Liquid quinine

Liquid quinine DEFAULT

What to know about quinine in tonic water

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Tonic water is a soft drink containing quinine, which gives it a bitter taste. Quinine is a common treatment for malaria. Some people believe that it can also help with leg cramps and restless legs syndrome.

Quinine comes from the bark of the cinchona tree. This tree is native to central and South America, as well as some islands in the Caribbean and western parts of Africa.

People have consumed quinine in tonic water to help treat cases of malaria for centuries.

In this article, learn about what quinine is and what its side effects and possible benefits are.

Quinine uses

Doctors continue to use quinine as a part of malaria treatment. However, that newer treatments may eventually replace quinine as a malaria treatment due to quinine’s adverse effects at .

Researchers cite the poor tolerability of the drug and difficulties complying with complex dosing routines as reasons to be concerned about regular medicinal use.

As a food additive, quinine offers a bitter taste. Manufacturers usually add it to tonic water.

Some people use tonic water to help treat nighttime leg cramps, but there is little evidence to suggest that this is effective.

Tonic water is available for purchase online.

Is quinine safe?

Experts consider quinine safe to consume in small doses. The United States Food and Drug Administration (FDA) have approved up to 83 parts per million in carbonated beverages.

The FDA also specify that manufacturers must place quinine on the label for consumers to easily see.

Some people may experience allergic reactions to quinine. If this is the case, a person should avoid tonic water and any other products that contain quinine.

People who should avoid quinine in medications include:

  • women who are pregnant or breastfeeding
  • those with abnormal heart rhythms
  • those with liver or kidney disease
  • those with low blood sugar

Some medications can interact with quinine. These include:

The amount of quinine in tonic water is not likely to interact with a person’s medication or cause issues for people with the medical conditions listed above. However, people with these risk factors should not take quinine supplements or medications unless a doctor prescribes it.

Benefits of drinking tonic water

Many people believe that drinking tonic water helps with nighttime leg cramps and restless legs syndrome. However, there is no scientific evidence verifying this belief.

In fact, the FDA have warned doctors against prescribing quinine to treat leg cramps or restless legs syndrome.

Tonic water is a carbonated soft drink that may contain sugar and has little nutritional value. The quinine present in tonic water provides a distinctive bitter flavor. While not dangerous, tonic water does not have any benefits and could lead to an unnecessary increase in calorie consumption.

Side effects

Quinine is very diluted in tonic water. The likelihood of a person experiencing any side effects from drinking tonic water is slim. However, side effects of quinine can include:

  • ringing in the ears
  • vomiting
  • stomach cramps
  • nervousness
  • nausea
  • diarrhea
  • confusion

As a medication, quinine may have more severe side effects. Some of the possible side effects of taking quinine as a medication include:

  • abnormal heartbeat
  • kidney damage
  • severe allergic reaction
  • electrolyte imbalance
  • vision or eye issues
  • problems with bleeding
  • thrombocytopenia (decreased blood platelets)
  • lung toxicity

People who regularly drink tonic water may also want to consider the extra sugar and calories that they are consuming. Soft drinks, including tonic water, have little nutritional value but contribute to a person’s daily calorie intake.

Summary

The quinine in tonic water helps give it a bitter taste. People should not mistake tonic water for a healthful drink, as it may contain sugar and provides no additional nutritional value.

Tonic water cannot help a person with leg cramps or restless legs syndrome. The quinine in tonic water is very diluted.

It is unlikely that a person will experience even mild side effects from drinking tonic water, but they should be cautious if they are taking quinine as a medication and try to report any side effects to a doctor.

Sours: https://www.medicalnewstoday.com/articles/323692

Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria

Jane Achan

1Department of Pediatrics and Child Health, Makerere University College of Health Sciences, P.O. Box 7475, Kampala, Uganda

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Ambrose O Talisuna

2Department of Epidemiology and Biostatistics, Makerere University School of Public Health, P.O Box 7072, Kampala, Uganda

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Annette Erhart

3Department of Parasitology, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium

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Adoke Yeka

4Epidemiology Unit, Uganda Malaria Surveillance Project, P.O Box 7475, Kampala, Uganda

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James K Tibenderana

5Communicable Diseases Control Department, Malaria Consortium Africa, P.O Box 8045, Kampala, Uganda

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Frederick N Baliraine

6Department of Medicine, University of California San Francisco, 1001 Potrero Ave, SFGH 30, San Francisco, CA, 94143, USA

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Philip J Rosenthal

6Department of Medicine, University of California San Francisco, 1001 Potrero Ave, SFGH 30, San Francisco, CA, 94143, USA

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Umberto D'Alessandro

3Department of Parasitology, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium

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Author informationArticle notesCopyright and License informationDisclaimer

1Department of Pediatrics and Child Health, Makerere University College of Health Sciences, P.O. Box 7475, Kampala, Uganda

2Department of Epidemiology and Biostatistics, Makerere University School of Public Health, P.O Box 7072, Kampala, Uganda

3Department of Parasitology, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium

4Epidemiology Unit, Uganda Malaria Surveillance Project, P.O Box 7475, Kampala, Uganda

5Communicable Diseases Control Department, Malaria Consortium Africa, P.O Box 8045, Kampala, Uganda

6Department of Medicine, University of California San Francisco, 1001 Potrero Ave, SFGH 30, San Francisco, CA, 94143, USA

corresponding authorCorresponding author.

Jane Achan: [email protected]; Ambrose O Talisuna: [email protected]; Annette Erhart: [email protected]; Adoke Yeka: [email protected]; James K Tibenderana: [email protected]; Frederick N Baliraine: [email protected]; Philip J Rosenthal: [email protected]; Umberto D'Alessandro: [email protected]

Received 2011 Jan 31; Accepted 2011 May 24.

Copyright ©2011 Achan et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Abstract

Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.

Background and historical perspective

The discovery of quinine is considered the most serendipitous medical discovery of the 17th century [1] and malaria treatment with quinine marked the first successful use of a chemical compound to treat an infectious disease[2]. Quinine, as a component of the bark of the cinchona (quina-quina) tree, was used to treat malaria from as early as the 1600s, when it was referred to as the "Jesuits' bark," "cardinal's bark," or "sacred bark." These names stem from its use in 1630 by Jesuit missionaries in South America, though a legend suggests earlier use by the native population[2]. According to this legend, an Indian with a high fever was lost in an Andean jungle. Thirsty, he drank from a pool of stagnant water and found that it tasted bitter. Realizing that the water had been contaminated by the surrounding quina-quina trees he thought he was poisoned. Surprisingly, his fever soon abated, and he shared this accidental discovery with fellow villagers, who thereafter used extracts from the quina-quina bark to treat fever [3]. The legend of quinine's discovery accepted in Europe differs though, and involves the Spanish Countess of Chinchon who, while in Peru, contracted a fever that was cured by the bark of a tree. Returning to Spain with the bark, she introduced quinine to Europe in 1638 and, in 1742, botanist Carl Linnaeus called the tree "Cinchona" in her honour [4].

Before 1820, the bark of the cinchona tree was first dried, ground to a fine powder, and then mixed into a liquid (commonly wine) before being drunk. In 1820, quinine was extracted from the bark, isolated and named by Pierre Joseph Pelletier and Joseph Caventou. Purified quinine then replaced the bark as the standard treatment for malaria [5]. Quinine and other cinchona alkaloids including quinidine, cinchonine and cinchonidine are all effective against malaria. The efficacies of these four alkaloids were evaluated in one of the earliest clinical trials, conducted from 1866 to 1868 in 3600 patients using prepared sulfates of the alkaloids. With the main outcome measure of "cessation of febrile paroxysms", all four alkaloids were found to be comparable, with cure rates of >98%[6]. However, after 1890 quinine became the predominantly used alkaloid, mainly due to a change in supply from South American to Javan cinchona bark, which contained a higher proportion of quinine [7]. Quinine remained the mainstay of malaria treatment until the 1920s, when more effective synthetic anti-malarials became available. The most important of these drugs was chloroquine, which was extensively used, especially beginning in the 1940s [6]. With heavy use, chloroquine resistance developed slowly. Resistance of Plasmodium falciparum to chloroquine was seen in parts of Southeast Asia and South America by the late 1950s, and was widespread in almost all areas with falciparum malaria by the 1980s. With increasing resistance to chloroquine, quinine again played a key role, particularly in the treatment of severe malaria [6]. To-date quinine continues to play a significant role in the management of malaria. This review, discusses the historical role of quinine, considers its current usage, and provides insight into the appropriate future use of quinine for the treatment of malaria. Information was obtained by searching published literature in the National Library of Medicine via Pub Med and MEDLINE search engines for research articles, reviews, books, and other reports. Identification of published reports was done using key word searches such as quinine and malaria treatment, quinine and drug resistance, quinine in pregnancy, quinine and antibiotic combinations, and quinine and HIV/TB infected populations.

Quinine properties

Quinine is a cinchona alkaloid that belongs to the aryl amino alcohol group of drugs. It is an extremely basic compound and is, therefore, always presented as a salt[6]. Various preparations exist, including the hydrochloride, dihydrochloride, sulphate, bisulphate, and gluconate salts; of these the dihydrochloride is the most widely used. Quinine has rapid schizonticidal action against intra-erythrocytic malaria parasites. It is also gametocytocidal for Plasmodium vivax and Plasmodium malariae, but not for Plasmodium falciparum. Quinine also has analgesic, but not antipyretic properties. The anti-malarial mechanism of action of quinine is unknown.

Quinine is rapidly absorbed both orally and parenterally, reaching peak concentrations within 1-3 hours[8]. It is distributed throughout the body fluids and is highly protein bound, mainly to alpha-1 acid glycoprotein. The binding capacity in plasma is concentration dependent, but also depends on the levels of alpha-1 acid glycoprotein, which therefore makes comparisons between different studies difficult[9]. Quinine readily crosses the placental barrier and is also found in cerebral spinal fluid. Excretion is rapid - 80% of the administered drug is eliminated by hepatic biotransformation and the remaining 20% is excreted unchanged by the kidney [10-12]. The half-life of quinine ranges between 11-18 hours [13,14]. Several pharmacokinetic characteristics of quinine differ according to the age of the subject and are also affected by malaria. The volume of distribution is less in young children than in adults, and the rate of elimination is slower in the elderly than in young adults. In patients with acute malaria the volume of distribution is reduced and systemic clearance is slower than in healthy subjects; these changes are proportional to the severity of the disease. As a result, plasma quinine levels are higher in patients with malaria. Protein binding of quinine is increased in patients with malaria as a result of an increased circulating concentration of alpha-1 acid glycoprotein [15].

Quinine has a low therapeutic index, and adverse effects with its use are substantial [16]. The side effects commonly seen at therapeutic concentrations are referred to as cinchonism, with mild forms including tinnitus, slight impairment of hearing, headache and nausea. Impairment of hearing is usually concentration dependent and reversible [17]. More severe manifestations include vertigo, vomiting, abdominal pain, diarrhea, marked auditory loss, and visual symptoms, including loss of vision. Hypotension may occur if the drug is given too rapidly, and venous thrombosis may occur following intravenous injections [10]. Intramuscular administration is painful and may cause sterile abscesses. Hypoglycaemia is yet another common side effect of quinine therapy [15,18] and is a particular problem in pregnant women[19]. Hypoglycaemia has been reported to occur in up to 32% of patients receiving quinine therapy[18]. However in more recent studies, hypoglycaemia occurred in only 3% of adults and 2.8% of African children receiving quinine [20,21]. Less frequent but more serious side effects of quinine therapy include skin eruptions, asthma, thrombocytopaenia, hepatic injury and psychosis [22].

Overview of quinine use in the management of malaria

Quinine remains an important anti-malarial drug, almost 400 years after Jesuit priests first documented its effectiveness. The 2010 World Health Organisation (WHO) guidelines recommend a combination of quinine plus doxycycline, tetracycline or clindamycin as second-line treatment for uncomplicated malaria (to be used when the first-line drug fails or is not available) and quinine plus clindamycin for treatment of malaria in the first trimester of pregnancy [23]. Based on recent trials, intravenous artesunate should be used for the treatment of severe falciparum malaria in adults [20] and children[21], in preference to quinine.

