter the markedly elevated plasma quinine levels observed during the first 48-72 hours of intravenous quinine infusion. To avoid quinine toxicity and potential fatalities, reduced dosage (600 mg. per 24 hours) should be used until the patient is in the recovery phase of renal failure and malaria.

Fatal Dosage of Quinine

Fatal Dosage of Quinine

Dosage of quinine in labor: Heyrowski, K.: Deutsche med. Wchnschr. 66: 576, 1940

Dosage of quinine in labor: Heyrowski, K.: Deutsche med. Wchnschr. 66: 576, 1940

The induction of labor

Castor Oil and Quinine.—Efficacious in 40 to 50 per cent of patients at term; harmless if dosage of quinine is 10 gr. or less.Castor Oil, Quinine, and Pituitrin.—Efficacious in 60 or 70 per cent of patients at term; harmless if dosage of quinine is low and if administration of pituitrin (preferably nasal) is vigilantly supervised. Contraindicated in toxemias.Artificial Rupture of Membranes.—Efficacious in 98 per cent of patients at term, provided contraindications are followed. Labor is usually shortened. In about 2 per cent of the patients the latent period is unusually long and in these cases the likelihood of infection is increased. The method is therefore not without some small danger and should be used only on definite indication, that is, when the hazard of allowing the pregnancy (presumably pathologic) to continue is greater than the slight hazard involved in the induction.Bougie Induction.—Useful in cases in which artificial rupture of the membranes is contraindicated, particularly when patient is three or four weeks from her expected date of confinement. At that time efficacy is probably 70 or 80 per cent. Danger imposed on mother and child is greater than artificial rupture of membranes and should be used only on urgent indication.Bag Induction.—Field of usefulness is limited to (1) occasional cases of premature rupture of membranes in which medicinal methods have failed to induce labor and (2) certain cases of uterine inertia.