Rectal artesunate for severe malaria, implementation research, Zambia.

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Role for antimalarials in the management of COVID-19.

PURPOSE OF REVIEW: The current review highlights recent insights into direct antiviral effects by antimalarials against severe acute respiratory syndrome (SARS)-CoV-2 and other viruses and their potential indirect effects on the host by avoiding exaggerated immune responses (reduced cytokine release, Toll-like receptor response, antigen presentation related to lysosomal processing). RECENT FINDINGS: Currently, there is a large debate on the use of antimalarials for prophylaxis and treatment of SARS-CoV-2-induced disease based on preclinical in-vitro data, small case series and extrapolation from earlier studies of their effect on intracellular pathogens, including many viruses. Hydroxychloroquine (HCQ) or chloroquine have not demonstrated robust efficacy in prior randomized controlled studies against several other viruses. In-vitro data indicate a reduced viral replication of SARS-CoV-2. Especially immunomodulatory effects of antimalarials might also contribute to a clinical efficacy. For SARS-CoV-2 various large studies will provide answers as to whether antimalarials have a place in prophylaxis or treatment of the acute virus infection with SARS-CoV-2 but compelling data are missing so far. SUMMARY: In-vitro data provide a theoretical framework for an efficacy of antimalarials in SARS-CoV-2-induced disease but clinical proof is currently missing.

Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy.

Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

Investigation of Four Cases of Stevens-Johnson Syndrome among Participants in a Mass Drug Administration Campaign with Sulfadoxine-Pyrimethamine and Primaquine in Haiti, 2020.

In 2018, a mass drug administration (MDA) campaign for malaria elimination was piloted in Haiti. The pilot treated 36,338 people with sulfadoxine-pyrimethamine (SP) and primaquine; no severe adverse events were detected. In 2020, another MDA campaign using the same medications was implemented to mitigate an upsurge in malaria cases during the COVID-19 pandemic. Four cases of Stevens-Johnson syndrome (SJS) were identified among the 42,249 people who took the medications. Three of these individuals required hospitalization; all survived. In addition to SP ingestion, an investigation of potential causes for increased SJS cases identified that all four cases had human leukocyte antigens A*29 and/or B*44:03, another known risk factor for SJS. Additionally, three of the four case individuals had antibodies to SARS-CoV-2, and the fourth may have been exposed around the same time. These findings raise the possibility that recent SARS-CoV-2 infection may have contributed to the increased risk for SJS associated with SP exposure during the 2020 campaign.

The length of hospital stays and clinical and therapeutic characteristics of patients with COVID-19 early in the pandemic in Taif City, KSA: A retrospective study.

The coronavirus disease-2019 (COVID-19) pandemic is unprecedented in the healthcare sector worldwide. This retrospective study focused on the length of hospital stay and clinical and therapeutic characteristics of patients with COVID-19. Retrospective data of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) positive patients were collected between March 12 and June 30, 2020, and categorized into mild, moderate, and severe disease groups based on symptoms and severity of COVID-19. A total of 843 SARS-COV-2-positive patients were identified in this study (mildly symptomatic, 132; moderately symptomatic, 168; severely symptomatic, 17). The mean lengths (days) of hospital stay of Groups 1 to 8 were 16.38, 13.18, 13.72, 9.30, 6.96, 10.86, 5.77, and 7.37, respectively. Treatment Group 1 had the highest mean. In the treatment group, 7 patients who were not treated had the shortest stay. The patients with heart failure and Group 1 received antiviral, antimalarial, and antibiotic therapy; patients in Group 3 received antimalarial and antibiotic therapy; patients in Group 4 received antiviral and antibiotic therapy were tended to have a longer hospital stay. The length of hospital stay and clinical and therapeutic characteristics are crucial indicators of pandemic management, a shorter hospital stay is a positive outcome of better COVID-19 management.

Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.

