Fiebre biliosa hemoglobinúrica como forma de presentación de la malaria aguda grave por Plasmodium falciparum / Hemoglobinuric bilious fever as a presentation of severe acute Plasmodium falciparum malaria

RESUMEN Introducción: La fiebre biliosa hemoglobinúrica es una de las complicaciones del paludismo grave, notificada con poca frecuencia, que se caracteriza por una hemólisis intravascular aguda en ocasiones masiva que conduce a hemoglobinuria y, finalmente, a una lesión renal aguda. Objetivo: Describir un caso de fiebre biliosa hemoglobinúrica como forma clínica de presentación de la malaria aguda grave. Caso clínico: Paciente masculino procedente de una zona endémica de paludismo con antecedentes de episodios recurrentes de malaria, quien, al tercer día de indicarle quimioprofilaxis antipalúdica con mefloquina, presentó un cuadro clínico de decaimiento, marcada astenia, fatiga, náuseas, vómitos, dolor abdominal difuso y emisión de orina oscura escasa, descritas por el paciente como "coca cola". Se diagnosticó fiebre biliosa hemoglobinúrica como forma clínica de presentación de una malaria aguda grave con baja parasitemia, constatado mediante examen de diagnóstico rápido y gota gruesa positivos a paludismo y hemoglobinuria masiva en el examen de orina con tira reactiva. La evolución del paciente fue favorable. Conclusiones: Este caso representa una forma no habitual de presentación de la enfermedad, que aunque no se sospecha usualmente, puede ocurrir. Este artículo es una alerta a los médicos que ejercen en áreas endémicas de malaria a permanecer atentos. Esta temible complicación puede ser la forma clínica de presentación de la malaria grave, particularmente en paciente expuestos crónicamente a infección por Plasmodium falciparum, que presenten una reacción hemolítica aguda masiva en ausencia de parasitemia elevada, cuando se administra quinina o mefloquina como tratamiento preventivo o curativo contra la malaria.

ABSTRACT Introduction: Hemoglobinuric bilious fever is one of the complications of severe malaria, infrequently notified, characterized by an acute intravascular hemolysis, massive in occasions, that leads to homoglobinuria and, finally to an acute renal lesion. Objective: To describe a case of hemoglobinuric bilious fever as clinical presentation of severe acute malaria. Clinical case: Male patient from a malaria-endemic area with a history of recurrent events of malaria, who, on the third day after receiving antimalarial chemoprophylaxis with mefloquine, presented with malaise, marked asthenia, fatigue, nausea, vomiting, diffuse abdominal pain, and scanty and dark urine emission, described by the patient as "Coca-Cola" like. Hemoglobinuric bilious fever was diagnosed as clinical presentation of severe acute malaria of low parasitemia, confirmed by malaria-positive quick diagnostic test and thick film, and massive homoglobinuria on urine dipstick test. Conclusions: This case represents an uncommon presentation of the disease, which is not usually suspected. This paper alerts physicians working in malaria-endemic areas to be attentive. This dread complication could be the clinical presentation of severe malaria, especially in patients chronically exposed to Plasmodium falciparum infection, who present with massive acute hemolytic reaction in the absence of high parasitemia when quinine or mefloquine is administered as preventive or curative treatment against malaria.

Treatment of Artemisinin-Resistant Plasmodium falciparum Malaria in India

Background: Treatment failure in P. falciparum malaria is a major dilemma that faces health care workers throughout the country. True drug resistance is one of the causes after ruling out compliance and drug quality issues. The other cause is re-infection with a new strain of the parasite during the treatment period. Objectives: To find out what are the antimalarials prescribed in India for the treatment of Artemisininresistant P. falciparum malaria. Methods: By reviewing documents published by the National Vector Borne Disease Control Programme. Results: It is found that a combination of oral Quinine and oral Clindamycin can be given for Artemisinin-resistant P. falciparum malaria. Conclusions: There is a lack of awareness among health care providers on how to treat artemisinin-resistant P. falciparum malaria. This paper addresses this concern.

