Atraumatic splenic rupture - unexpected consequences of a world trip.

Diagnostic routine and knowledge about the therapy regimes of infectious diseases like malaria gain in importance due to globalization, global warming, and increasing numbers of refugees. We report a case of a 66-year-old patient who presented with severe abdominal pain, most prominent in the left upper abdomen. He was recently hospitalized with severe falciparum malaria, diagnosed after returning from a trip around the world. Upon readmission, laboratory results showed post-artesunate delayed hemolysis. The ultrasound examination was highly suspicious of splenic rupture, confirmed by the immediately performed CT scan. In this case, the prompt diagnosis allowed the initiation of adequate conservative therapy including intensive care monitoring and hemodynamic stabilization.

Post-artesunate Delayed Hemolysis in Patients With Severe Malaria in the United States-April 2019 Through July 2021.

BACKGROUND: Studies have demonstrated the safety and efficacy of intravenous artesunate (IVAS) for treatment of severe malaria in endemic and nonendemic countries. However, post-artesunate delayed hemolysis (PADH) is an increasingly recognized phenomenon after its administration. This study describes the prevalence and outcomes of PADH events among severe malaria cases treated with IVAS in the United States. METHODS: Patients diagnosed with severe malaria and treated with IVAS from April 2019 to July 2021 were included. Demographic, clinical, laboratory, therapeutic, and outcome measures were described using proportions, medians, and interquartile range. Patients reported to experience PADH were compared with those not reported to have PADH, and tests of significance were performed. RESULTS: Of 332 patients included in our analysis, 9 (2.7%) experienced PADH. The majority of infections in both groups were in non-Hispanic Black individuals. Parasite density (11.0% vs 8.0%), admission hemoglobin (11.0 g/dL vs 11.8 g/dL) were similar in the 2 groups. Total bilirubin levels at admission (4.7 mg/dL vs 2.2 mg/dL) and within 8 hours after completion of IVAS (2.6 mg/dL vs 1.2 mg/dL) were notably higher in PADH patients. Cumulative IVAS dose of >9.5 mg/kg and >3 doses of IVAS were risk factors for PADH. The majority (7 of 9) of PADH cases were diagnosed within 2 weeks after initiation of IVAS. Five patients (56%) required blood transfusions, and all recovered without sequelae. CONCLUSIONS: PADH is an uncommon and self-limiting adverse event in many cases; weekly monitoring of hemoglobin and hemolytic markers may identify cases requiring intervention in a timely manner.

Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Mechanism and effects of artesunate on the liver function of rats with type 1 diabetic periodontitis.

Periodontitis is an inflammatory disease of the gums. Periodontitis in diabetic patients can aggravate insulin resistance; however, its molecular and biological mechanism remains unclear. This study aimed to explore the effects of diabetic periodontitis on liver function and determine the mechanism by which artesunate improves liver function. Rats with streptozotocin-induced diabetes were divided into five groups: normal control (NC), diabetic periodontitis (DM + PD), artesunate intervention (ART), insulin intervention (INS), and combined medication intervention (ART + INS) groups. Drug interventions were then administered to the rats in each group as follows: 50 mg/kg artesunate to the ART group, 6 U/kg insulin to the INS group, and 50 mg/kg artesunate + 6 U/kg insulin to the ART + INS group. Blood samples, liver tissues, and the maxillary alveolar bone were collected postsacrifice. ART was found to significantly ameliorate hyperglycemia, blood lipid concentrations, and liver function. The levels of inflammatory factors reduced; the effect was more pronounced in the ART + INS group. Artesunate presumably inhibits the TLR4/NF-κB signaling pathway and expression of downstream inflammatory factors, thereby exerting a protective effect on diabetes-related liver function. This offers a fresh approach to treat diabetes mellitus.

Artesunate protects pancreatic ß-cells from streptozotocin-induced diabetes via inhibition of the NLRP3/caspase-1/GSDMD pathway.

