Artemisinin-based Combination Therapy Research Articles

POSC98 A Model to Evaluate the Cost-Effectiveness of a Highly-Sensitive Rapid Diagnostic Test for Malaria in a Community Setting in Uganda

Malaria remains a major cause of morbidity in Uganda, despite the presence of effective and low-cost interventions such as artemisinin-based combination therapy (ACT) and sulfadoxine/pyrimethamine (SP). This is largely attributed to the prevalence of asymptomatic low-density infections that often go undetected and hence untreated. A new generation of highly-sensitive rapid diagnostic tests (HS-RDTs) has been shown to detect asymptomatic low-density infections, offering a potential tool to help move Uganda towards Malaria elimination. A pragmatic literature review informed the conceptualisation and structuring of a cost-effectiveness model to evaluate use of the HS-RDT compared with conventional diagnostic tests (c-RDT) in three patient cohorts – febrile patients presenting at community health facilities, pregnant women attending ante-natal clinics, and asymptomatic household members of febrile children aged <5. A decision tree model will be used for the analysis to compare clinical (DALY) and cost outcomes, with patients entering the model at diagnosis stage. Clinical inputs, direct and indirect costs (including testing, treatment, disease management and mortality) are sourced from local publications. Prevalence, rapid diagnostic test (RDT) sensitivity and false positive rates will be based on data from a community based observational study in Mpigi District, Uganda. Results from the observational study and model outputs, will be used to test the hypothesis that the higher detection rate using HS-RDT translates into a larger number of asymptomatic malaria cases detected in all three patient cohorts, leading to clinical and cost benefits. Targeting and treating asymptomatic infections is also anticipated to help reduce the asymptomatic Malaria reservoir, thereby contributing towards the goal of Malaria elimination. One way sensitivity analysis will be conducted to test model sensitivity to key inputs. A limitation of this approach is that the model is not a dynamic transmission model and does not therefore model long-term consequences and seasonal effects.

Optimization of a new artemisinin-based combination therapy of artesunate-piperaquine fixed-dose combination tablet with enhanced in vivo antimalarial effects

A post-market quality assessment of first-line, fixed-dose combination antiretrovirals in South AfricaKim Ward, Reem Suleiman, Yunus Kippie, Admire Dube

Efficacy and Safety Assessment of Three Artemisinin-Based Combination Therapy (Acts) in the Treatment of P. falciparum Malaria in Cameroon

Artemisinin-based Combination Therapies (ACTs), have been reported to be effective against multidrug-resistant <em>Plasmodium falciparum</em>. There are controversies in the choice of the type of ACTs to be used at hospitals settings and health centers. This is mostly determined by the cost and less side effects reported for each drug leading to an over prescription and consumption of some ACTs compared to others and consequently to drug resistance.

Perceived Adverse Drug reactions to Artemether Lumefantrine and Artesunate Amodiaquine in Lagos, Nigeria

