In vitro evaluation of ganaplacide/lumefantrine combination against Plasmodium falciparum in a context of artemisinin resistance.

BACKGROUND: Ganaplacide, also known as KAF156, is among the new antimalarial drug candidates that have successfully reached Phase III clinical trials, and is proposed in combination with lumefantrine. This combination could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs. Indeed, the African continent, where the malaria burden is the highest, is currently experiencing worrying multiple emergences and spread of artemisinin resistance, which urges for the exploration of the antiparasitic properties of KAF156 in this context. OBJECTIVES AND METHODS: The objectives of this work were firstly to evaluate the risk of cross-resistance between artemisinins and KAF156 alone, and in combination with lumefantrine, using a panel of artemisinin-resistant strains carrying different pfk13 mutations and markers of other antiplasmodial drug resistances; secondly to explore in vitro the relevance of combining KAF156 and lumefantrine with artemisinins, based on the model of triple ACTs. RESULTS: Our results highlighted that KAF156 activity was not impaired by mutations in pfk13, pfcrt, pfmdr1, pfmdr2, pfdhps and pfdhfr genes or by pfmdr1 amplification. Moreover, we demonstrated that KAF156 alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent. CONCLUSIONS: All these in vitro results evidence that multi-drug resistant parasites currently in circulation in the field might not affect KAF156 efficacy, and are encouraging signs for KAF156 use in a triple ACT to preserve the use of artemisinins for as long as possible.

Nanomaterials in Drug Delivery: Strengths and Opportunities in Medicine.

There is a myriad of diseases that plague the world ranging from infectious, cancer and other chronic diseases with varying interventions. However, the dynamism of causative agents of infectious diseases and incessant mutations accompanying other forms of chronic diseases like cancer, have worsened the treatment outcomes. These factors often lead to treatment failure via different drug resistance mechanisms. More so, the cost of developing newer drugs is huge. This underscores the need for a paradigm shift in the drug delivery approach in order to achieve desired treatment outcomes. There is intensified research in nanomedicine, which has shown promises in improving the therapeutic outcome of drugs at preclinical stages with increased efficacy and reduced toxicity. Regardless of the huge benefits of nanotechnology in drug delivery, challenges such as regulatory approval, scalability, cost implication and potential toxicity must be addressed via streamlining of regulatory hurdles and increased research funding. In conclusion, the idea of nanotechnology in drug delivery holds immense promise for optimizing therapeutic outcomes. This work presents opportunities to revolutionize treatment strategies, providing expert opinions on translating the huge amount of research in nanomedicine into clinical benefits for patients with resistant infections and cancer.

Protective effects of Dialium guineense pulp on aspirin-induced gastric mucosal injury in albino rats.

The numerous challenges and detrimental effects connected with the treatment of peptic ulcers in the world today calls for alternative attention. Ethnomedicinally, Dialium guineense pulp (DAGP) has numerous pharmacological activities. This study investigated the anti-ulcer activities of Dialium guineense pulp on gastric mucosa injury induced with aspirin in albino Wistar rats. DAGP extract was orally administered at doses of 250, 500 and 1000 mg/kg bw (mg per kg of the body weight) per day for 3 or 7 days followed by 400 mg/kg bw oral aspirin administration. Ulcer indices were determined, followed by a biochemical estimation of antioxidant enzymes using gastric mucosal tissue from the stomach. Student's t-test was used to compare significant differences among groups of animals at P ≤ 0.05. The results showed that Dialium guineense pulp caused a significant decrease (P ≤ 0.05) in the ulcer index in aspirin induced rats. This decrease in ulcer index is dose dependent and 1000 mg/kg bw per day caused the highest decrease in 7 days. The results showed a significant increase (P ≤ 0.05) in lipid peroxidation and a decrease (P ≤ 0.05) in antioxidant enzymes activities in the aspirin-induced ulcerated rats. Oral administration of DAGP increased antioxidant enzymes activities and decreased injury in the gastric mucosa in ulcer induced rats. Therefore, this study showed that DAGP exhibited anti-ulcer potential and that the gastrointestinal protection may be through the scavenging action of free radicals by its constituent antioxidants. Thus, Dialium guineense pulp has ameliorative medicinal potential for the curing of gastric disorders.

Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites.

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

Combating Lassa Fever in West African Sub-Region: Progress, Challenges, and Future Perspectives.