BACKGROUND: Reports in recent years have shown that pancreatic ß-cell pyroptosis represents a critical mechanism involved with the progressive failure of pancreatic function. Previous research from our laboratory has indicated that artemether can increase the number of cells in pancreatic islets of db/db mice. In this study, we further examined whether artesunate (ART) protects pancreatic ß-cells from the damage of streptozotocin (STZ) by inhibiting pyroptosis. MATERIALS AND METHODS: In vitro, MIN6 cells exposed to 1 mM STZ were treated with ART (0.8 or 1.6 µM). The effects of ART on STZ-treated cells were evaluated through CCK-8 assay, flow cytometry and western blot, and further compared the effects of ART with the NLRP3 inhibitor, Mcc950 upon pyroptosis pathway proteins using western blot. In vivo, Male C57 mice were administered with a single intraperitoneal injection of STZ, and those with confirmed diabetes mellitus were given ART (0.5 or 1.0 mg/ml in drinking water) for 18 days. The effects of ART on STZ-induced diabetes were assessed by the observation of the general situation, glucose tolerance test, hematoxylin-eosin (HE) staining and immunohistochemistry. RESULTS: In MIN6 cells treated with STZ, we found that ART increased cell viability, decreased the number of late apoptotic cells (including pyroptosis cells) and inhibited the expression of proteins associated with the pyroptosis pathway. In STZ-induced animal model, the administration of ART reduced blood glucose levels, improved the consumption status within this diabetic mouse model and inhibited the expression of proteins include in the pyroptosis pathway in mice pancreats. CONCLUSIONS: Inhibition of pyroptosis may be a critical mechanism through which artesunate exerts protective effects upon pancreatic ß cells.

Diagnosis, Treatment, and Prevention of Malaria in the US: A Review.

Importance: Malaria is caused by protozoa parasites of the genus Plasmodium and is diagnosed in approximately 2000 people in the US each year who have returned from visiting regions with endemic malaria. The mortality rate from malaria is approximately 0.3% in the US and 0.26% worldwide. Observations: In the US, most malaria is diagnosed in people who traveled to an endemic region. More than 80% of people diagnosed with malaria in the US acquired the infection in Africa. Of the approximately 2000 people diagnosed with malaria in the US in 2017, an estimated 82.4% were adults and about 78.6% were Black or African American. Among US residents diagnosed with malaria, 71.7% had not taken malaria chemoprophylaxis during travel. In 2017 in the US, P falciparum was the species diagnosed in approximately 79% of patients, whereas P vivax was diagnosed in an estimated 11.2% of patients. In 2017 in the US, severe malaria, defined as vital organ involvement including shock, pulmonary edema, significant bleeding, seizures, impaired consciousness, and laboratory abnormalities such as kidney impairment, acidosis, anemia, or high parasitemia, occurred in approximately 14% of patients, and an estimated 0.3% of those receiving a diagnosis of malaria in the US died. P falciparum has developed resistance to chloroquine in most regions of the world, including Africa. First-line therapy for P falciparum malaria in the US is combination therapy that includes artemisinin. If P falciparum was acquired in a known chloroquine-sensitive region such as Haiti, chloroquine remains an alternative option. When artemisinin-based combination therapies are not available, atovaquone-proguanil or quinine plus clindamycin is used for chloroquine-resistant malaria. P vivax, P ovale, P malariae, and P knowlesi are typically chloroquine sensitive, and treatment with either artemisinin-based combination therapy or chloroquine for regions with chloroquine-susceptible infections for uncomplicated malaria is recommended. For severe malaria, intravenous artesunate is first-line therapy. Treatment of mild malaria due to a chloroquine-resistant parasite consists of a combination therapy that includes artemisinin or chloroquine for chloroquine-sensitive malaria. P vivax and P ovale require additional therapy with an 8-aminoquinoline to eradicate the liver stage. Several options exist for chemoprophylaxis and selection should be based on patient characteristics and preferences. Conclusions and Relevance: Approximately 2000 cases of malaria are diagnosed each year in the US, most commonly in travelers returning from visiting endemic areas. Prevention and treatment of malaria depend on the species and the drug sensitivity of parasites from the region of acquisition. Intravenous artesunate is first-line therapy for severe malaria.