By 2009, 31 African countries recommended quinine as second-line treatment for uncomplicated malaria, 38 as first-line treatment of severe malaria and 32 for treatment of malaria in the first trimester of pregnancy [24]. In most of Africa, quinine is still used as monotherapy, contrary to the WHO recommendations[23,24]; the reason for this practice may be the higher costs of quinine-antibiotic combinations. Quinine continues to play a significant role in the management of malaria in sub-Saharan Africa and other malaria endemic areas, and its use in routine practice may not be restricted to the stated WHO recommendations. In Cameroon, even one year after the introduction of ACT, quinine continued to be used as first-line therapy, with 45% of adults receiving oral quinine for uncomplicated malaria [25]. Recent surveillance data from sentinel sites in Uganda showed that quinine was prescribed for up to 90% of children < 5 years with uncomplicated malaria [26].

The use of quinine for uncomplicated malaria cases should have decreased due to toxicities, poor compliance and the implementation of newer and better tolerated therapies such as ACT. However, the limited availability of ACT and the increasing resistance to chloroquine and antifolates have actually increased its use in recent times [27]. Therefore, studies evaluating the role of quinine in the management of malaria have been reviewed.

Quinine for uncomplicated malaria

In several settings, oral quinine continues to be used as treatment for uncomplicated malaria, a practice mainly resulting from frequent stock-outs of the recommended ACT [26,28]. Previous studies of the effectiveness and efficacy of quinine for uncomplicated malaria showed mixed results (Table ​1). The majority of these studies were conducted in settings with reported declining efficacy of quinine in Southeast Asia and South America. Earlier studies in these regions, using varying dosing regimens, showed cure rates ranging from 76% to 98%. The lower cure rates were mainly observed with shorter regimens (3 days) and higher cure rates when the drug was combined with sulphadoxine-pyrimethamine, tetracycline or clindamycin [29-34]. Similar findings were reported in Vietnam, where a three-day course of quinine plus artesunate had a cure rate of only 50%, compared to a five-day course, which had a cure rate of 76%[35]. Studies in Southeast Asia using quinine monotherapy for 7 days showed cure rates of 85-87% [29,33], which is similar to what was observed over 15 years earlier [36], (Table ​1).

Table 1

Summary of studies of quinine for the treatment of uncomplicated malaria

Study siteYearSample size and study populationDrug RegimensDuration of follow-upTreatment outcomeCommentReference
Thailand, region with multidrug resistant malaria1984-198566 children
2-12 years
Quinine Quinidine28 days
DOT
Cure rates:
Quinine - 85%
Quinidine - 88%
Treatment failures only RI responses[29]

Cambodia, region with multidrug resistant malaria1983119 adults,
>15 years
Mefloquine +SP (MSP)
3 days quinine+tetracycline (Q3T7)
7 days of quinine+ tetracycline (Q7T7)
28 days
DOT
Cure rates:
MSP: 98%
Q3T7: 76%
Q7T7: 92%
Q7T7 still gives good cure rate[30]

Brazil, setting with quinine resistance1985100 patients
18-55 years
Mefloquine 1000 mg single dose (MQ)
3 days quinine+SP (Q3+SP)
42 days
DOT
Cure rates:
MQ:
96%
Q3 + SP: 98%
Four RI responses in Q3 + SP group[31]

Thailand, region with multidrug resistant malaria1994102 patients
16-60 years
Mefloquine+tetracycline (MQT)
7 days of Quinine+ tetracycline (Q7T7)
28 days
DOT
Cure rates:
MQT: 94%
Q7T7: 98%
MQ + Tetra as effective as Q7T7[34]

Thailand, region with multidrug resistant malaria1995-1997204 male patients
15-64 years
7 days quinine (Q7)
Quinine + tetracycline (Q7T7)
Quinine + clindamycin (Q7C7)
28 days
Directly observed therapy
Cure rates:
Q7: 87%
Q7T7: 98%
Q7C7: 100%
Tetracycline or clindamycin improves quinine cure rates[33]

Equatorial Guinea, setting with no quinine resistance1999114 children
6-59 months
7days quinine (Q7)
Chloroquine (CQ)
Sulfadoxine/pyrimethamine (SP)
114 day follow-upCure rates:
Q7: 94.5%
CQ: 60%
SP: 90%
Quinine is effective against P.falciparum malaria[43]

Cameroon, High transmission setting200530 children
0.5-6 years
5 days quinine (Q5)14 day follow-upCure rates: 100%[41]

Burundi Perennial transmission setting1992-1995472 children
0-14 years
Chloroquine (CQ)
5 days quinine (Q5)
7 day follow-upFailure rates Q5:
1992-1993: 4.2%
1994-1995: 7.1%
[40]

Guinea-Bissau Perennial transmission setting1994-1995203 children
0.7-13 years
3 days quinine (Q3)
5 days quinine (Q5)
7 days quinine (Q7)
28-35 day follow-upDay 28 recurrent parasitemia:
Q3: 79%
Q5: 90%
Q7: 11%
3 day quinine regimens should not be used.[37]

Gabon High transmission setting1993-1994120 adults = 15years3 days quinine (Q3)
3 days quinine+clindamycin (Q3C3)
3 days quinine+doxycycline (Q3D3)
28 day follow-upDay 28 cure rates:
Q3: 38%
Q3C3: 92%
Q3D3: 91%
The two short course combinations of quinine had excellent cure rates[109]

Uganda Meso-endemic transmission setting2007-2008175 children
6months - 5 years
7 days quinine (Q7)
3 days artemether-lumefantrine (AL)
28 day follow-upCure rates:
Q7: 64%
AL: 97%
Results question the advisability of quinine use for uncomplicated malaria[45]

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Moreover, the addition of either tetracycline or clindamycin to quinine in the Thai study improved cure rates to 98% and 100% respectively and also delayed the appearance of Plasmodium vivax infection, suggesting additional activity against this species [33].

In Africa, studies evaluating three-day quinine treatment regimens have usually found unacceptably high failure rates [37], with recurrent infections at day 28 post-treatment experienced in 30% - 50% of patients[37-39]. However most of these studies did not perform PCR analyses to distinguish between recrudescence and re-infection, leading to possible underestimation of efficacy. In interpreting these results, the malaria transmission intensity at the study sites needs to be taken into consideration, as high treatment failure rates in high transmission settings may be due to a high risk of new infections. Additional PCR unadjusted studies that have evaluated five-day regimens of quinine have found recurrent infection rates on day 7 between 4% and 7% [40] and day 14 treatment failure rates of 0 to 5% (Table ​1) [41,42]. In Equatorial Guinea, five-day courses of quinine were associated with day 14 PCR unadjusted failure rates as high as 22%. These latter results prompted a change in the quinine treatment regimen for this region to a 7 day course, with subsequent significant decrease in treatment failure rates to 3%-5.5% [43]. This study also reported that treatment failure rates with quinine remained stable over the five-year period of surveillance.

Even with seven-day treatment durations, evaluations of different quinine dosage regimens have revealed interesting trends. Doses of 10 mg/kg/day given twice daily for 7 days were associated with day 28 treatment failure rates as high as 30%[37]. Increasing the quinine dosage to 15 mg/kg/day or 20 mg/kg/day improved treatment outcomes, with failure rates ranging from 8% to 14%[37], although potential increases in toxicity with higher dosages are a concern. The treatment regimen currently recommended in sub-Saharan Africa is 10 mg/kg of the base given 8 hourly for 7 days. This regimen was associated with a lower rate of recurrent infections on day 28 (6.3%) compared to the 10 mg/kg twice daily regimen (16.1%)[44].

The advent of ACT has provided important new therapeutic options for the management of uncomplicated malaria in regions with high prevalence of multi-drug resistant malaria. A few available trials have shown superiority of ACT over quinine in the management of uncomplicated malaria [32,45,46]. In Brazil, patients treated with artemether-lumefantrine (AL) had significantly faster parasite clearance times when compared to those treated with quinine+doxycycline [46]. Considering the extensive available data, quinine should not be used to treat uncomplicated malaria when ACT is available [27,45]. ACT has the advantages of simplicity of dosing, which promotes adherence to therapy when compared with the seven-day treatment courses of quinine [32,45], better tolerance and decreased risks of serious toxicity.

Nevertheless, despite their scale up in Africa, the cost and availability of ACT in the public sector remains a major challenge. In 2008, ACT coverage in the public sector in high-burden African countries was only 42%[47]. Similarly, a survey carried out during the same year in seven African countries showed that the percentage of fever cases in children < 5 years treated with ACT was only 16% [47]. The sustainability of ACT supplies in resource limited settings therefore presents a huge problem, with stock-outs consistently occurring in health facilities [48]. Quinine, on the other hand, is a relatively cheap drug and often the only available option, rendering its rapid withdrawal for uncomplicated malaria cases risky. The best approach in these settings would be to proactively identify solutions to ACT stock-outs and maintain quinine as a fall-back drug only in case of ACT stock-outs. Additionally, improving quinine treatment outcomes by combining it with antibiotics, such as tetracycline or clindamycin [49-51], could be investigated and promoted. More recently, combinations of quinine and newer antibiotics with shorter treatment regimens that would improve adherence to therapy as well as minimize related adverse events have been evaluated. One such combination is that with azithromycin which is of particular interest, as the drugs act synergistically [52]. This combination offers promise for use especially in pregnant women and children < 8 years, since, unlike tetracyclines, both drugs are safe in these groups. A study in Thailand showed comparable efficacy in the treatment of multidrug resistant malaria, with cure rates of 100%, for a seven-day course of quinine+doxycycline and a three-day course of quinine+azithromycin [49]. These drug combinations will need further evaluation to confirm these findings and may offer a solution to the compliance problems associated with seven-day courses of quinine.

Quinine for malaria in pregnancy

Malaria in pregnancy causes several adverse outcomes that include maternal anaemia, intrauterine growth retardation, low birth weight, preterm deliveries and abortion. Prevention and treatment of malaria in pregnancy is, therefore, critical to avoid these adverse outcomes. Currently the WHO recommends the use of quinine plus clindamycin for treating malaria in the first trimester of pregnancy, as the safety of artemisinin compounds during this period is not yet established [23]. As most clinical trials exclude women in their first trimester of pregnancy, information on the efficacy and safety of anti-malarial drugs during this period is extremely limited. Evidence for the safety of quinine in pregnancy is mostly historical and there are few clinical trials published [50,53]. Clindamycin on the other hand has a good safety record in pregnancy [54] and its pharmacokinetic properties are usually unchanged by pregnancy[55]. The combination of quinine and clindamycin has proven highly efficacious against multidrug-resistant strains of P. falciparum, with 42 day cure rates of 100% in one study [50]. The only concern with this combination is that it is usually not affordable for most resource limited settings. For the second and third trimester of pregnancy, quinine monotherapy seems to have unacceptably low efficacy in areas with multidrug resistant malaria when compared to ACT. Studies in these regions have shown that ACT performs better than oral quinine in terms of parasite clearance and fever clearance. Two studies in Thailand [56,57] reported fewer treatment failures at day 63 with artesunate plus atovaquone-proguanil and artesunate plus mefloquine, when compared with quinine. The occurrence of adverse events experienced by the pregnant women was similar in all groups, although tinnitus was more frequent in the quinine group. In these studies, the considerably inferior efficacy of quinine was attributed to both drug resistance and to the varying pharmacokinetic properties of quinine during pregnancy. In Africa however, available evidence suggests that Plasmodium. falciparum generally remains sensitive to quinine [58] and low cure rates with quinine monotherapy in pregnant women has been mainly attributed to poor compliance to treatment [59]. Thus in Africa, quinine monotherapy remains the most widely used treatment for malaria in the first trimester of pregnancy and is also considered safe during all trimesters of pregnancy. A recent study from Uganda provides important reassurance of continued efficacy of quinine monotherapy in these regions of Africa. In this study, quinine and artemether-lumefantrine had similar efficacy for the treatment of uncomplicated malaria in the second and third trimesters of pregnancy [60]. The evidence for safety of ACT use during the first trimester of pregnancy is currently limited [61]. Therefore, until more data become available, the recommendation to use quinine in the first trimester of pregnancy will remain and ACT should only be used in the second and third trimesters of pregnancy. Patient education and counseling will however be critical to promote compliance with therapy.

