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.

Effective Treatment of Cutaneous Mold Infections by Antimicrobial Blue Light That Is Potentiated by Quinine.

BACKGROUND: Cutaneous mold infections commonly result from an array of traumatic injuries that involve direct inoculation of contaminated soil into wounds. Here, we explored the use of antimicrobial blue light (aBL; 405 nm wavelength) and the combination of aBL with quinine hydrochloride (aBL + Q-HCL) for the treatment of cutaneous mold infections. METHODS: Efficacy of aBL and aBL + Q-HCL in killing clinically important pathogenic molds (Aspergillus fumigatus, Aspergillus flavus, and Fusarium oxyprorum) was investigated. Ultraperformance liquid chromatography identified and quantified endogenous porphyrins in the mold conidia. Finally, a mouse model of dermabrasion wound infected with a bioluminescent variant of A. fumigatus was developed to investigate the efficacy of aBL in treating cutaneous mold infections. RESULTS: We demonstrated that mold conidia are tolerant to aBL, but Q-HCL enhances efficacy. Transmission electron microscopy revealed intracellular damage by aBL. aBL + Q-HCL resulted in intracellular and cell wall damage. Porphyrins were observed in all mold strains, with A. fumigatus having the highest concentration. aBL and aBL + Q-HCL effectively reduced the burden of A. fumigatus within an established dermabrasion infection and limited recurrence posttreatment. CONCLUSIONS: aBL and aBL + Q-HCL may offer a novel approach for the treatment of mold infections.

Quinine-Based Semisynthetic Ion Transporters with Potential Antiproliferative Activities.

Synthetic ion transporters have attracted tremendous attention for their therapeutic potential against various ion-transport-related diseases, including cancer. Inspired by the structure and biological activities of natural products, we synthesized a small series of squaramide and thiourea derivatives of quinine and investigated their ion transport activities. The involvement of a quinuclidine moiety for the cooperative interactions of Cl- and H+ ions with the thiourea or squaramide moiety resulted in an effectual transport of these ions across membranes. The interference of ionic equilibrium by the potent Cl- ion carrier selectively induced cancer cell death by endorsing caspase-arbitrated apoptosis. In vivo assessment of the potent ionophore showed an efficient reduction in tumor growth with negligible immunotoxicity to other organs.

Quinine Improves the Fungicidal Effects of Antimicrobial Blue Light: Implications for the Treatment of Cutaneous Candidiasis.

BACKGROUND AND OBJECTIVE: Candida albicans is an opportunistic fungal pathogen of clinical importance and is the primary cause of fungal-associated wound infections, sepsis, or pneumonia in immunocompromised individuals. With the rise in antimicrobial resistance, it is becoming increasingly difficult to successfully treat fungal infections using traditional antifungals, signifying that alternative non-traditional approaches must be explored for their efficacy. STUDY DESIGN/MATERIALS AND METHODS: We investigated the combination of antimicrobial blue light (aBL) and quinine hydrochloride (Q-HCL) for improved inactivation of C. albicans, in vitro and in vivo, relative to either monotherapy. In addition, we evaluated the safety of this combination therapy in vivo using the TUNEL assay. RESULTS: The combination of aBL (108 J/cm2 ) with Q-HCL (1 mg/mL) resulted in a significant improvement in the inactivation of C. albicans planktonic cells in vitro, where a 7.04 log10 colony forming units (CFU) reduction was achieved, compared with aBL alone that only inactivated 3.06 log10 CFU (P < 0.001) or Q-HCL alone which did not result in a loss of viability. aBL + Q-HCL was also effective at inactivating 48-hour biofilms, with an inactivation 1.73 log10 CFU at the dose of 108 J/cm2 aBL and 1 mg/mL Q-HCL, compared with only a 0.73 or 0.66 log10 CFU by aBL and Q-HCL alone, respectively (P < 0.001). Transmission electron microscopy revealed that aBL + Q-HCL induced morphological and ultrastructural changes consistent with cell wall and cytoplasmic damage. In addition, aBL + Q-HCL was effective at eliminating C. albicans within mouse abrasion wounds, with a 2.47 log10 relative luminescence unit (RLU) reduction at the dose of 324 J/cm2 aBL and 0.4 mg/cm2 Q-HCL, compared with a 1.44 log10 RLU reduction by aBL alone. Q-HCL or nystatin alone did not significantly reduce the RLU. The TUNEL assay revealed some apoptotic cells before and 24 hours following treatment with aBL + Q-HCL. CONCLUSION: The combination of aBL + Q-HCL was effective at eliminating C. albicans both in vitro and in vivo. A comprehensive assessment of toxicity (cytotoxicity and genotoxicity) is required to fully determine the safety of aBL + Q-HCL therapy at different doses. In conclusion, the combination of aBL and Q-HCL may be a viable option for the treatment of cutaneous candidiasis. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Quinine Enhances Photo-Inactivation of Gram-Negative Bacteria.

