Oral Antimalarials Research Articles

Quality of care and post-discharge morbidity among children diagnosed with severe malaria in rural Uganda: A prospective cohort study.

Pediatric severe malaria is a significant contributor of morbidity and mortality in Uganda. Most information is derived from tertiary referral centers and urban centers. Little is known about routine care or post-discharge outcomes in rural areas. We conducted a longitudinal cohort study of pediatric severe malaria at St. Paul's Level IV Health Center (SPHC) in Kasese, Uganda. We collected demographic, clinical, and laboratory results, and conducted follow-up 14 days post-discharge to assess patient outcomes in the immediate post-discharge period. The initial cohort included 187 children aged 0 to 17 years enrolled between July 9th, 2023 and January 9th, 2024. Almost all (94.7%) participants had a parasitological confirmed malaria diagnosis by rapid diagnostic tests or blood smear. While at SPHC, 95.7% of patients received 3+ doses of intravenous Artesunate, and 92.0% also received oral antimalarials. 62.0% had at least one symptom of severe malaria, with altered consciousness (40.6%) and convulsions (29.9%) the most frequently reported. 26.1% had evidence of severe malarial anemia (Hb <5 g/dl), of whom 93.5% received a blood transfusion. Most (82.2%) patients received care that we assessed as consistent with key elements of WHO management guidelines. We were able to contact 183 of the 187 patient caregivers post-discharge. Caregivers reported that 25.6% of patients were experiencing symptoms related to their hospitalization, with fever (18.5%) and nausea/ not feeding well (10.3%) reported most frequently. Children who experienced altered consciousness during their acute illness had 1.69 times the adjusted risk of reporting symptoms 14-days post-discharge compared to those who did not have altered consciousness (aRR: 1.69, 95% CI: 1.01-2.82). Six deaths were recorded, including three at SPHC and three post-transfer or discharge. Findings suggest that at private health facilities in rural areas, treatment appears to be consistent with guidelines. Future research should investigate high morbidity in the immediate post-discharge period.

Transdermal antimalarial drug delivery to improve poor adherence to antimalarials: A new light at the end of the tunnel

Malaria, a perilous disease caused by Plasmodium parasites and characterized by a substantial mortality rate, has persistently posed as a global health challenge. Conventional antimalarial formulations, although effective, grapple with issues surrounding their bioavailability and palatability, and potentially hampering patient adherence and inadvertently fueling drug resistance and poor treatment outcomes. This paper meticulously delves into the predicaments associated with prevailing antimalarial delivery methods – oral, intravenous, and intramuscular. The paper navigates through the compelling merits of the transdermal pathway, drawing inspiration from its triumphant deployment in other medical realms. The investigation extends to encompass preclinical inquiries dedicated to exploring the transdermal administration of antimalarials. Transdermal antimalarials have shown complete suppression and elimination of Plasmodium parasites, as suggested by the preclinical studies. These preclinical studies emerge as a beacon of hope, exhibiting heightened bioavailability, enhanced safety margins, and notable cost-effectiveness when compared with oral antimalarials. Moreover, this innovative avenue for drug delivery not only offers convenience but also holds the potential to be a transformative solution to the adherence problems of traditional antimalarials, which currently afflicts standard therapeutic options.

Evaluating the activity of N-89 as an oral antimalarial drug.

Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t1/2 was 0.97 h, Tmax was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED50) and ED90 values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

Systemic-onset Juvenile Idiopathic Arthritis in a young child

We present a 31-month-old female child who was referred by the pediatricians with 1-year history of recurrent high-grade fever associated with polyarthritis and recurrent skin rash, which disappears within 24 hours of resolution of fever. She had lost the ability to walk unsupported because of persistent arthritis. Her Full Blood Count (FBC) was remarkable for marked leucocytosis, thrombocytosis, and a mild normocytic normochromic anemia; Erythrocyte Sedimentation Rate (ESR) and C-reactive Protein (CRP) were both elevated at 110mm/hour and 200mg/L (&lt;7) respectively while serial blood cultures were negative for septicemia and blood films were negative for acute leukemia; HIV, hepatitis B and C virus, tuberculosis, rheumatic fever, rheumatoid arthritis, and connective tissue disease screenings were all negative. Her hemoglobin genotype is AA. She had repeatedly received treatments for malaria and ‘sepsis’ with parenteral and oral antimalarials and antibiotics with no permanent relief, hence the reason for referral to the rheumatologist. An assessment of Systemic-onset Juvenile Idiopathic Arthritis (SoJIA) was made when her serum ferritin came back elevated at 670ng/mL (4.63 – 204) and she was commenced on oral ibuprofen with remarkable improvement evidenced by resolution of fever, joint pain and rash and normalization of ESR, CRP and serum ferritin within 8 weeks of treatment. Although SoJIA is rare, it would be worthwhile to include this disease in the differential diagnoses and subsequent evaluation in any child presenting with unexplained recurrent fever associated with body rash and polyarthritis.

Artemether-lumefantrine, mefloquine and atovaquone-proguanil in the treatment of uncomplicated Plasmodium falciparum malaria in travellers: A retrospective comparative study of efficacy and treatment failures.

The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p<0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p<0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.

Association between oral antimalarial medication administration and mortality among patients with Ebola virus disease: a multisite cohort study

BackgroundEmpiric antimalarial treatment is a component of protocol-based management of Ebola virus disease (EVD), yet this approach has limited clinical evidence for patient-centered benefits.MethodsThis retrospective cohort study evaluated the association between antimalarial treatment and mortality among patients with confirmed EVD. The data was collected from five International Medical Corps operated Ebola Treatment Units (ETUs) in Sierra Leone and Liberia from 2014 through 2015. The standardized protocol used for patient care included empiric oral treatment with combination artemether and lumefantrine, twice daily for three days; however, only a subset of patients received treatment due to resource variability. The outcome of interest was mortality, comparing patients treated with oral antimalarials within 48-h of admission to those not treated. Analysis was conducted with logistic regression to generate adjusted odds ratios (aORs). Multivariable analyses controlled for ETU country, malaria rapid diagnostic test result, age, EVD cycle threshold value, symptoms of bleeding, diarrhea, dysphagia and dyspnea, and additional standard clinical treatments.ResultsAmong the 424 cases analyzed, 376 (88.7%) received early oral antimalarials. Across all cases, mortality occurred in 57.5% (244). In comparing unadjusted mortality prevalence, early antimalarial treated cases yielded 55.1% mortality versus 77.1% mortality for those untreated (p = 0.005). Multivariable analysis demonstrated evidence of reduced aOR for mortality with early oral antimalarial treatment versus non-treatment (aOR = 0.34, 95% Confidence Interval: 0.12, 0.92, p = 0.039).ConclusionEarly oral antimalarial treatment in an EVD outbreak was associated with reduced mortality. Further study is warranted to investigate this association between early oral antimalarial treatment and mortality in EVD patients.

Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria.

Malaria affects millions of people annually, especially in third-world countries. The mainstay of treatment is oral anti-malarial drugs and vaccination. An increase in resistant strains of malaria parasites to most of the current anti-malarial drugs adds to the global burden. Moreover, existing and new anti-malarial drugs are hampered by significantly poor aqueous solubility and low permeability, resulting in low oral bioavailability and patient noncompliance. Lipid formulations are commonly used to increase solubility and efficacy and decrease toxicity. The present review discusses the findings from studies focusing on specialised oral lipophilic drug delivery systems, including self-emulsifying drug delivery systems (SEDDSs). SEDDSs facilitate the spontaneous formation of liquid emulsions that effectively solubilise the incorporated drugs into the gastrointestinal tract and thereby improve the absorption of poorly-soluble anti-malaria drugs. However, traditional SEDDSs are normally in liquid dosage forms, which are delivered orally to the site of absorption, and are hampered by poor stability. This paper discusses novel solidification techniques that can easily and economically be up-scaled due to already existing industrial equipment that could be utilised. This method could, furthermore, improve product stability and patient compliance. The possible impact that solid oral SEDDSs can play in the fight against malaria is highlighted.

Pediatric discoid lupus erythematosus: Short report.

Pediatric discoid lupus erythematosus (DLE) is a rare inflammatory skin disorder. This article aims to review all the available clinical and therapeutic data on reported cases of pediatric DLE. A systematic review of the literature was conducted using Pubmed and Embase with no limitation on publication date, sex, or nationality. Thirty-two articles were included with 201 cases, a mean age of 8.9 years (2 months-16 years) and an F:M ratio of 1.8. Lesions were located on the head and neck in 58.5% and were disseminated in 36.5% of the cases. Associated symptoms were pruritus (10.1%) and alopecia (8.7%). 12% progressed to systemic lupus erythematosus (SLE) and 14.5% had concurrent SLE. The only statistically significant predictor for progression to SLE was the onset of symptoms before or at the age of 10 years (p= 0.004). Treatments consisted mainly of sunscreens (26.3%), topical corticosteroids (24.3%), and oral antimalarials (25.3%). Retrospective nature of the included studies, small sample size, short duration of follow-up and limited data on the patients' demographics. Pediatric DLE affects mostly the head and neck, with a female predominance, a possible association with inflammatory and autoimmune diseases, and overall good treatment response and prognosis.

A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors.

Simple SummaryMutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in high-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma. Due to the lack of effective treatment options, these aggressive types of cancer have a dismal outcome. The metabolism of IDH1-mutated cancer cells is reprogrammed in order to produce the oncometabolite D-2-hydroxyglutarate (D-2HG). In this clinical trial, we used the oral antidiabetic drug metformin and the oral antimalarial drug chloroquine to disrupt the vulnerable metabolism of IDH1-mutated solid tumors. We found that the combination regimen of metformin and chloroquine is well tolerated, but the combination did not induce a clinical response in this patient population. Secondly, we confirmed the clinical usefulness of D/L-2HG ratios in serum as a biomarker and the ddPCR-facilitated detection of an IDH1 mutation in circulating DNA from peripheral blood.Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

AB003. Increased CD69+ tissue-resident memory T cells and STAT3 expression in cutaneous lupus erythematosus patients recalcitrant to antimalarials

BackgroundCutaneous lupus erythematosus (CLE) is an autoimmune disease involving T lymphocytes, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells (mDCs). While oral antimalarials, including hydroxychloroquine (HCQ) and quinacrine (QC) are first-line systemic therapy for all CLE subtypes, some patients remain refractory to both HCQ and HCQ + QC. To better understand reasons for refractoriness in CLE, we investigated the immunologic characteristics of patients who responded to antimalarials versus those who did not.MethodsBiopsies from 65 CLE patients with well characterized treatment response to HCQ (n=22) and HCQ + QC (n=24), as well as treatment failure to HCQ + QC (n=19) were studied via immunohistochemistry and polymerase chain reaction. Lesional skin was biopsied prior to antimalarial treatment. The patient’s CLASI score—a measure of disease activity—at the time of the biopsy was also determined.ResultsImmunohistochemistry showed CD69+ tissue-resident memory T (TRM) cells were significantly higher in HCQ + QC-nonresponders compared to HCQ- and HCQ + QC-responders. mDCs were significantly higher in HCQ +QC-responders compared to HCQ-responders and HCQ + QC-nonresponders. There were significantly higher pDCs in the HCQ-responders compared to the nonresponders. CLASI scores of HCQ + QC-nonresponders correlated positively with the number of TRM cells (r=0.6254, P=0.017) and macrophages (r=0.5726, P=0.041). mRNA expression demonstrated high STAT3 expression in HCQ + QC-nonresponders.ConclusionsAn increased number of CD69+ TRM cells and correlation between CD69+ TRM cells and macrophages with CLASI scores in the HCQ + QC-nonresponders, a finding not seen in either HCQ or HCQ + QC-responders, may suggest CD69+ TRM cells and macrophages are involved in antimalarial-refractory skin disease.

Recent Insight on the Management of Lupus Erythematosus Alopecia.

Lupus erythematosus (LE) is a chronic autoimmune condition with a wide spectrum of clinical presentations. Alopecias, both non-scarring and scarring, frequently occur in the context of LE and can assume several different patterns. Furthermore, alopecia occurring with LE may be considered LE-specific if LE-specific features are present on histology; otherwise, alopecia is considered non-LE-specific. Non-scarring alopecia is highly specific to systemic LE (SLE), and therefore has been regarded as a criterion for the diagnosis of SLE. Variants of cutaneous LE (CLE), including acute, subacute, and chronic forms, are also capable of causing hair loss, and chronic CLE is an important cause of primary cicatricial alopecia. Other types of hair loss not specific to LE, including telogen effluvium, alopecia areata, and anagen effluvium, may also occur in a patient with lupus. Lupus alopecia may be difficult to treat, particularly in cases that have progressed to scarring. The article summarizes the types of lupus alopecia and recent insight regarding their management. Data regarding the management of lupus alopecia are sparse and limited to case reports, and therefore, many studies including in this review report the efficacy of treatments on CLE as a broader entity. In general, for patients with non-scarring alopecia in SLE, management is aimed at controlling SLE activity with subsequent hair regrowth. Topical medications can be used to expedite recovery. Prompt treatment is crucial in the case of chronic CLE due to potential for scarring and irreversible damage. First-line therapies for CLE include topical corticosteroids and oral antimalarials, with or without oral corticosteroids as bridging therapy. Second and third-line systemic treatments for CLE include methotrexate, retinoids, dapsone, mycophenolate mofetil, and mycophenolate acid. Additional topical and systemic medications as well as physical modalities used for the treatment of lupus alopecia and CLE are discussed herein.

A Rare Case of Tumid Lupus Erythematosus with Unilateral Linear Distribution in A Young Child

Tumid lupus erythematosus (TLE) as a rare variant of cutaneous lupus erythematosus (CLE) is characterized by edematous, urticarial-like annular papules and plaques. TLE has similar histopathologic findings to CLE such as periadnexal lymphocytic infiltration and interstitial mucin deposition. Although TLE develops on sun-exposed areas at any age, it is rarely distributed along the Blaschko lines and develops in infancy and childhood. Unlike CLE, skin lesion of TLE heals without leaving scarring or dyspigmentation. Here, we report a rare case of unilateral linear TLE in a 4-year-old girl, which was improved by intralesional corticosteroid injection and oral antimalarial drug with leaving postinflammatory hyperpigmentation.

The effect of recurrent malaria infections on bone and cartilage at the distal femoral epiphysis of rats: A histological study

Objective: The aim of this study was to investigate the normal changes that occur at the distal femoral epiphysis of rats and determine whether recurrent bouts of malaria altered them in anyway. Materials and Methods: The 1st phase of the study made use of 30 Sprague-Dawley rats aged 4 weeks. Two rats were culled each week for 15 weeks, the femoral bones of the rats were then harvested. Histological sections of the distal femora were prepared and studied. The 2nd phase involved 32 animals that were randomly assigned to four groups of 8 animals each. (Group A to D) Group A was given oral antimalarial drugs only, Group B was inoculated with Plasmodium berghei (NK65) only, Group C was inoculated with P. berghei (NK65) and treated with oral antimalarial drug, and Group D animals were neither inoculated nor given antimalarial drugs. At the end of the experiment histological sections of the femoral epiphysis of the rats were prepared and studied. Results: The microscopic architecture of the epiphyseal cartilage changed significantly as the animals aged. Significant differences were observed in mean bone thickness of the various experimental groups. There was however no significant difference in the mean cartilage thickness when comparison was made within the various groups. Conclusion: Although recurrent bouts of malaria infection appear not to alter the normal histological changes that occur in epiphyseal bone and cartilage layers, it most likely has an adverse effect on the rate of bone tissue deposition.

