[A drink with an unexpected ending... Adverse reaction by tonic water: A case report]. / Una copa con final inesperado... Reacción adversa por agua tónica: reporte de un caso.

BACKGROUND: Quinine is an alkaloid with antipyretic and anti-infective properties, and also an ingredient in tonic waters. Adverse reactions have been reported with this product, such as photosensitivity, vasculitis, and contact dermatitis. CASE REPORT: A 31-year-old male patient who, after 3-4 hours of consuming "Schweppes®" gin with tonic water, manifested ulcers on the lips and oral cavity, and a fixed erythematous lesion on the second phalanx of the hand, 24 hours later. Skin tests with aeroallergens and food were negative, and 48-hour patch tests were positive (quinine [++] and "Schweppes®" [++]). Based on the test findings, the diagnosis of an adverse reaction to quinine, contained in the tonic water, will be established. CONCLUSIONS: Quinine can be found in other types of foods or medications, so it is important to establish an accurate diagnosis and offer adequate recommendations to the patient with the consumption of this product.

ANTECEDENTES: La quinina es un alcaloide con propiedades antipiréticas, antiinfecciosas y, además, un ingrediente del agua tónica. Se han descrito reacciones adversas con este producto, como fotosensibilidad, vasculitis y dermatitis de contacto. REPORTE DE CASO: Paciente masculino de 31 años, que luego de 3-4 horas de consumir ginebra con agua tónica "Schweppes®" manifestó úlceras en los labios y la cavidad bucal, y una lesión eritematosa fija en la segunda falange de la mano, 24 horas después. Las pruebas cutáneas con aeroalérgenos y alimentos resultaron negativas, y las pruebas epicutáneas de 48 horas positivas (quinina [++] y "Schweppes®" [++]). Con base en los hallazgos de las pruebas, se estableció el diagnóstico de reacción adversa por quinina, contenida en el agua tónica. CONCLUSIÓN: La quinina puede encontrarse en diferentes alimentos o medicamentos, por lo que es importante establecer el diagnóstico preciso y ofrecer recomendaciones adecuadas por el consumo de este producto.

Palatability profile in spontaneously hypertensive rats.

The spontaneously hypertensive rats (SHRs) have enhanced palatability for NaCl taste as measured by the increased number of hedonic versus aversive responses to intraoral infusion (1 mL/1 min) of 0.3 M NaCl, in a taste reactivity test in euhydrated condition or after 24 h of water deprivation + 2 h of partial rehydration (WD-PR). SHRs also ingested more sucrose than normotensive rats, without differences in quinine hydrochloride intake. Here, we investigated the palatability of SHRs (n = 8-10) and normotensive Holtzman rats (n = 8-10) to sucrose and quinine sulphate infused intraorally in the same conditions that NaCl palatability was increased in SHRs. SHRs had similar number of hedonic responses to 2% sucrose in euhydrated condition (95 ± 19) or after WD-PR (142 ± 25), responses increased when compared with normotensive rats in euhydrated condition (13 ± 3) or after WD-PR (21 ± 6). SHRs also showed increased number of aversive responses to 1.4 mM quinine sulphate compared with normotensive rats, whether in euhydrated condition (86 ± 6, vs. normotensive: 54 ± 7) or after WD-PR (89 ± 9, vs. normotensive: 40 ± 9). The results suggest that similar to NaCl taste, sweet taste responses are increased in SHRs and resistant to challenges in bodily fluid balance. They also showed a more intense aversive response in SHRs to bitter taste compared with normotensives. This suggests that the enhanced response of SHRs to taste rewards does not correspond to a decreased response to a typical aversive taste.

Chemosensory representation of first-time oral exposure to ethanol in the orbitofrontal cortex of mice.

Intermittent ethanol consumption changes the neuronal activity of the orbitofrontal cortex (OFC) in rodents, which has been attributed to important participation in the development of addiction, particularly alcoholism. The OFC participates in gustatory sensory integration. However, it is unknown whether this region can encode chemosensory elements of oral ethanol administration independently of the consumption movement (orofacial motor response) when administered for the first time (naïve mice). To answer this question, we used a sedated mouse model and a temporary analysis protocol to register extracellular neuronal responses during the oral administration of ethanol. Our results show an increase in neuronal frequency (in the first 500 ms) when low (0.6, 1, and 2.1 M) and high (3.2, 4.3, and 8.6 M) concentrations of ethanol are orally administered. The modulatory effect of ethanol was observed from low and high concentrations and differed from the tastants. There was consistent neuronal activity independent of the concentration of ethanol. Our results demonstrate a sensory representation of oral ethanol stimulation in the OFC neurons of naïve mice under sedation.

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.

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.

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

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.(AU)

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.(AU)

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 Surface Characteristics of Polymeric Nanocapsules on the Pharmacokinetics and Efficacy of Antimalarial Quinine.

INTRODUCTION: The surface charge of nanoparticles, such as nanospheres (NS) and nanocapsules (NC), has been studied with the purpose of improving the in vivo performance of drugs. The aim of this study was to develop, characterize, and evaluate the in vitro antimalarial efficacy of NCP80 and NSP80 (polysorbate coated) or NCEUD and NSEUD (prepared with Eudragit RS 100) loading quinine (QN). METHODS: Formulations were prepared by the nanoprecipitation method, followed by wide physicochemical characterization. Antimalarial activity in Plasmodium berghei-infected mice and populational pharmacokinetics (PopPK) in rats were evaluated. RESULTS: The formulations showed a nanometric range (between 138 ± 3.8 to 201 ± 23.0 nm), zeta potential (mV) of -33.1 ± 0.7 (NCP80), -30.5 ± 1 (UNCP80), -25.5 ± 1 (NSP80), -20 ± 0.3 (UNSP80), 4.61 ± 1 (NCEUD), 14.1 ± 0.9 (UNCEUD), 2.86 ± 0.3 (NSEUD) and 2.84 ± 0.6 (UNSEUD), content close to 100%, and good QN protection against UVA light. There was a twofold increase in the penetration of QN into infected erythrocytes with NC compared to that with NS. There was a significant increase in t1/2 for all NC evaluated compared to that of Free-QN, due to changes in Vdss. PopPK analysis showed that NCP80 acted as a covariate to Q (intercompartmental clearance) and V2 (volume of distribution in the peripheral compartment). For NCEUD, V1 and Q were modified after QN nanoencapsulation. Regarding in vivo efficacy, NCEUD increased the survival of mice unlike Free-QN. CONCLUSION: Cationic nanocapsules modified the pharmacology of QN, presenting a potential alternative for malaria treatment.

Co-nanoencapsulation of antimalarial drugs increases their in vitro efficacy against Plasmodium falciparum and decreases their toxicity to Caenorhabditis elegans.

Drugs used for the treatment and prevention of malaria have resistance-related problems, making them ineffective for monotherapy. If properly associated, many of these antimalarial drugs may find their way back to the treatment regimen. Among the therapeutic arsenal, quinine (QN) is a second-line treatment for uncomplicated malaria but has side effects that limit its use. Curcumin (CR) is a natural compound with anti-plasmodial activities and low bioavailability. In this context, the aim of this work was to develop and characterize co-encapsulated QN + CR-loaded polysorbate-coated polymeric nanocapsules (NC-QC) to evaluate their activity on Plasmodium falciparum and the safety of the nanoformulations for Caenorhabditis elegans. NC-QC displayed a diameter of approximately 200 nm, a negative zeta potential and a slightly basic pH. The drugs are homogeneously distributed in the NCs in the amorphous form. Co-encapsulated NCs exhibited a significant reduction in P. falciparum parasitemia, better than QN/CR. The worms exposed to NC-QC showed higher survival and longevity and no decrease in their reproductive capacity compared to free and associated drugs. It was possible to prove that the NCs were absorbed orally by the worms using fluorescence microscopy. Co-encapsulation of QN and CR was effective against P. falciparum, minimizing the toxic effects caused by chronic exposure of the free drugs in C. elegans.

Influence of prenatal pre-exposure to an odor on intake behavior of an aversive solution in newborn rats.

Early pre- or postnatal sensory experiences significantly influence flavor preference and food intake, and can induce liking for innately unpalatable flavors. Previous work found that newborn rats stimulated with an odor experienced shortly after birth exhibited heightened intake and seeking towards an artificial nipple containing quinine. This result suggests that odors made familiar trough early postnatal pre-exposure can shift the motivational value of unconditional stimuli. The objective of the current study was to assess the effect of an odor (lemon) experienced in-utero on the first intake responses towards an artificial nipple supplying quinine. The hypothesis, which was corroborated, was that stimulation with the olfactory stimulus experienced in-utero would increase the newborn's intake and grasp responses to the artificial nipple containing quinine. Exposure to the odor that had been pre-exposed in utero increased quinine intake and seeking (i.e., latency to grasp and total time in contact with the nipple, as well as number of and mean duration of nipple grasps) in 3-h-old pups. These results replicate those previously found with postnatal odor pre-exposure, and extend the phase for pre-exposure to the prenatal stage.

Synthesis of novel quinine analogs and evaluation of their effects on Trypanosoma cruzi.

AIM: Chagas disease is a tropical disease caused by the hemoflagellate protozoan Trypanosoma cruzi. There is no vaccine for Chagas disease and available drugs (e.g., benznidazole) are effective only during the acute phase, displaying a variable curative activity in the established chronic form of the disease. New leads with high efficacy and better toxicity profiles are urgently required. Materials & methods: A library of novel quinine derivatives was synthesized using Heck chemistry and evaluated against the various developmental forms of T. cruzi. RESULTS AND CONCLUSION: Several novel quinine analogs with trypanocidal activity have been identified with the para-nitro-substituted derivative displaying a submicromolar IC50, which is 83-times lower than quinine and three-times lower than benznidazole. Transmission electron microscopy analysis demonstrated that these compounds induced a marked vacuolization of the kinetoplast of intracellular amastigotes and cell-derived trypomastigotes.

Quinine and carbenoxolone enhance the anticonvulsant activity of some classical antiepileptic drugs.

Objective Quinine (QUIN) and carbenoxolone (CNX) elicit anticonvulsant effects typically characterized by the reduction of the epileptiform activity as well as changes in behavioral parameters related to seizures. Therefore, the aim of this study was to analyze the effects of these molecules on the anticonvulsant activity of some classical antiepileptic drugs. Methods Male Wistar rats were used. Valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) was administered at sub-therapeutic doses for intraperitoneal via. Subsequently, animals were administered with a single dose of QUIN or CNX. The anticonvulsant activity was evaluated with the maximal electroshock (MES) test and pentylenetetrazole (PTZ) administration. Additionally, the plasma levels of CBZ were determined using an HPLC method. Results All the control rats presented generalized tonic-clonic seizures after the MES test or the administration of PTZ. For the MES test, all of the antiepileptic drugs increased their anticonvulsant activity when were co-administered with QUIN. For the PTZ test, only the combination CBZ plus QUIN significantly increased the percentage of protection against the generalized tonic-clonic seizures. The co-administration of CBZ plus QUIN resulted in an augmented concentration of CBZ in plasma. Discussion The present study shows that QUIN and CNX enhance the anticonvulsant activity of some classical antiepileptic drugs. However, only the combination CBZ/QUIN had significant effects on both MES and PTZ models. Such anticonvulsant activity could be attributed to increased levels of CBZ in plasma. We propose that these molecules could improve the pharmacological actions of antiepileptic drugs administered at sub-therapeutic doses.

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.

Phylogeny Predicts the Quantity of Antimalarial Alkaloids within the Iconic Yellow Cinchona Bark (Rubiaceae: Cinchona calisaya).

Considerable inter- and intraspecific variation with respect to the quantity and composition of plant natural products exists. The processes that drive this variation remain largely unknown. Understanding which factors determine chemical diversity has the potential to shed light on plant defenses against herbivores and diseases and accelerate drug discovery. For centuries, Cinchona alkaloids were the primary treatment of malaria. Using Cinchona calisaya as a model, we generated genetic profiles of leaf samples from four plastid (trnL-F, matK, rps16, and ndhF) and one nuclear (ITS) DNA regions from twenty-two C. calisaya stands sampled in the Yungas region of Bolivia. Climatic and soil parameters were characterized and bark samples were analyzed for content of the four major alkaloids using HPLC-UV to explore the utility of evolutionary history (phylogeny) in determining variation within species of these compounds under natural conditions. A significant phylogenetic signal was found for the content of two out of four major Cinchona alkaloids (quinine and cinchonidine) and their total content. Climatic parameters, primarily driven by changing altitude, predicted 20.2% of the overall alkaloid variation, and geographical separation accounted for a further 9.7%. A clade of high alkaloid producing trees was identified that spanned a narrow range of altitudes, from 1,100 to 1,350 m. However, climate expressed by altitude was not a significant driver when accounting for phylogeny, suggesting that the chemical diversity is primarily driven by phylogeny. Comparisons of the relative effects of both environmental and genetic variability in determining plant chemical diversity have scarcely been performed at the genotypic level. In this study we demonstrate there is an essential need to do so if the extensive genotypic variation in plant biochemistry is to be fully understood.

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.

Kissing bugs can generalize and discriminate between different bitter compounds.

Animals make use of contact chemoreception structures to examine the quality of potential food sources. During this evaluation they can detect nutritious compounds that promote feeding and recognize toxins that trigger evasive behaviors. Although animals can easily distinguish between stimuli of different gustatory qualities (bitter, salty, sweet, etc.), their ability to discriminate between compounds of the same quality may be limited. Numerous plants produce alkaloids, compounds that elicit aversive behaviors in phytophagous insects and almost uniformly evoke a bitter taste for man. In hematophagous insects, however, the effect of feeding deterrent molecules has been barely studied. Recent studies showed that feeding in Rhodnius prolixus can be negatively modulated by the presence of alkaloids such as quinine (QUI) and caffeine (CAF), compounds that elicit similar aversive responses. Here, we applied associative and non-associative learning paradigms to examine under two behavioral contexts the ability of R. prolixus to distinguish, discriminate and/or generalize between these two bitter compounds, QUI and CAF. Our results show that bugs innately repelled by bitter compounds can change their behavior from avoidance to indifference or even to preference according to their previous experiences. After an aversive operant conditioning with QUI or CAF, R. prolixus modified its behavior in a direct but also in a cross-compound manner, suggesting the occurrence of a generalization process between these two alkaloids. Conversely, after a long pre-exposure to each alkaloid, bugs decreased their avoidance to the compound used during pre-exposure but still expressed an avoidance of the novel compound, proving that QUI and CAF are detected separately. Our results suggest that R. prolixus is able to discriminate between QUI and CAF, although after an associative conditioning they express a symmetrical cross-generalization. This kind of studies adds insight into the gustatory sense of a blood-sucking model but also into the learning abilities of hematophagous insects.

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.

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.

Relationship between plasma and red blood cell concentrations of quinine in Brazilian children with uncomplicated Plasmodium falciparum malaria on oral therapy / Relação entre as concentrações plasmáticas e eritrocitárias de quinina em crianças com malária por Plasmodium falciparum não complicada em terapia via oral

We determined the relationship between plasma and red blood cell concentrations of quinine in children with uncomplicated falciparum malaria from an endemic area of Amazonian region. Quinine was determined by high performance liquid chromatography with ultraviolet detection. In the steady state the ratio between plasma and red blood cell quinine concentration was 1.89 ± 1.25 ranging from 1.05 to 2.34. This result demonstrated that quinine do not concentrate in red blood cell of Brazilian children and characterize the absence of interracial difference in this relationship.

Neste estudo foi determinada a relação entre as concentrações plasmáticas e eritrocitárias de quinina em crianças com malária falciparum não complicada, oriundas de área endêmica da Região Amazônica. A quinina foi detrminada por cromatografia líquida de alta eficiência. No estado de equilíbrio, a relação foi 1,89 ± 1,25 variando de 1,05 a 2,34. Estes resultados demonstraram que a quinina não se concentra nos eritrócitos das crianças e caracterizaram a ausência de diferença racial nesta relação.