Lassa fever (LF) is a rodent-borne disease that threatens human health in the sub-region of West Africa where the zoonotic host of Lassa virus (LASV) is predominant. Currently, treatment options for LF are limited and since no preventive vaccine is approved for its infectivity, there is a high mortality rate in endemic areas. This narrative review explores the transmission, pathogenicity of LASV, advances, and challenges of different treatment options. Our findings indicate that genetic diversity among the different strains of LASV and their ability to circumvent the immune system poses a critical challenge to the development of LASV vaccines/therapeutics. Thus, understanding the biochemistry, physiology and genetic polymorphism of LASV, mechanism of evading host immunity are essential for development of effective LASV vaccines/therapeutics to combat this lethal viral disease. The LASV nucleoprotein (NP) is a novel target for therapeutics as it functions significantly in several aspects of the viral life cycle. Consequently, LASV NP inhibitors could be employed as effective therapeutics as they will potentially inhibit LASV replication. Effective preventive control measures, vaccine development, target validation, and repurposing of existing drugs, such as ribavirin, using activity or in silico-based and computational bioinformatics, would aid in the development of novel drugs for LF management.

Assessment of the Antimalarial Treatment Failure in Ebonyi State, Southeast Nigeria.

The fight against malaria is a continuum as the epidemic is not abating. For proper deployment of tools in the fight against malaria, an assessment of the situation is necessary. This work assessed the level of antimalarial drug treatment failure in Ebonyi State, Nigeria. Both survey and in vitro analyses were adopted. The survey was used to obtain qualitative information from both the malaria subjects and the pharmacies where antimalarial drugs are sourced. The results from the survey were complemented by an in vitro assay of the level of active pharmaceutical ingredients (APIs) in the commonly used artemisinin combination in Nigeria; artemether/lumefantrine. Results from the survey revealed that artemisinin combination therapies (ACTs) remain the mainstay in the treatment of malaria, even though other non-artemisinin drugs are still used. It also revealed that many patients still self-medicate, although, this may not be connected to the treatment failure seen among some malaria subjects. The in vitro assay showed that ACT contains the right quantity of APIs. Further surveillance is, therefore, necessary to understand the real cause of treatment failure among malaria subjects in Nigeria.

Cucumeropsis mannii seed oil ameliorates Bisphenol-A-induced adipokines dysfunctions and dyslipidemia.

This study demonstrated the therapeutic potentials of Cucumeropsis mannii seed oil (CMSO) capable of alleviating BPA-induced dyslipidemia and adipokine dysfunction. In this study, we evaluated the effects of CMSO on adipokine dysfunctions and dyslipidemia in bisphenol-A (BPA)-induced male Wistar rats. Six-week-old 36 albino rats of 100-200 g weight were assigned randomly to six groups, which received varied doses of BPA and/or CMSO. The administration of BPA and CMSO was done at the same time for 42 days by oral intubation. The adipokine levels and lipid profile were measured in adipose tissue and plasma using standard methods. BPA induced significant (p < .05) increases in triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices in adipose tissue and plasma, as well as a decrease in adiponectin and HDL-C levels in Group II animals. BPA administration significantly (p < .05) elevated Leptin levels and reduced adiponectin levels. BPA plus CMSO reduced triglycerides, cholesterol, leptin, LDL-C, and atherogenic and coronary risk indices while increasing adiponectin levels and HDL-C in adipose tissue and plasma (p < .05). The results showed that BPA exposure increased adipose tissue as well as serum levels of the atherogenic index, triglycerides, cholesterol, coronary risk index, LDL-C, leptin, and body weight with decreased adiponectin levels and HDL-C. Treatment with CMSO reduced the toxicities caused by BPA in rats by modulating the body weight, adiponectin/leptin levels, and lipid profiles in serum and adipose tissue. This study has shown that CMSO ameliorates BPA-induced dyslipidemia and adipokine dysfunctions. We suggest for further clinical trial to establish the clinical applications.

Effects of Greek Honey and Propolis on Oxidative Stress and Biochemical Parameters in Regular Blood Donors.

Background and objectives: Honey products contain a lot of compounds, such as vitamins, enzymes, and minerals, which make honey and its products a great antioxidant with a critical role in health status. It is well accepted that honey and propolis can improve a lot of health problems when they are consumed in certain quantities. The objective of this study is to help regular blood donors improve their health status after donation. Material and methods: Eighty regular blood donor volunteers-30 males aged 19-61 and 30 females aged 21-64-were divided into 4 groups: group A (n = 20) consumed 2 spoons of Greek honey and 1 drop of propolis per day for 1 month, group B (n = 20) consumed 2 spoons of honey per day for 1 month, group C (n = 20) consumed 1 drop of propolis per day, and group D (n = 20) did not consume any Greek honey products. Blood samples were collected from all participants just before the consumption of the products, one month after the consumption, and six months after honey product consumption had ceased. All samples were analyzed for reactive oxygen species (ROS), lipid profiles, and ferritin levels. Results: The ROS were significantly (p < 0.05) lower in groups A, B, and C after the honey product consumption and increased significantly again after six months. No significant differences in lipid profiles were observed. Only triglyceride levels were increased after six months in all groups. On the other hand, ferritin levels were not statistically significantly decreased after six months in groups A and B, while they were increased in group C. Conclusions: In the present study, statistically significant decreases in ROS status was found after a small dose of honey product consumption, indicating a diet with an extra small dose of honey products after blood donation.

Impact of Drug Pressure versus Limited Access to Drug in Malaria Control: The Dilemma.

Malaria burden has severe impact on the world. Several arsenals, including the use of antimalarials, are in place to curb the malaria burden. However, the application of these antimalarials has two extremes, limited access to drug and drug pressure, which may have similar impact on malaria control, leading to treatment failure through divergent mechanisms. Limited access to drugs ensures that patients do not get the right doses of the antimalarials in order to have an effective plasma concentration to kill the malaria parasites, which leads to treatment failure and overall reduction in malaria control via increased transmission rate. On the other hand, drug pressure can lead to the selection of drug resistance phenotypes in a subpopulation of the malaria parasites as they mutate in order to adapt. This also leads to a reduction in malaria control. Addressing these extremes in antimalarial application can be essential in maintaining the relevance of the conventional antimalarials in winning the war against malaria.

Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon.

Malaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites.

The Potential Impact of Blood System on Dietary Habits and Smoking.

The 'Blood-Type' diet advises individuals to eat according to their ABO blood group to improve their health and decrease the risk of chronic diseases. However, the food preferences of individuals with different blood groups have not been examined. The aim of our study was to investigate, in healthy regular blood donors (rBDs), the associations of smoke, alcohol, caffeine, vitamin and fat intake with their different blood groups and if ABO groups could be a potential predictor tool for disease prevention. A total of 329 volunteers were divided into four groups according to their ABO types: Group 1 (A) comprised 141 rBDs; Group 2 (B), 65 rBDs; Group 3 (O), 96 rBDs; and Group 4, 27 rBDs. Additionally, they were divided into two groups according to their rhesus types and their preferences for smoke, too. Dietary intake was assessed using 3-day food recall and the Food Processor computer program for nutrient analysis. Alcohol, caffeine, sugar and Vitamin D consumption were significantly (p < 0.05) higher in the O group. The A group presented statistically significantly (p < 0.05) greater preferences for cholesterol intake and a higher trend for smoking (25%) habits compared with all the other groups, whereas Group B preferred more fatty foods. The blood group AB appeared to be the most controlled food intake group. Regarding the rhesus comparisons, alcohol; caffeine; and Vitamin C, D, E and K consumptions were significantly (p < 0.05) higher in rhesus-positive individuals than their rhesus-negative counterparts. For the non-smoker group, compared with the smokers, a higher consumption of Vitamin D and fibers was found. In conclusion, in the present study, statistically significant correlations of the ABO and rhesus system with some dietary parameters were found, indicating a consequent influence of these preferences on the progression of different diseases.

Current Advances in the Management of Diabetes Mellitus.

Diabetes mellitus (DM) underscores a rising epidemic orchestrating critical socio-economic burden on countries globally. Different treatment options for the management of DM are evolving rapidly because the usual methods of treatment have not completely tackled the primary causes of the disease and are laden with critical adverse effects. Thus, this narrative review explores different treatment regimens in DM management and the associated challenges. A literature search for published articles on recent advances in DM management was completed with search engines including Web of Science, Pubmed/Medline, Scopus, using keywords such as DM, management of DM, and gene therapy. Our findings indicate that substantial progress has been made in DM management with promising results using different treatment regimens, including nanotechnology, gene therapy, stem cell, medical nutrition therapy, and lifestyle modification. However, a lot of challenges have been encountered using these techniques, including their optimization to ensure optimal glycemic, lipid, and blood pressure modulation to minimize complications, improvement of patients' compliance to lifestyle and pharmacologic interventions, safety, ethical issues, as well as an effective delivery system among others. In conclusion, lifestyle management alongside pharmacological approaches and the optimization of these techniques is critical for an effective and safe clinical treatment plan.