Quinine in HIV or tuberculosis infected populations

Interactions between HIV and malaria remain a major public health concern in areas affected by both diseases. Very few studies have evaluated the role of quinine in the management of malaria in HIV infected populations. The earliest study was done in the Congo in 1986 and it showed malaria cure rates of 92% in HIV infected patients treated with oral quinine with comparable results in HIV-negative patients [62]. In a subsequent study in the same region, no significant differences in treatment response were observed between children with progressive HIV infection and HIV-uninfected controls treated with oral quinine [63]. Such findings and other available data suggest that malaria treatment policy in HIV infected populations can generally follow the standard practices. Concerns however remain about potential interactions between anti-malarial and anti-retroviral drugs. Currently, there is little published information on the co-administration of antiretroviral therapy (ART) and anti-malarial drugs, yet this will become increasingly important with the rapid scale-up of ART in Africa. In Nigeria, concurrent administration of nevirapine and quinine led to significant reductions in the plasma levels of quinine and elevated plasma levels of 3-hydroxyquinine, the major metabolite of quinine [64]. This could potentially reduce the efficacy of quinine while increasing toxicity, since 3-hydroxyquinine has higher toxicity and lower anti-malarial activity than quinine. Interactions with ritonavir have also been described, with concurrent administration of these drugs leading to marked elevations in plasma levels of quinine and decreases in levels of 3-hydroxyquinine [65]. These results suggest the need for downward dosage adjustments of quinine with concurrent administration of ritonavir, including ritonavir-boosted protease inhibitor regimens.

The co-existence of tuberculosis (TB), malaria and HIV in sub-Saharan Africa and other settings causes additional concerns about their treatment. Interactions between rifampicin (a major component of first-line anti-TB treatment regimens) and quinine would be expected as rifampicin is a potent inducer of hepatic enzymes and quinine is metabolised mainly by the human CYP 3A isoenzyme. In vivo studies in healthy volunteers showed that when quinine was administered with rifampicin its mean clearance was significantly greater and mean elimination half-life shorter [66]. Interesting observations of the effect of combined quinine and rifampicin therapy were additionally reported in Thai patients with uncomplicated malaria [67]. In this study, parasite clearance times were shorter in the quinine-rifampicin group than in the group given quinine monotherapy, suggesting that the anti-malarial activity of rifampicin augmented that of quinine initially. However, recrudescence rates were five times higher in the quinine-rifampicin group than in the quinine-alone group[67]. These observations were explained by marked differences in the plasma quinine concentrations when rifampicin was combined with quinine. These results suggest that the quinine dosage might need to be increased in patients receiving rifampicin as an anti-TB drug.

Concerns also exist about potential interactions with the concurrent use of antiretroviral drugs and artemisinin-based combination therapy [68-70]. Further research and pharmacovigilance will be critical to facilitate the development of targeted treatment recommendations. Presently, it is not possible to elucidate advantages associated with the use of any particular anti-malarial drug for HIV or TB infected populations.

Quinine in the management of severe malaria

The treatment of severe malaria requires prompt, safe, and effective intravenous anti-malarial drugs. Over the years, quinine has been the mainstay in the treatment of severe malaria and still remains the first line drug in most African countries [24]. Though quinine dosing regimens have varied, the WHO recommends a dose of 20 mg salt/kg by intravenous infusion, then 10 mg/kg every eight hours [23]. The rationale for the loading dose is the urgent need to achieve therapeutic plasma concentrations. One systematic review showed that a loading dose of quinine reduced fever and parasite clearance times, but there was insufficient data to demonstrate its impact on risk of death [71].

More recently, intravenous artesunate is the recommended treatment of choice for severe falciparum malaria in adults [23]. This recommendation was made on the basis of the dramatic results of the SEAQUAMAT trial conducted in Southeast Asia that showed a 35% reduction in the case-fatality rate in adults with severe malaria treated with intravenous artesunate compared to intravenous quinine[20]. Subsequent systematic reviews have also provided additional evidence for this recommendation [72]. However, about 80% of malaria deaths occur in sub-Saharan Africa among children aged < 5 years. The therapeutic options previously recommended by WHO for the paediatric group included intravenous artesunate, intramuscular artemether or intravenous quinine[23]. Several trials and meta-analyses comparing intramuscular artemether with intravenous quinine have consistently shown no benefit of treatment with artemether over quinine in children with severe malaria in sub-Saharan Africa [73-75] (Table ​2). The recently concluded AQUAMAT study now provides conclusive evidence of the superiority of intravenous artesunate over quinine in children <15 years, with a relative reduction of 23% in mortality associated with the use of artesunate[21]. These observations recently led to a change in WHO recommendations, with intravenous artesunate now advocated in preference to quinine for the management of severe malaria in children. The most critical issues that will need to be addressed, however, are the availability of intravenous artesunate for the patients who need it, especially in resource-limited settings, and its effectiveness in real-life settings. Until recently, the available formulations of injectable artesunate that have been used in several clinical trials were not produced according to Good Manufacturing Practices (GMP) and this could be a problem for African countries relying on donors who do not permit purchase of non-GMP artesunate. WHO recently pre-qualified intravenous artesunate manufactured by Guilin Pharmaceuticals in China and this may resolve problems of procurement of GMP artesunate. However, it is unclear whether supplies will be sufficient for the thousands of patients in need. Until these procurement and supplies issues are resolved, intravenous quinine may remain the only readily available drug for treating severe malaria in sub-Saharan Africa and other resource-limited settings. Furthermore, there are several health systems challenges related to the management of severe malaria in resource limited settings that impact on treatment outcomes, independent of the parenteral anti-malarial drugs used. Consequently, changes in treatment policies, in this case from quinine to artesunate, may not offer improvements without considering drug availability as well as additional measures to strengthen health systems.

Table 2

Summary of studies of quinine for the treatment of severe malaria

Study siteYearSample size and Study populationDrug RegimensTreatment outcomeCommentReference
Gambia1992-1994576 children
1-9 years Cerebral malaria
Intramuscular artemether (IMA)
Intravenous quinine (IVQ)
Mortality:
IMA:20.5%
IVQ: 21.5%
Neurological sequelae:
IMA: 3.3%
IVQ: 5.3%
Artemether is as effective as quinine in treatment of cerebral malaria in children[74]

Malawi1992-1994183 children
Cerebral malaria
Intramuscular artemether (IMA)
Intravenous quinine (IVQ)
Mortality:
IMA: 11%
IVQ: 16%
Survival with neurological sequelae:
IMA: 19%
IVQ: 12%
Results do not suggest artemether would confer a survival advantage over quinine[73]

Kenya2000-2002360 patients
1-60 years
Severe malaria
IV Quinine + oral malarone (QM)
IV Quinine +oral quinine (QQ)
Day 28 cure rates:
QM: 98.7%
QQ: 90%
Using malarone after IV quinine is safer and as effective as IV quinine +oral quinine[87]

Burkina Faso2001-2002898 children
1-15 years
Moderately severe malaria
Rectal quinine (RQ)
Intramuscular quinine (IMQ)
Early treatment failure (day 3):
RQ: 6%
IMQ: 3%
Fever recurrence on day 7:
RQ: 5%
IMQ: 10%
Rectal quinine had acceptable safety profile and could be used as early treatment for severe malaria[84]

Uganda2002-2003103 children
0.5-5 years
Cerebral malaria
Rectal artemether (RA)
Intravenous quinine (IVQ)
Mortality:
IVQ: 11.7%
RA: 19.2%
Rectal artemether was effective and well tolerated[76]

S.E Asia (Four countries)2003-20051461 patients
>2 years
Severe malaria
Intravenous artesunate (IVA)
Intravenous quinine (IVQ)
Mortality:
IVA: 15%
IVQ: 22%
Absolute reduction in mortality: 34.7%
Intravenous artesunate should be treatment of choice for severe malaria in adults[20]

Uganda2003-2004110 children
0.5-5 years
Cerebral malaria
Rectal quinine (RQ)
Intravenous quinine (IVQ)
Mortality:
RQ: 7%
IVQ: 9%
Comparable clinical and parasitological outcomes
Rectal quinine was efficacious and could be used as a treatment alternative[79]

Africa (Nine countries)2005-20105425 children
< 15 years Severe malaria
Intravenous artesunate (IVA)
Intravenous quinine (IVQ)
Mortality:
IVA: 8.5%
IVQ: 10.9%
Relative reduction in mortality: 22.5%
Parenteral artesunate should replace quinine as the treatment of choice for severe malaria[21]

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Another important aspect of severe malaria case management is pre-referral treatment, which is treatment given to a patient with severe malaria before they are referred to a health facility. This is critical, as most malaria deaths, especially in Africa, occur outside hospitals, either in the communities or at lower levels of care. Studies evaluating the role of rectal artesunate and artemether as pre-referral treatment have found these options to be highly efficacious [76,77]. However, the biggest challenge faced in resource limited settings has been the non-availability of these preparations in health facilities. A recent survey in Uganda found that rectal artemisinins were available in only 5% of the health facilities despite the fact that this is the recommended pre-referral drug [78]. A feasible alternative is rectal quinine, which has been found to have comparable efficacy with intravenous quinine in the management of severe malaria in children [79-84] (Table ​2) and could play a more significant role than currently acknowledged as pre-referral treatment for severe malaria. More recent studies in Senegal and Mali provide additional support for the efficacy and feasibility of this route and also show that a pre-referral kit of rectal quinine was acceptable to both caretakers and health workers [85,86].

Following successful administration of parenteral treatment for severe malaria, it is recommended to continue with an oral anti-malarial drug once a patient is able to tolerate oral therapy. The current practice is to continue the same medicine orally as given parenterally to complete a full treatment course [23]. The options for oral continuation therapy that are available in many African settings would therefore include oral quinine or an ACT. In non-pregnant adults, doxycyline would also be added to either of these drugs and given twice daily for 7 days. Where available, clindamycin may be substituted in children, since doxycyline is contraindicated in this age group [23]. The choice of oral continuation therapy following initial parenteral treatment of severe malaria may also have an impact on clinical outcomes, particularly on parasite clearance, fever clearance and potentially the risk of recurrent parasitaemia. In this regard completing intravenous quinine treatment with an ACT instead of oral quinine may improve the overall treatment outcome of parenteral quinine therapy. Studies evaluating this approach to therapy are limited. A study in Kenya during 2000-2002, showed that completing the intravenous quinine dose with oral malarone (atovaquone + proguanil) was associated with improved clinical outcomes compared to intravenous quinine followed by oral quinine [87] (Table ​2). Additional studies should explore other options, in particular ACT, for improving therapeutic outcomes with intravenous quinine treatment.

Potential explanations for quinine treatment failure

Quinine resistance

Parasite drug resistance is probably the greatest problem faced by malaria control programs worldwide and is an important public health concern. Over the years, malaria parasites have developed resistance to a number of commonly used anti-malarial drugs. However the development of resistance to quinine has been slow. Although its use started in the 17th century, resistance to quinine was first reported in 1910 [88]. In comparison, resistance to chloroquine and proguanil emerged within only 12 [89] and 1 year [88,90] of their introduction, respectively. Resistance to quinine is usually low grade, with the drug retaining some activity but having its action delayed or diminished. Diminished sensitivity of P. falciparum to quinine has been widely documented in Asia [91] and South America [92] but it seems relatively uncommon in Africa where conflicting results of no resistance [93,94] or varying degrees of resistance [95], [96] have been reported. A recent study from Thailand showed significant reductions in efficacy of quinine, artemisinin and mefloquine when compared to previous reports from the same area, suggesting further increase in drug resistance in this region [97]. No convincing evidence of high grade quinine resistance in the treatment of severe malaria has been reported. Findings from a recent systematic review of about 435 clinical trials published between 1966 and 2002 showed that the recrudescence rates for quinine reported over these past 30 years remained roughly constant [98]. These findings are encouraging and may suggest that efficacy of quinine has been preserved.