Quinine oxidoreductase 1 inhibits the secretion of IL-8 in Mycoplasma pneumoniae lipid-associated membrane proteins stimulated the THP-1 monocyte line / 中华微生物学和免疫学杂志

Objective:To investigate the effects and regulation mechanism of lipid-associated membrane proteins (LAMPs) derived from Mycoplasma pneumoniae( Mp) on the expression of quinine oxidoreductase 1 (NQO-1) in human monocyte cell line THP-1 cells, and to know the effect of NQO-1 to interleukin 8 secretion in LAMPs stimulated cells, so as to better understand the regulation mechanism upon Mp infection. Methods:Mp were cultivated and the precipitate was collected to extract LAMPs. The cytotoxicity of LAMPs to THP-1 cells was analyzed by using CCK8 test. THP-1 cells were cultured in vitro with different concentrations of LAMPs for different times, and the expression of NQO-1 protein was detected by Western blot. Nrf2 siRNA was used to investigate the role of Nrf2 in NQO-1 expression in LAMPs induced cells, and NQO-1 inhibitor Diminutol was performed to test whether they blocked interleukin 8 (IL-8) secretion when treated with LAMPs in THP-1 cells. Results:LAMPs extracted from Mp had no cytotoxicity to THP-1 cells. The expression of NQO-1 protein in LAMPs-stimulated THP-1 cells showed a dose-dependent and time-dependent manner. The production of NQO-1 protein reached peaks when treated with 5.0 μg/ml or 7.5 μg/ml of LAMPs for 12 h. Silencing of Nrf2 by siRNA significantly decreased NQO-1 production, and blocking NQO-1 by Dim increased the level of IL-8 in LAMPs-stimulated cells. Conclusions:LAMPs derived from Mp induced the expression of NQO-1 protein in THP-1 cells via Nrf2, and NQO-1 can inhibit IL-8 secretion in LAMPs stimulated monocytes.

Atovaquone, chloroquine, primaquine, quinine and tetracycline: antiproliferative effects of relevant antimalarials on Neospora caninum / Atovaquona, cloroquina, primaquina, quinino e tetraciclina: efeitos antiproliferativos de antimaláricos relevantes em Neospora caninum

Abstract Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis, and drug repositioning is a fast strategy to test possible candidates against N. caninum. In this article, we describe the effects of atovaquone, chloroquine, quinine, primaquine and tetracycline on N. caninum proliferation. The IC50 concentrations in N. caninum were compared to the current information based on previous studies for Plasmodium and Toxoplasma gondii, correlating to the described mechanisms of action of each tested drug. The inhibitory patterns indicate similarities and differences among N. caninum, Plasmodium and T. gondii. For example, atovaquone demonstrates high antiparasitic activity in all the analyzed models, while chloroquine does not inhibit N. caninum. On the other hand, tetracycline is effective against Plasmodium and N. caninum, despite its low activity in T. gondii models. The repurposing of antimalarial drugs in N. caninum is a fast and inexpensive way to develop novel formulations using well-established compounds.

Resumo Neospora caninum é um parasita Apicomplexa relacionado a abortos no gado bovino, que resultam em impactos econômicos. Não há tratamento comercial para neosporosis e o reposicionamento de drogas indica uma estratégia rápida para testar candidatos anti-N. caninum. Neste artigo, são descritos os efeitos da atovaquona, cloroquina, quinino, primaquine e tetraciclina na proliferação de N. caninum. As concentrações IC50 em N. caninum foram comparadas com a informação disponível, baseada em estudos publicados previamente para Plasmodium e Toxoplasma gondii, incluindo a correlação com os mecanismos de ação descritos para cada droga testada. Os padrões de inibição indicam pontos de similaridades e diferenças entre N. caninum, Plasmodium e T. gondii. Por exemplo, a atovaquona demonstra uma alta atividade antiparasitária em todos os modelos testados, enquanto a cloroquina não inibe N. caninum. Por outro lado, a tetraciclina é efetiva contra Plasmodium e N. caninum, em contraste com a baixa atividade em modelos de T. gondii. O reposicionamento de drogas antimaláricas em N. caninum é uma forma rápida e de baixo custo para o desenvolvimento de novas formulações que usam compostos bem estabelecidos.