Introduction: Medications produce a therapeutic effect that modulates a disorder and unwarranted effects that may be intrinsically harmful. Adverse drug reactions (ADRs) are undesirable effects that results from drug administration at usual doses and are the primary focus of regulatory agencies and post-marketing surveillance. Aim and objectives: To evaluate ADRs to Artemisinin-based Combination Therapies (ACTs) such as Artemether-Lumefantrine (AL) and Artesunate-Amodiaquine (AA) among adults with the objectives of (i) estimating and comparing the frequency of ADRs associated with AL and AA and (ii) developing a list of classical adverse drug reactions to both antimalarials. Materials and Methods: This cross-sectional, quantitative study was conducted from March to May 2013 at Ikorodu, a peri-urban settlement in Lagos State of Nigeria among 252 patients diagnosed with malaria and randomized into Artemether Lumefantrine (AL) arm and Artesunate Amodiaquine (AA) arm. Results: The mean age (years) of all the study subjects was 34.4 (10.6) with 58% of them who attained secondary level education. About 50% of them took other non-antimalarial medication together with prescribed ACT during their illness. Overall mean duration of illness (days) before taking ACT was 2.8 (1.14) which was significantly longer (t-est=-3.57, P-value=0.0002) in AA arm (3.1 ± 1.2) than in AL arm (2.6 ± 1.0). In all, 234 (96.4%) and 169 (67.1%) severally completed the full dose of treatment and ate pre-medication fatty meal. Overall prevalence of ADRs was 47.6% - 27.8% in the AL arm and 69.8% in the AA arm. Among those who did not take fatty meal, the risk of ADRs was higher (χ²=0.69, P-value=0.40, RR=1.26, 95% CI=0.72, 2.21) in the AA arm compared to the AL arm. Weakness, dizziness and headache were the most prevalent ADRs reported in both AL (25.9%, 13.8%, 15.5% respectively) and AA (50.0%, 10.0%, 16.4% respectively) arms. Conclusion: In general, the frequency of ADRs, though mild or moderate in severity, was significantly higher in the AA arm than in the AL arm and the frequency of serious ADR was very low. The most prevalent ADRs reported were weakness/fatigue, headache and dizziness. Pre-medication consumption of fatty meal reduced the frequency of ADRs in both arms of the study. Programmes on the management of malaria with ACT should consider this baseline information for active surveillance for ADRs in Nigeria.

Synergism in Antiplasmodial Activities of Artemether and Lumefantrine in Combination with Securidaca longipedunculata Fresen (Polygalaceae).

Malaria is the most lethal parasitic disease in the world. The frequent emergence of resistance by malaria parasites to any drug is the hallmark of sustained malaria burden. Since the deployment of artemisinin-based combination therapies (ACTs) it is clear that for a sustained fight against malaria, drug combination is one of the strategies toward malaria elimination. In Sub-Saharan Africa where malaria prevalence is the highest, the identification of plants with a novel mechanism of action that is devoid of cross-resistance is a feasible strategy in drug combination therapy. Thus, artemether and lumefantrine were separately combined and tested with extracts of Securidaca longipedunculata, a plant widely used to treat malaria, at fixed extract–drug ratios of 4:1, 3:1, 1:1, 1:2, 1:3, and 1:4. These combinations were tested for antiplasmodial activity against three strains of Plasmodium falciparum (W2, D6, and DD2), and seven field isolates that were characterized for molecular and ex vivo drug resistance profiles. The mean sum of fifty-percent fractional inhibition concentration (FIC50) of each combination and singly was determined. Synergism was observed across all fixed doses when roots extracts were combined with artemether against D6 strain (FIC50 0.403 ± 0.068) and stems extract combined with lumefantrine against DD2 strain (FIC50 0.376 ± 0.096) as well as field isolates (FIC50 0.656 ± 0.067). Similarly, synergism was observed in all ratios when leaves extract were combined with lumefantrine against W2 strain (FIC50 0.456 ± 0.165). Synergism was observed in most combinations indicating the potential use of S. longipedunculata in combination with artemether and lumefantrine in combating resistance.

Repurposing Dihydroartemisinin-Piperaquine-Doxycycline as an Antimalarial Drug: A Study in Plasmodium berghei-Infected Mice

