Quinine for the treatment of malaria in pregnancy
... It has not yet shown serious resistance problems (Parquet, et al., 2010), but it has a bitter taste, side effects are common (NA 2004, p. 291), and requires a 7-day course of treatment. Its continued use in Africa as a monotherapy has recently been debated (Yeka et al. 2009; Barennes et al. 2010;Chico et al. 2010). (Also see: ...
... A recent study in Zambia is reported in . It has also been suggested that quinine might play a role in combination therapies with azithomycin for uncomplicated malaria throughout pregnancy (see Chico and Chandramohan 2010; on this combination more generally, see Noedl et al. 2006, Noedl 2009, Barennes et al. 2010 problem has been accentuated in the case of artemisinin-based drugs, in part due to their cost, shelf life, and the extent to which they essentially take the form of a monotherapy and thereby -paradoxically -threaten the efficacy of ACTs. Artemisinin is necessary, but is not sufficient by itself; the correct combination is essential. ...
The key ingredient in the leading treatment for malaria in Africa -artemisinin -comes not from high-tech research, but is an extract of an ancient medicinal plant, Artemisia annua, commonly known as Artemisia. Chloroquine and replacement drugs have lost effectiveness with the development of resistance and have increasingly been replaced by derivatives of artemisinin combined with other drugs. Known as artemisinin–based combination therapies (ACTs), they provide the most effective treatment at present. This has led to efforts to increase cultivated production of Artemisia in the short run and to develop, through biological and chemical research, synthetic substitutes in the longer run. The resulting juxtaposition of activities and players provides both opportunities and challenges for society. While individual components have been examined, there is little in the way of comprehensive analysis. This paper attempts to weave the many complex and dynamic components -historical, scientific, technical, economic -together in order to aid understanding of the issues and facilitate development of informed public/private policies and actions. Although focused on Africa, the main components and issues are global in nature and resolution and relate to more general issues in infectious disease control and economic development., I have continued work on the paper as a personal effort and may be contacted at dana.dalrymple@verizon.net. The views expressed are my own and not necessarily those of USAID. Mention of commercial firms and products does not imply endorsement. This is a revision and update of he December 10, 2009 version of the paper which was posted on the Medicines for Malaria Venture website [www.mmv.org/research-development/optimizing-artemisinin-production/related-publications].
... [30] [31] Tocolytic effects of quinine are discussed, thus the drug is contraindicated during pregnancy for treatment of cramps according to European summaries of product characteristics. [32] [33] However, quinine is a low-dosed ingredient of beverages such as tonic water. [34] Considering the contraindication , the prescription numbers, and the frequency of detection, it is most likely that the consumption of certain beverages is the reason for the detection of quinine and the corresponding metabolites in the urine samples. ...
Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so-called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. Copyright © 2014 John Wiley & Sons, Ltd.
Introduction:
In an era of increasing parasite drug resistance, the WHO has updated treatment recommendations for falciparum malaria including those for pregnant women. This review assesses the evidence for choice of treatment across pregnancy.
Areas covered:
Relevant studies, primarily those published since 2010, were identified from the main reference databases and were used to identify secondary data sources. Expert commentary: Intravenous artesunate is first-line treatment for severe malaria with maternal survival the priority, but intramuscular artesunate/artemether and parenteral quinine are alternatives. First-line treatment for uncomplicated malaria in the first trimester is quinine-clindamycin. Artemisinin combination therapy (ACT) may be promoted from second-line treatment should more reassuring fetal safety data become available but is first-line therapy for uncomplicated falciparum malaria during the second/third trimesters. Because fear of adverse outcomes has often excluded pregnant women from conventional drug development, tolerability, safety and efficacy data for novel therapies are usually based on preclinical studies and cases of inadvertent exposure. Requisite pharmacokinetic studies and clinical trials are usually done relatively late. Changes in antimalarial drug disposition in pregnancy have been observed but have not yet translated into specific treatment recommendations. Such targeted regimens may become important as parasite resistance demands that drug exposure is optimized.
Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower
drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance.
The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation
was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin
and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients.
Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150)
ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with
appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with
current antimalarial dosing regimens.
Clinical trials from the 1970s and 1980s have shown the efficacy, safety, and practicability of the treatment of Plasmodium falciparum malaria with clindamycin. Two reviews from the early 1990s have summarized these studies in detail (24, 25). Since then, interest in clindamycin as an antimalarial has renewed and a number of recent clinical trials have evaluated clindamycin, both alone and as a partner in a combination, as a treatment for malaria.