BACKGROUND: Antimicrobial resistance is a significant concern to public health, and there is a pressing need to develop novel antimicrobial therapeutic modalities. METHODS: In this study, we investigated the capacity for quinine hydrochloride (Q-HCL) to enhance the antimicrobial effects of antimicrobial blue light ([aBL] 405 nm wavelength) against multidrug-resistant (MDR) Gram-negative bacteria in vitro and in vivo. RESULTS: Our findings demonstrated the significant improvement in the inactivation of MDR Pseudomonas aeruginosa and Acinetobacter baumannii (planktonic cells and biofilms) when aBL was illuminated during Q-HCL exposure. Furthermore, the addition of Q-HCL significantly potentiated the antimicrobial effects of aBL in a mouse skin abrasion infection model. In addition, combined exposure of aBL and Q-HCL did not result in any significant apoptosis when exposed to uninfected mouse skin. CONCLUSIONS: In conclusion, aBL in combination with Q-HCL may offer a novel approach for the treatment of infections caused by MDR bacteria.

Integrated point-of-care testing (POCT) of HIV, syphilis, malaria and anaemia in antenatal clinics in western Kenya: A longitudinal implementation study.

BACKGROUND: In sub-Saharan Africa, HIV, syphilis, malaria and anaemia are leading preventable causes of adverse pregnancy outcomes. In Kenya, policy states women should be tested for all four conditions (malaria only if febrile) at first antenatal care (ANC) visit. In practice, while HIV screening is conducted, coverage of screening for the others is suboptimal and early pregnancy management of illnesses is compromised. This is particularly evident at rural dispensaries that lack laboratories and have parallel programmes for HIV, reproductive health and malaria, resulting in fractured and inadequate care for women. METHODS: A longitudinal eight-month implementation study integrating point-of-care diagnostic tests for the four conditions into routine ANC was conducted in seven purposively selected dispensaries in western Kenya. Testing proficiency of healthcare workers was observed at initial training and at three monthly intervals thereafter. Adoption of testing was compared using ANC register data 8.5 months before and eight months during the intervention. Fidelity to clinical management guidelines was determined by client exit interviews with success defined as ≥90% adherence. FINDINGS: For first ANC visits at baseline (n = 529), testing rates were unavailable for malaria, low for syphilis (4.3%) and anaemia (27.8%), and near universal for HIV (99%). During intervention, over 95% of first attendees (n = 586) completed four tests and of those tested positive, 70.6% received penicillin or erythromycin for syphilis, 65.5% and 48.3% received cotrimoxazole and antiretrovirals respectively for HIV, and 76.4% received artemether/lumefantrine, quinine or dihydroartemisinin-piperaquine correctly for malaria. Iron and folic supplements were given to nearly 90% of women but often at incorrect doses. CONCLUSIONS: Integrating point-of-care testing into ANC at dispensaries with established HIV testing programmes resulted in a significant increase in testing rates, without disturbing HIV testing rates. While more cases were detected and treated, treatment fidelity still requires strengthening and an integrated monitoring and evaluation system needs to be established.

A randomized, control and comparative study of polyherbal formulation use for Malaria (Plasmodium falciparum).