A world free of malaria: It is time for Africa to actively champion and take leadership of elimination and eradication strategies.

The global burden of malaria seems unabated. Africa carries the greatest burden accounting for over 95% of the annual cases of malaria. For the vision of a world free of malaria by Global Technical Strategy to be achieved, Africa must take up the stakeholder's role. It is therefore imperative that Africa rises up to the challenge of malaria and champion the fight against it. The fight against malaria may just be a futile or mere academic venture if Africans are not directly and fully involved. This work reviews the roles playable by Africans in order to curb the malaria in Africa and the world at large.

In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin Derivative.

Artemisinin-based Combination Therapies (ACTs) are currently the frontline treatment against Plasmodium falciparum malaria, but parasite resistance to artemisinin (ART) and its derivatives, core components of ACTs, is spreading in the Mekong countries. In this study, we report the synthesis of several novel artemisinin derivatives and evaluate their in vitro and in silico capacity to counteract Plasmodium falciparum artemisinin resistance. Furthermore, recognizing that the malaria parasite devotes considerable resources to minimizing the oxidative stress that it creates during its rapid consumption of hemoglobin and the release of heme, we sought to explore whether further augmentation of this oxidative toxicity might constitute an important addition to artemisinins. The present report demonstrates, in vitro, that FM-AZ, a newly synthesized artemisinin derivative, has a lower IC50 than artemisinin in P. falciparum and a rapid action in killing the parasites. The docking studies for important parasite protein targets, PfATP6 and PfHDP, complemented the in vitro results, explaining the superior IC50 values of FM-AZ in comparison with ART obtained for the ART-resistant strain. However, cross-resistance between FM-AZ and artemisinins was evidenced in vitro.

Reactive Oxygen Species as the Brainbox in Malaria Treatment.

Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.

Superoxide: A major role in the mechanism of action of essential antimalarial drugs.

Understanding the mode of action of antimalarials is central to optimizing their use and the discovery of new therapeutics. Currently used antimalarials belong to a limited series of chemical structures and their mechanisms of action are coutinuously debated. Whereas the involvement of reactive species that in turn kill the parasites sensitive to oxidative stress, is accepted for artemisinins, little is known about the generation of such species in the case of quinolines or hydroxynaphtoquinone. Moreover, the nature of the reactive species involved has never been characterized in Plasmodium-infected erythrocytes. The aim of this work was to determine and elucidate the production of the primary radical, superoxide in Plasmodium-infected erythrocytes treated with artemisinin, dihydroartemisinin, chloroquine and atovaquone, as representatives of three major classes of antimalarials. The intracellular generation of superoxide was quantified by liquid chromatography coupled to mass spectrometry (LC-MS). We demonstrated that artemisinins, atovaquone and to a lesser extent chloroquine, generate significant levels of superoxide radicals in Plasmodium falciparum sensitive strains. More so, the production of superoxide was lowered in chloroquine-resistant strain of Plasmodium treated with chloroquine. These results consolidate the knowledge about the mechanism of action of these different antimalarials and should be taken into consideration in the design of future drugs to fight drug-resistant parasites.

Effect of Silica Based Nanoparticles against Plasmodium falciparum and Leishmania infantum parasites.

Malaria and Leishmaniasis are two major parasitic diseases, endemic in large areas of tropical countries with high morbidity and mortality across the world. Nanoparticles in small sizes are specifically considered in medicine due to their ability to enter the cells, control the distribution of the administered drug and carry the drug specifically to the place of action. The present study aims to introduce the application of silica nanoparticles as new promising nanotools in malaria and leishmaniasis treatment. Ion doped silica nanomaterials revealed antileishmanial activities indicating the positive role of calcium, magnesium and copper to the surface of the particles against Leishmania parasites. Artemisinin-loaded nanoparticles presented the most promising antiparasitic properties with a sustained release able to overcome the parasite invasion. The sustainable release of artemisinin guarantee both the maintenance of its potential efficacy and also introduce an administration of drug to avoid subsequent drug resistance.