Safety and Effectiveness of Intravenous Artesunate for Treatment of Severe Malaria in the United States-April 2019 Through December 2020.

BACKGROUND: Severe malaria can be deadly and requires treatment with intravenous artesunate (IVAS). The Centers for Disease Control and Prevention provided IVAS starting 1 April 2019 for all patients with severe malaria in the United States. This study describes the safety and effectiveness of IVAS in these patients. METHODS: Patients meeting criteria for severe malaria April 2019-December 2020 who received IVAS were included. Demographic, clinical, laboratory, adverse event, and outcome information were collected. Clinical presentation, time to reach 1% and 0% parasitemia, adverse events, and death were described using proportions, medians, interquartile range (IQR), and tests of significance for differences in proportions. RESULTS: Of 280 patients included, the majority were male (61.4%), Black (75.0%), with a median age of 35 years (IQR: 15.8-53.9). Most had Plasmodium falciparum (83.6%) with median parasitemia of 8.0% (IQR: 4.6-13.2). Of 170 patients with information, 159 (93.5%) reached ≤1% parasitemia by the third IVAS dose with a median time of 17.6 hours (IQR: 10.8-28.8), and 0% parasitemia in a median of 37.2 hours (IQR 27.2-55.2). Patients with parasite densities >10% and those requiring adjunct therapy had significantly higher parasite clearance times. Adverse events associated with IVAS were reported in 4.8% (n = 13 of 271). Eight patients had post-artesunate delayed hemolysis that resolved. There were 5 (1.8%) deaths, all attributable to severe malaria. CONCLUSIONS: IVAS is a safe and effective drug for the treatment of severe malaria in the United States; timely administration can be lifesaving.

Pyronaridine-artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study.

BACKGROUND: In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine-artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. METHODS AND FINDINGS: This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine-artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine-artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine-artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. CONCLUSIONS: Pyronaridine-artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine-artesunate as an operationally useful addition to the management of acute uncomplicated malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT03201770.

Hepatic safety of repeated treatment with pyronaridine-artesunate versus artemether-lumefantrine in patients with uncomplicated malaria: a secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso.

BACKGROUND: The use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether-lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso. METHODS: This study analysed data from a clinical trial conducted from 2012 to 2015, in which participants with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression model. RESULTS: A total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin in 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy's law condition was recorded in a first treated participant of the PA arm. Participants from the retreatment group were 76% and 84% less likely to have elevated ALT and AST, respectively, in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms. CONCLUSIONS: Pyronaridine-artesunate and artemether-lumefantrine showed similar hepatic safety when used repeatedly in participants with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line anti-malarial drugs in use in endemic areas. Trial registration Pan African Clinical Trials Registry. PACTR201105000286876.

Safety and parasite clearance of artemisinin-resistant Plasmodium falciparum infection: A pilot and a randomised volunteer infection study in Australia.

BACKGROUND: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria. METHODS AND FINDINGS: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background. CONCLUSIONS: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum. TRIAL REGISTRATION: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

Efficacy and Safety of Pyronaridine-Artesunate plus Single-Dose Primaquine for the Treatment of Malaria in Western Cambodia.

This single-arm trial (n = 104) in western Cambodia showed high efficacy for 3-day treatment with pyronaridine-artesunate plus single-dose primaquine in Plasmodium falciparum malaria. Day 42 PCR-adjusted adequate clinical and parasitological response (ACPR) was 98.3% (58/59) (95% confidence interval [CI], 90.9 to 100.0) in Trapeng Chau in Kampong Speu and 100% (41/41) (95% CI, 91.4 to 100) in Veal Veng in Pursat; 80.6% (83/103) of the patients had P. falciparum with drug resistance molecular markers. For Plasmodium vivax malaria, pyronaridine-artesunate day 28 ACPR was 98.3% (59/60) (95% CI, 91.1 to 100) and 100% (60/60) (95% CI, 94.0 to 100), respectively. (This study is registered in the Australian New Zealand Clinical Trials Registry [ANZCTR] under reference no. ACTRN12618001999224.).

Artemether for severe malaria.

BACKGROUND: In 2011 the World Health Organization (WHO) recommended parenteral artesunate in preference to quinine as first-line treatment for people with severe malaria. Prior to this recommendation many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. This Cochrane Review evaluates intramuscular artemether compared with both quinine and artesunate. OBJECTIVES: To assess the efficacy and safety of intramuscular artemether versus any other parenteral medication in the treatment of severe malaria in adults and children. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library), MEDLINE, Embase, and LILACS, ISI Web of Science, conference proceedings, and reference lists of articles. We also searched the WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, and the metaRegister of Controlled Trials (mRCT) for ongoing trials up to 7 September 2018. We checked the reference lists of all studies identified by the search. We examined references listed in review articles and previously compiled bibliographies to look for eligible studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing intramuscular artemether with intravenous/intramuscular quinine or artesunate for treating severe malaria. DATA COLLECTION AND ANALYSIS: The primary outcome was all-cause death. Two review authors independently screened each article by title and abstract, and examined potentially relevant studies for inclusion using an eligibility form. Two review authors independently extracted data and assessed risk of bias of included studies. We summarized dichotomous outcomes using risk ratios (RRs) and continuous outcomes using mean differences (MDs), and have presented both measures with 95% confidence intervals (CIs). Where appropriate, we combined data in meta-analyses and used the GRADE approach to summarize the certainty of the evidence. MAIN RESULTS: We included 19 RCTs, enrolling 2874 adults and children with severe malaria, carried out in Africa (12 trials) and in Asia (7 trials).Artemether versus quinineFor children, there is probably little or no difference in the risk of death between intramuscular artemether and quinine (RR 0.97, 95% CI 0.77 to 1.21; 13 trials, 1659 participants, moderate-certainty evidence). Coma resolution time may be about five hours shorter with artemether (MD -5.45, 95% CI -7.90 to -3.00; six trials, 358 participants, low-certainty evidence). Artemether may make little difference to neurological sequelae (RR 0.84, 95% CI 0.66 to 1.07; seven trials, 968 participants, low-certainty evidence). Compared to quinine, artemether probably shortens the parasite clearance time by about nine hours (MD -9.03, 95% CI -11.43 to -6.63; seven trials, 420 participants, moderate-certainty evidence), and may shorten the fever clearance time by about three hours (MD -3.73, 95% CI -6.55 to -0.92; eight trials, 457 participants, low-certainty evidence).For adults, treatment with intramuscular artemether probably results in fewer deaths than treatment with quinine (RR 0.59, 95% CI 0.42 to 0.83; four trials, 716 participants, moderate-certainty evidence).Artemether versus artesunateArtemether and artesunate have not been directly compared in randomized trials in children.For adults, mortality is probably higher with intramuscular artemether (RR 1.80, 95% CI 1.09 to 2.97; two trials, 494 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS: Artemether appears to be more effective than quinine in children and adults. Artemether compared to artesunate has not been extensively studied, but in adults it appears inferior. These findings are consistent with the WHO recommendations that artesunate is the drug of choice, but artemether is acceptable when artesunate is not available.

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT. OBJECTIVES: To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018. SELECTION CRITERIA: Efficacy analysis: randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine-artesunate or pyronaridine for treating P falciparum or P vivax malaria. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently re-extracted all data and assessed certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. MAIN RESULTS: We included 10 relevant studies. Seven studies were co-funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)-adjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence), artesunate-amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence).For unadjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence), and probably has fewer failures compared to artesunate-amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence).For PCR-adjusted failures at day 42, pyronaridine-artesunate may make little or no difference compared to artemether-lumefantrine (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence) and artesunate-amodiaquine (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence), but may have higher failures than mefloquine plus artesunate (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Overall, pyronaridine-artesunate had a PCR-adjusted treatment failure rate of less than 5%.For unadjusted failures at day 42, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence), may make little or no difference compared to mefloquine plus artesunate (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence), and probably makes little or no difference compared to artesunate-amodiaquine (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence).For the safety analysis of severe adverse events and liver function, we identified eight RCTs with 6614 participants comparing pyronaridine-artesunate to other antimalarials, four of which were not in the previous version of this review. A further two RCTs, comparing pyronaridine alone to other treatments, contributed to the synthesis of all adverse events.Raised alanine aminotransferase (ALT) greater than five times the upper limit of normal (> 5 x ULN) is more frequent with pyronaridine-artesunate compared to other antimalarials (RR 3.34, 95% CI 1.63 to 6.84; 8 RCTS, 6581 participants, high-certainty evidence). There is probably little or no difference for raised bilirubin > 2.5 x ULN between pyronaridine-artesunate and other antimalarials (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin, meeting criteria for moderate drug-induced liver injury. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns. AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria, achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42, and may be at least as good as, or better than other marketed ACTs.Pyronaridine-artesunate increases the risk of episodes of raised ALT > 5 x ULN. This meets criteria for mild drug-induced liver injury. On one instance this was linked to raised bilirubin, indicating moderate drug-induced liver injury. No episodes of severe drug-induced liver injury were reported. The findings of this review cannot fully inform a risk-benefit assessment for an unselected population. Readers should remain aware of this uncertainty when considering use of pyronaridine-artesunate in patients with known or suspected pre-existing liver dysfunction, and when co-administering with other medications which may cause liver dysfunction.

Markers of oxidative-nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes.

Artesunate (ARS) is a semi-synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti-inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non-neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative-nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O2- ) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere-positive MN (C+ MN) and centromere-negative MN (C- MN). These alterations were accompanied by an increase in both cellular levels of O2- and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative-nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.

Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial.

Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration: NCT01641289.

Artemisinins-a Promising New Treatment for Systemic Lupus Erythematosus: a Descriptive Review.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a complex, potentially fatal autoimmune disease with no complete cure. Current treatments for SLE are limited by suboptimal efficacy and increased risk of infections and malignancies, and cannot meet the clinical demands of patients with SLE. Artemisinin and its derivatives (artemisinins), a new class of anti-malarial drugs, have recently been reported to have an immunosuppressive effect on lupus patients. In this review, we evaluate the therapeutic properties and potential mechanisms of artemisinins for the treatment of SLE. RECENT FINDINGS: Both clinical and animal studies suggest that artemisinins have potential beneficial effects for SLE. The beneficial effects associated with artemisinin treatment include improving symptoms, reducing level of antibodies and proteinuria, ameliorating renal damage, and diminishing the dosage of prednisone use. Animal studies suggest that mechanisms of action of artemisinins may include regulating T cell subsets, inhibiting activation of B cells and production of inflammatory cytokines, as well as blocking the NF-κB signal transduction pathway, thus playing a role in anti-inflammation and immunomodulation. Artemisinin family drugs are a promising potential new medication that may challenge the current treatment paradigms available for SLE.

Delayed haemolysis after artesunate therapy in a cohort of patients with severe imported malaria due to Plasmodium falciparum.

INTRODUCTION: Delayed haemolytic anaemia is one of the more frequent events after treatment with intravenous artesunate in patients with severe malaria. Little is known about its frequency and the outcomes of patients with this condition. METHODS: A retrospective study was conducted to describe the incidence of delayed haemolysis in a cohort of patients with severe malaria by Plasmodium falciparum treated with artesunate between August 2013 and July 2015. RESULTS: The study included 52 patients with malaria due to Plasmodium falciparum, with 21 having severe malaria. The majority were male (66.7%), and the median age was 43 years. Four patients (19%) presented post-artesunate delayed haemolysis 11-13 days from the initiation of treatment. Two patients required hospital admission and red blood cell transfusion. CONCLUSION: Post-artesunate delayed haemolysis is frequent in patients with severe malaria treated with intravenous artemisinins. These patients should be monitored for 4 weeks after treatment is started.

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate-mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6-14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg-1 single dose; n = 364) or to artesunate-mefloquine (antimalarial dosage: artesunate 4 mg kg-1 and mefloquine 8 mg kg-1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate-mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate-mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of -2.5% (95% confidence interval (CI) -9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate-mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate-mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .