Ex vivo susceptibilities to ganaplacide and diversity in potential resistance mediators in Ugandan Plasmodium falciparum isolates.

Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the Plasmodium falciparum cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-galactose transporter (PfUGT). To characterize parasites causing disease in Africa, we assessed ex vivo drug susceptibilities to ganaplacide in 750 P. falciparum isolates collected in Uganda from 2017 to 2023. Drug susceptibilities were assessed using a 72-hour SYBR Green growth inhibition assay. The median IC50 for ganaplacide was 13.8 nM, but some isolates had up to 31-fold higher IC50s (31/750 with IC50 > 100 nM). To assess genotype-phenotype associations, we sequenced genes potentially mediating altered ganaplacide susceptibility in the isolates using molecular inversion probe and dideoxy sequencing methods. PfCARL was highly polymorphic, with eight mutations present in >5% of isolates. None of these eight mutations had previously been selected in laboratory strains with in vitro drug pressure and none were found to be significantly associated with decreased ganaplacide susceptibility. Mutations in PfACT and PfUGT were found in ≤5% of isolates, except for two frequent (>20%) mutations in PfACT; one mutation in PfACT (I140V) was associated with a modest decrease in susceptibility. Overall, Ugandan P. falciparum isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with in vitro drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility.

Antimalarial Drugs at the Intersection of SARS-CoV-2 and Rheumatic Diseases: What Are the Potential Opportunities?

Background and Objectives: The coronavirus disease of 2019 (COVID-19) pandemic has posed a serious threat to humanity and is considered a global health emergency. Antimalarial drugs (ADs) have been used in the treatment of immuno-inflammatory arthritis (IIA) and coronavirus infection (COVID-19). The aim of this review is to analyze the current knowledge about the immunomodulatory and antiviral mechanisms of action, characteristics of use, and side effects of antimalarial drugs. Material and Methods: A literature search was carried out using PubMed, MEDLINE, SCOPUS, and Google Scholar databases. The inclusion criteria were the results of randomized and cohort studies, meta-analyses, systematic reviews, and original full-text manuscripts in the English language containing statistically confirmed conclusions. The exclusion criteria were summary reports, newspaper articles, and personal messages. Qualitative methods were used for theoretical knowledge on antimalarial drug usage in AIRDs and SARS-CoV-2 such as a summarization of the literature and a comparison of the treatment methods. Results: The ADs were considered a "candidate" for the therapy of a new coronavirus infection due to mechanisms of antiviral activity, such as interactions with endocytic pathways, the prevention of glycosylation of the ACE2 receptors, blocking sialic acid receptors, and reducing the manifestations of cytokine storms. The majority of clinical trials suggest no role of antimalarial drugs in COVID-19 treatment or prevention. These circumstances do not allow for their use in the treatment and prevention of COVID-19. Conclusions: The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for COVID-19. Furthermore, the need for high doses in the treatment of viral infections increases the likelihood of gastrointestinal side effects, the prolongation of QT, and retinopathy. Large randomized clinical trials (RCTs) have refuted the fact that there is a positive effect on the course and results of COVID-19.

In vitro interaction of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen in the asexual blood stage of Plasmodium falciparum 3D7.

Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies. IMPORTANCE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.

Exploring the unexplored chemical space: Rational identification of new Tafenoquine analogs with antimalarial properties.

Patents tend to define a huge chemical space described by the combinatorial nature of Markush structures. However, the optimization of new principal active ingredient is frequently driven by a simple Free Wilson approach. This procedure leads to a highly focused study on the chemical space near a hit compound leaving many unexplored regions that may present highly biological active reservoirs. This study aims to demonstrate that this unveiled chemical space can hide compounds with interesting potential biological activity that would be worth pursuing. This underlines the value and necessity of broadening an approach beyond conventional strategies. Hence, we advocate for an alternative methodology that may be more efficient in the early drug discovery stages. We have selected the case of Tafenoquine, a single-dose treatment for the radical cure of P. vivax malaria approved by the FDA in 2018, as an example to illustrate the process. Through the deep exploration of the Tafenoquine chemical space, seven compounds with potential antimalarial activity have been rationally identified and synthesized. This small set is representative of the chemical diversity unexplored by the 58 analogs reported to date. After biological assessment, results evidence that our approach for rational design has proven to be a very efficient exploratory methodology suitable for the early drug discovery stages.