BACKGROUND: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS. METHODS: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332. FINDINGS: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection. INTERPRETATION: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

The CARAMAL study could not assess the effectiveness of rectal artesunate in treating suspected severe malaria.

CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that "pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival". We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment.

Whole sporozoite immunization with Plasmodium falciparum strain NF135 in a randomized trial.

BACKGROUND: Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes. METHODS: In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135. RESULTS: Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%). CONCLUSIONS: These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT03813108.

Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs. We investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. Chloroquine (EC50 = 2.1 µM and EC90 = 3.8 µM), hydroxychloroquine (EC50 = 1.5 µM and EC90 = 3.0 µM), ferroquine (EC50 = 1.5 µM and EC90 = 2.4 µM), desethylamodiaquine (EC50 = 0.52 µM and EC90 = 1.9 µM), mefloquine (EC50 = 1.8 µM and EC90 = 8.1 µM), pyronaridine (EC50 = 0.72 µM and EC90 = 0.75 µM) and quinine (EC50 = 10.7 µM and EC90 = 38.8 µM) showed in vitro antiviral effective activity with IC50 and IC90 compatible with drug oral uptake at doses commonly administered in malaria treatment. The ratio Clung/EC90 ranged from 5 to 59. Lumefantrine, piperaquine and dihydroartemisinin had IC50 and IC90 too high to be compatible with expected plasma concentrations (ratio Cmax/EC90 < 0.05). Based on our results, we would expect that countries which commonly use artesunate-amodiaquine or artesunate-mefloquine report fewer cases and deaths than those using artemether-lumefantrine or dihydroartemisinin-piperaquine. It could be necessary now to compare the antimalarial use and the dynamics of COVID-19 country by country to confirm this hypothesis.

Recent Trends on Production Sources, Biosynthesis Pathways and Antiviral Efficacies of Artemisinin: A Candidate Phytomedicine against SARS-CoV-2.

BACKGROUND: Artemisinin is a lactone sesquiterpenoid with an endo-peroxide bridge in the 1, 2, 3-trioxane structure employed for the treatment and management of lethal viral diseases. In the current review, emphasis has been given on the production of artemisinin from natural sources with biosynthesis pathways and potential antiviral activity. METHODS: A wide-ranging inquiry on artemisinin was made electronically on the basis of articles published in peer-reviewed journals, abstracts, published in conference proceedings, government reports, preprints, books, Master's and Ph.D. theses, etc. The research was carried out in different International scientific databases like Academic Search, Biological Abstracts, BIOSIS, BioOne Previews, CabDirect, Cochrane Library, Pubmed/Medline, GeoRef, Google Scholar, JSTOR, Journal Citation Reports, Mendeley, Publons, Researchgate, Scopus, SciELO, Springer Link, Science Direct, Web of Science, Taylor and Francis with particular keywords. RESULTS: The evidence reviewed here indicates that out of the hundreds of species of the genus Artemisia mentioned in the literature, only 37 Artemisia species are reported to possess artemisinin naturally in their extracts with variable concentrations. This review further discusses the biosynthesis pathways and antiviral activities of artemisinin and its derivatives which have been used against more than 12 viral disease categories. CONCLUSION: On the whole, it is concluded that the primary natural sources of artemisinin and its derivatives are the Artemisia plants with antiviral activity, which are essential candidates for drug development against SARS-CoV-2 mainly from those Artemisia species screened for SARS-CoV- 2 infection.

Factors associated with delay in seeking healthcare for imported malaria: a retrospective study in a French hospital.