Hidroxicloroquina: Del fármaco de herencia Inca hasta la inmunología moderna / Hydroxychloroquine: Inca inheritance drug to modern immunology

Resumen La hidroxicloroquina es un antiguo fármaco proveniente del árbol de quino (Cinchona pubescens), a partir del componente químico alcaloide llamado quinina. Sus primeros usos se documentaron en el Imperio Inca del Perú. Se caracteriza por distintos efectos beneficiosos en enfermedades inmunológicas, al disminuir los procesos de autoinflamación y autoinmunidad persistente. Esta revisión se enfoca en describir los mecanismos inmunomoduladores de la hidroxicloroquina, así como los efectos del fármaco en algunas de las enfermedades autoinmunes más prevalentes: lupus eritematoso sistémico, artritis reumatoide, síndrome de Sjögren, vasculitis sistémicas, nefropatía por IgA, síndrome antifosfolípido, distintas enfermedades inmunológicas de la piel. También se revisarán los efectos adversos descritos para este fármaco, especialmente la toxicidad de retina, que es el más temido.

Abstract Hydroxychloroquine is an old drug derived from the quino tree (Cinchona pubescens), from the alkaloid chemical component called quinine. Its first uses trace back to the Inca empire of Peru. It is characterized by different beneficial effects in immunological diseases, decreasing the processes of autoinflammation and persistent autoimmunity. This review focuses on describing the immunomodulatory mechanisms of hydroxychloroquine as well as the effects of the drug on some of the most prevalent autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, systemic vasculitis, IgA nephropathy, antiphospholipid syndrome, different skin-related autoimmune disorders. The main adverse effects will be revised, focusing in the retinal toxicity.

Effects of Intraduodenal Infusion of the Bitter Tastant, Quinine, on Antropyloroduodenal Motility, Plasma Cholecystokinin, and Energy Intake in Healthy Men

BACKGROUND/AIMS: Nutrient-induced gut hormone release (eg, cholecystokinin [CCK]) and the modulation of gut motility (particularly pyloric stimulation) contribute to the regulation of acute energy intake. Non-caloric bitter compounds, including quinine, have recently been shown in cell-line and animal studies to stimulate the release of gastrointestinal hormones by activating bitter taste receptors expressed throughout the gastrointestinal tract, and thus, may potentially suppress energy intake without providing additional calories. This study aims to evaluate the effects of intraduodenally administered quinine on antropyloroduodenal pressures, plasma CCK and energy intake. METHODS: Fourteen healthy, lean men (25 ± 5 years; BMI: 22.5 ± 2.0 kg/m²) received on 4 separate occasions, in randomized, double-blind fashion, 60-minute intraduodenal infusions of quinine hydrochloride at doses totaling 37.5 mg (“Q37.5”), 75 mg (“Q75”) or 225 mg (“Q225”), or control (all 300 mOsmol). Antropyloroduodenal pressures (high-resolution manometry), plasma CCK (radioimmunoassay), and appetite perceptions/gastrointestinal symptoms (visual analog questionnaires) were measured. Ad libitum energy intake (buffet-meal) was quantified immediately post-infusion. Oral quinine taste-thresholds were assessed on a separate occasion using 3-alternative forced-choice procedure. RESULTS: All participants detected quinine orally (detection-threshold: 0.19 ± 0.07 mmol/L). Intraduodenal quinine did not affect antral, pyloric or duodenal pressures, plasma CCK (pmol/L [peak]; control: 3.6 ± 0.4, Q37.5: 3.6 ± 0.4, Q75: 3.7 ± 0.3, Q225: 3.9 ± 0.4), appetite perceptions, gastrointestinal symptoms or energy intake (kcal; control: 1088 ± 90, Q37.5: 1057 ± 69, Q75: 1029 ±70, Q225: 1077 ± 88). CONCLUSION: Quinine, administered intraduodenally over 60 minutes, even at moderately high doses, but low infusion rates, does not modulate appetite-related gastrointestinal functions or energy intake.

A novel quantified bitterness evaluation model for traditional Chinese herbs based on an animal ethology principle

Traditional Chinese herbs (TCH) are currently gaining attention in disease prevention and health care plans. However, their general bitter taste hinders their use. Despite the development of a variety of taste evaluation methods, it is still a major challenge to establish a quantitative detection technique that is objective, authentic and sensitive. Based on the two-bottle preference test (TBP), we proposed a novel quantitative strategy using a standardized animal test and a unified quantitative benchmark. To reduce the difference of results, the methodology of TBP was optimized. The relationship between the concentration of quinine and animal preference index (PI) was obtained. Then the PI of TCH was measured through TBP, and bitterness results were converted into a unified numerical system using the relationship of concentration and PI. To verify the authenticity and sensitivity of quantified results, human sensory testing and electronic tongue testing were applied. The quantified results showed a good discrimination ability. For example, the bitterness of Coptidis Rhizoma was equal to 0.0579 mg/mL quinine, and Nelumbinis Folium was equal to 0.0001 mg/mL. The validation results proved that the new assessment method for TCH was objective and reliable. In conclusion, this study provides an option for the quantification of bitterness and the evaluation of taste masking effects.

Morpho-anatomy and chemical profile of native species used as substitute of quina (Cinchona spp.) in Brazilian traditional medicine. Part II: Remijia ferruginea

ABSTRACT This research is part of a larger study of the Brazilian species that are commonly referred to as "quinas" and used as substitute of Cinchona species. In this study, we have performed the botanical characterization of the stem bark of Remijia ferruginea (A. St.-Hil.) DC., Rubiaceae, by morphological and anatomical description, and the analysis of its chemical profile. Stem bark is thin and has the color and the texture of its external and internal surfaces as diagnostic features. Types and sizes of sclerified cells in the cortical parenchyma and in the secondary phloem are important features for analysis of the transversal sections and in the macerate. Alkaloids, flavonoids and chlorogenic acid were detected in the chemical analysis for TLC. These standard references can be used in the quality control of the bark of quinas.

Correlation between mRNA and protein expression of quinine nicotinamide adenine dinucleotide dehydrogenase 1 and heme oxygenase 1 and liver injury due to coal arsenic poisoning / 中华地方病学杂志