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.

Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of antimalarial drug resistant strains of Plasmodium falciparum. Heat shock proteins (HSPs), particularly P. falciparum HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages. Despite structural similarities between human and malarial HSPs posing challenges, there is substantial evidence for subtle differences that could be exploited for selective drug targeting. This review provides an update on the potential of targeting various PfHSP families (particularly PfHSP40, PfHSP70, and PfHSP90) and their interactions within PfHSP complexes as a strategy to develop new antimalarial drugs. In addition, the need for a deeper understanding of the role of HSP complexes at the host-parasite interface is highlighted, especially heterologous partnerships between human and malarial HSPs, as this opens novel opportunities for targeting protein-protein interactions crucial for malaria parasite survival and pathogenesis.

Nanotherapeutics against malaria: A decade of advancements in experimental models.

Malaria, caused by different species of protists of the genus Plasmodium, remains among the most common causes of death due to parasitic diseases worldwide, mainly for children aged under 5. One of the main obstacles to malaria eradication is the speed with which the pathogen evolves resistance to the drug schemes developed against it. For this reason, it remains urgent to find innovative therapeutic strategies offering sufficient specificity against the parasite to minimize resistance evolution and drug side effects. In this context, nanotechnology-based approaches are now being explored for their use as antimalarial drug delivery platforms due to the wide range of advantages and tuneable properties that they offer. However, major challenges remain to be addressed to provide a cost-efficient and targeted therapeutic strategy contributing to malaria eradication. The present work contains a systematic review of nanotechnology-based antimalarial drug delivery systems generated during the last 10 years. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease.

Ex vivo drug susceptibility and resistance mediating genetic polymorphisms of Plasmodium falciparum in Bobo-Dioulasso, Burkina Faso.

Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the ex vivo susceptibility of Plasmodium falciparum to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022. IC50 values were derived using a standard 72 h growth inhibition assay. Parasite DNA was sequenced to characterize known drug resistance-mediating polymorphisms. Isolates were generally susceptible, with IC50 values in the low-nM range, to chloroquine (median IC5010 nM, IQR 7.9-24), monodesethylamodiaquine (22, 14-46) piperaquine (6.1, 3.6-9.2), pyronaridine (3.0, 1.3-5.5), quinine (50, 30-75), mefloquine (7.1, 3.7-10), lumefantrine (7.1, 4.5-12), dihydroartemisinin (3.7, 2.2-5.5), and atovaquone (0.2, 0.1-0.3) and mostly resistant to cycloguanil (850, 543-1,290) and pyrimethamine (33,200, 18,400-54,200), although a small number of outliers were seen. Considering genetic markers of resistance to aminoquinolines, most samples had wild-type PfCRT K76T (87%) and PfMDR1 N86Y (95%) sequences. For markers of resistance to antifolates, established PfDHFR and PfDHPS mutations were highly prevalent, the PfDHPS A613S mutation was seen in 19% of samples, and key markers of high-level resistance (PfDHFR I164L; PfDHPS K540E) were absent or rare (A581G). Mutations in the PfK13 propeller domain known to mediate artemisinin partial resistance were not detected. Overall, our results suggest excellent susceptibilities to drugs now used to treat malaria and moderate, but stable, resistance to antifolates used to prevent malaria.

Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) of Plasmodium falciparum.