Variations in quinine pharmacokinetics

Treatment failures with quinine could also be explained by varying pharmacokinetic profiles of the drug. It is known that quinine pharmacokinetic properties and therapeutic responses vary with age, pregnancy, immunity and disease severity [99]. Also, as patients recover from malaria, there is usually an expansion of the volume of distribution and an increase in systemic clearance of quinine resulting in a decline in the average concentration of quinine in plasma [100]. These variations may lead to drug levels that may be inadequate to completely clear infection. The possibility that pharmacokinetic factors may explain quinine treatment failure was initially raised about 20 years ago when a Thai patient who had fatal severe malaria and apparent RIII resistance was found to have abnormally low levels of quinine despite adequate dosing [101]. Additional evidence for the impact of unusual quinine pharmacokinetics on treatment outcomes was provided by a more recent study describing early treatment failure in a patient with severe malaria with an abnormally high volume of distribution and increased quinine clearance, resulting in abnormally low quinine concentrations [102]. A few studies have proposed that an increase in the quinine dosage after the third day could compensate for declines in plasma drug levels during recovery, especially in areas with resistant P. falciparum [99]. However, this is not routinely practiced. Despite these anecdotal observations, there is little evidence for large variations in quinine pharmacokinetics [103] and the exact role that variations in drug levels play in quinine treatment responses is unclear.

Quinine drug quality and treatment compliance

The quality of quinine used in routine care could play a key role in clinical outcomes. Poor quality drugs remain a problem worldwide and are a serious public health threat. A study in Nigeria evaluating the quality of different anti-malarial drugs found that 37% of 225 anti-malarial drugs did not meet the tolerance limits set by United Sates Pharmacopeia (USP) for the amount of active ingredient, and 46% of these were formulations of quinine [104]. In Congo, Burundi and Angola only 89% of the declared active substance was found in quinine tablets, with high quantities of impurities reported [105]. Another worrying situation was unveiled in a survey in Cameroon, where nearly 74% of 70 quinine samples had no active ingredient [106]. Several other studies have also described varying problems with quinine drug quality in different settings [107,108]. Ideally, branded anti-malarial drugs should be used, but unfortunately, branded quinine products are not universally available in Africa and other malaria endemic settings. In addition, national drug regulators need to strengthen their roles in the monitoring of anti-malarial drug quality.

Another potential explanation for quinine treatment failures may be poor compliance. Quinine's prolonged treatment course and significant tolerability problems may lead to poor compliance, and hence poor therapeutic outcomes [32,45,59]. In this aspect, ACT has an advantage over quinine since it is administered once or twice daily over three days. A recent study in Uganda showed comparable compliance on day 3 of treatment in patients taking either quinine or artemether-lumefantrine. However, non-compliance to quinine greatly increased with increasing days on therapy to about 44% by day 7[45]. Promotion of shorter courses of quinine, especially in combination with antibiotics, should improve compliance as well as treatment outcomes [39,109].

Conclusion

In the near future, quinine will continue to play a significant role in the management of malaria, particularly in resource limited settings. Following the results of the SEAQUAMAT and AQUAMAT trials, artesunate is now recommended as the treatment of choice for severe malaria patients, with quinine only acting as an alternative when artesunate is not available. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but this remains a promising intervention given the limited availability of rectal artemisinin preparations in resource limited settings. Quinine continues to play a critical role in the management of malaria in the first trimester of pregnancy, and will remain so until safer alternatives become available. The continued use of quinine in the management of uncomplicated malaria is a concern. Clearly, the seven day duration of therapy and thrice daily administration of quinine present a major challenge to completion of therapy, leading to sub-optimal treatment outcomes. In these situations, ACT is a better option given the simplicity of dosing and shorter treatment duration. However, because of the frequent ACT stock outs, the rapid withdrawal of quinine as a treatment option for uncomplicated malaria cases is risky. The best approach would be, besides improving the supply system, to maintain quinine as a fall-back drug in case of ACT stock-outs.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

AJ, PJR and UD conceived the idea and wrote the first draft of the manuscript. All authors read and approved the final version

Acknowledgements and funding

We thank colleagues who have made useful comments on this manuscript. No funding was obtained for the preparation of this manuscript.