Plasmodium falciparum is the most well-known reason for extreme and life-debilitating malaria. Falciparum malaria causes more than 1 million deaths annually. Malaria remains a noteworthy reason for major morbidity and mortality in the tropics, with Plasmodium falciparum accountable for the mainstream of the disease weight and Plasmodium vivax being the geologically greatest broadly dispersed cause of malaria. The controlling of severe malaria comprises quick direction of suitable parenteral anti-malarial agents and initial acknowledgement and treatment of the complications. This clinical trial was piloted in 100 patients, in which 50 received the test drug (Malarina) and 50 received the control drug (Quinine Bisulphate). The age range of patients was 12 years to above 50 years. The sample paired t-test was applied to evaluate the significant level. Malarina was very effective in treating malaria sign and symptoms. The new treatment Malarina was safe and well tolerated in all patients.

Optimization of Curcuma Oil/Quinine-Loaded Nanocapsules for Malaria Treatment.

Quinine, a treatment used in chloroquine-resistant falciparum malaria, was loaded into poly(ɛ-caprolactone) or Eudragit® RS100 nanocapsules using Curcuma oil as the oil-based core. Until now, the effect of cationic nanocapsules on malaria has not been reported. A 24 factorial design was adopted using, as independent variables, the concentration of Curcuma oil, presence of quinine, type of polymer, and aqueous surfactant. Diameter, zeta potential, and pH were the responses studied. The formulations were also evaluated for drug content, encapsulation efficiency, photostability, and antimalarial activity against Plasmodium berghei-infected mice. The type of polymer influenced all of the responses studied. Quinine-loaded Eudragit® RS100 (F13) and PCL nanocapsules (F9), both with polysorbate 80 coating, showed nanometric particle size, positive zeta potential, neutral pH, high drug content, and quinine photoprotection ability; thus, these nanocapsules were selected for in vivo tests. Both formulations showed lower levels of parasitemia from the beginning of the experiment (5.78 ± 3.60 and 4.76 ± 3.46% for F9 and F13, respectively) and highest survival mean time (15.3 ± 2.0 and 14.9 ± 5.6 days for F9 and F13, respectively). F9 and F13 showed significant survival curve compared to saline, thus demonstrating that nanoencapsulation improved bioefficacy of QN and co-encapsulated curcuminoids, regardless of the surface charge.

Effects of quinine on gastric ulcer healing in Wistar rats.

Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6±2.35 %) was significantly higher (p<0.05) than in QT rats (49.0±2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion.

Perspectiva histórica de antimaláricos de origen natural / Historical perspective of antimalarials of natural origin

Hoy, muchas enfermedades son tratadas gracias al descubrimiento de compuestos a partir de las plantas, lo que evidencia que estas juegan un papel significativo en el descubrimiento y desarrollo de nuevos fármacos. Una de las alternativas para el control de la morbi-mortalidad por malaria es la quimioterapia, la cual ha sido posible gracias al descubrimiento de compuestos a partir de las plantas. En la actualidad, cerca de la mitad de los fármacos antimaláricos disponibles son compuestos naturales o están relacionados con ellos. En esta revisión se hace un recuento histórico del origen y desarrollo de los principales antimaláricos como instrumento de hechos arquitectónicos, que mantienen una estrecha relación con los referentes antimaláricos, que sirven de modelos para profundizar en la búsqueda de nuevas sustancias químicas naturales que podrían contribuir al control de una devastadora enfermedad como la malaria, donde se están presentando cepas resistentes de Plasmodium a los principales tratamientos, falla terapéutica, además de un escaso acceso a los medicamentos, entre otros factores; que complican su prevención y tratamiento (AU)

Today, many diseases are treated thanks to the discovery of compounds from plants, which shows that they play a significant role in the discovery and development of new drugs. One of the alternatives for the control of malaria morbidity and mortality is chemotherapy, which has been made possible by the discovery of compounds from plants. At present, about half of the available antimalarials drugs are naturally occurring compounds or are related to them. This review provides a historical account of the origin and development of the main antimalarials as an instrument of architectural facts, which maintains a close relationship with the antimalarials referents, which serve as models to deepen the search for new natural chemical substances that could contribute to the Control of a devastating disease like malaria, where resistant strains of Plasmodium are being presented to the main treatments, therapeutic failure, in addition to poor access to medicines, among other factors; which complicate their prevention and treatment (AU)