6-Pyruvoyl tetrahydropterin synthase (6-PTPS) is a lyase involved in the synthesis of tetrahydrobiopterin. In Plasmodium species where dihydroneopterin aldolase (DHNA) is absent, it acts in the folate biosynthetic pathway necessary for the growth and survival of the parasite. The 6-pyruvoyl tetrahydropterin synthase of Plasmodium falciparum (PfPTPS) has been identified as a potential antimalarial drug target. This study identified potential inhibitors of PfPTPS using molecular docking techniques. Molecular docking and virtual screening of 62 compounds including the control to the deposited Protein Data Bank (PDB) structure was carried out using AutoDock Vina in PyRx. Five of the compounds, N,N-dimethyl-N'-[4-oxo-6-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-3H-pteridin-2-yl]methanimidamide (140296439), 2-amino-6-[(1R)-3-cyclohexyl-1-hydroxypropyl]-3H-pteridin-4-one (140296495), 2-(2,3-dihydroxypropyl)-8,9-dihydro-6H-pyrimido[2,1-b]pteridine-7,11-dione (144380406), 2-(dimethylamino)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-hydroxymethyl]-3H-pteridin-4-one (135573878), and [1-acetyloxy-1-(2-methyl-4-oxo-3H-pteridin-6-yl)propan-2-yl] acetate (136075207), showed better binding affinity than the control ligand, biopterin (135449517), and were selected and screened. Three conformers of 140296439 with the binding energy of -7.2, -7.1, and -7.0 kcal/mol along with 140296495 were better than the control at -5.7 kcal/mol. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted good pharmacokinetic properties of all the compounds while reporting a high risk of irritant toxicity in 140296439 and 144380406. The study highlights the five compounds, 140296439, 140296495, 144380406, 135573878 and 136075207, as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development.

Hematological Indicators of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in Malaria-Infected Individuals

@#Introduction: Malaria, a life-threatening infectious disease caused by Plasmodium parasites, continues to be a major global health concern, particularly in regions with high transmission rates. This retrospective cohort study aimed to investigate the hematological indicators of G6PD deficiency in individuals infected with malaria. The study utilized medical records and laboratory test results to analyze the hematological parameters and markers in individuals with confirmed malaria and G6PD deficiency. Methods: Data were collected from the laboratory unit of Mosul Teaching Hospitals in Ninevah Province, Iraq, from March 2021 to November 2022. The study population consisted of individuals diagnosed with malaria and with available G6PD deficiency test results. G6PD deficiency was determined by measuring the G6PD enzyme activity in the patient’s blood. Hematological parameters, including complete blood counts, platelet counts, and red blood cell indices, were recorded using a laboratory information system. Results: The study population exhibited a relatively low prevalence of G6PD deficiency, with no significant differences observed in age or gender distribution between individuals with and without G6PD deficiency. The distribution of malaria types did not differ significantly between the two groups. However, patients with G6PD deficiency showed a significantly higher monocyte count, indicating a potential association between G6PD deficiency and altered monocyte response during malaria infection. The clinical significance of this finding requires further investigation. Conclusion: This study sheds light on the hematological indicators of G6PD deficiency in individuals infected with malaria. The findings suggest a potential relationship between G6PD deficiency and altered monocyte response during malaria infection.

Incidence of malarial infection and response to antimalarial drugs at Districts Lower Dir and Swat of Khyber Pakhtunkhwa, Pakistan.

Malaria is the leading cause of mortality and morbidity all over the world. Several antimalarial drugs are available for the treatment of malaria. The main objective of this study was to investigate the incidence of malarial infection and the use of prescribed antimalarial drugs. A cross-sectional study was carried out to collect quantitative data from selected sites in District Lower Dir and Swat of Malakand Division Khyber Pakhtunkhwa (K.P.), Pakistan. Screening of selected patients was performed using both thick and thin films and was observed with the help of a light microscope. In this study, a total of 2517 blood samples were tested. Overall positive infection was 12% Plasmodium vivax (99.07%) and Plasmodium falciparum (0.92%). Our results evaluate that infection with Plasmodium vivax was higher than Plasmodium falciparum. No other Plasmodium species or mixed infections were observed. The rate of infection was more frequent in males as compared to female patients. The highest percentage was recorded in the summer season (35.07%), while the lowest was documented in the winter (11.7%). Out of 325 patients, 311 (95.7%) were treated with Chloroquine, and the remaining were treated with Artemether. Chloroquine was used as a drug of choice for Plasmodium vivax infection. The present study concludes that Plasmodium vivax and Plasmodium falciparum are the two common agents for malaria in Malakand Division. However, Plasmodium vivax was dominant over Plasmodium falciparum. The infection rate was high in males from District Lower Dir during the summer season.

