Treatment Of Severe Malaria Research Articles

Artemisinin Partial Resistance and the Treatment of Severe Malaria.

Artemisinin Partial Resistance and the Treatment of Severe Malaria.

Artemisinin-resistant malaria.

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

Improving adherence to severe malaria treatment guidelines in children at a Ugandan regional hospital: assessment of a quality improvement initiative

BackgroundMalaria is the leading cause of hospitalizations and death in Uganda, particularly in children under the age of five. Studies have shown that adherence to the World Health Organization (WHO) guidelines for the management of severe malaria reduces mortality in hospitalized children. This study aimed to determine the impact of targeted interventions on adherence to the WHO severe malaria treatment guidelines in children at a Ugandan hospital as part of a quality improvement initiative.MethodsInterventions included workflow changes, such as obtaining patient blood samples for diagnostic testing by the admitting healthcare provider as well as utilizing patient caregivers to assist nursing staff in timing medications. An additional intervention was the use of an admission checklist sticker. The post-intervention sample was compared to the baseline assessment. The primary outcome was the proportion of patients receiving care consistent with all aspects of the WHO guidelines. Secondary outcomes included the proportion of patients receiving malaria diagnostic testing, those receiving at least 3 doses of artesunate, the timely administration of artesunate, and adherence to other guideline components. Statistical analyses were conducted using GraphPad PRISM 9.0. Comparisons between groups were analysed using Chi-square or Fisher’s exact test for categorical variables and Mann–Whitney test for continuous variables.ResultsThe post-intervention group included 230 patients with a median age of 5 years [4–8], and 58% of patients were male. Adherence to all aspects of the WHO guidelines was achieved in 10% of patients in the post-intervention group compared to 3% of patients in the baseline (P = 0.007). Appropriate malaria diagnostic testing was performed in 85% of patients post-intervention compared to 66% of patients in the baseline (P < 0.0001). Patients in the post-intervention group were more likely to receive the minimum 3 doses of artesunate (86%) than in the baseline (74%) (P = 0.008). Patients in the post-intervention group were more likely to receive artesunate doses on time than in the baseline (dose 2 P = 0.02, dose 3 P = 0.003).ConclusionsTargeted, low-cost interventions led to improvement in adherence to severe malaria treatment guidelines. The most notable changes were in malaria diagnostic testing and antimalarial administration.

SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART).

Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes. Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences. A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient's APTT results using standard methods. The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021).

Use of National Guidelines in the Treatment of Severe Malaria: A Retrospective Study of Severe Malaria Management in Under 5s in Benue State

Use of National Guidelines in the Treatment of Severe Malaria: A Retrospective Study of Severe Malaria Management in Under 5s in Benue State

Health workers’ adherence to malaria case management protocols in Northern Sudan: a qualitative study

BackgroundNonadherence to national standards for malaria diagnosis and treatment has been reported in Sudan. In this study, qualitative research examined the clinical domains of nonadherence, factors influencing nonadherent practices and health workers’ views on how to improve adherence.MethodsIn September 2023, five Focus Group Discussions (FGDs) were undertaken with 104 health workers from 42 health facilities in Sudan’s Northern State. The participants included medical assistants, doctors, nurses, laboratory personnel, pharmacists and public health officers. The FGDs followed a semi-structured guide reflecting the national malaria case management protocol. Qualitative thematic analysis was performed.ResultsNonadherent practices included disregarding parasitological test results, suboptimal paediatric artemether–lumefantrine (AL) dosing, lack of counselling, use of prohibited artemether injections for uncomplicated and severe malaria, artesunate dose approximations and suboptimal preparations, lack of AL follow on treatment for severe malaria; and rare use of primaquine for radical Plasmodium vivax treatment and dihydroartemisinin-piperaquine as the second-line treatment for uncomplicated malaria. Factors influencing nonadherence included stock-outs of anti-malarials and RDTs; staff shortages; lack of training, job aids and supervision; malpractice by specialists; distrust of malaria microscopy and RDTs; and patient pressure for diagnosis and treatment. Health workers recommended strengthening the supply chain; hiring personnel; providing in-service protocol training including specialists; establishing external quality assurance for malaria diagnosis; and providing onsite supportive supervision and public health campaigns.ConclusionsThis study revealed a broad spectrum of behavioural and systemic challenges in malaria management among frontline health workers in Northern Sudan, including nonadherence to protocols due to resource shortages, training gaps, a lack of supportive supervision and patient pressure. These insights, including health workers’ views about improvements, will inform evidence-based interventions by Sudan’s National Malaria Control Programme to improve health systems readiness and the quality of malaria case management.

Antineoplastic Drug Synergy of Artesunate with Navitoclax in Models of High-Grade Serous Ovarian Cancer.

Artesunate belongs to a class of medications derived from the sweet wormwood plant (Artemisia annua) known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis. In the current study, we investigated the ability of navitoclax, an inhibitor of the antiapoptotic Bcl-2 protein family, to enhance artesunate efficacy in ovarian cancer cells. Artesunate and navitoclax both demonstrated antiproliferative effects on 2D and 3D ovarian cancer cell models as single agents. Upon combination of navitoclax with artesunate, antineoplastic drug synergy was also observed in each of the 2D cell lines and ovarian tumor organoid models tested. Further investigation of this drug combination using intraperitoneal CAOV3 xenograft models in BALB/scid mice showed that the artesunate/navitoclax doublet was superior to single-agent artesunate and vehicle control treatment. However, it did not outperform single-agent navitoclax. With optimization, this drug combination could provide a new therapeutic option for ovarian cancer and warrants further preclinical investigation.

Impact of the Severe Malaria "Champions Program" on the Management of Severe Malaria Cases in 12 Hospitals of the North and Far North Regions of Cameroon.

Malaria remains a main cause of morbidity and mortality in Cameroon. Since 2021, the U.S. President's Malaria Initiative Impact Malaria Project has supported the National Malaria Control Program to develop the Champions program in two northern regions. We assessed this program's preliminary effectiveness on the performance of hospitals in the management of severe malaria and reduction of malaria-related deaths. We conducted a secondary analysis of Outreach Training and Supportive Supervision (OTSS) data from four rounds (one round pre-Champions program and three rounds post-Champions program and 2020-2022 malaria-related mortality data for 12 hospitals). Using linear regressions, we measured changes in hospital readiness and competency of health workers in the management of severe malaria between baseline and subsequent rounds. There were statistically significant improvements in overall management of severe malaria scores in post-Champions OTSS rounds, with post-Champions round 3 exhibiting an increase of +14% (P = 0.013) over baseline. Overall health facility readiness scores exhibited an increase of +7% (P = 0.006) from baseline to post-Champions round 3. There were no statistically significant findings associated with providing the right treatment, as nearly all patients hospitalized with severe malaria were treated with a recommended severe malaria treatment. Reported inpatient malaria deaths and case fatality rates trended downward from 2020 to 2022, but these differences were not statistically significant. The Champions program resulted in significant improvements in quality of inpatient care for severe malaria. The downward trends in malaria deaths and case fatality rate will require further monitoring to determine whether the Champions program is having the desired impact of reducing inpatient deaths from malaria.

Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Adjunctive rosiglitazone treatment for severe pediatric malaria: A randomized placebo-controlled trial in Mozambican children

ObjectivesWe tested the hypothesis that adjunctive rosiglitazone treatment would reduce levels of circulating angiopoietin-2 (Angpt-2) and improve outcomes of Mozambican children with severe malaria. MethodsA randomized, double-blind, placebo-controlled trial of rosiglitazone vs placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. A 0.045 mg/kg/dose of rosiglitazone or matching placebo were administered, in addition to standard of malaria care, twice a day for 4 days. The primary endpoint was the rate of decline of Angpt-2 over 96 hours. Secondary outcomes included the longitudinal dynamics of angiopoietin-1 (Angpt-1) and the Angpt-2/Angpt-1 ratio over 96 hours, parasite clearance kinetics, clinical outcomes, and safety metrics. ResultsOverall, 180 children were enrolled; 91 were assigned to rosiglitazone and 89 to placebo. Children who received rosiglitazone had a steeper rate of decline of Angpt-2 over the first 96 hours of hospitalization compared to children who received placebo; however, the trend was not significant (P = 0.28). A similar non-significant trend was observed for Angpt-1 (P = 0.65) and the Angpt-2/Angpt-1 ratio (P = 0.34). All other secondary and safety outcomes were similar between groups (P >0.05). ConclusionAdjunctive rosiglitazone at this dosage was safe and well tolerated but did not significantly affect the longitudinal kinetics of circulating Angpt-2.

Widened Scope of Drug Repurposing/Chiral Switches, Elements of Secondary Pharmaceuticals: The Quinine/Quinidine Case

Drug repurposing to new medical uses and chiral switches are elements of secondary pharmaceuticals. This article focuses on drug repurposing/chiral switches of the diastereomeric quasi-enantiomeric antimalarial quinine and antiarrhythmic quinidine, based on the histories of these drugs (1638–2022), applying a widened scope. Quinine, an essential medicine, changed the world. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs outside the scope of the original medical indications. Potential drugs are not included in the definition of drug repurposing. Drug repurposing may be within or outside the therapeutic group, e.g., quinidine to quinine repurposing, from treatment of arrhythmia or severe malaria to uncomplicated malaria. The scope of chiral switches included racemate to single enantiomer and other switches of the status of chirality, e.g., racemate and quasi-racemate to scalemic mixtures. There are 16 quinine/quinidine stereoisomers. Given the multiple pharmacological activities of Cinchona alkaloid stereoisomers, this article calls for subjecting them to comprehensive drug repurposing/chiral switch searches for new medical uses.

SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART)

Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (&lt;24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes . Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences. Methods A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (&gt; 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)

Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria.

The majority of deaths from malaria are in young African children. Parenteral artesunate (ARS) is the first-line treatment for severe falciparum malaria. Since 2015, the World Health Organization has recommended individual doses of 3 mg/kg for children weighing < 20 kg. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic (PK) modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of ARS intravenously. Bayesian hierarchical modeling and a two-compartment parent drug-metabolite PK model for ARS were used to describe the population PKs of ARS and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first-dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous ARS do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower ARS dose recommendation as parenteral ARS is an extremely safe and well-tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.

Management of severe &lt;i&gt;Plasmodium falciparum&lt;/i&gt; malaria in adults: A review of national and regional guidelines and their adherence to World Health Organization guidelines

BACKGROUND: Plasmodium falciparum is the most prevalent and pathogenic malaria parasite associated with severe illness and death. In nonendemic countries like the Russian Federation, P. falciparum malaria is a relatively rare but potentially fatal disease found in travelers returning from countries with high malaria burden.&#x0D; AIMS: This review aimed to analyze the recommendations for managing severe P. falciparum malaria in different World Health Organization (WHO) malaria-endemic regions and considered their adherence to WHO guidelines.&#x0D; MATERIALS AND METHODS: Countries with the highest number of indigenous P. falciparum malaria cases from four WHO regions were identified, and malaria treatment guidelines were searched using databases.&#x0D; RESULTS: Intravenous administration of artesunate is the mainstay of treatment for severe P. falciparum malaria. Most guidelines lack a mechanism for referring patients with severe malaria, between different levels of health facilities, and lack specific criteria for intensive care unit admission.&#x0D; CONCLUSIONS: Mefloquine, artemisinin, combination products containing mefloquine, should be used with caution in cerebral malaria because of neuropsychiatric and cognitive complications. Understanding how guidelines and recommendations for the clinical management of malaria are adopted in different epidemiological settings will help contextualize the value and validity of recommendations for the treatment of severe malaria.

Prescription patterns and compliance with World Health Organization recommendations for the management of uncomplicated and severe malaria: A prospective, real-world study in sub-Saharan Africa

BackgroundThis study aimed to evaluate the gap between guidelines and local clinical practice for diagnosis and treatment of uncomplicated and severe malaria, the patient characteristics, diagnostic approach, treatment, and compliance to standard guideline recommendations.MethodsThis was a multicentre, observational study conducted between October 2020 and March 2021 in which patients of all ages with symptoms suggestive of malaria and who visited a healthcare facility were prospectively enrolled in six countries in sub-Saharan Africa (The Democratic Republic of the Congo, Mozambique, Nigeria, Rwanda, The United Republic of Tanzania, and Zambia).ResultsOf 1001 enrolled patients, 735 (73.4%) patients had confirmed malaria (based on overall judgment by investigator) at baseline (uncomplicated malaria: 598 [81.4%] and severe malaria: 137 [18.6%]). Of the confirmed malaria patients, 533 (72.5%) were administered a malaria rapid diagnostic test. The median age of patients was 11 years (range: 2 weeks–91 years) with more patients coming from rural (44.9%) than urban (30.6%) or suburban areas (24.5%). At the community level, 57.8% of patients sought advice or received treatment for malaria and 56.9% of patients took one or more drugs for their illness before coming to the study site. In terms of early access to care, 44.1% of patients came to the study site for initial visit ≥ 48 h after symptom onset. In patients with uncomplicated malaria, the most prescribed treatments were artemisinin-based combination therapy (ACT; n = 564 [94.3%]), primarily using artemether-lumefantrine (82.3%), in line with the World Health Organization (WHO) treatment guidelines. In addition, these patients received antipyretics (85.6%) and antibiotics (42.0%). However, in those with severe malaria, only 66 (48.2%) patients received parenteral treatment followed by oral ACT as per WHO guidelines, whereas 62 (45.3%) received parenteral treatment only. After receiving ambulatory care, 88.6% of patients with uncomplicated malaria were discharged and 83.2% of patients with severe malaria were discharged after hospitalization. One patient with uncomplicated malaria having multiple co-morbidities and three patients with severe malaria died.ConclusionsThe findings of this study suggest that the prescribed treatment in most patients with uncomplicated malaria, but not of those with severe malaria, was in alignment with the WHO recommended guidelines.

Quinine: Redesigned and Rerouted

Quinine hydrochloride (QHCl) has remained a very relevant antimalarial drug 400 years after its effectiveness was discovered. Unlike other antimalarials, the development of resistance to quinine has been slow. Hence, this drug is to date still used for the treatment of severe and cerebral malaria, for malaria treatment in all trimesters of pregnancy, and in combination with doxycycline against multidrug-resistant malaria parasites. The decline in its administration over the years is mainly associated with poor tolerability due to its gastrointestinal (GIT) side effects such as cinchonism, complex dosing regimen and bitter taste, all of which result in poor compliance. Hence, our research was aimed at redesigning quinine using nanotechnology and investigating an alternative route for its administration for the treatment of malaria. QHCl nanosuspension (QHCl-NS) for intranasal administration was prepared using lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising Phospholipon® 90H and lipids (Softisan® 154 or Compritol®) in a 1:2 ratio, while Poloxamer® 188 (P188) and Tween® 80 (T80) were used as a stabilizer and a surfactant, respectively. The QHCl-NS formulated were in the nanosize range (68.60 ± 0.86 to 300.80 ± 10.11 nm), and highly stable during storage, though zeta potential was low (≤6.95 ± 0.416). QHCl-NS achieved above 80% in vitro drug release in 6 h. Ex vivo permeation studies revealed that formulating QHCl as NS resulted in a 5-fold and 56-fold increase in the flux and permeation coefficient, respectively, thereby enhancing permeation through pig nasal mucosa better than plain drug solutions. This implies that the rate of absorption as well as ease of drug permeation through porcine nasal mucosa was impressively enhanced by formulating QHCl as NS. Most importantly, reduction in parasitaemia in mice infected with Plasmodium berghei ANKA by QHCl-NS administered through the intranasal route (51.16%) was comparable to oral administration (52.12%). Therefore, redesigning QHCl as NS for intranasal administration has great potential to serve as a more tolerable option for the treatment of malaria in endemic areas.

Rectal artesunate for severe malaria, implementation research, Zambia.

To determine whether the positive results of a single-district pilot project focused on rectal artesunate administration at the community level in Zambia could be replicated on a larger scale. In partnership with government, in 10 rural districts during 2018-2021 we: (i)trained community health volunteers to administer rectal artesunate to children with suspected severe malaria and refer them to a health facility; (ii)supported communities to establish emergency transport, food banks and emergency savings to reduce referral delays; (iii)ensured adequate drug supplies; (iv)trained health workers to treat severe malaria with injectable artesunate; and (v)monitored severe malaria cases and associated deaths via surveys, health facility data and a community monitoring system. Intervention communities accessed quality-assured rectal artesunate from trained community health volunteers, and follow-on treatment for severe malaria from health workers. Based on formal data from the health management information system, reported deaths from severe malaria reduced significantly from 3.1% (22/699; 95% confidence interval, CI: 2.0-4.2) to 0.5% (2/365; 95% CI: 0.0-1.1) in two demonstration districts, and from 6.2% (14/225; 95% CI: 3.6-8.8) to 0.6% (2/321; 95% CI: 0.0-1.3) in eight scale-up districts. Despite the effects of the coronavirus disease, our results confirmed that pre-referral rectal artesunate administered by community health volunteers can be an effective intervention for severe malaria among young children. Our results strengthen the case for wider expansion of the pre-referral treatment in Zambia and elsewhere when combined with supporting interventions.

A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

431 Acetaminophen as a Renoprotective Treatment in Severe Malaria

431 Acetaminophen as a Renoprotective Treatment in Severe Malaria

Acetaminophen as Renoprotective Treatment in a Patient With Severe Malaria

Severe falciparum malaria with renal impairment carries a significant risk of poor outcomes, including death. Previous randomized controlled trials using acetaminophen as adjunctive treatment for malaria-associated renal failure have demonstrated improvements in renal function and kidney injury progression. A 50-year-old man with severe falciparum malaria presented with hemolytic anemia, oliguric acute kidney injury, nephrotic range proteinuria, and significant architectural changes on renal ultrasound. Treatment with oral acetaminophen 975 mg every 6 hours was based on the randomized controlled trial protocol to salvage his renal function and avoid dialysis. During the acetaminophen course, urine output and cystatin C level improved with only mild, asymptomatic elevations in aminotransferases that were corrected on follow-up. The patient recovered without requiring dialysis. Acetaminophen's potential to mitigate the oxidative damage of hemoproteins suggests its use as a treatment in severe malaria with renal impairment.