Functional Components from Nature-Derived Drugs for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by persistent synovitis and systemic inflammation. Currently, the widely used drugs for the treatment of RA are disease-modifying antirheumatic drugs, biological agents and glucocorticoids. But their clinical use has been limited because of their adverse effects with a high frequency and high cost of treatment. It is essential to find novel candidate agents. Traditional Chinese medicine (TCM) has been used for RA treatment for a long period of time. In recent years, significant amounts of studies have shown that some TCMs and their active ingredients have obvious therapeutic effects on RA. In this review, the compounds in TCMs that have an effect in clinic or animal experiments of RA are critically reviewed and summarized. Moreover, the relationship between chemical structures of the compound and their activities is analyzed. The relevant researches are described from the aspects of source, methods, result, and related mechanism analysis. The existing studies show that most effective compounds in TCM for RA treatment belong to alkaloids, flavonoids, terpenoids, phenols and quinines. It is hoped that the data summarized in this review will be beneficial to the screening of new nature-derived antirheumatic drugs.

On the history of Cinchona bark in the treatment of Malaria.

How and when the medical value of Cinchona bark was discovered is obscure, but it is said that the powder was given to a European for malaria for the first time in the 1630s. The bark was brought to Europe by Spanish missionaries and it was recommended by the cardinal Juan de Lugo. In the 1660s, the use of Cinchona bark became known in England - and in Denmark by Thomas Bartholin. It was used for the treatment of malaria, but several debates on its value continued up to the 1730s. However, successful treatment of malaria was obtained by Thomas Sydenham, Robert Tabor and Francesco Torti. Sydenham emphasized a modern view that Cinchona bark was a unique specific drug for the treatment of malaria, and the treatment was fully accepted when Torti's Therapeutice specialis appeared. In the early 18th century, botanical expeditions were arranged in search of the most valuable Cinchona species for cultivation. The content of quinine was impor- tant, and determination of quinine was realized when Pierre Pelletier and Joseph Caventou isolated the alkaloid from the bark in 1820. Dutch plantations and quinine industry dominated the market, but the supply of quinine came to an end when the Japanese occupied Indonesia in 1942, cutting off the rest of the world from the main supplies of Cinchona. Synthetic antimalarials were developed and chloroquine became the drug of choice, but the intensive use of these drugs caused drug resistance. Chloroquine-resistant strains of P. falciparum are now treated with other drugs as artemisinin and artemether.

Science in the service of colonial agro-industrialism: the case of cinchona cultivation in the Dutch and British East Indies, 1852-1900.

The isolation of quinine from cinchona bark in 1820 opened new possibilities for the mass-production and consumption of a popular medicine that was suitable for the treatment of intermittent (malarial) fevers and other diseases. As the 19th century European empires expanded in Africa and Asia, control of tropical diseases such as malaria was seen as crucial. Consequently, quinine and cinchona became a pivotal tool of British, French, German and Dutch empire-builders. This comparative study shows how the interplay between science, industry and government resulted in different historical trajectories for cinchona and quinine in the Dutch and British Empires during the second half of the 19th century. We argue that in the Dutch case the vectors of assemblage that provided the institutional and physical framework for communication, exchange and control represent an early example of commodification of colonial science. Furthermore, both historical trajectories show how the employment of the laboratory as a new device materialised within the colonial context of agricultural and industrial production of raw materials (cinchona bark), semi-finished product (quinine sulphate) and plant-based medicines like quinine. Hence, illustrating the 19th century transition from 'colonial botany' and 'green imperialism' to what we conceptualise as 'colonial agro-industrialism'.

Amazonian plant natural products: perspectives for discovery of new antimalarial drug leads.