Desarrollo y validación interna de un modelo de predicción clínica del riesgo de infección bacteriana nosocomial en pacientes con lupus eritematoso sistémico / Development and internal validation of a clinical prediction model of the risk of nosocomial bacterial infection in patients with systemic lupus erythematosus

RESUMEN Introducción: Los pacientes con lupus eritematoso sistémico (LES) tienen un riesgo aumen tado de padecer infecciones tanto adquiridas en la comunidad como asociadas con el cuidado de la salud. Las infecciones bacterianas son las más frecuentes y graves durante la hospitalización de estos pacientes. Objetivo: Desarrollar y validar internamente un modelo de predicción clínica de pronóstico del riesgo de infección bacteriana adquirida en el hospital en pacientes con LES, usando datos clínicos y de laboratorio obtenidos durante las primeras horas de hospitalización. Métodos: Se analizó una cohorte retrospectiva de pacientes con LES mayores de 16 arios, hos pitalizados por motivos diferentes a infección bacteriana en 2 hospitales de alta complejidad de Medellín entre 2011 y 2016. Se compararon las características de los pacientes que des arrollaron el desenlace de infección bacteriana entre el día 3 y el día 15 de hospitalización con aquellos que no lo presentaron. Las variables significativas en el análisis bivariado fueron consideradas para la construcción del modelo por medio de regresión logística multivariada. Resultados: Se incluyeron 765 episodios, de los cuales 98 (12,8%) presentaron el desenlace de interés. Se consideraron 35 predictores candidatos. Las variables incorporadas en el modelo final fueron: edad, recuento de neutrófilos, puntaje de actividad lúpica SLEDAI, uso de sonda vesical, uso de catéter venoso central en las primeras 72 h, dosis de glucocorticoides en el mes previo y el uso de un antimalárico en los 3 meses previos. La capacidad de discrimi nación del modelo fue aceptable a buena (AUC-ROC 0,74; IC 95% 0,69-0,80). La prueba de bondad de ajuste de Hosmer-Lemeshow (p = 0,637) evidenció una adecuada calibración. Conclusión: Desarrollamos un modelo de predicción clínica de pronóstico del riesgo de infec ción bacteriana nosocomial en pacientes con LES. El modelo desarrollado está compuesto por variables clínicas y de laboratorio simples disponibles en el momento del ingreso al hospital. Se requieren estudios de validación externa y de impacto clínico antes de su implementación rutinaria.

ABSTRACT Introduction: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing community-acquired infections, as well as those associated with health care. Bacterial infections are the most common and serious while these patients are in hospital. Objective: To develop, and internally validate, a clinical prediction model for the prognosis of the risk of hospital-acquired bacterial infection in SLE patients using clinical and laboratory data obtained during the first hours of hospital admission. Methods: An analysis was performed on retrospective cohort of patients with SLE older than 16 years and admitted for reasons other than bacterial infection in 2 highly complex hospitals in Medellín between 2011 and 2016. The characteristics of the patients who developed a bacterial infection were compared between day 3 and day 15 of hospital admission with those who did not develop one. The significant variables in the bivariate analysis were used for the construction of the model using multivariate logistic regression. Results: A total of 765 episodes were included, of which 98 (12.8%) presented the outcome of interest. Thirty-five candidate predictors were considered. The variables incorporated in the final model were: age, neutrophil count, SLEDAI lupus activity score, use of a bladder catheter, use of a central venous catheter in the first 72 h, glucocorticoid doses in the previous month, and use of an antimalarial drug in the 3 previous months. The discrimination capacity of the model was acceptable to good (AUC-ROC 0.74; 95% CI 0.69-0.80). The Hosmer-Lemeshow goodness of fit test (P = .637) suggested adequate calibration. Conclusion: A clinical prediction model of prognostic risk of nosocomial bacterial infection in patients with SLE has been developed. This model is made up of simple clinical and laboratory variables available at the time of hospital admission. External validation and clinical impact studies are required before routine implementation.