Artemisinin-based combination (ACT) therapy is the mainstay for malaria treatment. However, Plasmodium parasite with decreased susceptibility to ACT has emerged. Hence, it is imperative to discover new drugs or explore new drug combinations that can decrease Plasmodium parasite resistance. This study assessed the antiplasmodial activity of dihydroartemisinin-piperaquine- doxycycline (D-P-DX) on mice infected with Plasmodium berghei. Swiss albino mice (25-30g) of both sexes inoculated with 1x107 Plasmodium berghei intraperitoneally were used. The mice were randomly grouped and orally treated with DX (2.2 mg/kg), D-P (1.71/13.7 mg/kg) and D-P-DX daily in curative, suppressive and prophylactic studies. The negative and the positive controls were treated daily with normal saline (0.2mL) and chloroquine (CQ) (10mg/kg), respectively. After treatment, blood samples were assessed for percentage parasitemia, hematological and lipid parameters. Also, the mice were observed for mean survival time. D-P, DX, and D-P-DX produced significant decreases in percentage parasitemia at p&lt;0.05, p&lt;0.01 and p&lt;0.001, respectively when compared to negative control. In the curative study, D-P, DX, and D-P-DX produced 64.9%, 71.1%, and 93.6% parasitemia inhibitions when compared to 70.0% inhibition produced by CQ. Plasmodium berghei -induced alterations in packed cell volume, white blood cells, red blood cells, hemoglobin, high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were significantly restored by DX (p&lt;0.05) and D-P (p&lt;0.01) and D-P-DX (p&lt;0.001) when compared to the negative control. D-P-DX showed significant antiplasmodial activity against Plasmodium berghei- infected mice. It may be clinically useful for the treatment of malaria.

The medical cost of liver cancer in a referral hospital in Indonesia during 2020

Direct Medical Cost of Treatment of uncomplicated malaria after the Adoption of artemisinin-Based Combination Therapy in NigeriaEbere Emilia Ayogu, Adaobi Uchenna Mosanya, Jude Chidiebere Onuh, Maxwell Ogochukwu Adibe, Chukwuemeka Michael Ubaka, Chinwe Victoria Ukwe

Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites.

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or Artemisia afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of Plasmodium falciparum and the pre-erythrocytic (i.e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for Plasmodium vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

Efficacy and Safety of Artemisinin-Based Combination Therapy for the Treatment of Uncomplicated Malaria in Pregnant Women: A Systematic Review and Meta-Analysis.

IntroductionMalaria is one of the infectious diseases with substantial risks for pregnant women, the fetus and the newborn child. Thus, prevention and treatment of malaria with safe and effective drugs is of paramount importance. Pregnant women are mostly excluded from clinical trials, and systematic approaches of pharmacovigilance in pregnancy are limited. This means the safety and efficacy of antimalarial agents during pregnancy are unclear.PurposeThis study was designed to carry out a systematic review and aggregate data meta-analysis of literature published on efficacy and safety of artemisinin-based combination therapy (ACT) for uncomplicated malaria in pregnant women.MethodsA search of literature published between 1998 to 2020 on efficacy and safety of artemisinin-based combination therapy (ACT) in pregnant women was made using Cochrane Library, Medline and the Malaria in Pregnancy Consortium Library. Data were extracted independently by two reviewers, and any discrepancies were resolved by consensus. Meta-analysis was carried out using Open Meta-Analyst software. Random effects model was applied, and the heterogeneity of studies was evaluated using Higgins I2.ResultsTwenty-four studies that fulfilled the inclusion criteria were included in the final assessment. Overall, days 28 to 63 malaria treatment success rate was 96.1%. Overall days 28 to 63 cure rates for AL, AS+AQ, AS+MQ, DHA+PQ, AS+ATQ+PG and AS+SP were 95.1%, 92.2%, 97.0%,94.3%, 96.5% and 97.4%, respectively. Comparison of ACTs with non-ACTs revealed that the risk of treatment failure was substantially lower in patients treated with ACTs than with non-ACTs (risk ratio 0.20, 95% C.I. 0.09–0.43). The overall prevalences of miscarriage, stillbirth and congenital anomalies were 0.3%, 2.1% and 1.0%, respectively, and found to be comparable among various ACTs. There was comparable tolerability across ACTs during pregnancy.ConclusionACTs demonstrated a high cure rate, safety and tolerability against Plasmodium falciparum infection in pregnant women. The higher treatment success and comparable tolerability could be used as an input for decision makers to support the continued usage of ACTs for treatment of uncomplicated falciparum malaria in pregnant women.

Temporal evolution of the resistance genotypes of Plasmodium falciparum in isolates from Equatorial Guinea during 20\xa0years (1999 to 2019)

BackgroundMalaria is one of the deadliest diseases in the world, particularly in Africa. As such, resistance to anti-malarial drugs is one of the most important problems in terms of global malaria control. This study assesses the evolution of the different resistance markers over time and the possible influence of interventions and treatment changes that have been made in Equatorial Guinea.MethodsA total of 1223 biological samples obtained in the period 1999 to 2019 were included in the study. Screening for mutations in the pfdhfr, pfdhps, pfmdr1, and pfcrt genes was carried out by nested PCR and restriction-fragment length polymorphisms (RFLPs), and the study of pfk13 genes was carried out by nested PCR, followed by sequencing to determine the presence of mutations.ResultsThe partially and fully resistant haplotypes (pfdhfr + pfdhps) were found to increase over time. Moreover, in 2019, the fully resistant haplotype was found to be increasing, although its super-resistant counterpart remains much less prevalent. A continued decline in pfmdr1 and pfcrt gene mutations over time was also found. The number of mutations detected in pfk13 has increased since 2008, when artemisinin-based combination therapy (ACT) were first introduced, with more mutations being observed in 2019, with two synonymous and five non-synonymous mutations being detected, although these are not related to resistance to ACT. In addition, the non-synonymous A578S mutation, which is the most frequent on the African continent, was detected in 2013, although not in the following years.ConclusionsWithdrawal of the use of chloroquine (CQ) as a treatment in Equatorial Guinea has been shown to be effective over time, as wild-type parasite populations outnumber mutant populations. The upward trend observed in sulfadoxine-pyrimethamine (SP) resistance markers suggest its misuse, either alone or in combination with artesunate (AS) or amodiaquine (AQ), in some areas of the country, as was found in a previous study conducted by this group, which allows selective pressure from SP to continue. Single nucleotide polymorphisms (SNPs) 540E and 581G do not exceed the limit of 50 and 10%, respectively, thus meaning that SP is still effective as an intermittent preventive treatment (IPT) in this country. As for the pfk13 gene, no mutations have been detected in relation to resistance to ACT. However, in 2019 there is a greater accumulation of non-synonymous mutations compared to years prior to 2008.Graphical

Risk factors associated with malaria infection identified through reactive case detection in Zanzibar, 2012\u20132019

BackgroundOver the past two decades, Zanzibar substantially reduced malaria burden. As malaria decreases, sustainable improvements in control interventions may increasingly depend on accurate knowledge of malaria risk factors to further target interventions. This study aimed to investigate the risk factors associated with malaria infection in Zanzibar.MethodsSurveillance data from Zanzibar’s Malaria Case Notification system from August 2012 and December 2019 were analyzed. This system collects data on malaria cases passively detected and reported by all health facilities (index cases), and household-based reactive case detection (RCD) activities linked to those primary cases. All members of households of the index cases were screened for malaria using a malaria rapid diagnostic test (RDT). Individuals with a positive RDT were treated with artemisinin-based combination therapy. Univariate and multivariate logistic regression analyses were done to investigate the association between RDT positivity among the household members and explanatory factors with adjustment for seasonality and clustering at Shehia level.ResultsA total of 30,647 cases were reported of whom household RCD was completed for 21,443 (63%) index case households and 85,318 household members tested for malaria. The findings show that younger age (p-value for trend [Ptrend] < 0.001), history of fever in the last 2 weeks (odds ratio [OR] = 35.7; 95% CI 32.3–39.5), travel outside Zanzibar in the last 30 days (OR = 2.5; 95% CI 2.3–2.8) and living in Unguja (OR = 1.2; 95% CI 1.0–1.5) were independently associated with increased odds of RDT positivity. In contrast, male gender (OR=0.8; 95% CI 0.7–0.9), sleeping under an LLIN the previous night (OR = 0.9; 95% CI 0.7–0.9), having higher household net access (Ptrend < 0.001), and living in a household that received IRS in the last 12 months (OR = 0.8; 95% CI 0.7–0.9) were independently associated with reduced odds of RDT positivity. A significant effect modification of combining IRS and LLIN was also noted (OR = 0.7; 95% CI 0.6–0.8).ConclusionsThe findings suggest that vector control remains an important malaria prevention intervention: they underscore the need to maintain universal access to LLINs, the persistent promotion of LLIN use, and application of IRS. Additionally, enhanced behavioural change and preventive strategies targeting children aged 5–14 years and travellers are needed.

Trends and predictive factors for treatment failure following artemisinin-based combination therapy among children with uncomplicated malaria in Ghana: 2005\u20132018

BackgroundSince the introduction of artemisinin-based combination therapy (ACT) in Ghana in 2005 there has been a surveillance system by the National Malaria Control Programme (NMCP) and the University of Ghana Noguchi Memorial Institute for Medical Research (UG-NMIMR) to monitor the therapeutic efficacy of ACTs for the treatment of uncomplicated malaria in the country. We report trends and determinants of failure following treatment of Ghanaian children with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) combinations.MethodsPer protocol analyses as well as cumulative incidence of day 28 treatment failure from Kaplan Meier survival analyses were used to describe trends of failure over the surveillance period of 2005–2018. Univariable and multivariable cox regression analyses were used to assess the determinants of treatment failure over the period.ResultsDay 28 PCR-corrected failure, following treatment with ASAQ, significantly increased from 0.0% in 2005 to 2.0% (95% CI: 1.1–3.6) in 2015 (p = 0.013) but significantly decreased to 0.4% (95% CI: 0.1–1.6) in 2018 (p = 0.039). Failure, following treatment with AL, decreased from 4.5% (95% CI: 2.0–9.4) in 2010 to 2.7% (95% CI: 1.4–5.1) in 2018, though not statistically significant (p = 0.426). Risk of treatment failure, from multivariable cox regression analyses, was significantly lower among children receiving ASAQ compared with those receiving AL (HR = 0.24; 95% CI: 0.11–0.53; p < 0.001); lower among children with no parasitaemia on day 3 compared with those with parasitaemia on day 3 (HR = 0.02; 95% CI: 0.01–0.13; p < 0.001); and higher among children who received ASAQ and had axillary temperature ≥ 37.5 °C on day 1 compared with those with axillary temperature < 37.5 °C (HR = 3.96; 95% CI: 1.61–9.75; p = 0.003).ConclusionsTreatment failures for both ASAQ and AL have remained less than 5% (below WHO’s threshold of 10%) in Ghana since 2005. Predictors of treatment failure that need to be considered in the management of uncomplicated malaria in the country should include type of ACT, day 3 parasitaemia, and day 1 axillary temperature of patients being treated.

Impact of malaria control interventions on malaria infection and anaemia in areas with irrigated schemes: a cross-sectional population-based study in Sudan

BackgroundWhile the overall burden of malaria is still high, the global technical strategy for malaria advocates for two sets of interventions: vector control-based prevention and diagnosis and prompt effective treatment of malaria cases. This study aimed to assess the performance of malaria interventions on malaria infection and anaemia in irrigated areas in Sudan.MethodsBased on the Sudan 2016 national malaria indicator survey, data for two states (Gezira and Sennar), characterized by large-irrigated schemes, were analysed. Four community-level malaria interventions were used as contextual variables: utilization of malaria diagnosis, utilization of Artemisinin-based combination therapy (ACT), utilization of long-lasting insecticidal nets (LLINs) and coverage with indoor residual spraying (IRS). Association between these interventions and two outcomes: malaria infection and anaemia, was assessed separately. Malaria infection was assessed in all age groups while anaemia was assessed in children under 5 years. Multilevel multiple logistic regression analysis were conducted.ResultsAmong 4478 individuals involved in this study distributed over 47 clusters, the overall malaria infection rate was 3.0% and 56.5% of the children under 5 years (total = 322) were anaemic. Except for IRS coverage (69.6%), the average utilization of interventions was relatively low: 52.3% for utilization of diagnosis, 33.0% for utilization of ACTs and 18.6% for LLINs utilization. The multi-level multiple logistic regression model showed that only IRS coverage was associated with malaria infection (Odds ratio 0.83 per 10% coverage, 95%Confidence Interval (95%CI) 0.74–0.94, p = 0.003) indicating that a higher level of IRS coverage was associated with less malaria infection. Anaemia was not associated with any intervention (all p values larger than 0.1).ConclusionsMalaria transmission in Gezira and Sennar areas is low. IRS, with insecticide to which vectors are susceptible, is an effective malaria control intervention in irrigated schemes. Community utilization of other interventions was not associated with malaria infection in this study. This may be due to the low utilization of these interventions. However, individual use of LLINs provide personal protection. This study failed to establish an association between anaemia and malaria control interventions in low transmission areas. The higher level of malaria infection in urban areas is a cause for concern.

Four decades of epidemiological data reveal trajectories towards malaria elimination in Kheda district (Gujarat), western part of India

BackgroundMalaria is a main public health problem in India and was so particularly in the state of Gujarat in the western part of the country. This study assesses the effects...

Dynamic changes in genetic diversity, drug resistance mutations, and treatment outcomes of falciparum malaria from the low-transmission to the pre-elimination phase on the islands of S\xe3o Tom\xe9 and Pr\xedncipe

BackgroundWith effective vector control and case management, substantial progress has been made towards eliminating malaria on the islands of São Tomé and Príncipe (STP). This study assessed the dynamic changes in the genetic diversity of Plasmodium falciparum, the anti-malarial drug resistance mutations, and malaria treatment outcomes between 2010 and 2016 to provide insights for the prevention of malaria rebounding.MethodsPolymorphic regions of merozoite surface proteins 1 and 2 (msp1 and msp2) were sequenced in 118 dried blood spots (DBSs) collected from malaria patients who had visited the Central Hospital in 2010–2016. Mutations in the multi-drug resistance I (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (pfk13) genes were analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and sequencing in 111 DBSs. A total of 7482 cases that completed a 28-day follow-up were evaluated for treatment outcomes based on the microscopic results. Regression models were used to characterize factors associated with levels of parasite density and treatment failures.ResultsParasite strains in STP showed significant changes during and after the peak incidence in 2012. The prevalent allelic type in msp1 changed from K1 to MAD20, and that in msp2 changed from 3D7/IC to FC27. The dominant alleles of drug-resistance markers were pfmdr1 86Y, 184F, D1246, and pfcrt 76 T (Y-F-D-T, 51.4%). The average parasite density in malaria cases declined threefold from low-transmission (2010–2013) to pre-elimination period (2014–2016). Logistic regression models showed that patients with younger age (OR for age = 0.97–0.98, p < 0.001), higher initial parasite density (log10-transformed, OR = 1.44, p < 0.001), and receiving quinine treatment (compared to artemisinin-based combination therapy, OR = 1.91–1.96, p < 0.001) were more likely to experience treatment failures during follow-up.ConclusionsPlasmodium falciparum in STP had experienced changes in prevalent strains, and increased mutation frequencies in drug-resistance genes from the low-transmission to the pre-elimination settings. Notably, patients with younger age and receiving quinine treatment were more likely to show parasitological treatment failure during follow-up. Therapeutic efficacy should be carefully monitored to inform future treatment policy in STP.

Development of single- and multiplex immunoassays for rapid detection and quantitation of amodiaquine in ACT drugs and rat serum.

Amodiaquine (AQ) is a commonly used antimalarial drug, and N-desethyl-AQ (N-DEAQ) is an active metabolite of AQ. Given the significance of drug quality in the management of malaria cases, this study aims to develop antibody-based assays for the detection and quantitation of AQ without the need for sophisticated equipment. Two monoclonal antibodies (mAbs) against AQ, designated as JUN7 and TE7, were selected, which showed 72.7% and 9.5% cross-reactivity to N-DEAQ, respectively. These mAbs showed <0.1% cross-reactivity to other commonly used antimalarial drugs. An indirect competitive enzyme-linked immunosorbent assay (icELISA) based on JUN7 showed a 50% inhibitory concentration (IC50) of 0.16ng/mL and a working range of 0.06-0.46ng/mL. A lateral flow immunoassay (LFIA) based on JUN7 was also developed with a working range of 2.58-30.86ng/mL. The icELISA and LFIA were applied for the quantification of AQ in commercial drugs, and the results were comparable to those determined using high-performance liquid chromatography. In addition, a combination dipstick for simultaneous, qualitative analysis of AQ and artesunate was developed. All immunoassays based on JUN7 can be applied for quality control of AQ-containing artemisinin-based combination therapies. As TE7 showed low cross-reactivity to N-DEAQ, an icELISA based on TE7 was developed with an IC50 of 0.38ng/mL and a working range of 0.14-1.67ng/mL. The TE7 icELISA was applied for the study of pharmacokinetics of AQ in rat serum after intragastric administration, and the results were consistent with those of previous studies.

In-vivo Antiplasmodial Effect of Dihydroartemisinin-Piperaquine-Nitrofurantoin on Plasmodium berghei- Infected Mice

Nitrofurantoin (NT) used for the treatment of urinary tract infections may have antiplasmodial activity. Dihydroartemisinin-piperaquine (DP) is an artemisinin based combination therapy used for the treatment of malaria. This study evaluated the antiplasmodial effect of dihydroartemisinin-piperaquine-nitrofurantoin (DP-NT) on mice infected with Plasmodium berghei. Adult Swiss albino mice (30-35 g) of both sexes were used. The mice were randomly grouped, inoculated with Plasmodium berghei, and treated orally with DP (1.7/13.7 mg/kg), NT (57.1 mg/kg) and DP-NT (1.71/13.7/ 57.1 mg/kg), respectively using curative, prophylactic and suppressive tests. The negative control was orally treated with normal saline (0.3 mL), while the positive control was orally treated with chloroquine CQ (10mg/kg). After treatment, blood samples were collected and evaluated for percentage parasitemia, inhibitions and hematological parameters. Liver samples were evaluated for histological changes. The mice were observed for mean survival time (MST). Treatment with DP-NT decreased parasitemia levels when compared to individual doses of DP and NT with significant difference observed at p&lt;0.05. DP-NT prolonged MST when compared to individual doses of DP and NT with significant difference observed at p&lt;0.05. The decrease in packed cell volume, red blood cells, hemoglobin and increase in white blood cells in parasitized mice were significantly restored by DP-NT when compared to individual doses of DP and NT with difference observed at p&lt;0.05. DP-NT eradicated liver Plasmodium parasite. NT remarkably increased the antiplasmodial activity of DP. DP-NT may be used for the treatment of malaria.

Self-medication as a factor in treatment failure in patients treated for malaria with ACTs in a rural community of Enugu State, Southeast Nigeria

Background: Self-medication (SM) is the taking of drugs, herbs or home remedies on one’s own initiative, or following the advice of another person, without consulting the doctor. Drugs that are prone to SM include analgesics, antibiotics, cough syrups, and antimalarials. Treatment failure (TF) in malaria is defined as the inability to clear malarial parasitaemia or resolve clinical symptoms despite administration of an antimalarial medicine. Among other factors, SM has been implicated as a cause of TF. The study aimed to determine the role of SM in TF observed in patients treated with artemisinin-based combination therapies (ACTs) and the strategies employed to tackle this problem.Methods: 172 patients diagnosed with malaria within the period of the study, were interviewed and 102 of them who engaged in SM with ACTs prior to presentation to the hospital were purposively selected. Data were collected over a period of one month (January 2021) and analysed as descriptive statistics of proportion.Results: Prevalence of SM among the patients diagnosed with malaria was 59%, and TF in those who engaged in SM 99%. 100% cure rate was recorded using modified triple ACT (TACT) and drug cycling with chloroquine tablets.Conclusions: The prevalence of SM was 59%, TF 99% and cure rate with modified TACT and drug cycling 100%. The drug regulatory body needs to ensure quality assurance of the ACTs used in the country, and in addition, promote patient education on the adverse effects of irrational SM.

Safety and efficacy of intermittent presumptive treatment with sulfadoxine-pyrimethamine using rapid diagnostic test screening and treatment with dihydroartemisinin-piperaquine at the first antenatal care visit (IPTp-SP+): study protocol for a randomized controlled trial

BackgroundIntermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization for the prevention of malaria in pregnancy (MIP)-associated adverse outcomes in high burden areas. However, the efficacy of IPTp-SP has decreased in step with increasing parasite drug resistance. Suitable alternative strategies are needed.MethodsThis is a protocol for a phase IIIb open-label, two-armed randomized controlled superiority trial to assess the safety and efficacy of a hybrid approach to IPTp combining screening and treatment with dihydroartemisinin-piperaquine (DP) to the current IPTp-SP regimen at the first antenatal care clinic visit. Pregnant women without HIV infection and without signs or symptoms of malaria will be randomized to either standard IPTp-SP or hybrid IPTp-SP plus screening and treatment (IPTp-SP+). In the IPTp-SP+ arm, participants who screen positive by rapid diagnostic test for P. falciparum will be treated with DP at the first antenatal visit while those who screen negative will receive SP per current guidelines. All participants will be administered SP on days 35 and 63 and will be actively followed biweekly up to day 63 and then monthly until delivery. Infants will be followed until 1 year after delivery. The primary endpoint is incident PCR-confirmed MIP at day 42. Secondary endpoints include incident MIP at other time points, placental malaria, congenital malaria, hemoglobin trends, birth outcomes, and incidence of adverse events in infants up to the first birthday.DiscussionA hybrid approach to IPTp that combines screening and treatment with an artemisinin-based combination therapy at the first visit with standard IPTp-SP is hypothesized to confer added benefit over IPTp-SP alone in a high malaria transmission area with prevalent SP resistant parasites.Trial registrationPan African Clinical Trials Registry 201905721140808. Registered retrospectively on 11 May 2019

Potential Emergence of Plasmodium Resistance to Artemisinin Induced by the Use of Artemisia annua for Malaria and COVID-19 Prevention in Sub-African Region.

Plasmodium resistance to antimalarial drugs is an obstacle to the elimination of malaria in endemic areas. This situation is particularly dramatic for Africa, which accounts for nearly 92% of malaria cases worldwide. Drug pressure has been identified as a key factor in the emergence of antimalarial drug resistance. Indeed, this pressure is favoured by several factors, including the use of counterfeit forms of antimalarials, inadequate prescription controls, poor adherence to treatment regimens, dosing errors, and the increasing use of other forms of unapproved antimalarials. This resistance has led to the replacement of chloroquine (CQ) by artemisinin-based combination therapies (ACTs) which are likely to become ineffective in the coming years due to the uncontrolled use of Artemisia annua in the sub-Saharan African region for malaria prevention and COVID-19. The use of Artemisia annua for the prevention of malaria and COVID-19 could be an important factor in the emergence of resistance to Artemisinin-based combination therapies.