Malaria Diagnosis at the Pediatric Emergency Unit of a Teaching Hospital in Makurdi, North Central Nigeria.

Background: Globally, there were 241 million cases of malaria in 2020, with an estimated 627,000 deaths with Nigeria accounting for 27% of the global malaria cases. In sub-Saharan Africa, testing is low with only 28% of children with a fever receiving medical advice or a rapid diagnostic test in 2021. In Nigeria, there are documented reports of over-diagnosis and over-treatment of malaria in children. Therefore, this study examined the diagnosis of malaria at the Benue State University Teaching Hospital, Makurdi. Methods: A 5-year (2018-2022) retrospective study was carried out at the Emergency Pediatric Unit (EPU). Records of all children presenting to the EPU with an assessment of malaria were retrieved and reviewed. Data was analyzed using SPSS 23. Results: Out of 206 children reviewed, 128 (62.1%) were tested using either malaria RDT or microscopy while 78(37.9%) were not tested. Out of the number tested, 59(46.1%) were negative while 69(53.9%) tested positive, of which 14(20.3%) had uncomplicated malaria while 55(79.7%) had severe malaria. However, while 97.1% (n=67) of the positive cases were treated with IV artesunate, 69.5% (n=41) of those who tested negative and 88.5% (69) of those who were not tested also received IV artesunate. Moreover, while 85.5% (n=59) of those who tested positive received oral artemisinin-based combination therapy (ACT), 72.9% (n=43) of those who tested negative and 67.9% (53) of those who were not tested also received oral ACT. Conclusion: There was over-diagnosis of malaria, and subsequently, over-treatment. Hence continued emphasis on parasitological confirmation of malaria before treatment is recommended.

Pharmacokinetics of piperaquine and its association with intermittent malaria preventive therapy outcomes during pregnancy.

BACKGROUND: Dihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). We investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy. METHODS: Malaria-free (mRDT) pregnant women (n = 400) who received monthly IPTp-DHP were enrolled and followed till delivery. Day 7 Plasma piperaquine concentrations were determined after each IPTp dose using UPLC/MS/MS. IPTp outcomes (symptomatic malaria and parasitemia during pregnancy, placental malaria, and maternal malaria at delivery) were monitored. Linear mixed model and Cox regression were used to assess predictors of day 7 piperaquine concentration and treatment outcome, respectively. RESULTS: The incidences of symptomatic malaria and parasitemia during pregnancy per 100 person-year at risk were 2 and 33, respectively. The prevalence of histopathologically confirmed placental malaria and maternal malaria at delivery were 3% and 9.8%, respectively. Repeated monthly IPTp-DHP resulted in significantly increased day 7 plasma piperaquine concentration (p < 0.001). Following the 1st, 2nd, and 3rd monthly IPTp-DHP doses, the proportions of women with day 7 piperaquine concentration below the therapeutic threshold (< 30 ng/mL) were 6.1%, 4.1% and 3.6%, respectively. Factors such as maternal age, body weight and trimester were not significant predictors of day 7 piperaquine concentration. However, having a low day 7 piperaquine plasma concentration (< 30 ng/mL) was significantly associated with a higher risk of parasitemia during pregnancy (p = 0.004). CONCLUSION: Lower day 7 piperaquine plasma concentration is a risk factor for parasitemia during pregnancy. Single plasma sampling at day 7 can be used to monitor piperaquine effectiveness during IPTp-DHP. TRIAL REGISTRATION: Registered 09/12/2016, PACTR201612001901313.

Inter-Species Pharmacokinetic Modeling and Scaling for Drug Repurposing of Pyronaridine and Artesunate.

Even though several new targets (mostly viral infection) for drug repurposing of pyronaridine and artesunate have recently emerged in vitro and in vivo, inter-species pharmacokinetic (PK) data that can extend nonclinical efficacy to humans has not been reported over 30 years of usage. Since extrapolation of animal PK data to those of humans is essential to predict clinical outcomes for drug repurposing, this study aimed to investigate inter-species PK differences in three animal species (hamster, rat, and dog) and to support clinical translation of a fixed-dose combination of pyronaridine and artesunate. PK parameters (e.g., steady-state volume of distribution (Vss), clearance (CL), area under the concentration-time curve (AUC), mean residence time (MRT), etc.) of pyronaridine, artesunate, and dihydroartemisinin (an active metabolite of artesunate) were determined by non-compartmental analysis. In addition, one- or two-compartment PK modeling was performed to support inter-species scaling. The PK models appropriately described the blood concentrations of pyronaridine, artesunate, and dihydroartemisinin in all animal species, and the estimated PK parameters in three species were integrated for inter-species allometric scaling to predict human PKs. The simple allometric equation (Y = a × Wb) well explained the relationship between PK parameters and the actual body weight of animal species. The results from the study could be used as a basis for drug repurposing and support determining the effective dosage regimen for new indications based on in vitro/in vivo efficacy data and predicted human PKs in initial clinical trials.