This minireview summarizes the data on the drug, with special attention given to developments during the last 10 years. Since no studies with animals and few in vitro studies have been published since publication of the last review, this minireview will concentrate on human clinical trials.
Azithromycin has demonstrated in vitro and in vivo activity against Plasmodium falciparum, but small treatment studies have given mixed results.
Participants with fever and with both a blood smear and a rapid diagnostic test positive for falciparum malaria were randomly assigned to groups that were treated with either azithromycin or chloroquine or to matched groups receiving a placebo. After an interim analysis, open-label combination therapy with both drugs was initiated.
At day 28, 5 (33%) of 15 participants in the azithromycin-treated group had remained free of fever, compared with 4 (27%) of 15 in the chloroquine-treated group. All subsequently enrolled participants then received combination therapy with azithromycin and chloroquine. In 61 (97%) of 67 participants, resolution of fever and parasitemia had occurred by day 7, and, through day 28, no clinical or parasitologic relapse had occurred in them.
Resolution of parasitemia was inadequate with monotherapy with either azithromycin or chloroquine, but combination therapy provided substantially improved clinical and parasitologic outcomes. The combination of azithromycin and chloroquine may be an effective alternative treatment for falciparum malaria and deserves further study.
In 1993, Malawi became the first country in Africa to replace chloroquine with the combination of sulfadoxine and pyrimethamine for the treatment of malaria. At that time, the clinical efficacy of chloroquine was less than 50%. The molecular marker of chloroquine-resistant falciparum malaria subsequently declined in prevalence and was undetectable by 2001, suggesting that chloroquine might once again be effective in Malawi.
We conducted a randomized clinical trial involving 210 children with uncomplicated Plasmodium falciparum malaria in Blantyre, Malawi. The children were treated with either chloroquine or sulfadoxine\#8211;pyrimethamine and followed for 28 days to assess the antimalarial efficacy of the drug.
In analyses conducted according to the study protocol, treatment failure occurred in 1 of 80 participants assigned to chloroquine, as compared with 71 of 87 participants assigned to sulfadoxine\#8211;pyrimethamine. The cumulative efficacy of chloroquine was 99% (95% confidence interval [CI], 93 to 100), and the efficacy of sulfadoxine\#8211;pyrimethamine was 21% (95% CI, 13 to 30). Among children treated with chloroquine, the mean time to parasite clearance was 2.6 days (95% CI, 2.5 to 2.8) and the mean time to the resolution of fever was 10.3 hours (95% CI, 8.1 to 12.6). No unexpected adverse events related to the study drugs occurred.
Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi. (ClinicalTrials.gov number, NCT00125489 [ClinicalTrials.gov].).
Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI]=0.77 to 1.08) and 0.78 (95% CI=0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI=2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R=0.53; P=0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R=0.34; P=0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.
Several African countries that have adopted artemisinin-based combination therapy (ACT) as first-line treatment of uncomplicated Plasmodium falciparum malaria also use quinine monotherapy as second-line therapy. This policy goes against WHO recommendations for combination therapy and could be considered an inappropriate public health policy. Adherence to a 7-day quinine treatment schedule is likely to be poor and may increase the risk of selecting resistant parasites. Furthermore, because quinine has limited post-treatment prophylaxis, it will not prevent, in areas of intense transmission, recurrent malaria infections, which can lead to additional morbidity, including anaemia. Therefore, ACTs and not quinine should be used as second-line treatment, because these are well tolerated, highly efficacious, and have the advantage of reducing gametocyte carriage and consequently malaria transmissibility, particularly in areas of less intense transmission.
In areas where multidrug-resistant Plasmodium falciparum (MDR-Pf) is prevalent, only quinine is known to be safe and effective in pregnant women. On the western border of Thailand, 7 days
of supervised quinine (30 mg/kg daily) cures two-thirds of P. falciparum-infected women in the 2nd and 3rd trimesters of pregnancy. Artesunate is effective against MDR-Pf and the limited data on its use in pregnancy suggest it is safe. An open randomized comparison of supervised quinine (10
mg salt/kg every 8 h) in combination with clindamycin (5 mg/kg every 8 h) for 7 days (QC7) versus artesunate 2 mg/kg per day
for 7 days (A7) was conducted in 1997–2000 in 129 Karen women with acute uncomplicated falciparum malaria in the 2nd or 3rd
trimesters of pregnancy. There was no difference in the day-42 cure rates between the QC7 (n = 65) and A7 (n = 64) regimens with an efficacy of 100% in both, confirmed by parasite genotyping. The A7 regimen was also associated with
less gametocyte carriage; the average person-gametocyte-weeks for A7 was 3 (95% CI 0–19) and for QC7 was 39 (95% CI 21–66)
per 1000 person-weeks, respectively (P < 0·01). There was no difference in gastrointestinal symptoms between the groups but there was significantly more tinnitus
in the QC7 group compared to the A7 group (44·9% vs 8·9%; RR 5·1; 95% CI 1·9–13·5; P < 0·001). The favourable results with quinine-clindamycin mean that there is a useful back-up treatment for women with falciparum
malaria who experience quinine and artesunate failures in pregnancy. Adherence to the 7-day regimen and cost (US$ 18·50 per
treatment) are likely to be the main obstacles to this regimen.
Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand 1995–2000). Parasites
were still present on day 6 or 7 in 4·7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance
rate following quinine was 28·7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted
in a high rate of gametocyte carriage: person-gametocyte-weeks = 42·5 (95% CI 27·8–62·1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4·5% (5/111). Significantly more women complained of tinnitus following
quinine treatment compared to on admission: 64·5% (78/121) vs 31·6% (59/187), P < 0·001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy,
17·8% (16·5–19·0), did not differ significantly from rates in women treated with quinine: 22·9% (95% CI 15·5–30·3), or chloroquine:
18·3% (95% CI 9·3–27·3), P = 0·42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality,
stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in
the first trimester of pregnancy.
Azithromycin, the most potent antimalarial macrolide antibiotic, is synergistic with quinine against Plasmodium falciparum in vitro. We assessed combinations of azithromycin and quinine against uncomplicated P. falciparum malaria at the Armed Forces Research Institute of Medical Sciences-Kwai River Clinical Center along the Thailand-Myanmar border, an area with a high prevalence of multidrug-resistant P. falciparum. Four regimens were assessed in an open-label dose-ranging design involving 61 volunteers. All received oral quinine (Q; 30 mg/kg/day divided every 8 hours for 3 days) with oral azithromycin (Az; 500 mg twice a day for 3 days, 500 mg twice a day for 5 days, or 500 mg three times a day for 3 days). A comparator group received quinine and doxycycline (Dx; 100 mg twice a day for 7 days). Study observation was 28 days per protocol. Sixty volunteers completed the study. Seven days of QDx cured 100% of the volunteers. One failure occurred in the lowest QAz regimen (on day 28) and none occurred in either of the two higher Az regimens. Cinchonism occurred in nearly all subjects. Overall, the azithromycin regimens were well tolerated, and no volunteers discontinued therapy. Three- and five-day azithromycin-quinine combination therapy appears safe, well tolerated, and effective in curing drug-resistant P. falciparum malaria. Further evaluation, especially in pediatric and obstetric populations, is warranted.
Azithromycin, an azalide analog of erythromycin was assayed for its in vitro activity against multidrug-resistant Plasmodium falciparum K1 strain by measuring the 3H-hypoxanthine incorporation. Azithromycin caused inhibitory effects on the parasite growth with IC50 and IC90 values of 8.4+/-1.2 microM and 26.0+/-0.9 microM, respectively. Erythromycin inhibited growth of P. falciparum with IC50 and IC90 values of 58.2+/-7.7 microM and 104.0+/-10.8 microM, respectively. The activity of antimalarial drugs in combination with azithromycin or erythromycin against P. falciparum K1 were compared. Combinations of chloroquine with azithromycin or erythromycin showed synergistic effects against parasite growth in vitro. Combinations of quinine-azithromycin and quinine-erythromycin showed potentiation. Additive effects were observed in mefloquine-azithromycin and mefloquine-erythromycin combinations. Similar results were also produced by pyronaridine in combination with azithromycin or erythromycin. However, artesunate-azithromycin and artesunate-erythromycin combinations had antagonistic effects. The in vitro data suggest that azithromycin and erythromycin will have clinical utility in combination with chloroquine and quinine. The worldwide spread of chloroquine-resistant P. falciparum might inhibit the ability to treat malaria patients with chloroquine-azithromycin and chloroquine-erythromycin in areas of drug-resistant. The best drug combinations against multidrug-resistant P. falciparum are quinine-azithromycin and quinine-erythromycin.