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.

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.

High malaria mortality coupled with increased emergence of resistant multi-drug resistant strains of Plasmodium parasite, warrants the development of new and effective antimalarial drugs. However, drug design and discovery are costly and time-consuming with many active antimalarial compounds failing to get approved due to safety reasons. To address these challenges, the current study aimed at testing the antiplasmodial activities of approved drugs that were predicted using a target-similarity approach. This approach is based on the fact that if an approved drug used to treat another disease targets a protein similar to Plasmodium falciparum protein, then the drug will have a comparable effect on P. falciparum. In a previous study, in vitro antiplasmodial activities of 10 approved drugs was reported of the total 28 approved drugs. In this study, six out of 18 drugs that were previously not tested, namely epirubicin, irinotecan, venlafaxine, palbociclib, pelitinib, and PD153035 were tested for antiplasmodial activity. The drug susceptibility in vitro assays against five P. falciparum reference strains (D6, 3D7, W2, DD2, and F32 ART) and ex vivo assays against fresh clinical isolates were done using the malaria SYBR Green I assay. Standard antimalarial drugs were included as controls. Epirubicin and irinotecan showed excellent antiplasmodial ex vivo activity against field isolates with mean IC₅₀ values of 0.044 ± 0.033 μM and 0.085 ± 0.055 μM, respectively. Similar activity was observed against W2 strain where epirubicin had an IC₅₀ value of 0.004 ± 0.0009 μM, palbociclib 0.056 ± 0.006 μM, and pelinitib 0.057 ± 0.013 μM. For the DD2 strain, epirubicin, irinotecan and PD 153035 displayed potent antiplasmodial activity (IC₅₀ < 1 μM). Epirubicin and irinotecan showed potent antiplasmodial activities (IC₅₀ < 1 μM) against DD2, D6, 3D7, and F32 ART strains and field isolates. This shows the potential use of these drugs as antimalarials. All the tested drugs showed antiplasmodial activities with IC₅₀ values below 20 μM, which suggests that our target similarity-based strategy is successful at predicting antiplasmodial activity of compounds thereby circumventing challenges in antimalarial drug discovery.

Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety concerns that prevent approval. The current study aimed to determine antiplasmodial activities of approved drugs in combination with artemether (ART) and lumefantrine (LU). Methods: Using the SYBR Green I assay test, this study investigated the efficacy of epirubicin (EPI) and pelitinib (PEL) combined with ART and LU at fixed drug–drug ratios (4:1, 3:1, 1:1, 1:2, 1:3 and 1:4) and volume/volume. These combinations, as well as single drug treatments, were tested against cultured strains of Plasmodium falciparum (W2, DD2, D6, 3D7 and F32-ART) and fresh and cultured clinical isolates. The fifty percent inhibition concentration (IC₅₀) and a mean sum of fifty percent fractional inhibition concentration (FIC₅₀) were determined. Results: Synergism was observed when EPI was combined with both ART and LU across all fixed ratios with a mean of mean FIC₅₀ values of 1) when tested against strains of P. falciparum and clinical isolates. Conclusions: This study underscores the utility of alternative drug discovery and development strategies to bypass cost, time, and safety barriers, thereby enriching the antimalarial drug pipeline and accelerating the transition from lab to market.

Ginger (Zingiber officinale) is a widely cultivated plant due to its pharmacological properties and its use as a spice. The plant species enjoys a good reputation in most regions of the world mainly because of its anti-inflammatory, antitumor, and antioxidant activities. To enhance these pharmacological properties, ginger is mostly used in combination. Drug combination therapy is also a worthwhile strategy for the prevention of various diseases. Therefore, the current chapter concerted on pharmacological activities of ginger combinations. The plant species has been combined with other plant extracts, pure compounds, and approved drugs for antimicrobial, antioxidant, anticancer, antidiabetic, and antidepressant activities and also in herbal tea formulations. Most of these activities showed synergism with 50% inhibition concertation (IC50) values of less than 1. The highest activity was observed when ginger phytochemicals, shogaol, and gingerol derivatives were combined against prostate cancer cell lines with an IC50 value of 0.03. Interaction of different phytochemicals in ginger with other phytochemicals when used in combination account for the reported synergism. The observed synergism in most combinations depicts a potential use of ginger combinations in treatment and prevention of various diseases and disease conditions.