BACKGROUND: Delayed treatment is associated with a higher risk of severe malaria. In malaria-endemic areas, the main factors associated with delay in seeking healthcare are low educational level and traditional beliefs. In imported malaria, determinants of delay in seeking healthcare are currently unknown. METHODS: We studied all patients presenting with malaria, from 1 January 2017 to 14 February 2022, in the hospital of Melun, France. Demographic and medical data were recorded for all patients, and socio-professional data were recorded for a subgroup of hospitalized adults. Relative-risks and 95% confidence intervals were determined using univariate analysis by cross-tabulation. RESULTS: There were 234 patients included, all travelling from Africa. Among them, 218 (93%) were infected with P. falciparum, 77 (33%) had severe malaria, 26 (11%) were <18 years old and 81 were included during the SARS-CoV-2 pandemic. There were 135 hospitalized adults (58% of all patients). The median time to hospital admission (THA) , defined by the period from onset of symptoms to arrival at hospital, was 3 days (IQR = 2-5). A THA ≥3 days tended to be more frequent in travellers visiting friends and relatives (VFR; RR = 1.44, 95% CI = [1.0-2.05], P = 0.06), while it was less frequent in children and teenagers (RR = 0.58, 95% CI = [0.39-0.84], P = 0.01). Gender, African background, unemployment, living alone and absence of referring physician were not associated with delay in seeking healthcare. Consulting during the SARS-CoV-2 pandemic was neither associated with a longer THA nor with a higher rate of severe malaria. CONCLUSION: In contrast to an endemic area, socio-economic factors did not impact on delay in seeking healthcare in imported malaria. Prevention should focus on VFR subjects, who tend to consult later than other travellers.

A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19.

OBJECTIVES: The emergence of SARS-CoV-2 has presented clinicians with a difficult therapeutic dilemma. With supportive care as the current mainstay of treatment, the fatality rate of COVID-19 is 6.9%. There are currently several trials assessing the efficacy of different antivirals as treatment. Of these, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have garnered the most attention. METHODS: In this study, the literature currently available on CQ and HCQ as treatment of COVID-19 was surveyed using EMBASE, PubMed, Cochrane Library, MedRxiv, and one clinical trial registry. Upon gathering published and preprint trials, risk of bias was assessed using Cochrane Risk of Bias Tool 2.0. RESULTS: There are currently seven completed clinical trials and 29 registered clinical trials focusing on HCQ or CQ as a therapeutic avenue for COVID-19. Of these, five of seven trials have shown favorable outcomes for patients using CQ or HCQ and two of seven have shown no change compared to control. However, all seven trials carried varying degrees of bias and poor study design. CONCLUSION: There are currently not enough data available to support the routine use of HCQ and CQ as therapies for COVID-19. Pending further results from more extensive studies with more stringent study parameters, clinicians should defer from routine use of HCQ and CQ. There are several clinical trials currently under way with results expected soon.

Challenges Based on Antiplasmodial and Antiviral Activities of 7-Chloro-4-aminoquinoline Derivatives.

We report the structural functionalization of the terminal amino group of N1 -(7-chloroquinolin-4-yl) butane-1,4-diamine, leading to a series of 7-chloro-4-aminoquinoline derivatives, and their evaluation as potent anti-malarial and anti-viral agents. Some compounds exhibited promising anti-malarial effects against the Plasmodium falciparum 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains. In addition, these compounds were assayed in vitro against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compound 5 h, bearing an N-mesityl thiourea group, displayed pronounced anti-infectious effects against malaria, IAV, and SARS-CoV-2. These results provide new insights into drug discovery for the prevention or treatment of malaria and virus co-infection.

Return to Travel in the Coronavirus Disease 2019 Pandemic Recovery Period and Implications for Imported Malaria: Reinforcing Prevention, Early Diagnosis, and Appropriate Treatment of Malaria.

Return to international travel in the COVID-19 pandemic recovery period is expected to increase the number of patients with imported malaria in the United States (US). Malaria prevention in travelers and preparedness for timely diagnosis and appropriate treatment are key to minimize imported malaria morbidity and mortality. Intravenous artesunate (IVAS) is now available from commercial distributors in the US for the treatment of severe malaria. Hospitals and pharmacists should have a plan for malaria treatment, including stocking artemether-lumefantrine for uncomplicated malaria, and stocking or planning for rapid procurement of IVAS for the treatment of severe malaria.