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on haemoglobin levels in Ethiopia: a longitudinal cohort study.

BACKGROUND: To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency. METHODS: An observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone. RESULTS: A total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28-15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to - 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (- 0.60 g/dL) than in the G6PDd ACT alone group (- 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = - 0.00 to 0.20) and 0.05 g/dl (95% CI = - 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412). CONCLUSIONS: This study's findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

An overview of artemisinin-resistant malaria and associated Pfk13 gene mutations in Central Africa.

Malaria caused by Plasmodium falciparum is one of the deadliest and most common tropical infectious diseases. However, the emergence of artemisinin drug resistance associated with the parasite's Pfk13 gene, threatens the public health of individual countries as well as current efforts to reduce malaria burdens globally. It is of concern that artemisinin-resistant parasites may be selected or have already emerged in Africa. This narrative review aims to evaluate the published evidence concerning validated, candidate, and novel Pfk13 polymorphisms in ten Central African countries. Results show that four validated non-synonymous polymorphisms (M476I, R539T, P553L, and P574L), directly associated with a delayed therapy response, have been reported in the region. Also, two Pfk13 polymorphisms associated to artemisinin resistance but not validated (C469F and P527H) have been reported. Furthermore, several non-validated mutations have been observed in Central Africa, and one allele A578S, is commonly found in different countries, although additional molecular and biochemical studies are needed to investigate whether those mutations alter artemisinin effects. This information is discussed in the context of biochemical and genetic aspects of Pfk13, and related to the regional malaria epidemiology of Central African countries.

Artemisinin-resistant malaria in Africa demands urgent action.

Investment in community health workers is essential.

Examining Public Sector Availability and Supply Chain Management Practices for Malaria Commodities: Findings From Northern Nigeria.

BACKGROUND: Nigeria accounts for substantial proportions of global malaria infections and deaths, with children aged younger than 5 years being the most affected group. This suggests that access to lifesaving malaria interventions could be suboptimal, especially at public health facilities where most rural dwellers seek health care. We conducted this study to ascertain if public health facilities have the commodities and the robust supply chain management (SCM) system required to deliver malaria interventions to children younger than 5 years. METHOD: We conducted a cross-sectional survey in 1,858 health facilities across 7 states in Nigeria. Using structured questionnaires, we assessed the availability of selected malaria commodities required by children aged younger than 5 years. We also interviewed health workers to evaluate other core SCM activities. RESULT: More than 50% of health facilities in 5 states were stocked out of malaria rapid diagnostic tests (mRDTs), and stock-out rates for artemisinin-based combination therapies (ACTs) were over 50% for almost all assessed ACTs across all states. The percentage of health facilities that received malaria commodities within the recommended lead time was below average across most states (71%). States with a higher percentage of health workers who were aware of and placed orders following the national reporting timeline and those that delivered commodities to the last mile predominantly through third-party logistics service providers tended to have higher availability of mRDTs and artemether/lumefantrine combinations. The top 2 logistics challenges were insecurity and inadequate funding. CONCLUSION: The availability of lifesaving malaria commodities across the health facilities visited was suboptimal, possibly due to several SCM challenges. The results from this study underscore the urgent need to implement effective interventions to address the observed gaps. This will contribute to reducing malaria morbidity and mortality among children aged younger than 5 years in Nigeria.

Plasmodium falciparum artemisinin resistance: something gained in translation.

Small-Saunders et al. uncovered a new facet of artemisinin resistance in Plasmodium in which parasites use a previously underexplored arm of stress response mechanisms. Through altered epitranscriptomic modifications on tRNA, changed translation patterns adapt resistant cells to facilitate entry into a quiescent-like state which provides the parasite an escape from many drugs.

Development, characterization, and evaluation of withaferin-A and artesunate-loaded pH-responsive acetal-dextran polymeric nanoparticles for the management of malaria.