Effects of antimalarial drugs on mitochondrial respiration in erythrocytic stages of Plasmodium falciparum 3D7 / 中国临床药理学与治疗学

AIM: The Seahorse XFe96 analyzer was used to evaluate the effects of thirteen types of international first-line antimalarial drugs in six categories on the mitochondrial electron transport chain (ETC) of Plasmodium falciparum 3D7 (P. falciparum 3D7). METHODS: The antimalarial activity of in vitro drugs acting on P. falciparum 3D7 was evaluated using the three-day inhibition method and SYBR Green I fluorescence analysis method. MACS technology was used to separate and purify P. falciparum 3D7. The mitochondrial oxygen consumption rate (OCR) of Seahorse XF analysis system was used to characterize the bioenergy of P. falciparum 3D7 mitochondria at different times to investigate the effects of antimalarial drugs on mitochondrial aerobic respiration of Plasmodium falciparum. RESULTS: The results of flow cytometry showed that the Plasmodium of trophozoite stages was enriched successfully. The results of in vitro antimalarial activity evaluation showed that, except for the antimalarial drug proguanil (Pro), the other twelve antimalarial drugs were all of the nmol/L level against P. falciparum 3D7. The results of the mitochondrial aerobic respiration showed that the five concentrations of dihydroartemisinin (DHA) and chloroquine (CQ) (0.4, 1, 5, 10, 50×IC

Evaluación de la proteólisis en células aisladas vivas de Plasmodium falciparum aisladas durante los estadios asexuales sanguíneos / Proteolysis assessment in isolated Plasmodium falciparum living cells at the asexual blood stages

It has been demonstrated that proteases play crucial roles in Plasmodium falciparum infection and therefore have been considered as targets for the development of new therapeutic drugs. The aim of this study was to describe the specific proteolytic activity profile in all blood stages of P. falciparum isolated parasites in order to explore new antimalarial options. For this purpose, we used the fluorogenic substrate Z-Phe-Arg-MCA (Z: carbobenzoxy, MCA: 7-amino-4-methyl coumarine) and classic inhibitors for the different classes of proteolytic enzymes, such as phenylmethylsulfonyl fluoride (PMSF), 1.10-phenantroline, pepstatin A and E64 to study the inhibition profiles. As expected, due to the high metabolic activity in mature stages, the substrate was mostly degraded in the trophozoite and schizont, with specific activities ~ 20 times higher than in early stages (merozoite/rings). The major actors in substrate hydrolysis were cysteine proteases, as confirmed by the complete hydrolysis inhibition with E64 addition. Proteolytic activity was also inhibited in the presence of PMSF in all but the schizont stage. However, PMSF inhibition was the result of unspecific interaction with cysteine proteases as demonstrated by reversion of inhibition by dithiotreitol (DTT), indicating that serine protease activity is very low or null. To our knowledge, this is the first report aiming to describe the proteolytic profile of P. falciparum isolated parasites at all the erythrocytic cycle stages. The results and protocol described herein can be useful in the elucidation of stage specific action of proteolysis-inhibiting drugs and aid in the development of antimalarial compounds with protease inhibitory activity(AU)

e ha demostrado que las proteasas desempeñan funciones vitales en la infección por Plasmodium falciparum, y por lo tanto se consideran dianas en la elaboración de nuevos medicamentos terapéuticos. El objetivo del estudio era describir el perfil de actividad proteolítica específica de todas las etapas sanguíneas de parásitos aislados de P. falciparum con vistas a explorar nuevas opciones antimaláricas. Con ese propósito, utilizamos el sustrato fluorogénico Z-Phe-Arg-AMC (Z: carbobenzoxi, AMC: 7-amino-4-metilcumarina) e inhibidores clásicos para las diferentes clases de enzimas proteolíticas, tales como el fluoruro de fenilmetilsulfonilo (PMSF), 1,10-fenantrolina, pepstatina A y E64 para estudiar los perfiles de inhibición. Como se esperaba, debido a la elevada actividad metabólica de las etapas de madurez, el sustrato fue degradado mayormente en el trofozoíto y el esquizonte, con actividad específica ~ 20 veces superior a la de las etapas tempranas (merozoíto/ anillos). Los principales actores en la hidrólisis del sustrato fueron las cisteínas proteasas, lo que fue confirmado por la inhibición completa de la hidrólisis con la adición de E64. La actividad proteolítica también fue inhibida en presencia de PMSF en todas las etapas excepto el esquizonte. Sin embargo, la inhibición del PMSF fue resultado de una interacción inespecífica con las cisteínas proteasas, según lo demuestra la reversión de la inhibición con el ditiotreitol (DTT), lo que indica que la actividad de la serina proteasa es muy baja o inexistente. Que sepamos, este es el primer informe dirigido a describir el perfil proteolítico de parásitos aislados de P. falciparum en todas las etapas del ciclo eritrocítico. Los resultados y el protocolo que aquí se describen pueden ser útiles para dilucidar la acción específica de los medicamentos inhibidores de proteólisis en cada etapa, así como contribuir al desarrollo de compuestos antimaláricos con actividad inhibidora de la proteasa(AU)

Lupus erythematosus tumidus in childhood treated with antimalarials / Lupus eritematoso tumidus en la infancia tratado con antimalárico

Abstract Lupus erythematosus tumidus is a rare dermatosis. It is considered a subtype of chronic cutaneous lupus erythematosus of uncertain pathogenesis, favorable prognosis and rare association with systemic lupus erythematosus. Clinically, it manifests as urticarial-like plaques in photo exposed areas, mainly affecting adults, being extremely rare in pediatric age. Herein, we present two cases of six and nine-year-old male patients with clinical and histological characteristics typical of lupus erythematosus tumidus and poor response to first-line treatment (topical, intralesional steroids and topical calcineurin inhibitors); therefore, it was decided to start systemic therapy with antimalarials, obtaining a very good response.

Resumen El lupus eritematoso tumidus es una dermatosis poco frecuente. Es considerada una variante del lupus eritematoso cutáneo crónico, de patogénesis incierta, pronóstico favorable y rara asociación con lupus eritematoso sistémico. Clínicamente, se manifiesta como placas de aspecto urticarial en zonas fotoexpuestas, que principalmente afectan a los adultos, siendo extremadamente rara en edad pediátrica. A continuación presentamos dos casos de pacientes de sexo masculino de seis y nueve años, con características clínicas e histológicas típicas de lupus eritematoso tumidus y poca respuesta al tratamiento de primera línea (esteroides tópicos, intralesionales e inhibidores de calcineurina tópica), por lo que se decidió iniciar manejo sistémico con antimalárico, obteniendo muy buena respuesta terapéutica.

Discovery and Development of Artemisinin and Related Compounds / 中草药·英文版

Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, an herb employed in traditional Chinese medicine. Prof. You-you Tu discovered artemisinin in the 1960s, so she was awarded the 2015 Nobel Prize in Physiology or Medicine. Artemisinin and its semi-synthetic derivatives are a group of drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria. In this review, the author investigated history on discovery of artemisinin, ethnopharmacology of Artemisia plants, chemistry and pharmacological activities of the relative compounds, and introduced Tu and other Chinese and world scientists' contribution, development of artemisinin and the related compounds and registered and marketed artemisinin drugs in China, UK, and USA. The author also recalled the studies on the mechanism of action of artemisinins and artemisinin combination therapies and summed up the resistance issues. In Current Recommendations and the Global Plan for Insecticide Resistance Management in Malaria Vectors (GPIRM), that the WHO prevents the development and manages the spread of insecticide resistance is summarized in the technical basis for coordinated action against insecticide resistance: preserving the effectiveness of modern malaria vector control. Prof. Tu re-emphasized the artemisinin resistant on five principles to the WHO. She called on the world's scientists to pay attention to the study of drug resistance, and hopes scientists to contribute to break resistance of artemisinins.

Study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed Plasmodium berghei

A rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. Hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. Herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluorescent protein (GFP)-expressing Plasmodium berghei strain. By comparing flow cytometry and microscopic analysis to evaluate parasitaemia recrudescence, it was observed that flow cytometry was a more sensitive methodology. The nine hydroxyethylamine derivatives were obtained by inserting one of the following radical in the para position: H, 4Cl, 4-Br, 4-F, 4-CH3, 4-OCH3, 4-NO2, 4-NH2 and 3-Br. The antimalarial test showed that the compound that received the methyl group (4-CH3) inhibited 70% of parasite growth. Our results suggest that GFP-transfected P. berghei is a useful tool to study the recrudescence of novel antimalarial drugs through parasitaemia examination by flow cytometry. Furthermore, it was demonstrated that the insertion of a methyl group at the para position of the sulfonamide ring appears to be critical for the antimalarial activity of this class of compounds.

Quality of essential drugs in tropical countries: evaluation of antimalarial drugs in the Brazilian Health System / Qualidade de medicamentos essenciais em países tropicais: avaliação de medicamentos antimaláricos no Sistema de Saúde do Brasil

INTRODUCTION: The emergence of drug resistance is one of the main problems concerning malaria treatment. The use of counterfeit and/or substandard antimalarial drugs can contribute to the development of parasite resistance. Thus, the aim of this study was to evaluate the quality of antimalarial drugs distributed in Brazil. METHODS: Samples containing chloroquine phosphate, mefloquine hydrochloride, primaquine phosphate, and quinine sulfate tablets were delivered to the Rio de Janeiro central storeroom (CENADI), state storerooms (SS), and Basic Health Units (BHUs) in the north region of Brazil - a total of 10 sample sets. After 5 months of storage, the samples were collected, and in vitro quality control analyses according to official and published methods were performed. RESULTS: Inadequate drug storage conditions were found in two SS and in all BHUs evaluated. There were no quality deviations found in the chloroquine samples. The quinine samples exhibited weight variation above the allowed limits. The primaquine samples were found to have packaging deficiency. The release of mefloquine in samples from some regions showed a statistically significant difference when compared with the CENADI samples. CONCLUSIONS: It is important to periodically evaluate the quality and storage conditions of essential drugs. The quality deviations found with the primaquine and quinine samples are not related to storage conditions and must be addressed urgently. The decreased mefloquine release from tablets is related to formulation problems or influenced by inadequate storage conditions, prompting further investigation. Even with the mentioned problems, the samples would probably not contribute to resistant parasite selection.

INTRODUÇÃO: O aparecimento de resistência aos medicamentos é um dos maiores problemas do tratamento da malária. O uso de medicamentos falsos e/ou de má qualidade pode contribuir para o desenvolvimento de resistência no parasita. Este estudo tem por objetivo avaliar a qualidade dos medicamentos antimaláricos distribuídos no Brasil. MÉTODOS: Amostras contendo comprimidos de difosfato de cloroquina, cloridrato de mefloquina, difosfato de primaquina e sulfato de quinina foram enviadas ao almoxarifado central na Cidade do Rio de Janeiro (CENADI), almoxarifados estaduais (SS) e Unidades Básicas de Saúde (UBS) nos estados da região norte do Brasil, totalizando dez amostras. Após cinco meses de armazenamento, as amostras foram coletadas e analisadas segundo métodos oficiais e da literatura. RESULTADOS: Foram encontradas condições inadequadas de armazenamento de medicamentos em duas SS e em todas as UBS avaliadas. Não foram encontrados problemas de qualidade com as amostras de cloroquina. As amostras de quinina apresentaram variação de peso acima dos limites permitidos. Amostras de primaquina foram encontradas com problemas na embalagem. A cedência de mefloquina de comprimidos, em algumas regiões, apresentou diferença estatisticamente significativa quando comparada com a amostra do CENADI. CONCLUSÕES: É importante avaliar, periodicamente, a qualidade e as condições de armazenamento de medicamentos essenciais. Desvios de qualidade encontrados com as amostras de primaquina e quinina não estão relacionados às condições de armazenamento e devem ser corrigidos urgentemente. O decréscimo na cedência de mefloquina dos comprimidos está relacionado com a formulação ou foi influenciada por condições de armazenamento inadequadas, necessitando de uma investigação posterior. Apesar dos problemas mencionados, as amostras provavelmente não contribuiriam para a seleção de parasitas resistentes.