Update on antimalarials and systemic lupus erythematosus.

PURPOSE OF REVIEW: The purpose of this review is highlighting the most recent evidence on the clinical efficacy and toxicity of antimalarials in systemic lupus erythematosus (SLE). RECENT FINDINGS: New data confirm the effects of antimalarials in preventing SLE activity, damage and infections and in decreasing mortality. An important reduction in use of health resources is related to continued antimalarial use. Hydroxychloroquine (HCQ) may prevent preeclampsia in pregnant women with SLE. HCQ ocular toxicity is infrequent and could be associated with blood levels. Gastrointestinal and skin toxicity are underrecognized and could influence adherence. Prolongation of QT interval is extremely unusual with HCQ. Doses of HCQ of 200 mg/day seem to offer a good efficacy/toxicity balance. HCQ protection against herpes zoster and Pneumocystis jirovecii infection has been shown. On the contrary, HCQ prescription by doctors and adherence by patients are both under recommended standards. The recent coronavirus disease 2019 pandemic has resulted in a significant shortage of HCQ in many countries with possible consequences in the correct treatment of lupus patients. SUMMARY: Recent evidence reinforces the central role of HCQ in SLE therapy. The reduction in activity, damage accrual and mortality is consistent across studies, countries and ethnical groups. On the contrary, and despite the well established beneficial effects of prolonged regular HCQ therapy, many SLE patients do never take this drug or it is eventually stopped in the setting of severe flares, pregnancy or presumed toxicity. Every effort must be made to assure the correct prescription of HCQ and not to withdraw the drug unless unequivocal signs of toxicity are present.

Andrographis paniculata Dosage Forms and Advances in Nanoparticulate Delivery Systems: An Overview.

Andrographis paniculata is a well-known Asian medicinal plant with a major phytoconstituent of diterpene lactones, such as andrographolide, 14-deoxyandrographolide, and neoandrographolide. A World Health Organization (WHO) monograph on selected medicinal plants showed that A. paniculata extracts and its major diterpene lactones have promising anti-inflammatory, antidiabetic, antimalarial, anticancer, antifungal, antibacterial, antioxidant, and hypoglycemic activities. However, these active phytochemicals have poor water solubility and bioavailability when delivered in a conventional dosage form. These biological barriers can be mitigated if the extract or isolated compound are delivered as nanoparticles. This review discusses existing studies and marketed products of A. paniculata in solid, liquid, semi-solid, and gaseous dosage forms, either as an extract or isolated pure compounds, as well as their deficits in reaching maximum bioavailability. The pharmaceutics and pharmacological activity of A. paniculata as a nano-delivery system are also discussed.

Antiviral COVID-19 protein and molecular docking: In silico characterization of various antiviral compounds extracted from Arisaema jacquemontii Blume.

Arisaema jacquemontii Blume is a highly medicinal and poisonous plant belong to the family Araceae. It is used to treat several deadly diseases, including viral infections. It has antioxidant, anti-cancerous, antimalarial, anti-vermicidal, and antiviral activities. Therefore, five parts of the Arisaema jacquemontii Blume plant, such as leaf, seed, stem, pulp, and rhizome extract, were evaluated for metabolic and in silico characterization of probable compounds using gas chromatography-mass spectrometry (GC-MS) analysis. A total of 22 compounds were isolated from the methanolic extracts of A. jacquemontii Blume. A selected antiviral COVID-19 protein i.e., protease (6LU7) was docked against the obtained compounds. Different affinities were obtained through various compounds. The best results were shown by three different compounds identified in the rhizome. The maximum binding affinity of these compounds is 8.1 kJ/mol. Molecular docking (MD) indicate that these molecules have the highest binding energies and hydrogen bonding interactions. The binding mode of interaction was discovered to be reasonably effective for counteracting the SARS virus COVID-19. The findings of this study could be extremely useful in the development of more phytochemical-based COVID-19 therapeutics.