Artemisinin and its derivatives have been commonly used to treat malaria. However, the emergence of resistance against artemisinin derivatives has posed a critical challenge in malaria management. In the present study, we have proposed a combinatorial approach, utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria. The optimized WS-3 and Art Ac-Dex NPs demonstrated enhanced pH-responsive release profiles under parasitophorous mimetic conditions (pH 5.5). Computational molecular modeling reveals that Ac-Dex's polymeric backbone strongly interacts with merozoite surface protein-1 (MSP-1), preventing erythrocyte invasion. In-vitro antimalarial activity of drug-loaded Ac-Dex NPs reveals a 1-1.5-fold reduction in IC50 values compared to pure drug against the 3D7 strain of Plasmodium falciparum. Treatment with WS-3 Ac-Dex NPs (100 mg/kg) and Art Ac-Dex NPs (30 mg/kg) to Plasmodium berghei-infected mice resulted in 78.11 % and 100 % inhibition of parasitemia. Notably, the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.

Molecular Surveillance of Artemisinin-Resistant Plasmodium falciparum Parasites in Mining Areas of the Roraima Indigenous Territory in Brazil.

Multidrug- and artemisinin-resistant (ART-R) Plasmodium falciparum (Pf) parasites represent a challenge for malaria elimination worldwide. Molecular monitoring in the Kelch domain region (pfk13) gene allows tracking mutations in parasite resistance to artemisinin. The increase in illegal miners in the Roraima Yanomami indigenous land (YIL) could favor ART-R parasites. Thus, this study aimed to investigate ART-R in patients from illegal gold mining areas in the YIL of Roraima, Brazil. A questionnaire was conducted, and blood was collected from 48 patients diagnosed with P. falciparum or mixed malaria (Pf + P. vivax). The DNA was extracted and the pfk13 gene was amplified by PCR. The amplicons were subjected to DNA-Sanger-sequencing and the entire amplified fragment was analyzed. Among the patients, 96% (46) were from illegal mining areas of the YIL. All parasite samples carried the wild-type genotypes/ART-sensitive phenotypes. These data reinforce the continued use of artemisinin-based combination therapies (ACTs) in Roraima, as well as the maintenance of systematic monitoring for early detection of parasite populations resistant to ART, mainly in regions with an intense flow of individuals from mining areas, such as the YIL. This is especially true when the achievement of falciparum malaria elimination in Brazil is planned and expected by 2030.

Evaluation of Dihydroartemisinin-Piperaquine Efficacy and Molecular Markers in Uncomplicated Falciparum Patients: A Study across Binh Phuoc and Dak Nong, Vietnam.

Background and Objectives: Malaria continues to be a significant global health challenge. The efficacy of artemisinin-based combination therapies (ACTs) has declined in many parts of the Greater Mekong Subregion, including Vietnam, due to the spread of resistant malaria strains. This study was conducted to assess the efficacy of the Dihydroartemisinin (DHA)-Piperaquine (PPQ) regimen in treating uncomplicated falciparum malaria and to conduct molecular surveillance of antimalarial drug resistance in Binh Phuoc and Dak Nong provinces. Materials and Methods: The study included 63 uncomplicated malaria falciparum patients from therapeutic efficacy studies (TES) treated following the WHO treatment guidelines (2009). Molecular marker analysis was performed on all 63 patients. Methods encompassed Sanger sequencing for pfK13 mutations and quantitative real-time PCR for the pfpm2 gene. Results: This study found a marked decrease in the efficacy of the DHA-PPQ regimen, with an increased rate of treatment failures at two study sites. Genetic analysis revealed a significant presence of pfK13 mutations and pfpm2 amplifications, indicating emerging resistance to artemisinin and its partner drug. Conclusions: The effectiveness of the standard DHA-PPQ regimen has sharply declined, with rising treatment failure rates. This decline necessitates a review and possible revision of national malaria treatment guidelines. Importantly, molecular monitoring and clinical efficacy assessments together provide a robust framework for understanding and addressing detection drug resistance in malaria.

Efficacy and safety of single-dose artesunate plus sulfalene/pyrimethamine combined with praziquantel for the treatment of children with Schistosoma mansoni or Schistosoma haematobium in western Kenya: a randomised, open-label controlled trial.

BACKGROUND: Reliance on praziquantel for the treatment and control of schistosomiasis is likely to facilitate the emergence of drug resistance. Combination therapy targeting adult and juvenile schistosome worms is urgently needed to improve praziquantel efficacy and delay the potential development of drug resistance. We assessed the efficacy and safety of single-dose praziquantel combined with single-dose artesunate plus sulfalene-pyrimethamine in the treatment of Kenyan children with schistosomiasis. METHODS: This was an open-label, randomised clinical trial involving 426 school-aged children (7-15 years old) diagnosed with Schistosoma mansoni (by Kato-Katz) or S. haematobium (by urine filtration). They were randomly assigned (1:1:1) to receive a single dose of praziquantel (40 mg/kg), a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate) or combination therapy using a single dose of praziquantel (40 mg/kg) combined with a single dose of artesunate plus sulfalene-pyrimethamine (12 mg/kg artesunate). The primary outcome was cure and egg reduction rates at 6 weeks post-treatment in the available case population. Adverse events were assessed within 3 h after treatment. RESULTS: Of the 426 children enrolled, 135 received praziquantel, 150 received artesunate plus sulfalene-pyrimethamine, and 141 received combination therapy. Outcome data were available for 348 (81.7%) children. For S. mansoni-infected children (n = 335), the cure rates were 75.6%, 60.7%, and 77.8%, and the egg reduction rates were 80.1%, 85.0%, and 88.4% for praziquantel, artesunate plus sulfalene-pyrimethamine, and combination therapy, respectively. For S. haematobium-infected children (n = 145), the corresponding cure rates were 81.4%, 71.1%, and 82.2%, and the egg reduction rates were 95.6%, 97.1%, and 97.7%, respectively. Seventy-one (16.7%) children reported mild-intensity adverse events. The drugs were well tolerated and no serious adverse events were reported. CONCLUSIONS: A single oral dose of praziquantel combined with artesunate plus sulfalene-pyrimethamine cured a high proportion of children with S. haematobium but did not significantly improve the treatment efficacy for either urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may enhance the efficacy and safety outcomes.

High prevalence and risk of malaria among asymptomatic individuals from villages with high prevalence of artemisinin partial resistance in Kyerwa district of Kagera region, north-western Tanzania.

BACKGROUND: Although Tanzania adopted and has been implementing effective interventions to control and eventually eliminate malaria, the disease is still a leading public health problem, and the country experiences heterogeneous transmission. Recent studies reported the emergence of parasites with artemisinin partial resistance (ART-R) in Kagera region with high prevalence (> 10.0%) in two districts of Karagwe and Kyerwa. This study assessed the prevalence and predictors/risk of malaria infections among asymptomatic individuals living in a hyperendemic area where ART-R has emerged in Kyerwa District of Kagera region, north-western Tanzania. METHODS: This was a community-based cross-sectional survey which was conducted in July and August 2023 and involved individuals aged ≥ 6 months from five villages in Kyerwa district. Demographic, anthropometric, clinical, parasitological, type of house inhabited and socio-economic status (SES) data were collected using electronic capture tools run on Open Data Kit (ODK) software. Predictors/risks of malaria infections were determined by univariate and multivariate logistic regression, and the results were presented as crude (cORs) and adjusted odds ratios (aORs), with 95% confidence intervals (CIs). RESULTS: Overall, 4454 individuals were tested using rapid diagnostic tests (RDTs), and 1979 (44.4%) had positive results. The prevalence of malaria infections ranged from 14.4% to 68.5% and varied significantly among the villages (p < 0.001). The prevalence and odds of infections were significantly higher in males (aOR = 1.28, 95% CI 1.08 -1.51, p = 0.003), school children (aged 5-≤10 years (aOR = 3.88, 95% CI 3.07-4.91, p < 0.001) and 10-≤15 years (aOR = 4.06, 95% CI 3.22-5.13, p < 0.001)) and among individuals who were not using bed nets (aOR = 1.22, 95% CI 1.03-1.46, p = 0.024). The odds of malaria infections were also higher in individuals with lower SES (aOR = 1.42, 95% CI 1.17-1.72, p < 0.001), and living in houses without windows (aOR = 2.08, 95% CI 1.46-2.96, p < 0.001), partially open (aOR = 1.33, 95% CI 1.11-1.58, p = 0.002) or fully open windows (aOR = 1.30, 95%CI 1.05-1.61, p = 0.015). CONCLUSION: The five villages had a high prevalence of malaria infections and heterogeneity at micro-geographic levels. Groups with higher odds of malaria infections included school children, males, and individuals with low SES, living in poorly constructed houses or non-bed net users. These are important baseline data from an area with high prevalence of parasites with ART-R and will be useful in planning interventions for these groups, and in future studies to monitor the trends and potential spread of such parasites, and in designing a response to ART-R.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Exchange transfusion combined with artesunate (ET-AS) as a safe and effective therapy in severe P. falciparum malaria: a case series.

BACKGROUND: the mortality associated with severe malaria due to Plasmodiun falciparum remains high despite improvements in malaria management. Case prensentation: this case series aims to describe the efficacy and safety of the exchange transfusion combined with artesunate (ET-AS) regimen in severe P. falciparum malaria. Eight patients diagnosed with severe P. falciparum malaria were included. All patients underwent ET using the COBE Spectra system. The aimed for a post-exchange hematocrit of 30%. Half the estimated blood volume was removed and replaced using fresh frozen plasma. The regimen was well-tolerated without complications. The parasite clearance time ranged from 1 ~ 5 days. Five patients with cerebral malaria exhibited full improved consciousness within 3 days, while patient2 with hemolysis improved on day 2. Liver function improved within 1 ~ 6 days, and patient 1 and patient 6 showed improvements renal function on days 18 and 19, respectively. The length of intensive care unit stay range from 2 ~ 10 days, and all patients treated with ET-AS remained in the hospital for 3 ~ 19 days. CONCLUSIONS: these preliminary results suggest that ET-AS regimens are a safe and effective therapy for severe P. falciparum malaria and can benefit patients in clinical settings.

Increased sensitivity of malaria parasites to common antimalaria drugs after the introduction of artemether-lumefantrine: Implication of policy change and implementation of more effective drugs in fight against malaria.

Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi-drug resistance protein 1 (Pfmrp1) gene have previously been reported to confer resistance to Artemisinin-based Combination Therapies (ACTs) in Southeast Asia. A total of 300 samples collected from six sites between 2008 and 2019 under an ongoing malaria drug sensitivity patterns in Kenya study were evaluated for the presence of SNPs at Pfmrp1 gene codons: H191Y, S437A, I876V, and F1390I using the Agena MassARRAY® platform. Each isolate was further tested against artemisinin (ART), lumefantrine (LU), amodiaquine (AQ), mefloquine (MQ), quinine (QN), and chloroquine (CQ) using malaria the SYBR Green I-based method to determine their in vitro drug sensitivity. Of the samples genotyped, polymorphism at Pfmrp1 codon I876V was the most frequent, with 59.3% (163/275) mutants, followed by F1390I, 7.2% (20/278), H191Y, 4.0% (6/151), and S437A, 3.3% (9/274). A significant decrease in median 50% inhibition concentrations (IC50s) and interquartile range (IQR) was noted; AQ from 2.996 ng/ml [IQR = 2.604-4.747, n = 51] in 2008 to 1.495 ng/ml [IQR = 0.7134-3.318, n = 40] (P<0.001) in 2019, QN from 59.64 ng/ml [IQR = 29.88-80.89, n = 51] in 2008 to 18.10 ng/ml [IQR = 11.81-26.92, n = 42] (P<0.001) in 2019, CQ from 35.19 ng/ml [IQR = 16.99-71.20, n = 30] in 2008 to 6.699 ng/ml [IQR = 4.976-9.875, n = 37] (P<0.001) in 2019, and ART from 2.680 ng/ml [IQR = 1.608-4.857, n = 57] in 2008 to 2.105 ng/ml [IQR = 1.266-3.267, n = 47] (P = 0.0012) in 2019, implying increasing parasite sensitivity to the drugs over time. However, no significant variations were observed in LU (P = 0.2692) and MQ (P = 0.0939) respectively, suggesting stable parasite responses over time. There was no statistical significance between the mutation at 876 and parasite sensitivity to selected antimalarials tested, suggesting stable sensitivity for the parasites with 876V mutations. These findings show that Kenyan parasite strains are still sensitive to AQ, QN, CQ, ART, LU, and MQ. Despite the presence of Pfmrp1 mutations in parasites among the population.

2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin.

Purpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.

Late Parasitological Failure and Subsequent Isolated Gametocytemia of Uncomplicated Plasmodium falciparum Malaria in a Returned Traveler From Ghana, 2023.

Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per µL of blood (p/µL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/µL. However, at follow-up, parasite density increased to 7,630 p/µL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.