Objective To detect the mRNA and protein expression of downstream quinine nicotinamide adenine dinucleotide (NADH) dehydrogenase 1 (NQO1) and heme oxygenase 1 (HO-1) induced by blood nuclearrelated factor E2 (Nrf2) in the peripheral blood of those exposed to arsenic in the endemic area of coal arsenic poisoning in Guizhou Province,and to discuss its role in the process of occurrence and development of liver injury due to coal arsenic poisoning.Methods Jiaole and Changqing villages in coal-burning-borne arsenism areas in Xingren County of Guizhou were selected as the survey sites,and 161 cases of arsenic-exposed residents were selected as the arsenic exposed group based on physical examination.They were divided into non-patient group (21 cases) and patient group (140 cases) according to the Diagnostic Criteria of Endemic Arsenism (WS/T 211-2001),and the patient group was further divided into mild hepatosis group (52 cases),moderately severe hepatosis group (36 cases) and non-apparent hepatosis group (52 cases) according to the Diagnostic Criteria of Occupational Chronic (GBZ 59-2010).Moreover,45 residents from one village neighboring to non-epidemic area were selected as controls.Peripheral blood samples were collected from all subjects.And mRNA expression of NQO1 and HO-1 were detected by RT-qPCR.Content of NQQ1 and HO-1 were detected by enzyme linked immunosorbent assay (ELISA).Results (①)Results of mRNA expression of NQ01 and HO-1:the relative expression level of mRNA of NQO1 and HO-1 in peripheral blood went up gradually as the degree of liver injury of population exposed to arsenic increased (F =5.548,10.961,all P ＜ 0.05);thereinto,the relative expression level of mRNA of NQO1 of mild hepatosis group (median:0.918) was higher than that of the control group (0.576,P ＜ 0.05),the relative expression level of mRNA of NQO1 of moderately severe hepatosis group (1.243) was higher than those of control group,non-patient group (0.653),non-apparent hepatosis group (0.636) and mild hepatosis group (all P ＜ 0.05);the relative expression level of mRNA of HO-1 of non-patient group (1.059),non-apparent hepatosis group (1.225),mild hepatosis group (1.553) and moderately severe hepatosis group (1.604) were higher than that of control group (0.767,all P ＜ 0.05);the relative expression level of mRNA of HO-1 of mild hepatosis group was higher than that of non-patient group (P ＜ 0.05);the relative expression level of mRNA of HO-1 of moderately severe hepatosis group was higher than those of non-patient group and non-apparent hepatosis group (all P ＜ 0.05).②)Results of protein expression of NQO-1 and HO-1:the level of protein expression of NQO1 and HO-1 in serum went up gradually as the degree of liver injury of population exposed to arsenic increased (F =19.685,17.725,all P ＜ 0.05).Thereinto,the protein expression of NQO1 and HO-1 of non-apparent hepatosis group,mild hepatosis group and moderately severe hepatosis group [NQO1:(6.272 ± 0.744),(6.336 ± 0.628),(6.714 ± 0.540) U/L;HO-1:(45.150 ± 4.813),(45.283 ± 5.049),(48.610 ± 5.365) U/L] were higher than those of control group and non-patient group [NQO1:(5.550 ± 0.730),(5.750 ± 0.427) U/L;HO-1:(39.856 ± 5.249),(42.375 ± 3.014) U/L,all P ＜ 0.05],the protein expression of NQO1 and HO-1 of moderately severe hepatosis group were higher than those of non-apparent hepatosis group and mild hepatosis group (all P ＜ 0.05).Conclusion The expression of mRNA and protein of NQO1 and HO-1 is closely related to the occurrence and development of liver injury due to arsenic exposure in coal arsenic poisoning areas.

Blackwater Fever Followed by Severe Falciparum Malaria in a Child

Blackwater fever is a serious clinical syndrome manifested by acute intravascular hemolysis, fever, and the passage of black or red urine, which is classically associated with falciparum malaria and irregular administration of quinine. In Korea, Plasmodium vivax is the only endemic malaria circulating; a number of imported cases of falciparum malaria have been reported in patients following return from international travel to a malaria endemic area. Therefore, it is important for health care professionals including pediatricians to be aware of the falciparum malaria and its clinical courses. Herein, we report a case of a 14-year-old girl with severe falciparum malaria that was complicated by blackwater fever.

Research progress on chemical constituents, pharmacological action, and clinical application of Reduning Injection / 中草药

Reduning Injection (RI) has the effects of clearing heat, dispelling wind, and detoxification. It has been proved to be widely used for the treatment of wind-heat cold, cough, fever, upper respiratory tract infection, and acute bronchitis with good therapeutic effect and high security in clinical practice. Main chemical composition of RI includes iridoids, lignans, coumarins, sesquiterpenoids, flavonoids, coffee acyl quinine acids, phenolic acids, etc. This paper reviews domestic and foreign researches about RI in recent years and summarizes the chemical constituents, pharmacological action, and clinical application.

Quinine-Loaded Polymeric Nanoparticles: Validation of a simple HPLC-PDA Method to Determine Drug Entrapment and Evaluation of its Photostability.

Liquid chromatographic method was developed and validated for quantitative determination of quinine in polymeric nanoparticles. The method was performed using a Waters RP-18 column using a mobile phase consisting of acetonitrile:water:triethylamine (60:40:0.01 v/v/v, and pH aqueous phase adjusted to 3.0 with phosphoric acid). The flow rate was 1.0 mL min-1 and the detection was achieved with a UV-PDA set at 232 nm. The response was linear over a range of 12.0 to 24.0 μg.mL-1 (r = 0.9995). The relative standard deviation values for intra-day and inter-day precision studies were less than 2% and the accuracy was 98.8% to Nc1 and 97.3% to Nc2. The samples free of quinine and quinine-loaded polymeric nanoparticles were subjected to photodegradation conditions. A considerable reduction of degradation of quinine occurred in polymeric nanoparticles. Through these results, it was clear that the nanoencapsulation of quinine protects the drug from degradation by exposure to UV-A light. The analytical method was validated according to International Conference on Harmonization Guidelines and Center for Drug Evaluation and Research.

Establishment and application of screening model for anti-asthmatic natural active ingredients based on bitter taste receptors in lung tissue / 中草药

Objective: To construct high-throughput screening cell model targeting TAS2R14 receptor and lay the foundation for the search of effective, novel natural anti-asthma drugs with low toxicity. Methods: The pLVX-AcGFP1-N1-TAS2R14 lentivirus vector carrying green fluorescent protein (GFP) was constructed. The lentiviral vector was transfected into HEK HEK293T cells, collected high titer lentiviral concentration liquid and infected HEK293T cells, established cell model highly specific expressed TAS2R14 receptor gene. The TAS2R14 cell model was used to screen 120 kinds of Chinese herb extracts and chemical monomers. Results: The calculated Z' values of the cell model were 0.69 and 0.66, and Citri Reticulatae Pericarpium extract and its efficacy material limonin, Ginkgo Semen extract and its efficacy material rutin and quinine agitated TAS2R14 cell model. Conclusion: The constructed TAS2R14 cell model is stable and sensitive for screening anti-asthma drugs, and three kinds of Chinese materia medica monomers have the potential agonist the activity on TAS2R14 receptor.

Comparison of artesunate and quinine in the treatment of severe falciparum malaria: a randomized control trial.

Background: Severe malaria is a medical emergency that required prompt clinical assessment and management. Very few studies underwent to evaluate the best possible treatment for severe malaria. Methods: This is a prospective, randomized, open-labeled, study to evaluate the efficacy and safety of artesunate compared with quinine. Totally, 50 patients were included in each group. Patients above 18 years, peripheral smear positive and fulfilling the WHO criteria were included. The endpoint of the study was fever clearance time (FCT), parasite clearance time (PCT) and coma resolution time (CRT), and the adverse effect if any were compared for safety analysis. Results: FCT and PCT were much less with artesunate (29.64 and 39.72 hrs) as compared to quinine (51.12 and 55.20 hrs). CRT was less with quinine (25.80 hrs) than artesunate (42 hrs). The incidence of adverse effects such as hypoglycemia and QT prolongation are significant with quinine compared to artesunate. Conclusions: Artesunate is a better alternative for severe malaria with minimal side effects.

Historical story on natural medicinal chemistry: Great charm of study on natural product chemistry / 中草药

The new drugs and the novel theories developed from natural products chemistry study have made important contribution for scientific progress. In this paper, the success achieved in natural product research was briefly reviewed, which would broaden the outlook of young researchers and arouse their interest in this area.

The Bitter Taste Receptor Agonist Quinine Reduces Calorie Intake and Increases the Postprandial Release of Cholecystokinin in Healthy Subjects

BACKGROUND/AIMS: Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects. METHODS: Twenty healthy volunteers were enrolled in a double-blind cross-over study. On 2 different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status. RESULTS: Calorie intake was significantly lower when subjects received HCl quinine than placebo (514 +/- 248 vs 596 +/- 286 kcal; P = 0.007). Significantly higher CCK DeltaT90 vs T0 and DeltaT90 vs T60 were found when subjects received HCl quinine than placebo (0.70 +/- 0.69 vs 0.10 +/- 0.86 ng/mL, P = 0.026; 0.92 +/- 0.75 vs 0.50 +/- 0.55 ng/mL, P = 0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526 +/- 275 vs 659 +/- 320 kcal; P = 0.005), whereas no significant differences were found for PTC non-tasters (499 +/- 227 vs 519 +/- 231 kcal; P = 0.525). CONCLUSIONS: This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake.

Partial characterization of Plasmodium falciparum trophozoite proteome under treatment with quinine, mefloquine and the natural antiplasmodial diosgenone / Caracterización parcial del proteoma del trofozoíto de Plasmodium falciparum bajo tratamiento con quinina, mefloquina y el compuesto natural diosgenona

Introduction: Despite efforts to control malaria, around 10% of the world population is at risk of acquiring this disease. Plasmodium falciparum accounts for the majority of severe cases and deaths. Malaria control programs have failed due to the therapeutic failure of first-line antimalarials and to parasite resistance. Thus, new and better therapeutic alternatives are required. Proteomic analysis allows determination of protein expression levels under drug pressure, leading to the identification of new therapeutic drug targets and their mechanisms of action. Objective: The aim of this study was to analyze qualitatively the expression of P.falciparum trophozoite proteins (strain ITG2), after exposure to antimalarial drugs, through a proteomic approach. Materials and methods: In vitro cultured synchronized parasites were treated with quinine, mefloquine and the natural antiplasmodial diosgenone. Protein extracts were prepared and analyzed by two-dimensional electrophoresis. The differentially expressed proteins were selected and identified by MALDI-TOF mass spectrometry. Results: The following proteins were identified among those differentially expressed in the parasite in the presence of the drugs tested: enolase (PF10_0155), calcium-binding protein (PF11_0098), chaperonin (PFL0740c), the host cell invasion protein (PF10_0268) and proteins related to redox processes (MAL8P1.17). These findings are consistent with results of previous studies where the parasite was submitted to pressure with other antimalarial drugs. Conclusion: The observed changes in the P. falciparum trophozoite protein profile induced by antimalarial drugs involved proteins mainly related to the general stress response.

Introducción. A pesar de los esfuerzos para controlar la malaria, esta sigue siendo un problema de salud pública. Plasmodium falciparum es responsable de la mayoría de los casos graves y de las muertes. Los programas de control de la malaria han sido cuestionados debido al fracaso del tratamiento y a la resistencia del parásito a los antipalúdicos de primera línea, por lo que se requieren nuevas y mejores alternativas. El análisis proteómico permite identificar y determinar los niveles de expresión de las proteínas bajo la presión de los medicamentos, lo que posibilita la identificación de nuevos blancos terapéuticos y mecanismos de acción. Objetivo. Analizar cualitativamente la expresión diferencial de proteínas del citosol del trofozoíto de P. falciparum bajo tratamiento con quinina, mefloquina y el compuesto natural diosgenona mediante una aproximación proteómica. Materiales y métodos. Se trataron trofozoítos sincronizados y cultivados in vitro de P. falciparum (cepa ITG2) con quinina, mefloquina y el compuesto natural diosgenona. Los extractos proteicos se prepararon y analizaron por electroforesis bidimensional. Las proteínas con aparente expresión diferencial se seleccionaron e identificaron mediante espectrometría de masas MALDI-TOF. Resultados. Se encontraron las siguientes proteínas diferencialmente expresadas en el trofozoíto: la enolasa (PF10_0155), la proteína de unión a calcio (PF11_0098), la chaperonina (PFL0740c), la proteína de invasión a la célula del huésped (PF10_0268) y la proteína relacionada con procesos de reducción y oxidación (redox) (MAL8P1.17). Estos hallazgos son congruentes con resultados previos de estudios en los que el parásito fue presionado con otros medicamentos antipalúdicos. Conclusión. Los cambios observados en el perfil de proteínas del trofozoíto de P. falciparum tratado con antipalúdicos involucraron preferencialmente proteínas relacionadas con la respuesta al estrés general.

Effect of Combined Quinine and Ciprofloxacin Therapy in Experimental Murine Plasmodiasis.