Plasmodium falciparum and P. vivax malaria parasites are now resistant, or showing signs of resistance, to most drugs used in therapy. Novel chemical entities that exhibit new mechanisms of antiplasmodial action are needed. New antimalarials that block transmission of Plasmodium spp. from humans to Anopheles mosquito vectors are key to malaria eradication efforts. Although P. vivax causes a considerable number of malaria cases, its importance has for long been neglected. Vivax malaria can cause severe manifestations and death; hence there is a need for P. vivax-directed research. Plants used in traditional medicine, namely Artemisia annua and Cinchona spp. are the sources of the antimalarial natural products artemisinin and quinine, respectively. Based on these compounds, semi-synthetic artemisinin-derivatives and synthetic quinoline antimalarials have been developed and are the most important drugs in the current therapeutic arsenal for combating malaria. In the Amazon region, where P. vivax predominates, there is a local tradition of using plant-derived preparations to treat malaria. Here, we review the current P. falciparum and P. vivax drug-sensitivity assays, focusing on challenges and perspectives of drug discovery for P. vivax, including tests against hypnozoites. We also present the latest findings of our group and others on the antiplasmodial and antimalarial chemical components from Amazonian plants that may be potential drug leads against malaria.

Effect of vitamin A adjunct therapy for cerebral malaria in children admitted to Mulago hospital: a randomized controlled trial.

BACKGROUND: Malaria is a leading cause of mortality in Uganda accounting for 25% of deaths among children. Hitherto no adjunct therapy has been identified to improve outcome of cerebral malaria. Retinol suppresses growth of P.falciparum, scavenges free radicals, and exhibits synergistic action with quinine in parasite clearance. OBJECTIVE: To determine the effect of vitamin A supplementation on treatment outcome of cerebral malaria METHODS: In this randomised double-blind placebo controlled clinical trial we studied 142 children aged 6-59 months admitted with cerebral malaria in Mulago Hospital, Kampala. Children were randomised to either vitamin A or placebo and followed for 7 days. The main outcome measures were coma recovery time, time for convulsions to stop, and parasite and fever clearance. Secondary outcomes were overall mortality and time taken to start oral feeds. RESULTS: There was no difference in the coma recovery time (p=0.44), resolution of convulsions (p=0.37), fever clearance (p=0.92), parasite clearance (p=0.12), and starting oral feeds between the two treatment groups. Mortality was higher (16.2%) in the placebo than in the vitamin A group (8.1%): RR 1.4; 95% CI 1.0-2.1. CONCLUSIONS: Vitamin A as adjunct therapy did not significantly reduce coma duration but there were fewer deaths in the vitamin A arm.

Non-drug therapies for lower limb muscle cramps.

BACKGROUND: About one in every three adults are affected by lower limb muscle cramps. For some people, these cramps reduce quality of life, quality of sleep and participation in activities of daily living. Many interventions are available for lower limb cramps, but some are controversial, no treatment guidelines exist, and often people experience no benefit from the interventions prescribed. OBJECTIVES: To assess the effects of non-drug, non-invasive treatments for lower limb cramp. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (13 September 2011) using the terms: cramp, spasm, contracture, charley horse and lower limb, lower extremity, foot, calf, leg, thigh, gastrocnemius, hamstring, quadriceps. We also searched CENTRAL (2011, Issue 3), MEDLINE (January 1966 to August 2011) and EMBASE (January 1980 to August 2011) and the reference lists of included studies. There were no language or publication restrictions. SELECTION CRITERIA: All randomised controlled trials of non-drug, non-invasive interventions trialled over at least four weeks for the prevention of lower limb muscle cramps in any group of people. We excluded, for example, surgery, acupuncture and dry-needling, as invasive interventions. We selected only trials that included at least one of the following outcomes: cramp frequency, cramp severity, health-related quality of life, quality of sleep, participation in activities of daily living and adverse outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and cross checked data extraction and analysis. A third author was to arbitrate in the event of disagreement. We asked the authors of five trials for information to assist with screening studies for eligibility and received four responses. MAIN RESULTS: One trial was eligible for inclusion.  All participants were age 60 years or over and had received a repeat prescription from their general practitioner of quinine for nighttime cramps in the preceding three months. This review includes data from only those participants who were advised to continue taking quinine. Forty-nine participants were advised to complete lean-to-wall calf muscle stretching held for 10 s three times per day. Forty-eight participants were allocated to a placebo stretching group. After 12 weeks, there was no statistically significant difference in recalled cramp frequency between groups. No "significant" adverse effect was reported. Limitations in the study's design impede interpretation of the results and clinical applicability. AUTHORS' CONCLUSIONS: There is limited evidence on which to base clinical decisions regarding the use of non-drug therapies for the treatment of lower limb muscle cramp. Serious methodological limitations in the existing evidence hinder clinical application. There is an urgent need to carefully evaluate many of the commonly recommended and emerging non-drug therapies in well designed randomised controlled trials.

A phase II randomized controlled trial to evaluate the safety and efficacy of Praneem polyherbal vaginal tablets compared with betadine vaginal pessary in women with symptoms of abnormal vaginal discharge.

Abnormal vaginal discharge (AVD) caused by a variety of reproductive tract infections is a widespread syndrome among women in India and in other developing countries. The purpose of this study was to determine whether a polyherbal formulation, Praneem, can be used for the regression of the syndrome. A phase IotaIota randomized controlled study was carried out with Praneem polyherbal tablets and Betadine vaginal pessary in 99 women with AVD. The authors found that 92% of women using Praneem were relieved of their symptoms of AVD as against 81.6% women using Betadine. Significant reduction was also seen with both treatments in lower abdominal pain, vaginal itching, and dysuria. Thus, the study indicates the efficacy of Praneem for the treatment of AVD and provides a rationale for planning a further Phase III study on a larger sample size for definitive conclusions.

In vitro activity of pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assays.

BACKGROUND: Pyronaridine, a Mannich base anti-malarial with high efficacy against drug resistant Plasmodium falciparum, is currently evaluated as a fixed dose combination with artesunate for the treatment of uncomplicated malaria. In this study, the in vitro activity of pyronaridine against clinical isolates of P. falciparum from Lambaréné, Gabon, was assessed in order to obtain baseline data on its activity prior to its future use in routine therapy. Moreover, follow-up assessment on the in vitro activity of chloroquine, artesunate and quinine was performed. METHODS: In vitro response of field isolates of P. falciparum to pyronaridine, chloroquine, artesunate and quinine was assessed using the traditional WHO microtest. In addition, the histidine-rich protein 2 (HRP-2) assay was performed and evaluated for its future implementation for follow-up of drug susceptibility testing. RESULTS: Pyronaridine exhibited a high in vitro activity against P. falciparum, with a geometric mean cut-off concentration of 9.3 nmol/l. Fifty percent effective concentrations were 1.9 nmol/l and 2.0 nmol/l in the WHO microtest and HRP-2 assay, respectively. Results matched closely in vivo findings from a recent clinical trial on pyronaridine-artesunate treatment. One isolate showed diminished sensitivity to artesunate. For chloroquine and quinine resistance levels were comparable to prior studies from Lambaréné. Results from the novel HRP-2 assay corresponded well to those obtained by the WHO microtest. CONCLUSION: Pyronaridine is highly active in chloroquine-resistant parasites and seems a promising partner drug for artemisinin-based combination therapy in Africa.

Application of pharmacogenomics to malaria: a holistic approach for successful chemotherapy.

Drug resistance in malaria jeopardizes the most elementary objectives of malaria control--reducing suffering and eliminating mortality. An important, and so far the only known, mechanism of drug resistance appears to be polymorphisms in the malaria parasite genes. Efforts to circumvent antimalarial drug resistance now range from the use of combination therapies with existing agents to genomics-based studies directed toward discovering novel targets and agents. However, the potential contribution of host genetic/molecular factors, particularly those associated with antimalarial drug metabolism, remains largely unexplored. Our knowledge concerning the basic mechanisms involved in the pharmacokinetics of antimalarial drugs is fragmentary. In addition, the link between antimalarial drug pharmacokinetics and treatment outcomes is generally unclear. The purpose of this article is to provide general background information on antimalarial drug resistance and associated parasite genetic factors, and subsequently highlight the aforementioned unexplored and unclear areas, with a view to stimulate much needed further research.