A rare case of tumid lupus erythematosus with unilateral linear distribution in a young child

Tumid lupus erythematosus (TLE) as a rare variant of cutaneous lupus erythematosus (CLE) is characterized by edematous, urticarial-like annular papules and plaques. TLE has similar histopathologic findings to CLE such as periadnexal lymphocytic infiltration and interstitial mucin deposition. Although TLE develops on sun-exposed areas at any age, it is rarely distributed along the Blaschko lines and develops in infancy and childhood. Unlike CLE, skin lesion of TLE heals without leaving scarring or dyspigmentation. Here, we report a rare case of unilateral linear TLE in a 4-year-old girl, which was improved by intralesional corticosteroid injection and oral antimalarial drug with leaving postinflammatory hyperpigmentation.

Metabolic vulnerabilities in IDH1/2‐mutated solid tumours lead to phase IB/II clinical trial using metformin and chloroquine

IntroductionHotspot mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. Mutations induce a neoenzymatic activity that leads to the production and accumulation of D‐2‐hydroxyglutarate (D‐2HG). This causes metabolic rewiring and stress that is not fully understood. We previously postulated that the tricarboxylic acid (TCA) cycle, rather than glycolytic lactate production, is the predominant metabolic pathway in IDH1MUT glioma.ResultsTo confirm this hypothesis in a clinical setting, we used a novel technique of quantitative targeted next‐generation sequencing of 104 metabolic enzymes, on a cohort of 66 clinical gliomas. We confirmed the predominance of the oxidative metabolism in IDH1MUT gliomas, which is driven by lactate and glutamate anaplerosis. Preferential glutamate processing in IDH1MUT gliomas was confirmed by in situ enzyme activity mapping experiments in clinical gliomas of known IDH status, indicating that IDH1MUT gliomas depend on glutamatolysis, rather than glutaminolysis. We aim to specifically inhibit the metabolic processes that are essential to IDHMUT tumours using the oral antidiabetic metformin and the oral antimalarial drug chloroquine, which specifically target the metabolic vulnerabilities that are caused by IDHMUT.Clinical trialWe started a dose‐finding phase Ib/II clinical trial, in which patients with IDHMUT chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, (2) investigation of tumour responses to metformin plus chloroquine in IDHMUT cancers using CT/MRI scans; and (3) whether tumour responses can be measured by noninvasive D‐2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next‐generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDHMUT high‐grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.Support or Funding InformationThis work was supported by Dutch Cancer Society Grants KWF‐UVA 2014‐6839 (to M.K., R.J.M., and C.J.F.V.N.) and AMC2016.1‐10460 (to M.K., R.J.M., J.W.W., and C.J.F.V.N.). A) Targeted RNAseq of clinical glioma samples. Gene expression levels of genes involved in glycolysis, glutaminolysis and the TCA cycle. B) Metabolic mapping of glutamate dehydrogenase (GLUD) and glutaminase (GLS). Cryostat sections and (C) quantification activity levels in IDH1WT (n=5) and IDH1MUT (n=7)imageA) Targeted RNAseq of clinical glioma samples. Gene expression levels of genes involved in glycolysis, glutaminolysis and the TCA cycle. B) Metabolic mapping of glutamate dehydrogenase (GLUD) and glutaminase (GLS). Cryostat sections and (C) quantification activity levels in IDH1WT (n=5) and IDH1MUT (n=7) D) Cellular carbohydrate and glutamine metabolism showing the pathways in which IDH1 and IDH2 are functional. The conversion of glutamine into α‐ketoglutarate occurs in the glutaminolysis pathway and the last step is catalysed by glutamate dehydrogenase (GLUD), which is inhibited by chloroquine and metformin. Complex I of the electron transport chain (ETC) is also inhibited by metformin. E) Dosing schedule and study design for patients. MRS, magnetic resonance spectroscopy; MS, mass spectrometryimageD) Cellular carbohydrate and glutamine metabolism showing the pathways in which IDH1 and IDH2 are functional. The conversion of glutamine into α‐ketoglutarate occurs in the glutaminolysis pathway and the last step is catalysed by glutamate dehydrogenase (GLUD), which is inhibited by chloroquine and metformin. Complex I of the electron transport chain (ETC) is also inhibited by metformin. E) Dosing schedule and study design for patients. MRS, magnetic resonance spectroscopy; MS, mass spectrometryThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Ebola-effect in Guinea 2014-15: Tangled trends of malaria care in children under-five.

IntroductionThe 2014–15 Ebola outbreak in West Africa was disruptive for the general health services in the affected countries. This study assessed the impact of the outbreak on the reported number and management of malaria in children under-five in rural Guinea.Materials and methodsA retrospective cross-sectional study was conducted in nineteen health centres in two rural, malaria-endemic health districts, one at the epicentre of the outbreak (Guéckédou) and one (Koubia) spared by Ebola. Routine surveillance data at health facility level were compared over similar periods of high malaria transmission in both districts before, during and after the outbreak.ResultsThere were significant declines in the number of visits during the Ebola outbreak (3,700) in Guéckédou compared to before (4,616) and after it (4,195), while this trend remained more stable within the three periods for Koubia. Differences were nonetheless significant in both districts (p<0.001). In 2014, during the peak of the outbreak, the overall number of malaria cases treated exceeded the number of confirmed malaria cases in Guéckédou. There were decreases in antimalarial treatment provision in August and November 2014. In contrast, during 2015 and 2016, the proportion of malaria positive cases and those treated were closely aligned. During the peak of the Ebola outbreak, there was a significant decrease in oral antimalarial drug administration, which corresponded to an increase in injectable antimalarial treatments. Stock-outs in rapid diagnostic tests were evident and prolonged in Guéckédou during the outbreak, while more limited in Koubia.ConclusionThe Ebola outbreak of 2014–15 in Guinea had a significant impact on the admission and management of malaria in children under-five. This study identifies potential challenges in the delivery of care for those at highest risk for malaria mortality during an Ebola outbreak and the need to improve preparedness strategies pre-Ebola and health systems recovery post-Ebola.

Intravenous artesunate plus Artemisnin based Combination Therapy (ACT) or intravenous quinine plus ACT for treatment of severe malaria in Ugandan children: a randomized controlled clinical trial

BackgroundSevere malaria is a medical emergency associated with high mortality. Adequate treatment requires initial parenteral therapy for fast parasite clearance followed by longer acting oral antimalarial drugs for cure and prevention of recrudescence.MethodsIn a randomized controlled clinical trial, we evaluated the 42-day parasitological outcomes of severe malaria treatment with intravenous artesunate (AS) or intravenous quinine (QNN) followed by oral artemisinin based combination therapy (ACT) in children living in a high malaria transmission setting in Eastern Uganda.ResultsWe enrolled 300 participants and all were included in the intention to treat analysis. Baseline characteristics were similar across treatment arms. The median and interquartile range for number of days from baseline to parasite clearance was significantly lower among participants who received intravenous AS (2 (1–2) vs 3 (2–3), P < 0.001). Overall, 63.3% (178/281) of the participants had unadjusted parasitological treatment failure over the 42-day follow-up period. Molecular genotyping to distinguish re-infection from recrudescence was performed in a sample of 127 of the 178 participants, of whom majority 93 (73.2%) had re-infection and 34 (26.8%) had recrudescence. The 42 day risk of recrudescence did not differ with ACT administered. Adverse events were of mild to moderate severity and consistent with malaria symptoms.ConclusionIn this high transmission setting, we observed adequate initial treatment outcomes followed by very high rates of malaria re-infection post severe malaria treatment. The impact of recurrent antimalarial treatment on the long term efficacy of antimalarial regimens needs to be investigated and surveillance mechanisms for resistance markers established since recurrent malaria infections are likely to be exposed to sub-therapeutic drug concentrations. More strategies for prevention of recurrent malaria infections in the most at risk populations are needed.Trial registrationThe study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348).

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours

IntroductionHigh-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for...

Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar.

BackgroundArtemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts.MethodsA cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT.ResultsIn total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18–8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21–5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations.ConclusionPrivate healthcare facilities and drug shops and providers who prioritize consumers’ demand instead of recommended practices were more likely to stock oral AMT. Malaria elimination strategies should include targeted interventions to effectively reach those outlets.

The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei.

The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca(2+), and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei.