Quinine and chloroquine: Potential preclinical candidates for the treatment of tegumentary Leishmaniasis.

Leishmaniasis is an endemic disease in more than 90 countries, constituting a relevant public health problem. Limited treatment options, increase in resistance, and therapeutic failure are important aspects for the discovery of new treatment options. Drug repurposing may accelerate the discovery of antiLeishmanial drugs. Recent tests indicating the in vitro potential of antimalarials Leishmania resulted in the design of this study. This study aimed at evaluating the susceptibility of Leishmania (L.) amazonensis to chloroquine (CQ) and quinine (QN), alone or in combination with amphotericin B (AFT) and pentamidine (PTN). In the in vitro tests, first, we evaluated the growth inhibition of 50 % of promastigotes (IC50) and cytotoxicity for HepG2 and THP-1 cells (CC50). The IC50 values of AFT and PNT were below 1 µM, while the IC50 values of CQ and QN ranged between 4 and 13 µM. Concerning cytotoxicity, CC50 values ranged between 7 and 30 µM for AFT and PNT, and between 22 and 157 µM for the antimalarials. We also calculated the Selectivity Index (SI), where AFT and PTN obtained the highest values, while the antimalarias obtained values between 5 and 12. Both antimalarials were additive (Æ©FIC 1.05-1.8) in combination with AFT and PTN. For anti-amastigote activity, the drugs obtained the following ICA50 values: AFT (0.26 µM), PNT (2.09 µM), CQ (3.77 µM) and QN (24.5 µM). In the in vivo tests, we observed that the effective dose for the death of 50 % of parasites (ED50) of AFT and CQ were 0.63 mg/kg and 27.29 mg/kg, respectively. When combining CQ with AFT, a decrease in parasitemia was observed, being statistically equal to the naive group. For cytokine quantification, it was observed that CQ, despite presenting anti-inflammatory activity was effective at increasing the production of IFN-γ. Overall, our data indicate that chloroquine will probably be a candidate for repurposing and use in drug combination therapy.

Intracellular ROS production and apoptotic effect of quinoline and isoquinoline alkaloids on the growth of Trypanosoma evansi.

Trypanosoma evansi, a hemoflagellate poses huge economic threat to the livestock industry of several countries of Asia, Africa, South America and Europe continents of the world. Limited number of available chemical drugs, incidents of growing drug resistance, and related side effects encouraged the use of herbal substitutes. In the present investigation, the impact of six alkaloids of quinoline and isoquinoline group was evaluated on the growth and multiplication of Trypanosoma evansi and their cytotoxic effect was examined on horse peripheral blood mononuclear cells in an in vitro system. Quinine, quinindine, cinchonine, cinchonidine, berbamine and emetine showed potent trypanocidal activities with IC50/24 h values 6.631 ± 0.244, 8.718 ± 0.081, 16.96 ± 0.816, 33.38 ± 0.653, 2.85 ± 0.065, and 3.12 ± 0.367 µM, respectively, which was comparable to the standard anti-trypanosomal drug, quinapyramine sulfate (20 µM). However, in the cytotoxicity assay, all the drugs showed dose dependent cytotoxic effect and quinine, berbamine and emetine showed selectivity index more than 5, based of ration of CC50 to IC50. Among the selected alkaloids, quinidine, berbamine and emetine exhibited higher apoptotic effects in T. evansi. Likewise, drug treated parasites showed a dose-dependent and time-dependent increase in reactive oxygen species (ROS) production. Therefore, increased apoptosis in combination with ROS generation could be responsible for the observed trypanocidal effect which could be further evaluated in T. evansi-infected mice model.

Quinine overdose: Not quite gin and tonic.

Quinine has been used in Western medicine since the 16th century, and far longer in South America. It has gained an undeserved reputation as an effective treatment for leg cramps and continues to be widely used in the United Kingdom and elsewhere despite warnings from the Medicines and Healthcare products Regulatory Agency (MHRA) and the US Food and Drug Administration (FDA). The effects in overdose are outlined and a personal perspective of scientific investigation of treatments at one time advocated provided.

What Historical Records Teach Us about the Discovery of Quinine.

The origin of quinine from Peru remains a mystery because of the lack of primary data-in particular, those produced by the Jesuits working in Peru. The discovery of cinchona bark and its use in malaria treatment must have come from the Jesuits, who worked with the native Andeans, the Quichuan people, and learned how the bark of the cinchona tree could be used for chills. Unknown is whether the Andean people used it for fever that may have been the result of malaria. We explored the literature of the 1600s, 1700s, and later to trace the history of quinine that is available. All these secondary sources lack the primary data of the Jesuits in their work with native Andeans, nor is there information on how the discovery of its use for malaria-like fevers came about. One clue comes from the Jesuits who talked with the Andean people and learned about quinine. But was it used for fever? Why did the Jesuits test it against (tertian or quartan) fevers that could have been the result of malaria? The gap in our knowledge can only be resolved with the discovery of written documents by the Jesuits about quinine for malaria.

Antiangiogenic Activity of Quinine Alone and in Combination with vitamin C in both ex vivo and in vivo Assays.

BACKGROUND: Angiogenesis is the process of vascularization from preexisting blood vessels. It is essential for many physiological and pathological processes. Quinine is an anti-malarial agent belongs to the quinoline alkaloid that can inhibit angiogenesis. Vitamin C is also an important antioxidant and has been shown to reduce angiogenesis in tumor. OBJECTIVE: The study was aimed at investigating the effect of quinine alone and in combination with vitamin C on angiogenesis process. MATERIALS AND METHODS: 12 to 14 weeks old male albino rats were used for the study. Quinine was prepared by dissolving in DMSO and was serially diluted. The rat aorta ring assay was employed to investigate the antiangiogenic effect of quinine ex vivo. An in vivo chorioallantoic membrane (CAM) assay was used to measure the blood vessels inhibition zone by quinine. The zone of inhibition was calculated as the mean inhibition area of a blood vessel in mm±SD.The obtained data were statistically analyzed. RESULTS: The results revealed that quinine has a significant dose-dependent inhibition effect on the growth of blood vessels by 98% ± 0.07 in concentration 100µg/ml when compared to the negative control. moreover, the inhibition of blood vessels growth as a measure of the antiangiogenic activity of quinine in combination with vitamin C shows a synergistic effect when the concentration that inhibit 50% of blood vessels growth (IC50) which equals to 5.05 µg/ml resulted in 85% of growth inhibition when combined with IC50 of vitamin C which equals to 22..87µg/ml. CONCLUSION: The findings suggest that the activity of quinine with vitamin C synergism can greatly lower blood vessels growth in rat aorta rings and CAM assays. Quininehas an inhibitory effect on tumor and can be utilized as an antiangiogenic agent alone or in combination with vitamin C.

Human Babesiosis.

Babesiosis is caused by intraerythrocytic parasites that are transmitted primarily by ticks, infrequently through blood transfusion, and rarely through transplacental transmission or organ transplantation. Human babesiosis is found throughout the world, but the incidence is highest in the Northeast and upper Midwestern United States. Babesiosis has clinical features that resemble malaria and can be fatal in immunocompromised and older patients. Diagnosis is confirmed by identification of Babesia parasites on blood smear or Babesia DNA with polymerase chain reaction. Standard treatment consists of atovaquone and azithromycin or clindamycin and quinine for 7 to 10 days.

Multiple Plasmodium falciparum drug resistance polymorphisms identified in a pregnant woman with severe malaria and a concomitant spontaneous abortion in Cross River, Nigeria, West Africa.

BACKGROUND: The development of resistance by Plasmodium falciparum to anti-malarial drugs impedes any benefits of the drug. In addition, absence or delayed availability of current anti-malarial drugs in remote areas has the potential to results to parasite escape and continuous transmission. CASE PRESENTATION: The case of a 29-year old pregnant woman from Biase Local Government Area in Cross River State Nigeria presenting with febrile illness and high body temperature of 38.7 °C was reported. She looked pale and vomited twice on arrival at the health facility. Her blood smear on the first day of hospitalization was positive for P. falciparum by RDT, microscopy (21,960 parasite/µl) and real-time PCR, with a PCV of 18%. She was treated with 600 mg intravenous quinine in 500 ml of 5% Dextrose/0.9% Saline 8-hourly for 24 h. On the second day of hospitalization, she complained of weakness, persistent high-grade fever and vaginal bleeding. A bulging amnion from an extended cervix was observed. Following venous blood collection for laboratory investigations, 600 µg of misoprostol was inserted into the posterior fornix of her vagina as part of her obstetric care. Parenteral quinine was discontinued, and she was given full therapeutic regimen of artemether-lumefantrine 80/480 mg tablets to be taken for 3 days beginning from the second day. Her blood samples on the second and third day of hospitalization remained positive for P. falciparum by all three diagnostic methods. Single nucleotide polymorphism (SNP) assay on all three P. falciparum isolates revealed the presence of variants associated with multiple drug resistant markers. DISCUSSION: Infecting P. falciparum isolates may have been resistant to initial quinine treatment resulting from parasite cross-resistance with other quinoline associated resistant markers such as 86Y and 184 F. CONCLUSIONS: Therefore, the likely transmission of similarly resistant parasites in the study area calls for reinforcement of interventions and adherence to current World Health Organization guidelines in administering only approved drugs to individuals in order to mitigate parasite escape and eventual transmission to other susceptible individuals.

Need for optimized dosages in the design of comparative clinical trials of anti-malarial drugs.

We read with interest the publication on malaria treatment by Obonyo et al. (Malaria J 21:30, 2022). This commentary questions the methodology, especially the chosen time points of treatment outcome measures.

A Novel Morphine Drinking Model of Opioid Dependence in Rats.

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants' presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

Mystery of blackwater fever from an Australian perspective.

Blackwater fever is a haemolytic syndrome associated with malaria that coincided with the use of quinine chemoprophylaxis. Once quinine was no longer chronically used to prevent malaria, blackwater fever largely disappeared and its aetiology remains poorly understood. Blackwater fever is representative of classical tropical medicine and its history was reflected in Australia's colonial development of Papua New Guinea particularly as reported in the Australian medical literature.

Artesunate monotherapy versus artesunate plus quinine combination therapy for treatment of imported severe malaria: a TropNet retrospective cohort study.

BACKGROUND: The addition of intravenous quinine (IVQ) to intravenous artesunate (IVA) has been recently suggested by World Health Organization  in areas where artemisinin resistance is highly prevalent. Since IVA is not yet widely available as "Good Manufacturing Practices" product, for several years combination treatment with IVA and IVQ was used in some Italian centers to mitigate the legal risks in using an unlicensed drug. METHODS: A retrospective cohort study was designed to compare IVA + IVQ and IVA treatment for imported severe malaria. We collected data from three Italian centers. Adult and pediatric cohorts were analyzed separately. RESULTS: Forty-nine patients treated with IVA and 44 with IVA + IVQ were enrolled, 45 were adults and 48 children. All acquired malaria in Sub-Saharan Africa. In the adult cohort, median of fever clearance time (FCT) was similar in both groups (48 h vs 48 h, p = 0.19) but number of patients who reached apyrexia within 48 h (FCT48) was higher in IVA group (20/24, 83.3% vs 8/17, 47%, p = 0.002). The parasite clearance time (PCT) measure did not differ (median 48 h vs 48 h, p = 0.669). In the pediatric cohort, FCT did not differ in the two groups (median 30 vs 48 h, p = 0.50) while PCT was longer in IVA + IVQ group (median 72 vs 48 h, p = 0.002). Adverse events (AEs) in adults were more common in the combination treatment group (6/19, 31.58% vs 2/26, 7.69%, p = 0.055). CONCLUSION: IVA + IVQ treatment did not show better outcome with respect to IVA monotherapy. AEs were more frequent in the IVA + IVQ group compared to the monotherapy. Further studies are necessary to investigate whether IVA + IVQ could be an efficient strategy to treat severe malaria cases in areas at high risk of artemisinin resistance.

Efficacy of 3-day low dose quinine plus clindamycin versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children (CLINDAQUINE): an open-label randomized trial.

BACKGROUND: The World Health Organization recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available. The efficacy of quinine plus clindamycin was compared with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age. METHODS: An open-label, phase 3, randomized trial was conducted in western Kenya. Children aged 6-59 months with uncomplicated falciparum malaria were randomly assigned (1:1) via a computer-generated randomization list to receive 3 days of twice a day treatment with either oral quinine (20 mg/kg/day) plus clindamycin (20 mg/kg/day) or artemether-lumefantrine (artemether 20 mg, lumefantrine 120 mg) as one (for those weighing 5-14 kg) or two (for those weighing 15-24 kg) tablets per dose. The primary outcome was a PCR-corrected rate of adequate clinical and parasitological response (ACPR) on day 28 in the per-protocol population. RESULTS: Of the 384 children enrolled, 182/192 (94.8%) receiving quinine plus clindamycin and 171/192 (89.1%) receiving artemether-lumefantrine completed the study. The PCR-corrected ACPR rate was 44.0% (80 children) in the quinine plus clindamycin group and 97.1% (166 children) in the artemether-lumefantrine group (treatment difference - 53.1%, 95% CI - 43.5% to - 62.7%). At 72 h after starting treatment, 50.3% (94 children) in the quinine plus clindamycin group were still parasitaemic compared with 0.5% (1 child) in the artemether-lumefantrine group. Three cases of severe malaria were recorded as serious adverse events in the quinine plus clindamycin group. CONCLUSIONS: The study found no evidence to support the use of a 3-day low dose course of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective. TRIAL REGISTRATION: This trial is registered with the Pan-African Clinical Trials Registry, PACTR20129000419241.

Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review.

BACKGROUND: Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine. METHODS: Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values. RESULTS: Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups. CONCLUSIONS: The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.

Antimalarial Natural Products.

Natural products have made a crucial and unique contribution to human health, and this is especially true in the case of malaria, where the natural products quinine and artemisinin and their derivatives and analogues, have saved millions of lives. The need for new drugs to treat malaria is still urgent, since the most dangerous malaria parasite, Plasmodium falciparum, has become resistant to quinine and most of its derivatives and is becoming resistant to artemisinin and its derivatives. This volume begins with a short history of malaria and follows this with a summary of its biology. It then traces the fascinating history of the discovery of quinine for malaria treatment and then describes quinine's biosynthesis, its mechanism of action, and its clinical use, concluding with a discussion of synthetic antimalarial agents based on quinine's structure. The volume then covers the discovery of artemisinin and its development as the source of the most effective current antimalarial drug, including summaries of its synthesis and biosynthesis, its mechanism of action, and its clinical use and resistance. A short discussion of other clinically used antimalarial natural products leads to a detailed treatment of other natural products with significant antiplasmodial activity, classified by compound type. Although the search for new antimalarial natural products from Nature's combinatorial library is challenging, it is very likely to yield new antimalarial drugs. The chapter thus ends by identifying over ten natural products with development potential as clinical antimalarial agents.

Physiologically based pharmacokinetic modeling for dose optimization of quinine-phenobarbital coadministration in patients with cerebral malaria.

Patients with cerebral malaria with polymorphic Cytochrome P450 2C19 (CYP2C19) genotypes who receive concurrent treatment with quinine are at risk of inadequate or toxic therapeutic drug concentrations due to metabolic drug interactions. The study aimed to predict the potential dose regimens of quinine when coadministered with phenobarbital in adult patients with cerebral malaria and complications (e.g., lactic acidosis and acute renal failure) and concurrent with seizures and acute renal failure who carry wild-type and polymorphic CYP2C19. The whole-body physiologically based pharmacokinetic (PBPK) models for quinine, phenobarbital, and quinine-phenobarbital coadministration were constructed based on the previously published information using Simbiology®. Four published articles were used for model validation. A total of 100 virtual patients were simulated based on the 14-day and 3-day courses of treatment. using the drug-drug interaction approach. The predicted results were within 15% of the observed values. Standard phenobarbital dose, when administered with quinine, is suitable for all groups with single or continuous seizures regardless of CYP2C19 genotype, renal failure, and lactic acidosis. Dose adjustment based on area under the curve ratio provided inappropriate quinine concentrations. The recommended dose of quinine when coadministered with phenobarbital based on the PBPK model for all groups is a loading dose of 2000 mg intravenous (i.v.) infusion rate 250 mg/h followed by 1200 mg i.v. rate 150 mg/h. The developed PBPK models are credible for further simulations. Because the predicted quinine doses in all groups were similar regardless of the CYP2C19 genotype, genotyping may not be required.

Antimalarial Drug Discovery: From Quinine to the Most Recent Promising Clinical Drug Candidates.

Malaria is a tropical threatening disease caused by Plasmodium parasites, resulting in 409,000 deaths in 2019. The delay of mortality and morbidity has been compounded by the widespread of drug resistant parasites from Southeast Asia since two decades. The emergence of artemisinin-resistant Plasmodium in Africa, where most cases are accounted, highlights the urgent need for new medicines. In this effort, the World Health Organization and Medicines for Malaria Venture joined to define clear goals for novel therapies and characterized the target candidate profile. This ongoing search for new treatments is based on imperative labor in medicinal chemistry which is summarized here with particular attention to hit-to-lead optimizations, key properties, and modes of action of these novel antimalarial drugs. This review, after presenting the current antimalarial chemotherapy, from quinine to the latest marketed drugs, focuses in particular on recent advances of the most promising antimalarial candidates in clinical and preclinical phases.

Plasmodium falciparum clearance time in Malawian children with cerebral malaria: a retrospective cohort study.

BACKGROUND: Standard treatment for both uncomplicated and severe malaria is artemisinin derivatives. Delayed parasite clearance times preceded the appearance of artemisinin treatment failures in Southeast Asia. Most worldwide malaria cases are in sub-Saharan Africa (SSA), where clinically significant artemisinin resistance or treatment failure has not yet been detected. The recent emergence of a resistance-conferring genetic mutation in the Plasmodium falciparum parasite in Africa warrants continued monitoring throughout the continent. METHODS: An analysis was performed on data from a retrospective cohort study of Malawian children with cerebral malaria admitted between 2010 and 2019 to a public referral hospital, ascertaining parasite clearance times across years. Data were collected from patients treated for severe malaria with quinine or artesunate, an artemisinin derivative. Parasite density was determined at admission and every subsequent 6 h until parasitaemia was below 1000 parasites/µl.The mean parasite clearance time in all children admitted in any one year was compared to the parasite clearance time in 2014, the first year of artesunate use in Malawi. RESULTS: The median population parasite clearance time was slower from 2010 to 2013 (quinine-treated patients) compared to 2014, the first year of artesunate use in Malawi (30 h (95% CI: 30-30) vs 18 h (95% CI: 18-24)). After adjustment for admission parasite count, there was no statistically significant difference in the median population parasite clearance time when comparing 2014 with any subsequent year. CONCLUSION: Malaria parasite clearance times in Malawian children with cerebral malaria remained constant between 2014 and 2019, arguing against evolving artemisinin resistance in parasites in this region.