Sentinel network for monitoring in vitro susceptibility of Plasmodium falciparum to antimalarial drugs in Colombia: a proof of concept

Drug resistance is one of the principal obstacles blocking worldwide malaria control. In Colombia, malaria remains a major public health concern and drug-resistant parasites have been reported. In vitro drug susceptibility assays are a useful tool for monitoring the emergence and spread of drug-resistant Plasmodium falciparum. The present study was conducted as a proof of concept for an antimalarial drug resistance surveillance network based on in vitro susceptibility testing in Colombia. Sentinel laboratories were set up in three malaria endemic areas. The enzyme linked immunosorbent assay-histidine rich protein 2 and schizont maturation methods were used to assess the susceptibility of fresh P. falciparum isolates to six antimalarial drugs. This study demonstrates that an antimalarial drug resistance surveillance network based on in vitro methods is feasible in the field with the participation of a research institute, local health institutions and universities. It could also serve as a model for a regional surveillance network. Preliminary susceptibility results showed widespread chloroquine resistance, which was consistent with previous reports for the Pacific region. However, high susceptibility to dihydroartemisinin and lumefantrine compounds, currently used for treatment in the country, was also reported. The implementation process identified critical points and opportunities for the improvement of network sustainability strategies.

A resistência à cloroquina e a busca de antimalariais entre as décadas de 1960 e 1980 / Chloroquine resistance and the search for antimalarial drugs from the 1960s to 1980s

Em 1961, a Organização Mundial de Saúde (OMS) reconheceu a resistência de cepas de Plasmodium à cloroquina, o que estimulou programas de pesquisa e desenvolvimento de novas drogas sintéticas que pudessem substituí-la no combate à malária. Analiso o processo de pesquisa científica relativo à produção de antimalariais nos contextos nacional e internacional, em especial nos EUA e na China, entre as décadas de 1960 e 1980. Pontos de convergência e distanciamento são marcados pelas dinâmicas próprias de cada país e pelos interesses envolvidos nas relações internacionais, em relação aos quais fica evidente o papel central da OMS.

Using High Performance Liquid Chromatography to quantitate Artemether and Artesunate anti-malarial tablets in the National Capital District, Papua New Guinea

Malaria is a major public health problem in Papua New Guinea (PNG). The Artemisinin-based combination therapy is widely used as the first-line treatment for malaria in PNG. This study was to assess the quantity of the Artemether and Artesunate ingredients in the antimalarial drugs used for the treatment of malaria in the National Capital District (NCD) PNG. Artemether and Artesunate tablets were purchased from various pharmacies in NCD. Artemether and Artesunate solutions were prepared according to the Standard United States Pharmacopoeial protocol for assay of active ingredients by high performance liquid chromatography (HPLC). The results indicated that the percent Artemether content in the three brands (ART 01, ART 02 and ART 03) of Artemether purchased in the NCD were 93.2%, 87.6% and 89.3% respectively. Four brands (ATS 01/02, ATS 03/04, ATS 05, and ATS 06) of Artesunate were purchased in the NCD. The % Artesunate content in the four brands were 109.0%, 110.0%, 101.2% and 96.2%% respectively. The three Artemether brands (100%) and two (ATS 01/02 and ATS 03/04) of the Artesunate brands (50%) did not satisfy the USP specifications for the amount of active ingredients in the drugs. Our data indicate that poor quality Artemether and Artesunate antimalarial drugs are sold in the National Capital District in PNG. This indicates the urgent need to advocate for more efficient drug monitoring and effective enforcement of regulations that prevents importation of substandard drugs into the NCD.