References

  • How Was Quinine Discovered? http://www.ehow.com/facts_5828007_quinine-discovered_.html#ixzz1JrTqGgQq
  • David B, Jacoby RMY. Encyclopedia of Family Health. Third 2005. [Google Scholar]
  • Quinine. http://www.discoveriesinmedicine.com/Ni-Ra/Quinine.html
  • Cinchona bark. http://historyofmalaria.com/2010/02/cinchona-bark/
  • Dobson SMaM. In: Antimalarial Chemotherapy: Mechanisms of Action, Resistance, and New Directions in Drug Discovery. PJ R, editor. Totowa, New Jersey: Humana Press; 2001. The history of antimalarial drugs; pp. 15–25. [Google Scholar]
  • Yakoub AdenAbdi OE, Gustafsson Lars L, Ericsson Orjan, Urban Hellgren. Handbook of Drugs for Tropical Parasitic Infections. 2 1995. [Google Scholar]
  • BF H. Some notes on the Cinchona Industry. Chemical News. 1931;142:129–133.[Google Scholar]
  • Salako LA, Sowunmi A. Disposition of quinine in plasma, red blood cells and saliva after oral and intravenous administration to healthy adult Africans. Eur J Clin Pharmacol. 1992;42(2):171–174. doi: 10.1007/BF00278479. [PubMed] [CrossRef] [Google Scholar]
  • Mihaly GW, Ching MS, Klejn MB, Paull J, Smallwood RA. Differences in the binding of quinine and quinidine to plasma proteins. Br J Clin Pharmacol. 1987;24(6):769–774.[PMC free article] [PubMed] [Google Scholar]
  • White NJ. The treatment of malaria. N Engl J Med. 1996;335(11):800–806. doi: 10.1056/NEJM199609123351107. [PubMed] [CrossRef] [Google Scholar]
  • Tracy. WLaJ. e. Chemotherapy of parasitic infections. In: Alfred Goodman Gilman LEL JGH, editor. Goodman and Gilman's Pharmacological basis of therapeutics. 9. Vol. 7. pp. 978–981. [Google Scholar]
  • Esamai F, Ayuo P, Owino-Ongor W, Rotich J, Ngindu A, Obala A, Ogaro F, Quoqiao L, Xingbo G, Guangqian L. Rectal dihydroartemisinin versus intravenous quinine in the treatment of severe malaria: a randomised clinical trial. East Afr Med J. 2000;77(5):273–278. [PubMed] [Google Scholar]
  • Jamaludin A, Mohamed M, Navaratnam V, Mohamed N, Yeoh E, Wernsdorfer W. Single-dose comparative kinetics and bioavailability study of quinine hydrochloride, quinidine sulfate and quinidine bisulfate sustained-release in healthy male volunteers. Acta Leiden. 1988;57(1):39–46. [PubMed] [Google Scholar]
  • White NJ, Chanthavanich P, Krishna S, Bunch C, Silamut K. Quinine disposition kinetics. Br J Clin Pharmacol. 1983;16(4):399–403.[PMC free article] [PubMed] [Google Scholar]
  • White NJ. Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmacol. 1992;34(1):1–10.[PMC free article] [PubMed] [Google Scholar]
  • WHO. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 2000;94(Suppl 1):1–90. [PubMed] [Google Scholar]
  • Karlsson KK, Hellgren U, Alvan G, Rombo L. Audiometry as a possible indicator of quinine plasma concentration during treatment of malaria. Trans R Soc Trop Med Hyg. 1990;84(6):765–767. doi: 10.1016/0035-9203(90)90069-Q. [PubMed] [CrossRef] [Google Scholar]
  • Okitolonda W, Delacollette C, Malengreau M, Henquin JC. High incidence of hypoglycaemia in African patients treated with intravenous quinine for severe malaria. Br Med J (Clin Res Ed) 1987;295(6600):716–718. doi: 10.1136/bmj.295.6600.716.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Looareesuwan S, Phillips RE, White NJ, Kietinun S, Karbwang J, Rackow C, Turner RC, Warrell DA. Quinine and severe falciparum malaria in late pregnancy. Lancet. 1985;2(8445):4–8. [PubMed] [Google Scholar]
  • Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717–725. [PubMed] [Google Scholar]
  • Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ, AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. pp. 1647–1657. [PMC free article] [PubMed]
  • Antimalarial Martindale, The Extra Pharmacopoeia. 30. London: Pharmaceuitical Press; 1993. [Google Scholar]
  • WHO. Malaria treatment guidelines. 2010.
  • WHO. Global antimalarial drug policies database - WHO African region. 2009. September edn.
  • Sayang C, Gausseres M, Vernazza-Licht N, Malvy D, Bley D, Millet P. Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon. Malar J. 2009;8:174. doi: 10.1186/1475-2875-8-174.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • (UMSP) UMSP. UMSP sentinel site malaria surveillance report July 2010. 2010.
  • Yeka A, Achan J, D'Alessandro U, Talisuna AO. Quinine monotherapy for treating uncomplicated malaria in the era of artemisinin-based combination therapy: an appropriate public health policy? Lancet Infect Dis. 2009;9(7):448–452. doi: 10.1016/S1473-3099(09)70109-4. [PubMed] [CrossRef] [Google Scholar]
  • Wasunna B, Zurovac D, Goodman CA, Snow RW. Why don't health workers prescribe ACT? A qualitative study of factors affecting the prescription of artemether-lumefantrine. Malar J. 2008;7:29. doi: 10.1186/1475-2875-7-29.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Sabchareon A, Chongsuphajaisiddhi T, Sinhasivanon V, Chanthavanich P, Attanath P. In vivo and in vitro responses to quinine and quinidine of Plasmodium falciparum. Bull World Health Organ. 1988;66(3):347–352.[PMC free article] [PubMed] [Google Scholar]
  • Meek SR, Doberstyn EB, Gauzere BA, Thanapanich C, Nordlander E, Phuphaisan S. Treatment of falciparum malaria with quinne and tetracycline or combined mefloquine/sulfadoxine/pyrimethamine on the Thai-Kampuchean border. Am J Trop Med Hyg. 1986;35(2):246–250. [PubMed] [Google Scholar]
  • de Souza JM, Sheth UK, de Oliveira RM, Roulet H, de Souza SD. An open, randomized, phase III clinical trial of mefloquine and of quinine plus sulfadoxine-pyrimethamine in the treatment of symptomatic falciparum malaria in Brazil. Bull World Health Organ. 1985;63(3):603–609.[PMC free article] [PubMed] [Google Scholar]
  • Fungladda W, Honrado ER, Thimasarn K, Kitayaporn D, Karbwang J, Kamolratanakul P, Masngammueng R. Compliance with artesunate and quinine + tetracycline treatment of uncomplicated falciparum malaria in Thailand. Bull World Health Organ. 1998;76(Suppl 1):59–66.[PMC free article] [PubMed] [Google Scholar]
  • Pukrittayakamee S, Chantra A, Vanijanonta S, Clemens R, Looareesuwan S, White NJ. Therapeutic responses to quinine and clindamycin in multidrug-resistant falciparum malaria. Antimicrob Agents Chemother. 2000;44(9):2395–2398. doi: 10.1128/AAC.44.9.2395-2398.2000.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Looareesuwan S, Vanijanonta S, Viravan C, Wilairatana P, Charoenlarp P, Lasserre R, Canfield C, Kyle DE, Webster HK. Randomised trial of mefloquine-tetracycline and quinine-tetracycline for acute uncomplicated falciparum malaria. Acta Trop. 1994;57(1):47–53. doi: 10.1016/0001-706X(94)90092-2. [PubMed] [CrossRef] [Google Scholar]
  • de Vries PJBN, Van Thien H, Hung LN, Anh TK, Kager PA, Heisterkamp SH. Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics. Antimicrob Agents Chemother. 2000;44(5):1302–1308. doi: 10.1128/AAC.44.5.1302-1308.2000.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Harinasuta TBD. Drug resistant malaria with special reference to chemotherapy. Mosquito-Borne Diseases Bulletin. 1984;1(23-30)[Google Scholar]
  • Kofoed PE, Mapaba E, Lopes F, Pussick F, Aaby P, Rombo L. Comparison of 3, 5 and 7 days' treatment with Quinimax for falciparum malaria in Guinea-Bissau. Trans R Soc Trop Med Hyg. 1997;91(4):462–464. doi: 10.1016/S0035-9203(97)90286-8. [PubMed] [CrossRef] [Google Scholar]
  • Rogier C, Brau R, Tall A, Cisse B, Trape JF. Reducing the oral quinine-quinidine-cinchonin (Quinimax) treatment of uncomplicated malaria to three days does not increase the recurrence of attacks among children living in a highly endemic area of Senegal. Trans R Soc Trop Med Hyg. 1996;90(2):175–178. doi: 10.1016/S0035-9203(96)90128-5. [PubMed] [CrossRef] [Google Scholar]
  • Kremsner PG, Winkler S, Brandts C, Neifer S, Bienzle U, Graninger W. Clindamycin in combination with chloroquine or quinine is an effective therapy for uncomplicated Plasmodium falciparum malaria in children from Gabon. J Infect Dis. 1994;169(2):467–470. doi: 10.1093/infdis/169.2.467. [PubMed] [CrossRef] [Google Scholar]
  • Di Perri GOP, Nardi S, Deganello R, Allegranzi B, Bonora S, Vento S, Concia E. Response of uncomplicated falciparum malaria to oral chloroquine and quinine in Burundi highlands. Acta Trop. 1998;70(1):25–33. doi: 10.1016/S0001-706X(98)00010-2. [PubMed] [CrossRef] [Google Scholar]
  • Le Jouan MJV, Tetanye E, Tran A, Rey E, Treluyer JM, Tod M, Pons G. Quinine pharmacokinetics and pharmacodynamics in children with malaria caused by Plasmodium falciparum. Antimicrob Agents Chemother. 2005;49(9):3658–3662. doi: 10.1128/AAC.49.9.3658-3662.2005.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Roche J, Benito A, Ayecaba S, Amela C, Molina R, Alvar J. Resistance of Plasmodium falciparum to antimalarial drugs in Equatorial Guinea. Ann Trop Med Parasitol. 1993;87(5):443–449. [PubMed] [Google Scholar]
  • Roche J, Guerra-Neira A, Raso J, Benito A. Surveillance of in vivo resistance of Plasmodium falciparum to antimalarial drugs from 1992 to 1999 in Malabo (Equatorial Guinea) Am J Trop Med Hyg. 2003;68(5):598–601. [PubMed] [Google Scholar]
  • Ibrahim MH, Elbashir MI, Naser A, Aelbasit IA, Kheir MM, Adam I. Low-dose quinine is effective in the treatment of chloroquine-resistant Plasmodium falciparum malaria in eastern Sudan. Ann Trop Med Parasitol. 2004;98(5):441–445. doi: 10.1179/000349804225003488. [PubMed] [CrossRef] [Google Scholar]
  • Achan J, Tibenderana JK, Kyabayinze D, Wabwire Mangen F, Kamya MR, Dorsey G, D'Alessandro U, Rosenthal PJ, Talisuna AO. Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial. BMJ. 2009;339:b2763. doi: 10.1136/bmj.b2763.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Alecrim MG, Lacerda MV, Mourao MP, Alecrim WD, Padilha A, Cardoso BS, Boulos M. Successful treatment of Plasmodium falciparum malaria with a six-dose regimen of artemether-lumefantrine versus quinine-doxycycline in the Western Amazon region of Brazil. Am J Trop Med Hyg. 2006;74(1):20–25. [PubMed] [Google Scholar]
  • WHO. World Malaria Report 2009. 2009.
  • Kangwana BB, Njogu J, Wasunna B, Kedenge SV, Memusi DN, Goodman CA, Zurovac D, Snow RW. Malaria drug shortages in Kenya: a major failure to provide access to effective treatment. Am J Trop Med Hyg. 2009;80(5):737–738.[PMC free article] [PubMed] [Google Scholar]
  • Miller RS, Wongsrichanalai C, Buathong N, McDaniel P, Walsh DS, Knirsch C, Ohrt C. Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am J Trop Med Hyg. 2006;74(3):401–406. [PubMed] [Google Scholar]
  • McGready R, Cho T, Samuel, Villegas L, Brockman A, van Vugt M, Looareesuwan S, White NJ, Nosten F. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg. 2001;95(6):651–656. doi: 10.1016/S0035-9203(01)90106-3. [PubMed] [CrossRef] [Google Scholar]
  • Parola P, Ranque S, Badiaga S, Niang M, Blin O, Charbit JJ, Delmont J, Brouqui P. Controlled trial of 3-day quinine-clindamycin treatment versus 7-day quinine treatment for adult travelers with uncomplicated falciparum malaria imported from the tropics. Antimicrob Agents Chemother. 2001;45(3):932–935. doi: 10.1128/AAC.45.3.932-935.2001.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Noedl H, Krudsood S, Chalermratana K, Silachamroon U, Leowattana W, Tangpukdee N, Looareesuwan S, Miller RS, Fukuda M, Jongsakul K, Sriwichai S, Rowan J, Bhattacharyya H, Ohrt C, Knirsch C. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis. 2006;43(10):1264–1271. doi: 10.1086/508175. [PubMed] [CrossRef] [Google Scholar]
  • Adam I, Ibrahim MH, Ae IA, Elbashir MI. Low-dose quinine for treatment of chloroquine-resistant falciparum malaria in Sudanese pregnant women. East Mediterr Health J. 2004;10(4-5):554–559. [PubMed] [Google Scholar]
  • Lell B, Kremsner PG. Clindamycin as an antimalarial drug: review of clinical trials. Antimicrob Agents Chemother. 2002;46(8):2315–2320. doi: 10.1128/AAC.46.8.2315-2320.2002.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Philipson A, Sabath LD, Charles D. Erythromycin and clindamycin absorption and elimination in pregnant women. Clin Pharmacol Ther. 1976;19(1):68–77. [PubMed] [Google Scholar]
  • McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, Looareesuwan S, White NJ, Nosten F. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis. 2005;192(5):846–853. doi: 10.1086/432551. [PubMed] [CrossRef] [Google Scholar]
  • McGready R, Brockman A, Cho T, Cho D, van Vugt M, Luxemburger C, Chongsuphajaisiddhi T, White NJ, Nosten F. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg. 2000;94(6):689–693. doi: 10.1016/S0035-9203(00)90235-9. [PubMed] [CrossRef] [Google Scholar]
  • Quashie NB, Duah NO, Abuaku B, Koram KA. The in-vitro susceptibilities of Ghanaian Plasmodium falciparum to antimalarial drugs. Ann Trop Med Parasitol. 2007;101(5):391–398. doi: 10.1179/136485907X176553. [PubMed] [CrossRef] [Google Scholar]
  • Adegnika AA, Breitling LP, Agnandji ST, Chai SK, Schutte D, Oyakhirome S, Schwarz NG, Grobusch MP, Missinou MA, Ramharter M, Issifou S, Kremsner PG. Effectiveness of quinine monotherapy for the treatment of Plasmodium falciparum infection in pregnant women in Lambarene, Gabon. Am J Trop Med Hyg. 2005;73(2):263–266. [PubMed] [Google Scholar]
  • Piola P, Nabasumba C, Turyakira E, Dhorda M, Lindegardh N, Nyehangane D, Snounou G, Ashley EA, McGready R, Nosten F, Guerin PJ. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010;10(11):762–769. doi: 10.1016/S1473-3099(10)70202-4. [PubMed] [CrossRef] [Google Scholar]
  • Manyando C, Mkandawire R, Puma L, Sinkala M, Mpabalwani E, Njunju E, Gomes M, Ribeiro I, Walter V, Virtanen M, Schlienger R, Cousin M, Chipimo M, Sullivan FM. Safety of artemether-lumefantrine in pregnant women with malaria: results of a prospective cohort study in Zambia. Malar J. 2010;9:249. doi: 10.1186/1475-2875-9-249.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Colebunders R, Bahwe Y, Nekwei W, Ryder R, Perriens J, Nsimba K, Turner A, Francis H, Lebughe I, Van der Stuyft P, Piot P. Incidence of malaria and efficacy of oral quinine in patients recently infected with human immunodeficiency virus in Kinshasa, Zaire. J Infect. 1990;21(2):167–173. doi: 10.1016/0163-4453(90)91701-E. [PubMed] [CrossRef] [Google Scholar]
  • Greenberg AE, Nsa W, Ryder RW, Medi M, Nzeza M, Kitadi N, Baangi M, Malanda N, Davachi F, Hassig SE. Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children. N Engl J Med. 1991;325(2):105–109. doi: 10.1056/NEJM199107113250206. [PubMed] [CrossRef] [Google Scholar]
  • Soyinka JO, Onyeji CO, Omoruyi SI, Owolabi AR, Sarma PV, Cook JM. Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers. J Pharm Pharmacol. 2009;61(4):439–443.[PMC free article] [PubMed] [Google Scholar]
  • Soyinka JO, Onyeji CO, Omoruyi SI, Owolabi AR, Sarma PV, Cook JM. Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration. Br J Clin Pharmacol. 2010;69(3):262–270. doi: 10.1111/j.1365-2125.2009.03566.x.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Wanwimolruk S, Kang W, Coville PF, Viriyayudhakorn S, Thitiarchakul S. Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man. Br J Clin Pharmacol. 1995;40(1):87–91.[PMC free article] [PubMed] [Google Scholar]
  • Pukrittayakamee S, Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S, White NJ. Adverse effect of rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother. 2003;47(5):1509–1513. doi: 10.1128/AAC.47.5.1509-1513.2003.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Khoo S, Back D, Winstanley P. The potential for the interactions between antimalarial and antiretroviral drugs. AIDS. 2005;19(10):995–1005. doi: 10.1097/01.aids.0000174445.40379.e0. [PubMed] [CrossRef] [Google Scholar]
  • Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, Ruel T, Charlebois E, Staedke SG, Kekitiinwa A, Rosenthal PJ, Havlir D, Dorsey G. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis. 2008;46(7):985–991. doi: 10.1086/529192. [PubMed] [CrossRef] [Google Scholar]
  • German P, Parikh S, Lawrence J, Dorsey G, Rosenthal PJ, Havlir D, Charlebois E, Hanpithakpong W, Lindegardh N, Aweeka FT. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr. 2009;51(4):424–429. doi: 10.1097/QAI.0b013e3181acb4ff. [PubMed] [CrossRef] [Google Scholar]
  • Lesi A, Meremikwu M. High first dose quinine regimen for treating severe malaria. Cochrane Database Syst Rev. 2004. p. CD003341. [PMC free article] [PubMed]
  • Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2007. p. CD005967. [PubMed]
  • Taylor TE, Wills BA, Courval JM, Molyneux ME. Intramuscular artemether vs intravenous quinine: an open, randomized trial in Malawian children with cerebral malaria. Trop Med Int Health. 1998;3(1):3–8. doi: 10.1046/j.1365-3156.1998.00166.x. [PubMed] [CrossRef] [Google Scholar]
  • van Hensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, Enwere G, Forck S, Nusmeijer A, Bennett S, Greenwood B, Kwiatkowski D. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med. 1996;335(2):69–75. doi: 10.1056/NEJM199607113350201. [PubMed] [CrossRef] [Google Scholar]
  • Group TA-QM-aS. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg. 2001;95(6):637–650. [PubMed] [Google Scholar]
  • Aceng JR, Byarugaba JS, Tumwine JK. Rectal artemether versus intravenous quinine for the treatment of cerebral malaria in children in Uganda: randomised clinical trial. BMJ. 2005;330(7487):334. doi: 10.1136/bmj.330.7487.334.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Gomes MF, Faiz MA, Gyapong JO, Warsame M, Agbenyega T, Babiker A, Baiden F, Yunus EB, Binka F, Clerk C, Folb P, Hassan R, Hossain MA, Kimbute O, Kitua A, Krishna S, Makasi C, Mensah N, Mrango Z, Olliaro P, Peto R, Peto TJ, Rahman MR, Ribeiro I, Samad R, White NJ. Study 13 Research Group. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet. 2009;373(9663):557–566. doi: 10.1016/S0140-6736(08)61734-1.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Achan J, Tibenderana J, Kyabayinze D, Mawejje H, Mugizi R, Mpeka B, Talisuna A, D'Alessandro U. Case management of severe malaria--a forgotten practice: experiences from health facilities in Uganda. PLoS One. 2011;6(3):e17053. doi: 10.1371/journal.pone.0017053.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Achan J, Byarugaba J, Barennes H, Tumwine JK. Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial. Clin Infect Dis. 2007;45(11):1446–1452. doi: 10.1086/522972. [PubMed] [CrossRef] [Google Scholar]
  • Barennes H, Kailou D, Pussard E, Munjakazi JM, Fernan M, Sherouat H, Sanda A, Clavier F, Verdier F. [Intrarectal administration of quinine: an early treatment for severe malaria in children?] Sante. 2001;11(3):145–153. [PubMed] [Google Scholar]
  • Barennes H, Kahiatani D, Clavier F, Meynard D, Njifountawaouo S, Barennes-Rasoanandrasana F, Amadou M, Soumana M, Mahamansani A, Granic G, Verdier F. [Rectal quinine, an alternative to parenteral injections for the treatment of childhood malaria. Clinical, parasitological and pharmacological study] Med Trop (Mars) 1995;55(4 Suppl):91–94. [PubMed] [Google Scholar]
  • Barennes H, Kahiatani F, Pussard E, Clavier F, Meynard D, Njifountawouo S, Verdier F. Intrarectal Quinimax (an association of Cinchona alkaloids) for the treatment of Plasmodium falciparum malaria in children in Niger: efficacy and pharmacokinetics. Trans R Soc Trop Med Hyg. 1995;89(4):418–421. doi: 10.1016/0035-9203(95)90036-5. [PubMed] [CrossRef] [Google Scholar]
  • Barennes H, Munjakazi J, Verdier F, Clavier F, Pussard E. An open randomized clinical study of intrarectal versus infused Quinimax for the treatment of childhood cerebral malaria in Niger. Trans R Soc Trop Med Hyg. 1998;92(4):437–440. doi: 10.1016/S0035-9203(98)91083-5. [PubMed] [CrossRef] [Google Scholar]
  • Barennes H, Balima-Koussoube T, Nagot N, Charpentier JC, Pussard E. Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial. BMJ. 2006;332(7549):1055–1059. doi: 10.1136/bmj.332.7549.1055.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Ndiaye JL, Tine RC, Faye B, Dieyeel HL, Diack PA, Lameyre V, Gaye O, Sow HD. Pilot feasibility study of an emergency paediatric kit for intra-rectal quinine administration used by the personnel of community-based health care units in Senegal. Malar J. 2007;6:152. doi: 10.1186/1475-2875-6-152.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Thera MA, Keita F, Sissoko MS, Traore OB, Coulibaly D, Sacko M, Lameyre V, Ducret JP, Doumbo O. Acceptability and efficacy of intra-rectal quinine alkaloids as a pre-transfer treatment of non-per os malaria in peripheral health care facilities in Mopti, Mali. Malar J. 2007;6:68. doi: 10.1186/1475-2875-6-68.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • Esamai F, Tenge CN, Ayuo PO, Ong'or WO, Obala A, Jakait B. A randomized open label clinical trial to compare the efficacy and safety of intravenous quinine followed by oral malarone vs. intravenous quinine followed by oral quinine in the treatment of severe malaria. J Trop Pediatr. 2005;51(1):17–24. doi: 10.1093/tropej/fmh069. [PubMed] [CrossRef] [Google Scholar]
  • Peters W. Antimalarial drug resistance: an increasing problem. Br Med Bull. 1982;38(2):187–192. [PubMed] [Google Scholar]
  • Wernsdorfer WH, Landgraf B, Wiedermann G, Kollaritsch H. Chloroquine resistance of Plasmodium falciparum: a biological advantage? Trans R Soc Trop Med Hyg. 1995;89(1):90–91. doi: 10.1016/0035-9203(95)90672-X. [PubMed] [CrossRef] [Google Scholar]
  • Bjorkman A, Phillips-Howard PA. The epidemiology of drug-resistant malaria. Trans R Soc Trop Med Hyg. 1990;84(2):177–180. doi: 10.1016/0035-9203(90)90246-B. [PubMed] [CrossRef] [Google Scholar]
  • Mayxay M, Barends M, Brockman A, Jaidee A, Nair S, Sudimack D, Pongvongsa T, Phompida S, Phetsouvanh R, Anderson T, White NJ, Newton PN. In vitro antimalarial drug susceptibility and pfcrt mutation among fresh Plasmodium falciparum isolates from the Lao PDR (Laos) Am J Trop Med Hyg. 2007;76(2):245–250.[PMC free article] [PubMed] [Google Scholar]
  • Legrand E, Volney B, Meynard JB, Mercereau-Puijalon O, Esterre P. In vitro monitoring of Plasmodium falciparum drug resistance in French Guiana: a synopsis of continuous assessment from 1994 to 2005. Antimicrob Agents Chemother. 2008;52(1):288–298. doi: 10.1128/AAC.00263-07.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121651/
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Quinine

Not to be confused with quinidine, quinone, quinoline, chloroquine, or Quinine (album).

medication used to treat malaria and babesiosis

Quinine structure.svg
Quinine-3D-balls.png
Pronunciation, or KWIN-een
Trade namesQualaquin, Quinbisul, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa682322
License data
Pregnancy
category
Routes of
administration
By mouth, intramuscular, intravenous, rectal
ATC code
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
Protein binding70–95%[3]
MetabolismLiver (mostly CYP3A4 and CYP2C19-mediated)
Elimination half-life8–14 hours (adults), 6–12 hours (children)[3]
ExcretionKidney (20%)

IUPAC name

  • (R)-(6-Methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol

CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.004.550Edit this at Wikidata
FormulaC20H24N2O2
Molar mass324.424 g·mol−1
3D model (JSmol)
Melting point177 °C (351 °F)

SMILES

InChI

  • InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1 checkY
  • Key:LOUPRKONTZGTKE-WZBLMQSHSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Quinine is a medication used to treat malaria and babesiosis.[4] This includes the treatment of malaria due to Plasmodium falciparum that is resistant to chloroquine when artesunate is not available.[4][5] While sometimes used for nocturnal leg cramps, quinine is not recommended for this purpose due to the risk of serious side effects.[4] It can be taken by mouth or intravenously.[4] Malaria resistance to quinine occurs in certain areas of the world.[4] Quinine is also the ingredient in tonic water that gives it its bitter taste.[6]

Common side effects include headache, ringing in the ears, trouble seeing, and sweating.[4] More severe side effects include deafness, low blood platelets, and an irregular heartbeat.[4] Use can make one more prone to sunburn.[4] While it is unclear if use during pregnancy causes harm to the baby, treating malaria during pregnancy with quinine when appropriate is still recommended.[4] Quinine is an alkaloid, a naturally occurring chemical compound.[4] How it works as a medicine is not entirely clear.[4]

Quinine was first isolated in 1820 from the bark of a cinchona tree, which is native to Peru.[4][7][8] Bark extracts had been used to treat malaria since at least 1632 and it was introduced to Spain as early as 1636 by Jesuit missionaries from the New World.[9] It is on the World Health Organization's List of Essential Medicines.[10]

Uses[edit]

Medical[edit]

As of 2006, quinine is no longer recommended by the World Health Organization (WHO) as a first-line treatment for malaria, because there are other substances that are equally effective with fewer side effects. They recommend that it be used only when artemisinins are not available.[11][12][13][14] Quinine is also used to treat lupus and arthritis.

Quinine was frequently prescribed as an off-label treatment for leg cramps at night, but this has become less common due to a warning from the US Food and Drug Administration (FDA) that such practice is associated with life-threatening side effects.[15][16][17]

Available forms[edit]

Quinine is a basic amine and is usually provided as a salt. Various existing preparations include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin.

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR).[18][19] The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a further half dose. No injectable preparation of quinine is licensed in the US; quinidine is used instead.[20][21]

Name Quinine base equivalence
Quinine base 100 mg
Quinine bisulfate 169 mg
Quinine dihydrochloride 122 mg
Quinine gluconate 160 mg
Quinine hydrochloride 111 mg
Quinine sulfate dihydrate [(quinine)2H2SO4∙2H2O] 121 mg

Beverages[edit]

Quinine is a flavor component of tonic water and bitter lemondrink mixers. On the soda gun behind many bars, tonic water is designated by the letter "Q" representing quinine.[22]

According to tradition, because of the bitter taste of anti-malarial quinine tonic, British colonials in India mixed it with gin to make it more palatable, thus creating the gin and tonic cocktail, which is still popular today.[23]

In France, quinine is an ingredient of an apéritif known as quinquina, or "Cap Corse," and the wine-based apéritifDubonnet. In Spain, quinine (also known as "Peruvian bark" for its origin from the native cinchona tree) is sometimes blended into sweet Malaga wine, which is then called "Malaga Quina". In Italy, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs, and is served as a digestif. In Scotland, the company A.G. Barr uses quinine as an ingredient in the carbonated and caffeinated beverageIrn-Bru. In Uruguay and Argentina, quinine is an ingredient of a PepsiCo tonic water named Paso de los Toros. In Denmark, it is used as an ingredient in the carbonated sports drink Faxe Kondi made by Royal Unibrew.

As a flavouring agent in drinks, quinine is limited to less than 83 parts per million in the United States, and 100 mg⁄l in the European Union.[24][25][26]

Scientific[edit]

Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation as well as for numerous other chiral catalyst backbones. Because of its relatively constant and well-known fluorescencequantum yield, quinine is used in photochemistry as a common fluorescence standard.[27][28]

Contraindications[edit]

Because of the narrow difference between its therapeutic and toxic effects, quinine is a common cause of drug-induced disorders, including thrombocytopenia and thrombotic microangiopathy.[29] Even from minor levels occurring in common beverages, quinine can have severe adverse effects involving multiple organ systems, among which are immune system effects and fever, hypotension, hemolytic anemia, acute kidney injury, liver toxicity, and blindness.[29] In people with atrial fibrillation, conduction defects, or heart block, quinine can cause heart arrhythmias, and should be avoided.[30]

Quinine can cause hemolysis in G6PD deficiency (an inherited deficiency), but this risk is small and the physician should not hesitate to use quinine in people with G6PD deficiency when there is no alternative.[31]

Adverse effects[edit]

Quinine can cause unpredictable serious and life-threatening blood and cardiovascular reactions including low platelet count and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), long QT syndrome and other serious cardiac arrhythmias including torsades de pointes, blackwater fever, disseminated intravascular coagulation, leukopenia, and neutropenia.[4] Some people who have developed TTP due to quinine have gone on to develop kidney failure.[4][31] It can also cause serious hypersensitivity reactions including anaphylactic shock, urticaria, serious skin rashes, including Stevens–Johnson syndrome and toxic epidermal necrolysis, angioedema, facial edema, bronchospasm, granulomatous hepatitis, and itchiness.[4][31]

The most common adverse effects involve a group of symptoms called cinchonism, which can include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception.[4][29][31] More severe cinchonism includes vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in heart rhythms.[31] Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many people will vomit after ingesting quinine tablets).[4] Other drugs, such as Fansidar (sulfadoxine with pyrimethamine) or Malarone (proguanil with atovaquone), are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless,[32] but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Quinine has diverse unwanted interactions with numerous prescription drugs, such as potentiating the anticoagulant effects of warfarin.[4]

Mechanism of action[edit]

Quinine is used for its toxicity to the malarial pathogen, Plasmodium falciparum, by interfering with the parasite's ability to dissolve and metabolize hemoglobin.[4][33] As with other quinoline antimalarial drugs, the precise mechanism of action of quinine has not been fully resolved, although in vitro studies indicate it inhibits nucleic acid and protein synthesis, and inhibits glycolysis in P. falciparum.[4] The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoinbiocrystallization in the heme detoxification pathway, which facilitates the aggregation of cytotoxicheme.[medical citation needed] Free cytotoxic heme accumulates in the parasites, causing their deaths.[34] Quinine may target the malaria purine nucleoside phosphorylase enzyme.[35]

Chemistry[edit]

The UV absorption of quinine peaks around 350 nm (in UVA). Fluorescent emission peaks at around 460 nm (bright blue/cyan hue).[36] Quinine is highly fluorescent (quantum yield ~0.58) in 0.1 Msulfuric acid solution.[27][28] The 3D structure of quinine can be viewed using QRChem.net.

Synthesis[edit]

Main article: quinine total synthesis

Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure during World War II, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering.[37] Since then, several more efficient quinine total syntheses have been achieved,[38] but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organicdye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

Biosynthesis[edit]

In the first step of quinine biosynthesis, the enzyme strictosidine synthase catalyzes a stereoselective Pictet–Spengler reaction between tryptamine and secologanin to yield strictosidine.[39][40] Suitable modification of strictosidine leads to an aldehyde. Hydrolysis and decarboxylation would initially remove one carbon from the iridoid portion and produce corynantheal. Then the tryptamine side-chain were cleaved adjacent to the nitrogen, and this nitrogen was then bonded to the acetaldehyde function to yield cinchonaminal. Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The new quinoline heterocycle would then be formed by combining this amine with the aldehyde produced in the tryptamine side-chain cleavage, giving cinchonidinone. For the last step, hydroxylation and methylation gives quinine.[41][42]

History[edit]

See also: History of malaria

19th-century illustration of Cinchona calisaya

Quinine was used as a muscle relaxant by the Quechua people, who are indigenous to Peru, Bolivia and Ecuador, to halt shivering.[43] The Quechua would mix the ground bark of cinchona trees with sweetened water to offset the bark's bitter taste, thus producing something similar to tonic water.[44]

Spanish Jesuit missionaries were the first to bring cinchona to Europe. The Spanish had observed the Quechua's use of cinchona and were aware of the medicinal properties of cinchona bark by the 1570s or earlier: Nicolás Monardes (1571) and Juan Fragoso (1572) both described a tree, which was subsequently identified as the cinchona tree, whose bark was used to produce a drink to treat diarrhea.[45] Quinine has been used in unextracted form by Europeans since at least the early 17th century.[46]

A popular story of how it was brought to Europe by the Countess of Chinchon was debunked by medical historian Alec Haggis around 1941.[47] During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. It had caused the deaths of several popes, many cardinals and countless common Roman citizens. Most of the Catholic priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the febrile phase of the disease.

The Jesuit Agostino Salumbrino (1564–1642),[48] an apothecary by training who lived in Lima (now in present-day Peru), observed the Quechua using the bark of the cinchona tree to treat such shivering. While its effect in treating malaria (and malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment.[49] In the years that followed, cinchona bark, known as Jesuit's bark or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When King Charles II was cured of malaria at the end of the 17th Century with quinine, it became popular in London.[50] It remained the antimalarial drug of choice until the 1940s, when other drugs took over.[51]

The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737.[52][53] In 1820, French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou first isolated quinine from the bark of a tree in the genus Cinchona – probably Cinchona officinalis – and subsequently named the substance.[54] The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina, which means "bark of bark" or "holy bark". Prior to 1820, the bark was dried, ground to a fine powder, and mixed into a liquid (commonly wine) in order to be drunk. Large-scale use of quinine as a malaria prophylaxis started around 1850. In 1853 Paul Briquet published a brief history and discussion of the literature on "quinquina".[55]

Quinine played a significant role in the colonization of Africa by Europeans. The availability of quinine for treatment had been said to be the prime reason Africa ceased to be known as the "white man's grave". A historian said, "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa".[56]

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings in the early 19th century. The Dutch government persisted in its attempts to smuggle the seeds, and by the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the tree. In 1913 they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production.[57] By the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world's quinine production.[56] U.S. attempts to prosecute the Kina Bureau proved unsuccessful.[57]

During World War II, Allied powers were cut off from their supply of quinine when Germany conquered the Netherlands, and Japan controlled the Philippines and Indonesia. The US had obtained four million cinchona seeds from the Philippines and began operating cinchona plantations in Costa Rica. Additionally, they began harvesting wild cinchona bark during the Cinchona Missions. Such supplies came too late. Tens of thousands of US troops in Africa and the South Pacific died of malaria due to the lack of quinine.[56] Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result.[58][59][60][61]

Quinine remained the antimalarial drug of choice until after World War II. Since then, other drugs that have fewer side effects, such as chloroquine, have largely replaced it.[62]

Bromo Quinine were brand namecold tablets containing quinine, manufactured by Grove Laboratories. They were first marketed in 1889 and available until at least the 1960s.[63]

Conducting research in central Missouri, Dr. John S. Sappington independently developed an anti-malaria pill from quinine. Sappington began importing cinchona bark from Peru in 1820. In 1832, using quinine derived from the cinchona bark, Sappington developed a pill to treat a variety of fevers, such as scarlet fever, yellow fever, and influenza in addition to malaria. These illnesses were widespread in the Missouri and Mississippi valleys. He manufactured and sold "Dr. Sappington's Anti-Fever Pills" across Missouri. Demand became so great that within three years, Dr. Sappington founded a company known as Sappington and Sons to sell his pills nationwide.[64]

Society and culture[edit]

Natural occurrence[edit]

The bark of Remijia contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona. As it has an intense taste, it is used for making tonic water.[65]

Regulation in the US[edit]

From 1969, to 1992, the US Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death.[66] In 1994, the FDA banned the marketing of over-the-counter quinine as a treatment for nocturnal leg cramps. PfizerPharmaceuticals had been selling the brand name Legatrin for this purpose. Also sold as a Softgel (by SmithKlineBeecham) as Q-vel.[citation needed] Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps.[15][16] Quinine is approved for treatment of malaria, but was also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that affliction.[67]

Though Legatrin was banned by the FDA for the treatment of leg cramps, the drug manufacturer URL Mutual has branded a quinine-containing drug named Qualaquin. It is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States.[68]

Cutting agent[edit]

Quinine is sometimes detected as a cutting agent in street drugs such as cocaine and heroin.[69]

Other animals[edit]

Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium fish.[70]

References[edit]