The increasing spread of drug-resistant malaria parasite has necessitated the continuous search for even more effective malaria treatment including the combination of drugs known to have significant anti malarial potentials. Effort in this study was therefore, devoted to evaluating in vivo, anti plasmodial activity of combination of varying doses (4.3, 8.6, 12.9 mg/kg body weight) of quinine (a known anti malarial gradually loosing relevance) with varying doses (5.0, 10.0, 15.0 mg/kg body weight) of ciprofloxacin (a fluoroquinolone commonly used to treat bacterial infections and has been shown to possess significant anti malarial activity both in vitro and in vivo) in Plasmodium berghei infected mice. Parasitological activity and survival of the animal were assessed over 21 days. Parasitemia in non-treated control mice peaked at 75% on day 9 and none survived by day 11. The lower dosages of quinine (4.3 and 8.6 mg/kg body weight) and ciprofloxacin (5.0 and 10.0 mg/kg body weight) were not efficient. However, the combination of 12.9 mg/kg body weight of quinine with 15 mg/kg body weight of ciprofloxacin achieved 87% reduction in parasitemia level and significantly reduced mortality in the infected animals compared with other treatment groups. The results from this study support the potential use of ciprofloxacin in combination with quinine for the treatment of resistant malaria.

Historical story on natural medicinal chemistry: Isolation, structure, and total synthesis of quinine / 中草药

Quinine is a very famous natural medicine that has saved millions of lives, even being believed to affect the development process of human beings. The study of quinine has left a very important record in the history of science. In this paper, the historical stories on the discovery and study of quinine are summarized in memory of the great discoveries and in honor of the scientists. It also aims at providing the references for future related research. This article is one of the series of historical stories on natural product chemistry written by the authors.

Cuantificación de quinina en extractos de Cinchona pubescens y evaluación de la actividad antiplasmodial y citotóxica / Quantification of quinine in extracts from stems Cinchona pubescens and evaluation of antiplasmodial and cytotoxic activity

Plants belonging to the genus Cinchona L. (Rubiaceae), whose active ingredient is quinine, was used for centuries to treat malaria. Plants of this genus are a potential source of new structural templates in the search for new antimalarial candidates. This study aimed to the identification, quantification of quinine and other metabolites present in extracts of different polarity of the stems of Cinchona pubescens Vahl. , oxoquinovic acid isolation, antiplasmodial activity, and measuring its cytotoxic effect. The results show a high activity to antiplasmodial alkaloids extract (IC50 = 2.20 +/- 0.0325 ug/mL), cytotoxicity (CC50 = 80.2 +/- 12.2 ug/mL), and a quinine content of 21.3+/-0.0247 ppm. The compound known as acid antiplasmodial activity oxoquinovic presented in IC50 = 11.3 +/- 0.741 ug/mL, and cytotoxicity CC50 = 72.4 +/- 3.85 ug/mL. These results motivate phytochemical studies in the search for active structural analogues quinine and quinolinic core as a source of new antimalarial agents.

Las plantas pertenecientes al género Cinchona L. (familia Rubiaceae), cuyo principio activo es la quinina, fueron utilizadas durante siglos para tratar la malaria. Este género es una fuente potencial de nuevas plantillas estructurales en la búsqueda de nuevos candidatos antimaláricos. El presente trabajo tuvo como objetivo la identificación y, cuantificación de la quinina y de otros metabolitos presentes en los extractos de diferente polaridad, de los tallos de Cinchona pubescens Vahl. , el aislamiento del ácido oxoquinóvico, la actividad antiplasmodial y, además, la medición de su efecto citotóxico. Los resultados muestran una alta actividad antiplasmodial para el extracto de los alcaloides (IC50 = 2,20 +/- 0,0325 ug/mL), una baja citotoxicidad (CC50 = 80,2 +/- 12,2 ug/mL), y un alto contenido de quinina el cual fue 21,3+/-0,0247 ppm. El compuesto ácido oxoquinóvico presentó una actividad antiplasmodial de IC50 = 11,3 +/- 0.741 ug/mL, y una citotoxicidad de CC50 = 72,4 +/- 3,85 ug/mL. Estos resultados motivan los estudios fitoquímicos en la búsqueda de principios activos y análogos estructurales en diferentes especies de Cinchonas como una fuente de nuevos agentes antimaláricos.