Antihyperglycemic, antihyperlipidemic and hepatoprotective effects of Ficus ottoniifolia (Miq.) Miq. supplementation in alloxan-induced diabetic rats.

OBJECTIVE: Medicinal plants provide better and cheaper alternative therapy for management of several diseases compared to orthodox medicines. This study evaluated the effects of feed formulated with Ficus ottoniifolia (Miq.) Miq. (FFFO) leaves in the management of alloxan-induced diabetes mellitus (DM) in rats. MATERIALS AND METHODS: DM was induced in overnight-fasted rats by administration of alloxan monohydrate intraperitoneally. DM rats in Groups 1-3 were fed with graded FFFO while group 4 (diabetic control) and group 5 (normal control) were fed with commercial feeds (Vital-Feeds), daily for 21 days. Changes in body weight and some biochemical parameters were thereafter determined. RESULTS: Results showed significant decreases (p<0.05) in serum high-density lipoprotein (HDL) but significant increases (p<0.05) in blood glucose, serum low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC) and alanine aminotransferase (ALT) activities in DM-induced rats compared to the normal control group. Feeding with FFFO significantly increased (p<0.05) the body weight and HDL, decreased the blood glucose, serum LDL, TG and TC and attenuated ALT activities in FFFO-fed DM rats compared to the diabetic control group. CONCLUSION: This study revealed that FFFO-diet may mitigate hyperglycemia, dyslipidemia and liver-damage associated with DM.

Studies on Ethanol Extracts of Olax subscorpioidea Against Carbon Tetrachloride-Induced Hepatotoxicity in Rats.

<b>Background and Objective:</b> Liver disease orchestrated by noxious chemicals are serious health problems the world over. Traditionally, there are claims that ethanol extracts of leaves and stem barks of <i>Olax subscorpioidea</i> are used in the treatment of hepatic disorders. Thus, it investigated the impacts of ethanol extract of leaves and stem bark of <i>Olax subscorpioidea</i> against carbon tetrachloride (CCl₄)-induced liver damage in rats. <b>Materials and Methods:</b> Liver toxicity was induced by intraperitoneal injection of 2.5 mg kg¹ b.wt., of CCl₄ in experimental rats. Rats were treated with 200, 400 and 800 mg kg¹ dose ethanol leaves and stem bark of <i>Olax subscorpioidea</i>, respectively after induction of liver damage. <b>Results:</b> Obtained results showed a significant rise in the serum levels of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Malondialdehyde (MDA) and bilirubin as well as decreased Albumin (ALB), Superoxide Dismutase (SOD), Catalase (CAT), reduced Glutathione (GSH) in CCl₄-challenged rats. Treatment with the extracts attenuated serum levels of AST, ALT, ALP, MDA and bilirubin in addition to increased activities of SOD, CAT and the levels of ALB and GSH when compared to the CCl₄ group. Histopathological studies demonstrated that the extracts ameliorated liver necrosis and inflammation due to CCl₄ insult. <b>Conclusion:</b> These results concluded that ethanol extract of leaves and stem bark of <i>Olax subscorpioidea </i>may reduce hepatic oxidative injury caused by CCl₄ by its antioxidant potentials.

An LC-MS Assay to Measure Superoxide Radicals and Hydrogen Peroxide in the Blood System.

Red blood cells are constantly exposed to reactive species under physiological or pathological conditions or during administration of xenobiotics. Regardless of the source, its accurate quantification is paramount in the area of theragnostics, which had been elusive up until now. Even if there are a lot of approaches to evaluate the oxidative stress, very sensitive methods are missing for the blood system. We therefore sought to apply a highly sensitive approach, by liquid chromatography coupled to mass spectrometry (UPLC-MS), for the quantification of reactive species such as superoxide radical and hydrogen peroxide using dihydroethidium (DHE) and coumarin boronic acid (CBA) probes respectively through the detection of 2-hydroxyethidium (2OH-E+) and 7-hydroxycoumarin (COH). The use of the high-resolution mass spectrometry associated to UPLC ensured a selective detection of superoxide and hydrogen peroxide in the blood system under diverse conditions such as oxidized red blood cells (RBCs), untreated and treated parasitized RBCs. Moreover, this technique allowed the determination of reactive species in human plasma. This protocol provides a huge opportunity for in-depth study of several pathological conditions vis-a-vis their treatment in modern medicine.