  1. ^"Quinine International". Drugs.com. 2 November 2020. Retrieved 8 November 2020.
  2. ^ ab"Quinine Use During Pregnancy". Drugs.com. 25 March 2020. Retrieved 13 August 2020.
  3. ^ ab"Qualaquin (quinine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 2 February 2014. Retrieved 29 January 2014.
  4. ^ abcdefghijklmnopqrst"Quinine sulfate". Drugs.com. 20 February 2020. Retrieved 14 May 2020.
  5. ^Esu EB, Effa EE, Opie ON, Meremikwu MM (June 2019). "Artemether for severe malaria". The Cochrane Database of Systematic Reviews. 6: CD010678. doi:10.1002/14651858.CD010678.pub3. PMC 6580442. PMID 31210357.
  6. ^Olmsted J, Williams GM (1997). Chemistry: The Molecular Science. Jones & Bartlett Learning. p. 137. ISBN . Archived from the original on 15 September 2016.
  7. ^Willcox M (28 June 2004). Traditional Medicinal Plants and Malaria. CRC Press. p. 231. ISBN .
  8. ^Cechinel-Filho V (2012). Plant bioactives and drug discovery : principles, practice, and perspectives. Hoboken, N.J.: John Wiley & Sons. p. 2. ISBN . Archived from the original on 4 March 2016.
  9. ^Staines HM, Krishna S (2011). Treatment and Prevention of Malaria : Antimalarial Drug Chemistry, Action and Use. [S.l.]: Springer Verlag. p. 45. ISBN .
  10. ^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ^World Health Organization (2006). "Guidelines for the treatment of malaria"(PDF). World Health Organization. Archived from the original(PDF) on 5 August 2009. Retrieved 10 August 2009.
  12. ^Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005). "Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial". Lancet. 366 (9487): 717–25. doi:10.1016/S0140-6736(05)67176-0. PMID 16125588. S2CID 173027.
  13. ^Reyburn H, Mtove G, Hendriksen I, von Seidlein L (July 2009). "Oral quinine for the treatment of uncomplicated malaria"(PDF). BMJ. 339: b2066. doi:10.1136/bmj.b2066. PMID 19622550. S2CID 206891479.
  14. ^Achan J, Tibenderana JK, Kyabayinze D, Wabwire Mangen F, Kamya MR, Dorsey G, D'Alessandro U, Rosenthal PJ, Talisuna AO (July 2009). "Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial". BMJ. 339: b2763. doi:10.1136/bmj.b2763. PMC 2714631. PMID 19622553.
  15. ^ ab"FDA Drug Safety Communication: New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate)". U.S. Food and Drug Administration (FDA). 7 August 2010. Archived from the original on 19 February 2011. Retrieved 21 February 2011.
  16. ^ ab"Serious risks associated with using Quinine to prevent or treat nocturnal leg cramps (September 2012)". U.S. Food and Drug Administration (FDA). 31 August 2012. Archived from the original on 22 October 2016. Retrieved 19 January 2020.
  17. ^"Quinine for Night-Time Leg Cramps". Consumer Reports. Retrieved 20 January 2020.
  18. ^Barennes H, Pussard E, Mahaman Sani A, Clavier F, Kahiatani F, Granic G, Henzel D, Ravinet L, Verdier F (May 1996). "Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria". British Journal of Clinical Pharmacology. 41 (5): 389–95. doi:10.1046/j.1365-2125.1996.03246.x. PMC 2042609. PMID 8735679.
  19. ^Barennes H, Balima-Koussoubé T, Nagot N, Charpentier JC, Pussard E (May 2006). "Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial". BMJ. 332 (7549): 1055–9. doi:10.1136/bmj.332.7549.1055. PMC 1458599. PMID 16675812.
  20. ^Centers for Disease Control and Prevention (April 1991). "Treatment with quinidine gluconate of persons with severe Plasmodium falciparum infection: discontinuation of parenteral quinine from CDC Drug Service". MMWR. Recommendations and Reports. 40 (RR-4): 21–3. PMID 1850497.
  21. ^Magill A, Panosian C (July 2005). "Making antimalarial agents available in the United States". The New England Journal of Medicine. 353 (4): 335–7. doi:10.1056/NEJMp058167. PMID 16000347.
  22. ^Charming C (2006). Miss Charming's Guide for Hip Bartenders and Wayout Wannabes. USA: Sourcebooks, Inc. p. 189. ISBN .
  23. ^"Gin and Tonic: The fascinating story behind the invention of the classic English cocktail". India.com. 17 March 2017. Retrieved 8 June 2019.
  24. ^Ballestero JA, Plazas PV, Kracun S, Gómez-Casati ME, Taranda J, Rothlin CV, Katz E, Millar NS, et al. (September 2005). "Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors". Molecular Pharmacology. 68 (3): 822–9. doi:10.1124/mol.105.014431. PMID 15955868. S2CID 26907917.
  25. ^"Food Additive Status List". U.S. Food and Drug Administration. U.S. Department of Health and Human Services. Retrieved 9 October 2017.
  26. ^"COMMISSION IMPLEMENTING REGULATION (EU) No 872/2012". EUR-Lex. Official Journal of the European Union. Retrieved 9 October 2017.
  27. ^ abLakowicz, Joseph R. (2006). "2. Instrumentation for Fluorescence Spectroscopy". Principles of Fluorescence Spectroscopy (3rd ed.). Springer Science & Business Media. p. 54. ISBN .
  28. ^ abPrahl, Scott. "Quinine sulfate". OMLC. Retrieved 16 August 2013.
  29. ^ abcLiles NW, Page EE, Liles AL, Vesely SK, Raskob GE, George JN (May 2016). "Diversity and severity of adverse reactions to quinine: A systematic review". American Journal of Hematology. 91 (5): 461–6. doi:10.1002/ajh.24314. PMID 26822544.
  30. ^"Off-label use of sildenafil in valvular heart disease should be avoided". Clinical Pharmacist. 2017. doi:10.1211/cp.2017.20203778. ISSN 2053-6178.
  31. ^ abcde"US label: quinine sulfate"(PDF). FDA. April 2013. Archived(PDF) from the original on 20 January 2017.
  32. ^Jamaludin A, Mohamad M, Navaratnam V, Selliah K, Tan SC, Wernsdorfer WH, Yuen KH (February 1988). "Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine". British Journal of Clinical Pharmacology. 25 (2): 261–3. doi:10.1111/j.1365-2125.1988.tb03299.x. PMC 1386482. PMID 3358888.
  33. ^Wishart, David S.; Djombou Feunang, Yannick; Guo, An Chi; Lo, Elvis J.; Marcu, Ana; Grant, Jason R.; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael. "Quinine | DrugBank Online". DrugBank. 5.0.
  34. ^Foley M, Tilley L (February 1997). "Quinoline antimalarials: mechanisms of action and resistance". International Journal for Parasitology. 27 (2): 231–40. doi:10.1016/s0020-7519(96)00152-x. PMID 9088993.
  35. ^Lowe D (22 January 2019). "Quinine's Target". Science. Retrieved 28 January 2019.
  36. ^"Basic Concepts in Fluorescence". Archived from the original on 13 September 2012.
  37. ^Woodward R, Doering W (1944). "The Total Synthesis of Quinine". J Am Chem Soc. 66 (849): 849. doi:10.1021/ja01233a516.
  38. ^Kaufman TS, Rúveda EA (2005). "Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege". Angewandte Chemie International Edition (in German). 117 (6): 876–907. doi:10.1002/ange.200400663.
  39. ^Treimer JF, Zenk MH (November 1979). "Purification and properties of strictosidine synthase, the key enzyme in indole alkaloid formation". European Journal of Biochemistry. 101 (1): 225–33. doi:10.1111/j.1432-1033.1979.tb04235.x. PMID 510306.
  40. ^Mizukami H, Nordlöv H, Lee SL, Scott AI (August 1979). "Purification and properties of strictosidine synthetase (an enzyme condensing tryptamine and secologanin) from Catharanthus roseus cultured cells". Biochemistry. 18 (17): 3760–3. doi:10.1021/bi00584a018. PMID 476085.
  41. ^Medicinal natural products : a biosynthetic approach (3rdition ed.). Wiley. pp. 380–381. ISBN .
  42. ^O'Connor SE, Maresh JJ (August 2006). "Chemistry and biology of monoterpene indole alkaloid biosynthesis". Natural Product Reports. 23 (4): 532–47. doi:10.1039/b512615k. PMID 16874388.
  43. ^Flückiger, Friedrick A.; Daniel, Hanbury (1874). "Cortex Cinchonæ". Pharmacographia: A History of the Principal Drugs of Vegetable Origin, Met with in Great Britain and British India. London: Macmillan and Co. pp. 302–331.
  44. ^Hobbs K, West D (2020). The Story of Trees : and how they changed the way we live. illustrated by Thibaud Hérem. London: Laurence King. p. 148. ISBN .
  45. ^See:
    • Ortiz Crespo, Fernando Ignacio (1995). "Fragoso, Monardes and pre-Chinchonian knowledge of Cinchona". Archives of Natural History. 22 (2): 169–181. doi:10.3366/anh.1995.22.2.169. ISSN 0260-9541.
    • Stuart, David C. (2004). Dangerous Garden: The Quest for Plants to Change Our Lives. Cambridge, MA: Harvard University Press. p. 28. ISBN .
    • Monardes, Nicolás (1580). Primera y segunda y tercera partes de la Historia medicinal, de las cosas que se traen de nuestras Indias Occidentales, que sirven en Medicina (in Spanish). Seville, Spain: Fernando Díaz. pp. 74–75. [From the new kingdom, there is brought a bark, which is said to be from a tree, which is very large: it is said that it bears leaves in the form of a heart, and that it bears no fruit. This tree has a thick bark, very solid and hard, that in this and in its color looks much like the bark of the tree that is called guayacán: on the surface, it has a thin, discontinuous whitish film throughout it: it has bark more than one finger thick, solid and heavy: which, when tasted, has a considerable bitterness, like that of the gentian: it has in its taste a considerable astringency, with some aromaticity, because at the end of chewing it, one breathes with a sweet odor. The Indians hold this bark in high regard, and use it for all sorts of diarrhea, that are with blood [i.e., bloody] and without it. The Spanish [who are] tired of this disease, on the advice of the Indians, have used this bark and have healed many of those with it. They take as much as a small bean, make [it into] powder, take it in red wine or in appropriate water, if they have fever or illness: it must be taken in the morning on an empty stomach, three or four times: otherwise, using the order and regimen that suits those who have diarrhea.]
    • Fragoso, Juan (1572). Discursos de las cosas aromaticas, arboles y frutales, y de otras muchas medicinas simples que se traen de la India Oriental y que sirven al uso de medicina [Discourse on fragrant things, trees and fruits, as well as many other ordinary medicines that have been brought from India and the Orient and are of use to medicine] (in Spanish). Madrid, Spain: Francisco Sánchez. p. 35. [In the new world, there is a big tree that bears leaves in the form of a heart, and lacks fruit. It has two barks, one [is] thick, very solid, [and] hard, which in substance as well as in color is much like guayacan [i.e., lignum vitae]: the other is thinner and whitish, which is bitter with some styptic [i.e., astringent] quality: and besides this, it is aromatic. Our Indians regard it highly, because they use it against any diarrheas, taking a weight of a dram or a bit more of the powder, mixing it in mineral water, or red wine.]
  46. ^Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U (May 2011). "Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria". Malaria Journal. 10: 144. doi:10.1186/1475-2875-10-144. PMC 3121651. PMID 21609473.
  47. ^Stephanie Pain (15 September 2001). "The Countess and the cure". New Scientist.
  48. ^Alonso de Andrade (3 August 1642). "Vida del Devoto Hermano Agustin Salumbrino" [The life of the devout Brother Agustin Salumbrino]. Varones ilustres en santidad, letras y zelo de las almas de la Compañía de Jesús [Illustrious men in holiness, letters, and zeal for souls of the Society of Jesus]. Varones ilustres de la Compañía de Jesús (in Spanish). 5. Original series by Juan Eusebio Nieremberg. Madrid, Spain: José Fernandez de Buendía (published 1666). pp. 612–628. p. 612: [Brother Agustino Salumbrino was born in the year 1564 in the city of Forlì in Romagna]
  49. ^See:
    • Medina Rodríguez, Francisco; Aceves Ávila, Francisco Javier; Moreno Rodríguez, José (2007). "Precisions on the History of Quinine". Reumatología Clínica. Letters to the Editor. 3 (4): 194–196. doi:10.1016/S2173-5743(07)70246-0. ISSN 2173-5743.
    • Torres Saldamando, Enrique (June 1882). "El P. Diego de Torres Vazquez". Los antiguos jesuitas del Perú (in Spanish). Lima, Peru: Imprenta Liberal. pp. 180–181. p. 181: [In the following year [i.e., 1631] there went to Europe the procurators Father Alonso Messia Venegas and Father Hernando de Leon Garavito, taking a great quantity of cinchona bark, knowledge of which the Jesuits spread throughout the world.]
    • Bailetti, Alberto. "Capítulo 10: La Condesa de Chinchón". LA MISIÓN DEL JESUITA AGUSTÍN SALUMBRINO, la malaria y el árbol de quina. [Late in the afternoon of the 31st of May, 1631, the royal armada set sail in the direction of Panama, carrying its multimillion [dollar] cargo of gold and silver.
      On one of the ships traveled the Jesuit procurators Fathers Alonso Messia and Hernando León Garavito, guarding the cases of powdered cinchona bark, prepared by Salumbrino. After almost 20 days of sailing, medicine arrived in the city of Panama, where it was transloaded onto mules. It then traveled the malarial isthmus as far as Portobelo, thence to Cartagena [in Colombia] and Havana. It then traveled to Sanlúcar de Barrameda in Seville, [Spain]. […] Finally it followed the road to Rome and to its final destination, the Hospital of the Holy Spirit]
  50. ^Rocco F (2004). Quinine: malaria and the quest for a cure that changed the world. New York, NY: Perennial.
  51. ^Loren H (2000). Quinine and Quarantine.
  52. ^Charles Marie de la Condamine (29 May 1737). "Sur l'arbre du quinquina". Histoire de l'Académie royale des sciences. Imprimerie Royale (published 1740). pp. 226–243.
  53. ^De Jussieu accompanied de la Condamine on the latter's expedition to Peru: Joseph de Jussieu (1737). Description de l'arbre à quinquina. Paris: Société du traitement des quinquinas (published 1934).
  54. ^Pelletier PJ, Caventou JB (1820). "Recherches Chimiques sur les Quinquinas" [Continuation: Chemical Research on Quinquinas]. Annales de Chimie et de Physique (in French). Crochard. 15: 337–365. The authors name quinine on page 348: " …, nous avons cru devoir la nommer quinine, pour la distinguer de la cinchonine par un nom qui indique également son origine." ( …, we thought that we should name it "quinine" in order to distinguish it from cinchonine by means of a name that also indicates its origin.)
  55. ^Briquet, P. (1853). Traité thérapeutique du quinone et de ses préparations (in French). Paris: L. Martinet.
  56. ^ abcConner, Clifford D. (2005). A People's History of Science: Miners, Midwives, and 'Low Mechanicks'. New York: Nation Books. pp. 95–96. ISBN . Also cites Porter, Roy (1998). The Greatest Benefit to Mankind: A Medical History of Humanity. New York: W. W. Norton. pp. 465–466. ISBN .
  57. ^ abShah S (2010). The Fever: How Malaria Has Ruled Humankind for 500,000 Years. Farrar, Straus and Giroux. p. 94.
  58. ^Louis Morton (1953). "29". The Fall of the Philippines. Washington, D.C.: United States Army. p. 524. Archived from the original on 25 May 2017.
  59. ^Alan Hawk. "Remembering the war in New Guinea: Japanese Medical Corps – malaria". Archived from the original on 22 November 2011.
  60. ^Lt. Gen. Leonard D. Heaton, ed. (1963). "8". Preventive Medicine in World War II: Volume VI, Communicable Diseases: Malaria. Washington, D.C.: Department of the Army. pp. 401 and 434. Archived from the original on 29 January 2012.
  61. ^"Notes on Japanese Medical Services". Tactical and Technical Trends (36). 1943. Archived from the original on 14 October 2011.
  62. ^Shah S (2010). The Fever: How Malaria Has Ruled Humankind for 500,000 Years. Farrar, Straus and Giroux. p. 102.
  63. ^"Medicine: What's Good for a Cold?". Time. 22 February 1960. Archived from the original on 26 July 2010. Retrieved 27 April 2010.
  64. ^"John. S Sappington". Historic Missourians. State Historical Society of Missouri.
  65. ^Hobhouse H (2004). Šest rostlin, které změnily svět (in Czech). Prague: Akademie věd České republiky. p. 59. ISBN .
  66. ^"FDA Orders Stop to Marketing of Quinine for Night Leg Cramps". FDA Consumer Magazine. U.S. Food and Drug Administration (FDA). July–August 1995. Archived from the original on 15 January 2008. Retrieved 31 July 2009.
  67. ^"FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps" (Press release). U.S. Food and Drug Administration (FDA). 11 December 2006. Archived from the original on 28 July 2009. Retrieved 31 July 2009.
  68. ^Skarbinski J, James EM, Causer LM, Barber AM, Mali S, Nguyen-Dinh P, Roberts JM, Parise ME, Slutsker L, Newman RD (May 2006). "Malaria surveillance--United States, 2004"(PDF). MMWR Surveill Summ. 55 (SS-4): 23–37. PMID 16723971.
  69. ^"Microgram Bulletin, DIMETHYLTRYPTAMINE AND ECSTASY MIMIC TABLETS (ACTUALLY CONTAINING 5-METHOXY-METHYLISOPROPYLTRYPTAMINE) IN OREGON"(PDF). U.S. Department of Justice. Drug Enforcement Administration. October 2009. p. 79. Archived from the original(PDF) on 17 October 2012. Retrieved 22 September 2012.
  70. ^Porritt, Michael. "Cryptocaryon irritans". Reef Culture Magazine (1 ed.). Archived from the original on 24 October 2009. Retrieved 9 July 2009.

Further reading[edit]

  • Schroeder-Lein G (2008). The encyclopedia of Civil War medicine. Armonk, NY: Sharpe, Inc.
  • Hobhouse, Henry (2005) [1986]. Seeds of Change: Six Plants That Transformed Mankind. Berkeley, CA: Counterpoint. ISBN .
  • Stockwell HR (1982). "Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride". Aviation, Space, and Environmental Medicine. 3 (10): 1011–13. PMID 6983345.
  • Wolff RS, Wirtschafter D, Adkinson C (June 1997). "Ocular quinine toxicity treated with hyperbaric oxygen". Undersea & Hyperbaric Medicine. 24 (2): 131–4. PMID 9171472.
  • Slater L (2009). War and disease : biomedical research on malaria in the twentieth century. New Brunswick, NJ: Rutgers University Press.
  • Lloyd, Henry D. (June 1884). "Lords of Industry". The North American Review. University of Northern Iowa. 138 (331): 535–553. ISSN 0029-2397. JSTOR 25118388.
  • World Health Organization (2015). Guidelines for the treatment of malaria, 3rd ed (3rd ed.). World Health Organization (WHO). hdl:10665/162441. ISBN .

External links[edit]

Look up quinine in Wiktionary, the free dictionary.
  • Quinine at the Drug Information Portal
  • Quinine at the International Programme on Chemical Safety
Sours: https://en.wikipedia.org/wiki/Quinine
Talking health: Quinine

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