Статті в журналах: "Antimalarial combinations"

1

Kremsner, Peter Gottfried, and Sanjeev Krishna. "Antimalarial combinations." Lancet 364, no. 9430 (July 2004): 285–94. http://dx.doi.org/10.1016/s0140-6736(04)16680-4.

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Duncan, MR, and HA Capell. "The use of antimalarials in combination with other disease modifying agents in RA – the British experience." Lupus 5, no. 1_suppl (June 1996): 50–58. http://dx.doi.org/10.1177/0961203396005001121.

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Antimalarial drugs are effective disease modifying agents in RA with a low incidence of serious toxic effects. Recently, combinations of second-line agents have been used in RA in attempts to treat patients with no response to a number of single agents, or suboptimal response to a single agent. Combinations of drugs have been selected for maximum efficacy and minimum toxicity, but clinical trials are difficult to design and interpret. In particular, ensuring adequate power to detect small differences in response poses a major problem. Antimalarials are an attractive choice for combination therapy due to their efficacy, mechanisms of action and toxicity profile. In this review, the evidence for the use of antimalarials in combination in RA is examined. No advantage has been shown in combining antimalarials with gold, penicillamine or sulphasalazine compared with monotherapeutic regimens. There is some evidence to suggest a beneficial combination of antimalarials with methotrexate, but this is as yet inconclusive. Open non-randomised uncontrolled studies have shown that antimalarials combined with cytotoxic agents are effective but highly toxic. The authors conclude that there is little good evidence to support the introduction of combination second-line drug therapy for RA into widespread therapeutic use.

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3

White, Nicholas. "Antimalarial drug resistance and combination chemotherapy." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1384 (April 29, 1999): 739–49. http://dx.doi.org/10.1098/rstb.1999.0426.

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Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration–effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10 000–fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

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Guiguemde, W. Armand, Nicholas H. Hunt, Jintao Guo, Annael Marciano, Richard K. Haynes, Julie Clark, R. Kiplin Guy, and Jacob Golenser. "Treatment of Murine Cerebral Malaria by Artemisone in Combination with Conventional Antimalarial Drugs: Antiplasmodial Effects and Immune Responses." Antimicrobial Agents and Chemotherapy 58, no. 8 (June 9, 2014): 4745–54. http://dx.doi.org/10.1128/aac.01553-13.

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ABSTRACTThe decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications ofPlasmodium falciparumresistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to killP. falciparumin a high-throughputin vitroassay and to protect mice against lethal cerebral malaria caused byPlasmodium bergheiANKA when used alone or in combination with established antimalarial drugs. Artemisone effects againstP. falciparumin vitrowere synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cellsin vitrowere much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused byP. bergheiANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma ofP. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.

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Akompong, Thomas, Saliha Eksi, Kim Williamson, and Kasturi Haldar. "Gametocytocidal Activity and Synergistic Interactions of Riboflavin with Standard Antimalarial Drugs against Growth of Plasmodium falciparum In Vitro." Antimicrobial Agents and Chemotherapy 44, no. 11 (November 1, 2000): 3107–11. http://dx.doi.org/10.1128/aac.44.11.3107-3111.2000.

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ABSTRACT Our previous studies have shown that riboflavin has activity against Plasmodium falciparum asexual-stage parasites in vitro. In the present study we examine the gametocytocidal activity of riboflavin and the interaction of riboflavin with some commonly used antimalarial drugs against the asexual forms of P. falciparum in vitro. The addition of riboflavin to P. falciparum cultures killed gametocytes at all stages, even those at late stages (III to V), which are not affected by many of the commonly used antimalarials. Combinations of riboflavin with mefloquine, pyrimethamine, and quinine showed a marked potentiation of the activities of these drugs against asexual-stage parasites in vitro. The combination of riboflavin with artemisinin was additive, while that with chloroquine was mildly antagonistic. High doses of riboflavin are used clinically to treat several inborn errors of metabolism with no adverse side effects. Its efficacy in combination with standard antimalarial drugs in treating and preventing the transmission ofP. falciparum malaria can therefore be evaluated in humans.

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White, N. J. "Preventing antimalarial drug resistance through combinations." Drug Resistance Updates 1, no. 1 (March 1998): 3–9. http://dx.doi.org/10.1016/s1368-7646(98)80208-2.

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7

Fügi, Matthias A., Sergio Wittlin, Yuxiang Dong, and Jonathan L. Vennerstrom. "Probing the Antimalarial Mechanism of Artemisinin and OZ277 (Arterolane) with Nonperoxidic Isosteres and Nitroxyl Radicals." Antimicrobial Agents and Chemotherapy 54, no. 3 (December 22, 2009): 1042–46. http://dx.doi.org/10.1128/aac.01305-09.

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ABSTRACT Peroxidic antimalarials such as the semisynthetic artemisinins are critically important in the treatment of drug-resistant malaria. Nevertheless, their peroxide bond-dependent mode of action is still not well understood. Using combination experiments with cultured Plasmodium falciparum cells, we investigated the interactions of the nitroxide radical spin trap, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and four of its analogs with artemisinin and the ozonide drug development candidate OZ277. The antagonism observed for combinations of artemisinin or OZ277 with the TEMPO analogs supports the hypothesis that the formation of carbon-centered radicals is critical for the activity of these two antimalarial peroxides. The TEMPO analogs showed a trend toward greater antagonism with artemisinin than they did with OZ277, an observation that can be explained by the greater tendency of artemisinin-derived carbon-centered radicals to undergo internal self-quenching reactions, resulting in a lower proportion of radicals available for subsequent chemical reactions such as the alkylation of heme and parasite proteins. In a further mechanistic experiment, we tested both artemisinin and OZ277 in combination with their nonperoxidic analogs. The latter had no effect on the antimalarial activities of the former. These data indicate that the antimalarial properties of peroxides do not derive from reversible interactions with parasite targets.

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Skinner-Adams, T., and T. M. E. Davis. "Synergistic In Vitro Antimalarial Activity of Omeprazole and Quinine." Antimicrobial Agents and Chemotherapy 43, no. 5 (May 1, 1999): 1304–6. http://dx.doi.org/10.1128/aac.43.5.1304.

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ABSTRACT Previous studies have shown that the proton pump inhibitor omeprazole has antimalarial activity in vitro. The interactions of omeprazole with commonly used antimalarial drugs were assessed in vitro. Omeprazole and quinine combinations were synergistic; however, chloroquine and omeprazole combinations were antagonistic. Artemisinin drugs had additive antimalarial activities with omeprazole.

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9

Co, Edgie-Mark A., Richard A. Dennull, Drew D. Reinbold, Norman C. Waters, and Jacob D. Johnson. "Assessment of Malaria In Vitro Drug Combination Screening and Mixed-Strain Infections Using the Malaria Sybr Green I-Based Fluorescence Assay." Antimicrobial Agents and Chemotherapy 53, no. 6 (April 6, 2009): 2557–63. http://dx.doi.org/10.1128/aac.01370-08.

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ABSTRACT Several drug development strategies, including optimization of new antimalarial drug combinations, have been used to counter malaria drug resistance. We evaluated the malaria Sybr green I-based fluorescence (MSF) assay for its use in in vitro drug combination sensitivity assays. Drug combinations of previously published synergistic (atovaquone and proguanil), indifferent (chloroquine and azithromycin), and antagonistic (chloroquine and atovaquone) antimalarial drug interactions were tested against Plasmodium falciparum strains D6 and W2 using the MSF assay. Fifty percent inhibitory concentrations (IC50s) were calculated for individual drugs and in fixed ratio combinations relative to their individual IC50s. Subsequent isobologram analysis and fractional inhibitory concentration determinations demonstrated the expected drug interaction pattern for each combination tested. Furthermore, we explored the ability of the MSF assay to examine mixed parasite population dynamics, which are commonly seen in malaria patient isolates. Specifically, the capacity of the MSF assay to discern between single and mixed parasite populations was determined. To simulate mixed infections in vitro, fixed ratios of D6 and W2 strains were cocultured with antimalarial drugs and IC50s were determined using the MSF assay. Dichotomous concentration curves indicated that the sensitive and resistant parasites composing the genetically heterogeneous population were detectable. Biphasic analysis was performed to obtain subpopulation IC50s for comparison to those obtained for the individual malaria strains alone. In conclusion, the MSF assay allows for reliable antimalarial drug combination screening and provides an important method to discern between homogenous and heterogeneous parasite populations.

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10

Morrow, Richard H. "Antimalarial drug combinations in vastly different settings." Lancet 369, no. 9560 (February 2007): 444–45. http://dx.doi.org/10.1016/s0140-6736(07)60209-8.

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11

Laing, Lizahn, Lubbe Wiesner, Liezl Gibhard, and Richard K. Haynes. "Evaluation of efficacy of novel antimalarial combinations." Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (2018): PO2–11–3. http://dx.doi.org/10.1254/jpssuppl.wcp2018.0_po2-11-3.

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12

Shahinas, Dea, Gregory MacMullin, Christan Benedict, Ian Crandall, and Dylan R. Pillai. "Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin." Antimicrobial Agents and Chemotherapy 56, no. 8 (May 21, 2012): 4207–13. http://dx.doi.org/10.1128/aac.00328-12.

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ABSTRACTPrevious studies have shown an antimalarial effect of total alkaloids extracted from leaves ofGuiera senegalensisfrom Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibitedPlasmodium falciparumheat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [Kd] of 40 μM). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (Kdof 224 μM) more tightly than PfHsp90 (Kdof 7,010 μM). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisininin vitroand in thePlasmodium bergheimouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.

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13

Guo, Jin, Armand W. Guiguemde, Annael Bentura-Marciano, Julie Clark, Richard K. Haynes, Wing-Chi Chan, Ho-Ning Wong, Nicholas H. Hunt, R. Kiplin Guy, and Jacob Golenser. "Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria." Antimicrobial Agents and Chemotherapy 56, no. 1 (October 17, 2011): 163–73. http://dx.doi.org/10.1128/aac.05006-11.

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ABSTRACTThis research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both inPlasmodium falciparumculture andin vivoin a murine malaria model depicting cerebral malaria (CM).In vitrohigh-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.

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Shanks, G. D., M. D. Edstein, and D. Jacobus. "Evolution from double to triple-antimalarial drug combinations." Transactions of the Royal Society of Tropical Medicine and Hygiene 109, no. 3 (December 30, 2014): 182–88. http://dx.doi.org/10.1093/trstmh/tru199.

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Manirakiza, Alexandre, Georges Soula, Remi Laganier, Elise Klement, Djibrine Djallé, Moyen Methode, Nestor Madji, Luc Salva Heredeïbona, Alain Le Faou, and Jean Delmont. "Pattern of the Antimalarials Prescription during Pregnancy in Bangui, Central African Republic." Malaria Research and Treatment 2011 (July 15, 2011): 1–4. http://dx.doi.org/10.4061/2011/414510.

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Introduction. The aim of this study was to identify the antimalarials prescribed during the pregnancy and to document their timing. Method. From June to September 2009, a survey was conducted on 565 women who gave birth in the Castors maternity in Bangui. The antenatal clinics cards were checked in order to record the types of antimalarials prescribed during pregnancy according to gestational age. Results. A proportion of 28.8% ANC cards contained at least one antimalarial prescription. The commonest categories of antimalarials prescribed were: quinine (56.7%), artemisinin-based combinations (26.8%) and artemisinin monotherapy (14.4%). Among the prescriptions that occurred in the first trimester of pregnancy, artemisinin-based combinations and artemisinin monotherapies represented the proportions of (10.9%) and (13.3%). respectively. Conclusion. This study showed a relatively high rate (>80%) of the recommended antimalarials prescription regarding categories of indicated antimalarials from national guidelines. But, there is a concern about the prescription of the artemisinin derivatives in the first trimester of pregnancy, and the prescription of artemisinin monotherapy. Thus, the reinforcement of awareness activities of health care providers on the national malaria treatment during pregnancy is suggested.

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Zoleko-Manego, Rella, Dearie G. Okwu, Christian Handrich, Lia B. Dimessa-Mbadinga, Malick A. Akinosho, Wilfrid F. Ndzebe-Ndoumba, Saskia D. Davi, et al. "Effectiveness of antimalarial drug combinations in treating concomitant urogenital schistosomiasis in malaria patients in Lambaréné, Gabon: A non-randomised event-monitoring study." PLOS Neglected Tropical Diseases 16, no. 10 (October 31, 2022): e0010899. http://dx.doi.org/10.1371/journal.pntd.0010899.

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Background Urogenital schistosomiasis is prevalent in many malaria endemic regions of sub-Saharan Africa and can lead to long-term health consequences if untreated. Antimalarial drugs used to treat uncomplicated malaria have shown to exert some activity against Schistosoma haematobium. Here, we explore the efficacy on concomitant urogenital schistosomiasis of first-line recommended artemisinin-based combination therapies (ACTs) and investigational second-generation ACTs when administered for the treatment of uncomplicated malaria in Gabon. Methods Microscopic determination of urogenital schistosomiasis was performed from urine samples collected from patients with confirmed uncomplicated malaria. Egg excretion reduction rate and cure rate were determined at 4-weeks and 6-weeks post-treatment with either artesunate-pyronaridine, artemether-lumefantrine, artesunate-amodiaquine or artefenomel-ferroquine. Results Fifty-two (16%) out of 322 malaria patients were co-infected with urogenital schistosomiasis and were treated with antimalarial drug combinations. Schistosoma haematobium egg excretion rates showed a median reduction of 100% (interquartile range (IQR), 17% to 100%) and 65% (IQR, -133% to 100%) at 4-weeks and 6-weeks post-treatment, respectively, in the artesunate-pyronaridine group (n = 20) compared to 35% (IQR, −250% to 70%) and 65% (IQR, -65% to 79%) in the artemether-lumefantrine group (n = 18). Artesunate-amodiaquine (n = 2) and artefenomel-ferroquine combination (n = 3) were not able to reduce the rate of eggs excreted in this limited number of patients. In addition, cure rates were 56% and 37% at 4- and 6-weeks post-treatment, respectively, with artesunate-pyronaridine and no cases of cure were observed for the other antimalarial combinations. Conclusions Antimalarial treatments with artesunate-pyronaridine and artemether-lumefantrine reduced the excretion of S. haematobium eggs, comforting the hypothesis that antimalarial drugs could play a role in the control of schistosomiasis. Trial Registration This trial is registered with clinicaltrials.gov, under the Identifier NCT04264130.

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Semenov, Andrey, Jed E. Olson, and Philip J. Rosenthal. "Antimalarial Synergy of Cysteine and Aspartic Protease Inhibitors." Antimicrobial Agents and Chemotherapy 42, no. 9 (September 1, 1998): 2254–58. http://dx.doi.org/10.1128/aac.42.9.2254.

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ABSTRACT It has been proposed that the Plasmodium falciparumcysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparumparasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.

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Sims, P., P. Wang, and J. E. Hyde. "On `The Efficacy of Antifolate Antimalarial Combinations in Africa'." Parasitology Today 14, no. 4 (April 1998): 136–37. http://dx.doi.org/10.1016/s0169-4758(97)01203-9.

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19

McCarthy, James S., Louise Marquart, Silvana Sekuloski, Katharine Trenholme, Suzanne Elliott, Paul Griffin, Rebecca Rockett, et al. "Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development." Antimicrobial Agents and Chemotherapy 60, no. 6 (April 4, 2016): 3669–75. http://dx.doi.org/10.1128/aac.02883-15.

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Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ−/−(NSG) model, whereby mice are engrafted with noninfected andPlasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stagePlasmodium falciparumchallenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n =8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems.In vivo50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.)

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Watson, Daniel J., Paul R. Meyers, Kojo Sekyi Acquah, Godwin A. Dziwornu, Christopher Bevan Barnett, and Lubbe Wiesner. "Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin." Molecules 26, no. 24 (December 10, 2021): 7494. http://dx.doi.org/10.3390/molecules26247494.

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With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4–5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57–65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.

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Duarte, Diana, Armando Cardoso, and Nuno Vale. "Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs." International Journal of Molecular Sciences 22, no. 14 (July 10, 2021): 7408. http://dx.doi.org/10.3390/ijms22147408.

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Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC50 value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC50. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer.

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de Pilla Varotti, Fernando, Ana Cristina C. Botelho, Anderson Assunção Andrade, Renata C. de Paula, Elaine M. S. Fagundes, Alessandra Valverde, Lúcia M. U. Mayer, et al. "Synthesis, Antimalarial Activity, and Intracellular Targets of MEFAS, a New Hybrid Compound Derived from Mefloquine and Artesunate." Antimicrobial Agents and Chemotherapy 52, no. 11 (August 18, 2008): 3868–74. http://dx.doi.org/10.1128/aac.00510-08.

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ABSTRACT A new synthetic antimalarial drug, a salt derived from two antimalarial molecules, mefloquine (MQ) and artesunate (AS), here named MEFAS, has been tested for its pharmacological activity. Combinations of AS plus MQ hydrochloride are currently being used in areas with drug-resistant Plasmodium falciparum parasites; although AS clears parasitemia in shorter time periods than any other antimalarial drug, it does not cure infected patients; in addition, MQ causes side effects and is rather expensive, important problems considering that malaria affects mostly populations in poor countries. Here, we show that MEFAS is more effective than the combination of AS and MQ, tested in parallel at different mass proportions, against P. falciparum (chloroquine-resistant clone W2 and chloroquine-sensitive clone 3D7) in vitro and in mice infected with Plasmodium berghei, promoting cure of this infection. MEFAS tested against HepG2 hepatoma cells exhibited lower toxicity than the antimalarials AS and MQ alone or combined. Possible targets of MEFAS have been studied by confocal microscopy using fluorescent probes (Fluo-4 AM and BCECF-AM) in P. falciparum synchronous culture of W2-infected red blood cells. Dynamic images show that MEFAS exhibited intracellular action increasing cytoplasmic Ca2+ at 1.0 ng/ml. This effect was also observed in the presence of tapsigargin, an inhibitor of SERCA, suggesting an intracellular target distinct from the endoplasmic reticulum. Trophozoites loaded with BCECF-AM, when treated with MEFAS, were still able to mobilize protons from the digestive vacuole (DV), altering the pH gradient. However, in the presence of bafilomycin A1, an inhibitor of the H+ pump from acidic compartments of eukaryotic cells, MEFAS had no action on the DV. In conclusion, the endoplasmic reticulum and DV are intracellular targets for MEFAS in Plasmodium sp., suggesting two modes of action of this new salt. Our data support MEFAS as a candidate for treating human malaria.

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Sunitha G N, Satyavati Dulipala D, and Girish Gudi. "Effect of ritonavir on pharmacokinetics of antimalarial drug combinations in rats." International Journal of Research in Pharmaceutical Sciences 10, no. 3 (September 21, 2019): 2477–86. http://dx.doi.org/10.26452/ijrps.v10i3.1497.

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The current treatment for Human Immunodeficiency Virus (HIV) patients coinfected with malaria involves the coadministration of antimalarial and antiretroviral (ARV) drugs. The World Health Organization (WHO) recommends artemisinin-based therapy for malaria that usually consists of artemether, artesunate or dihydroartemisinin with non-artemisinin derivatives such as amodiaquine, lumefantrine and mefloquine. Protease inhibitors (PI) such as ritonavir contribute to the improved health of HIV-positive individuals, and the inclusion of ritonavir in antiretroviral regimens is common in clinical practice. Ritonavir is a potent inhibitor of human CYP3A4, which is the primary enzyme involved in the metabolism of many of artemisinin-based drugs, as well as amodiaquine and proguanil. Upon co-administration, ritonavir can potentially influence the metabolism and thus increase the systemic exposure of these drugs. In order to understand this pharmacokinetic (PK) drug interaction, the current work evaluated the effect of ritonavir (50 mg/kg orally) on the PK of antimalarial drug combinations in Sprague Dawley (SD) rats. When co-administered with ritonavir, the exposure (AUC) of the antimalarial drugs artemether, artesunate and proguanil was increased by approximately 3.5-fold. Correspondingly, peak plasma concentrations (Cmax) of these drugs increased as well. There was no apparent influence of ritonavir on the PK of lumefantrine, amodiaquine and atovaquone. This study demonstrates the potential influence of ritonavir on the pharmacokinetics of at least some anti-malarial drugs, likely a result of inhibition of CYP3A. Further evaluation of clinically relevant drug interaction in humans may be warranted to ensure safe and effective use of anti-malarial and anti-HIV drugs concomitantly.

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Wiseman, Virginia, Michelle Kim, Theonest K. Mutabingwa, and Christopher J. M. Whitty. "Cost-Effectiveness Study of Three Antimalarial Drug Combinations in Tanzania." PLoS Medicine 3, no. 10 (October 10, 2006): e373. http://dx.doi.org/10.1371/journal.pmed.0030373.

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Watkins, W. M., E. K. Mberu, P. A. Winstanley, and C. V. Plowe. "More on ‘The Efficacy of Antifolate Antimalarial Combinations in Africa'." Parasitology Today 15, no. 4 (April 1999): 131–32. http://dx.doi.org/10.1016/s0169-4758(99)01419-2.

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Pereira, Marcus R., Philipp P. Henrich, Amar bir Singh Sidhu, David Johnson, Joel Hardink, Jeffrey Van Deusen, Jian Lin, et al. "In VivoandIn VitroAntimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine." Antimicrobial Agents and Chemotherapy 55, no. 7 (April 4, 2011): 3115–24. http://dx.doi.org/10.1128/aac.01566-10.

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ABSTRACTEvidence of emergingPlasmodium falciparumresistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitiveP. falciparumparasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for theirin vitroandin vivoantimalarial properties.In vitro96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly culturedP. falciparumfield isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additionalin vitrotesting highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine.In vivoexperiments, using the Peters 4-day suppressive test in aP. yoeliimouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus theRenantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily ofR-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.

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Jibira, Yakubu, Elizabeth Cudjoe, Frederick M. Tei-Maya, Benjamin Ayensu, and Linda E. Amoah. "The Effectiveness of Varying Combination Ratios of A. cordifolia and M. indica against Field and Laboratory Strains of P. falciparum In Vitro." Journal of Parasitology Research 2020 (November 18, 2020): 1–6. http://dx.doi.org/10.1155/2020/8836771.

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Background. Drug resistance in malaria is a global problem, with reports of Plasmodium parasites resistant to the current first-line antimalarial drug, artemisinin, expanding from Southeast Asia to Africa. There is therefore an urgent need to identify new drug candidates that will be effective against the existing malaria parasites. Drug combination therapy presents a myriad of advantages over monotherapy including delayed onset of resistance, potentiation, and synergism. This present study explored the effectiveness of combinations of aqueous extracts of Alchornea cordifolia (A. cordifolia) and Mangifera indica (M. indica) at clearing both laboratory and field isolates of P. falciparum. Methods. Synchronized ring stage cultures of field (FA08) and laboratory strains (NF54 and CamWT_C580Y) of P. falciparum were subjected to combinations of different concentrations and ratios of aqueous extracts of A. cordifolia and M. indica. The growth inhibition of the individual plant extracts and their combinatory effects were studied in vitro using SYBR Green I drug assay. Results. The A. cordifolia extract exhibited 50% inhibitory concentration (IC50) of 2.71, 7.80, and 3.56 μg/mL against the NF54, CamWT_C580Y, and FA08 parasite strains, respectively. Mangifera indica exhibited IC50 of 18.11, 20.08, and 10.23 μg/mL against the NF54, CamWT_C580Y, and FA08 parasite strains, respectively. Additive, synergistic and antagonistic interactions were observed at different combinations of A. cordifolia and M. indica extracts. Conclusion. A combination product containing A. cordifolia and M. indica has the potential to serve as an effective antimalarial as majority of the tested combinations of aqueous extracts of A. cordifolia and M. indica extracts exhibited synergistic effects in vitro against the NF54, CamWT_C580Y, and FA08 P. falciparum strains.

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Davis, Timothy M. E., Juliana Hamzah, Kenneth F. Ilett, Harin A. Karunajeewa, John C. Reeder, Kevin T. Batty, Sara Hackett, and P. Hugh R. Barrett. "In Vitro Interactions between Piperaquine, Dihydroartemisinin, and Other Conventional and Novel Antimalarial Drugs." Antimicrobial Agents and Chemotherapy 50, no. 8 (August 2006): 2883–85. http://dx.doi.org/10.1128/aac.00177-06.

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ABSTRACT In an in vitro assessment of antimalarial combinations, dihydroartemisinin (DHA) showed no interaction or was mildly antagonistic when combined with piperaquine, pyronaridine, or naphthoquine. Interactions between 4-aminoquinolines and related drugs were also indifferent/antagonistic. The clinical significance of mildly antagonistic DHA combinations is uncertain but may become important if parasite drug sensitivity declines.

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Ounjaijean, Sakaewan, Nattida Benjasak, Suchanan Sae-lao, and Voravuth Somsak. "Kaempferol Addition Increases the Antimalarial Activity of Artesunate in Experimental Mice." Journal of Tropical Medicine 2020 (June 29, 2020): 1–4. http://dx.doi.org/10.1155/2020/6165928.

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Kaempferol (KMF) is a member of flavonol widely found in tea, broccoli, apples, strawberries, and beans. It has been demonstrated to present several pharmacological properties with potent antimalarial activity against Plasmodium berghei-infected mice. Hence, the search for a safe and new antimalarial compound with combinations to delay the development of resistance was the aim of this study. Thus, the therapeutic effect of the combination of KMF and artesunate (ART) in P. berghei-infected mice was evaluated. Combination of KMF and ART in P. berghei ANKA- (PbANKA-) infected ICR mice in a fixed-ratio combination (1 : 1) and fractions of their median effective dose (ED50) was also investigated using the standard 4-day suppressive test. The ED50 levels of KMF and ART in mice infected with PbANKA were 20.06 ± 2.65 and 6.06 ± 1.33 mg/kg, respectively. Moreover, KMF showed promising synergistic combination with ART at the doses of their ED50 and fixed-ratio combination (1 : 1) of their ED50 of 1/2 with combination index (CI) values of 0.86 and 0.47, respectively. Additionally, KMF, ART, and its combination at the doses of their ED50 and fixed-ratio combination (1 : 1) of their ED50 of 1/2 also presented significantly (P<0.001) prolonged mean survival time (MST). The findings of this study showed that a combination of KMF and ART enhanced the antimalarial activity of ART and prolonged MST. This study supports the basis for the selection of KMF as a prospective compound for further consideration as a partner drug for ART.

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Soares, R. P. P., A. U. Krettli, M. V. N. de Souza, T. R. A. Vasconcelos, and N. Boechat. "Evaluation of antimalarial and fluoroquinolone combinations against Plasmodium falciparum in vitro." International Journal of Antimicrobial Agents 28, no. 3 (September 2006): 271–72. http://dx.doi.org/10.1016/j.ijantimicag.2006.06.003.

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Akoachere, Monique, Kathrin Buchholz, Elisabeth Fischer, Jürgen Burhenne, Walter E. Haefeli, R. Heiner Schirmer, and Katja Becker. "In Vitro Assessment of Methylene Blue on Chloroquine-Sensitive and -Resistant Plasmodium falciparum Strains Reveals Synergistic Action with Artemisinins." Antimicrobial Agents and Chemotherapy 49, no. 11 (November 2005): 4592–97. http://dx.doi.org/10.1128/aac.49.11.4592-4597.2005.

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ABSTRACT Methylene blue (MB) represents a promising antimalarial drug candidate for combination therapies against drug-resistant parasite strains. To support and facilitate the application of MB in future field trials, we studied its antiparasitic effects in vitro. MB is active against all blood stages of both chloroquine (CQ)-sensitive and CQ-resistant P. falciparum strains with 50% inhibitory concentration (IC50) values in the lower nanomolar range. Ring stages showed the highest susceptibility. As demonstrated by high-performance liquid chromatography-tandem mass spectrometry on different cell culture compartments, MB is accumulated in malarial parasites. In drug combination assays, MB was found to be antagonistic with CQ and other quinoline antimalarials like piperaquine and amodiaquine; with mefloquine and quinine, MB showed additive effects. In contrast, we observed synergistic effects of MB with artemisinin, artesunate, and artemether for all tested parasite strains. Artemisinin/MB combination concentration ratios of 3:1 were found to be advantageous, demonstrating that the combination of artemisinin with a smaller amount of MB can be recommended for reaching maximal therapeutic effects. Our in vitro data indicate that combinations of MB with artemisinin and related endoperoxides might be a promising option for treating drug-resistant malaria and should be studied in future field trials. Resistance development under this drug combination is unlikely to occur.

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Wojnarski, Mariusz, Oussama Mouri, Charlotte Chambrion, Camille Roussel, Nathalie Chartrel, Bryan Smith, Philip Smith, Marc Thellier, Pierre Buffet, and Papa Alioune Ndour. "Plasmodium falciparum Clearance Is Pitting-Dependent With Artemisinin-Based Drugs but Pitting-Independent With Atovaquone-Proguanil or Mefloquine." Journal of Infectious Diseases 220, no. 3 (March 16, 2019): 535–39. http://dx.doi.org/10.1093/infdis/jiz115.

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AbstractPitting, the removal of dead parasites from their host erythrocyte, has been studied in patients with severe malaria treated parenterally with quinine or artesunate, and was recently shown to contribute to delayed hemolysis, a frequent adverse event of artesunate. We quantified pitting in 81 travelers treated with oral antimalarial therapy. Pitting rate was high (55.8%) with artemisinin-based combinations, but <10% with the nonartemisinin drugs quinine, mefloquine, and atovaquone-proguanil. This may, in part, explain the slower parasite clearance in patients treated with antimalarial drugs lacking an artemisinin component, as well as the absence of posttreatment hemolysis with these drugs.

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Winstanley, P. A., E. K. Mberu, I. S. Szwandt, A. M. Breckenridge, and W. M. Watkins. "In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs." Antimicrobial Agents and Chemotherapy 39, no. 4 (April 1995): 948–52. http://dx.doi.org/10.1128/aac.39.4.948.

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The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethamine-sulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.

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Allman, Erik L., Heather J. Painter, Jasmeet Samra, Manuela Carrasquilla, and Manuel Llinás. "Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways." Antimicrobial Agents and Chemotherapy 60, no. 11 (August 29, 2016): 6635–49. http://dx.doi.org/10.1128/aac.01224-16.

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ABSTRACTThe threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective againstPlasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated thein vitrometabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography–mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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Samuel Akintunde Odediran, Oluwayomi Rebecca Akosile, and Racheal Adebola Bamigboye. "In vivo chemosuppressive activities of combinations of four Nigerian ethnomedicinal antimalarial ferns." GSC Biological and Pharmaceutical Sciences 20, no. 1 (July 30, 2022): 145–58. http://dx.doi.org/10.30574/gscbps.2022.20.1.0278.

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Background to the study: The in vivo antimalarial activities and the effects of combining the methanol extracts of four ferns namely, Nephrolepis biserrata (NB), N. undulata (NU), Platycerium stemaria (PS), and P. angolense (PA) randomly and with chloroquine, was determined. Methods: The four ferns were collected, separately air-dried, powdered and the extracts was obtained by cold maceration with methanol and evaporation in vacuo. They were subsequently investigated (0-800mg/kg) for antimalarial potency against chloroquine-sensitive Plasmodium berghei berghei in mice using the Peters’ four-day test after preliminary toxicity studies, using Lorke’s method. They were further tested separately, combined with chloroquine and randomly combined with each other at their respective median effective doses. Result: NB and PS elicited comparable ED50 and lower activities than NU while PA was the least active. The percentage chemosuppression elicited by all the individual extracts were comparable [p>0.05] to that of chloroquine when combined, with chloroquine and each other, except for NU and PS. Also, NB+PA, NB+PS, NU+PA+PS, NU+NB+PS and NU+NB+PA gave comparable [p>0.05] chemosuppression to CQ. However, NU+PA, NU+CQ and PS+CQ elicited similar survival times and % survivor with chloroquine. The activities of the lower - acting PA and PS was only improved by combination with either NU or NB and did not give better effects than the most active individual drug. Conclusion: The study confirms the ethnomedicinal use of NU and NB for malaria and indicate that combining the ferns did not give any significant increase in activity better than the most active individual or the standard drug.

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Adebajo, Adeleke, Samuel Odediran, Fatimah Aliyu, Paul Nwafor, Ndifreke Nwoko, and Usenobong Umana. "In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants." Molecules 19, no. 9 (August 26, 2014): 13136–46. http://dx.doi.org/10.3390/molecules190913136.

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da Silva, Marcia F., Alexandre Y. Saito, Valnice J. Peres, Antonio C. Oliveira, and Alejandro M. Katzin. "In VitroAntimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway." Antimicrobial Agents and Chemotherapy 59, no. 8 (June 8, 2015): 5084–87. http://dx.doi.org/10.1128/aac.04161-14.

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ABSTRACTPrevious studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activityin vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism inErwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects.

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Zaveri, Mehul, and Neha Kawathekar. "SYNTHESIS AND ANTIMALARIAL ACTIVITY OF SOME NEW 3-PHENYL-2-THIOXOTHIAZOLIDIN-4-ONE DERIVATIVES." International Journal of Current Pharmaceutical Research 9, no. 3 (May 5, 2017): 58. http://dx.doi.org/10.22159/ijcpr.2017.v9i3.18897.

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Objective: Current therapies to treat P. falciparum malaria are heavily reliant on artemisinin-based combinations. However, resistance to artemisinin has recently been identified, and resistance to key artemisinin partner drugs is already widespread. Therefore, there is an urgent need for new antimalarial drugs with improved attributes over older therapies. The objective of this research work is to synthesize new antimalarial agents more effective against clinically relevant malarial strains.Methods: In present work, a series of ten 3-phenyl-2-thioxothiazolidin-4-one (MF1-MF10) derivatives, were synthesized by Knoevenagel condensation of N-phenyl rhodanine (I1) with substituted aromatic or hetro aromatic aldehydes using microwave irradiation. N-phenyl rhodanine (I1) was synthesized by a conventional reaction involving methyl-2-mercaptoacetate (1) and phenyl Isothiocyanates in presence of triethylamine. All the synthesized compounds were characterized by various spectroscopic techniques and evaluated for in-vitro antimalarial activity by microdilution technique against resistance strains of Plasmodium falciparum.Results: The antimalarial activity data showed that six compounds (MF1, MF3, MF4, MF5, MF7 and MF8) exhibited IC50 values ranging from 1.0-1.30 µg/ml, three compounds (MF2, MF6 and MF10) displayed IC50 values in the range of 0.9-1.0 µg/ml. Compound MF9 showed most significant result with maximum activity (IC50 = 0.85µg/ml).Conclusion: The antimalarial activity results revealed that compound MF9 possess potent activity and could be identified as a promising lead for further investigation.

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Skinner-Adams, T. S., K. T. Andrews, L. Melville, J. McCarthy, and D. L. Gardiner. "Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro." Antimicrobial Agents and Chemotherapy 51, no. 2 (November 6, 2006): 759–62. http://dx.doi.org/10.1128/aac.00840-06.

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ABSTRACT The antimalarial activity of several antiretroviral protease inhibitor combinations was investigated. Data demonstrate that ritonavir and saquinavir behave synergistically with chloroquine and mefloquine. These data, and interactions with pepstatin-A, E-64, and bestatin, suggest that human immunodeficiency virus protease inhibitors do not target digestive-vacuole plasmepsins.

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Neto, Zoraima, Marta Machado, Ana Lindeza, Virgílio do Rosário, Marcos L. Gazarini, and Dinora Lopes. "Treatment ofPlasmodium chabaudiParasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System." Journal of Parasitology Research 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/429736.

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Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin againstPlasmodiumspp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed.In vivoefficacy of curcumin was studied in BALB/c mice infected withPlasmodium chabaudiclones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group’s 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.

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Duarte, Diana, Alexandra Rêma, Irina Amorim, and Nuno Vale. "Drug Combinations: A New Strategy to Extend Drug Repurposing and Epithelial-Mesenchymal Transition in Breast and Colon Cancer Cells." Biomolecules 12, no. 2 (January 23, 2022): 190. http://dx.doi.org/10.3390/biom12020190.

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Despite the progressive research and recent advances in drug therapy to treat solid tumours, the number of cases and deaths in patients with cancer is still a major health problem. Drug repurposing coupled to drug combination strategies has been gaining interest among the scientific community. Recently, our group proposed novel drug combinations for breast and colon cancer using repurposed drugs from different classes (antimalarial and central nervous system (CNS)) and chemotherapeutic agents such as 5-fluorouracil (5-FU), paclitaxel (PTX), and found promising results. Here, we proposed a novel drug combination using different CNS drugs and doxorubicin (DOX), an antineoplastic used in breast cancer therapy, and studied their anticancer potential in MCF-7 breast cancer cells. Cells were treated with each drug alone and combined with increasing concentrations of DOX and cell viability was evaluated by MTT and SRB assays. Studies were also complemented with morphological evaluation. Assessment of drug interaction was performed using the CompuSyn and SynergyFinder software. We also compiled our previously studied drug pairs and selected the most promising ones for evaluation of the expression of EMT biomarkers (E-cadherin, P-cadherin, vimentin, and β-catenin) by immunohistochemistry (IHC) to assess if these drug combinations affect the expression of these proteins and eventually revert EMT. These results demonstrate that combination of DOX plus fluoxetine, benztropine, and thioridazine at their IC50 can improve the anticancer effect of DOX but to a lesser degree than when combined with PTX (previous results), resulting in most of the drug interactions being antagonist or additive. This suggests that the choice of the antineoplastic drug influences the success of the drug combination. Collectively, these results also allow us to conclude that antimalarial drugs as repurposed drugs have enhanced effects in MCF-7 breast cancer cells, while combination with CNS drugs seems to be more effective in HT-29 colon cancer cells. The IHC results demonstrate that combination treatments increase E-cadherin expression while reducing P-cadherin, vimentin, and β-catenin, suggesting that these treatments could induce EMT reversal. Taken together, these results could provide promising approaches to the design of novel drug combinations to treat breast and colon cancer patients.

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Arrey Tarkang, Protus, Kathrin Diehl Franzoi, Sukjun Lee, Eunyoung Lee, Diego Vivarelli, Lucio Freitas-Junior, Michel Liuzzi, et al. "In VitroAntiplasmodial Activities and Synergistic Combinations of Differential Solvent Extracts of the Polyherbal Product,Nefang." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/835013.

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Nefang, a polyherbal product composed ofMangifera indica(bark and leaf),Psidium guajava,Carica papaya,Cymbopogon citratus,Citrus sinensis, andOcimum gratissimum(leaves), is a potential therapy againstP. falciparummalaria.In vitroantiplasmodial activities of its constituent solvent extracts were analyzed on CQ-sensitive (3D7) and multidrug resistant (Dd2)P. falciparumstrains. The interactions involving the differential solvent extracts were further analyzed using a variable potency ratio drug combination approach. Effective concentration 50 (EC50) values were determined by nonlinear regression curve-fitting of the dose-response data and used in calculating the fractional inhibitory concentration 50 (FIC50) and combination indices (CI) for each pair. The derived EC50values (3D7/Dd2,μg/mL) areNefang-96.96/55.08,MiB-65.33/34.58,MiL-82.56/40.04,Pg-47.02/25.79,Cp-1188/317.5,Cc-723.3/141,Cs-184.4/105.1, andOg-778.5/118.9. Synergism was obtained withMiB/Pg(CI = 0.351),MiL/Pg(0.358),MiB/Cs(0.366),MiL/Cs(0.482),Pg/Cs(0.483), andCs/Og(0.414) when analyzed at equipotency ratios. Cytotoxicity testing ofNefangand the solvent extracts on two human cell lines (Hep G2 and U2OS) revealed no significant toxicity relative to their antiplasmodial activities (SI > 20). Taken together, our data confirm the antimalarial activities ofNefangand its constituent plant extracts and identified extract pairs with promising synergistic interactions for exploitation towards a rational phytotherapeutic and evidence-based antimalarial drug discovery.

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Lucantoni, Leonardo, Sandra Duffy, Sophie H. Adjalley, David A. Fidock, and Vicky M. Avery. "Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay." Antimicrobial Agents and Chemotherapy 57, no. 12 (September 23, 2013): 6050–62. http://dx.doi.org/10.1128/aac.00870-13.

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ABSTRACTThe design of new antimalarial combinations to treatPlasmodium falciparuminfections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinantP. falciparumline expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of >30, and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.

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Duarte, Diana, Mariana Nunes, Sara Ricardo, and Nuno Vale. "Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action." Biomolecules 12, no. 10 (October 16, 2022): 1490. http://dx.doi.org/10.3390/biom12101490.

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Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC50). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action.

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Dembele, Ousmane, Seydou Moussa Coulibaly, Bakary Moussa Cissé, Mody Cissé, Jacques Dakouo, Nana Houmama Cissé, and Benoît Yaranga Koumaré. "Risk-Based Post-Marketing Surveillance (RB-PMS) of antimalarial drugs and maternal, neonatal and reproductive health (MNCH) in Mali." Journal of Drug Delivery and Therapeutics 12, no. 2 (March 7, 2022): 6–10. http://dx.doi.org/10.22270/jddt.v12i2.5223.

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Objectives: In a world marked by the increase in chemoresistance leading to the adoption of therapeutic combinations, the advent of generic multi-source drugs, the spread of counterfeiting and substandard drugs, often without active ingredients or falsified active ingredients, a Greater vigilance by pharmaceutical regulatory authorities is needed. Drug Post-Marketing Surveillance (PMS) therefore plays an important role in detecting poor quality products on the market. Risk-Based Post-Marketing Surveillance (RB-PMS) is a new form of PMS that is emerging and was the subject of a recent WHO publication. Methods: The survey covered certain regions and certain points of sale identified by a Technical Working Group. It aimed to assess the quality of antimalarial and MNCRH drugs available at certain risk distribution levels based on priority sites. The selection of drugs and geographic areas was made using risk-based sampling using the Drug Risk Assessment Tool (MedRS) developed by USP / PQM +. Results: A total of 242 samples were taken and analyzed according to a risk-based protocol, of which 233 were compliant with a rate of 96% against 9 were non-compliant or 4% (P≤0,05). Non-compliant drugs were mainly from the public sector. We found 69% of the unregistered drugs that consisted mainly of antimalarial drugs and which came from India and China. Conclusion: In view of the scarcity of resources and its scientific nature, this risk-based sampling and analysis technique (RB-PMS) must be pursued, optimized and made sustainable to ensure health and guarantee access to quality medicines for the health and well-being of populations. Keywords: Antimalarials, MNCH, Quality Control, RB-PMS.

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Yusuf, Rahma Udu, Sabah Ahmed Omar, and Raphael Muchangi Ngure. "The effect of Point Mutations in Dihydrofolate reductase genes and Multidrug resistance gene 1-86 on treatment of falciparum malaria in Sudan." Journal of Infection in Developing Countries 4, no. 02 (November 21, 2009): 061–69. http://dx.doi.org/10.3855/jidc.630.

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Background: One of the major problems to the treatment of malaria is the emergence and spread of parasite resistant to antimalarial drugs. Due to increased chloroquine (CQ) resistance, the antifolate combinations are becoming important in the chemotherapy of falciparum malaria. However, resistance to antifolate exists and they are still effective in the above combinations. This study aimed at determining the prevalence of antimalarial drug resistance markers in P. falciparum isolates, involving the detection of mutations at the mdr 1- 86 which associates with amodiaquine resistance, and dhfr mutations associated with SP resistances. Methods: The dot-blot/ probe hybridization, which is more sensitive and specific; it detects parasitaemia of less than 100 parasites/µl of blood, and can identify a minority parasite genotype down to 1% in a mixture, was adopted to determine multi-drug resistance (mdr1-86) to show the correlation of Amodiaquine (AQ) resistance and PCR/ RFLP adopted to determine dihydrofolate reductase (dhfr) baseline resistance to Sulphadoxine- Pyrimethamine (SP) resistance in Nubian region of southern Sudan. A randomized open label trial of Artesunate (AS) + SP and AS+ SP was carried out in children less than 5 years. Molecular analysis of filter paper preserved blood samples collected was carried out to provide a baseline estimate of allele prevalences. Results: Baseline of the allele prevalence of the mdr1 86 locus in the AS+ AQ was successful for 80 isolates: 71(8.11%) carried parasites harbouring the mdr1-86 Tyr resistance allele, while 7 (89.19%) carried mdr1-86 Asn sensitivity allele and 2 (2.7%) were of mixed infection, having both resistance and wild type allele. Overall, the prevalence of the dhfr point mutation, codon 51, 59 and 108: 82.5% (132/160) carried mutations at dhfr (N51I, C59R or S108N), but triple mutants were rare (3.1%) in the AS + SP arm. Conclusion: The research provides the evidence that mutations present in dhfr and mdr1 86 has a significant effect on the type of treatment following SP and AQ chemotherapy. SP resistance may spread rapidly, and AS + AQ is likely to be a better option, provided AQ use is restricted to the combination. The significance of the study shows that definitely combination of drugs improves SP therapy at the study site. Keywords: Antimalarial drugs, P. falciparum, dhfr, mdr-1, dot-blot hybridisation technique, PCR/RFLP

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47

Ohrt, Colin, George D. Willingmyre, Patricia Lee, Charles Knirsch, and Wilbur Milhous. "Assessment of Azithromycin in Combination with Other Antimalarial Drugs against Plasmodium falciparum In Vitro." Antimicrobial Agents and Chemotherapy 46, no. 8 (August 2002): 2518–24. http://dx.doi.org/10.1128/aac.46.8.2518-2524.2002.

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ABSTRACT Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC50s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC50s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

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Andrews, Katherine T., David P. Fairlie, Praveen K. Madala, John Ray, David M. Wyatt, Petrina M. Hilton, Lewis A. Melville, et al. "Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 639–48. http://dx.doi.org/10.1128/aac.50.2.639-648.2006.

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ABSTRACT Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

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Senarathna, S. M. D. K. Ganga, and Kevin T. Batty. "Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing." Antimicrobial Agents and Chemotherapy 58, no. 10 (August 4, 2014): 6068–78. http://dx.doi.org/10.1128/aac.02538-14.

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ABSTRACTPharmacopeial recommendations for administration of antimalarial drugs are the same weight-based (mg/kg of body weight) doses for children and adults. However, linear calculations are known to underestimate pediatric doses; therefore, interspecies allometric scaling data may have a role in predicting doses in children. We investigated the allometric scaling relationships of antimalarial drugs using data from pharmacokinetic studies in mammalian species. Simple allometry (Y=a×Wb) was utilized and compared to maximum life span potential (MLP) correction. All drugs showed a strong correlation with clearance (CL) in healthy controls. Insufficient data from malaria-infected species other than humans were available for allometric scaling. The allometric exponents (b) for CL of artesunate, dihydroartemisinin (from intravenous artesunate), artemether, artemisinin, clindamycin, piperaquine, mefloquine, and quinine were 0.71, 0.85, 0.66, 0.83, 0.62, 0.96, 0.52, and 0.40, respectively. Clearance was significantly lower in malaria infection than in healthy (adult) humans for quinine (0.07 versus 0.17 liter/h/kg;P= 0.0002) and dihydroartemisinin (0.81 versus 1.11 liters/h/kg;P= 0.04; power = 0.6). Interpolation of simple allometry provided better estimates of CL for children than MLP correction, which generally underestimated CL values. Pediatric dose calculations based on simple allometric exponents were 10 to 70% higher than pharmacopeial (mg/kg) recommendations. Interpolation of interspecies allometric scaling could provide better estimates than linear scaling of adult to pediatric doses of antimalarial drugs; however, the use of a fixed exponent for CL was not supported in the present study. The variability in allometric exponents for antimalarial drugs also has implications for scaling of fixed-dose combinations.

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Wekesa Sifuna, Martin, Milka Wambui, Joseph Kang’ethe Nganga, Daniel Wainaina Kariuki, Francis Thuo Kimani, and Francis Wamakima Muregi. "Antiplasmodial Activity Assay of 3-Chloro-4-(4-chlorophenoxy) Aniline Combinations with Artesunate or Chloroquine In Vitro and in a Mouse Model." BioMed Research International 2019 (October 17, 2019): 1–7. http://dx.doi.org/10.1155/2019/5153482.

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Malaria is the eighth highest contributor to global disease burden with 212 million cases and 429,000 deaths reported in 2015. There is an urgent need to develop multiple target drug to curb growing resistance by Plasmodia due to use of single target drugs and lack of vaccines. Based on a previous study, 3-chloro-4-(4-chlorophenoxy) aniline (ANI) inhibits Plasmodia enoyl acyl carrier protein reductase. This study aimed at evaluating the antiplasmodial activity of ANI combinations with artesunate (AS) or chloroquine (CQ) against P. falciparum in vitro based on the semiautomated microdilution assay and P. berghei in vivo based on Peters’ 4-day test. Data were analysed by linear regression using version 5.5 of Statistica, 2000. From the results, on the one hand, a combination of 1.1 ng/ml AS and 3.3 μg/ml of ANI inhibited 50% growth of W2, while a combination of 0.8 ng/ml of AS and 2.6 μg/ml of ANI inhibited 50% growth of 3D7. On the other hand, a combination of 22 ng/ml CQ and 3.7 μg/ml of ANI inhibited 50% growth of W2, while a combination of 4.6 ng/ml CQ and 3.1 μg/ml of ANI inhibited 50% growth of 3D7. In in vivo assays, a combination of ED50 concentrations of AS and ANI cleared all parasites, while 1/2 and 1/4 ED50 combinations inhibited 67.0% and 35.4% parasite growth, respectively. ED50 combinations of CQ and ANI inhibited 81.0% growth of parasites, while 1/2 and 1/4 ED50 combinations inhibited 27.3% and 10.2% parasite growth. Assuming a linear relationship between percentage chemosuppression and combination ratios, only 0.88 mg/kg of AS combined with 1.68 mg/kg of ANI or 1.78 mg/kg of CQ with 3.15 mg/kg of ANI inhibited 50% parasite growth in vivo. ANI combinations with AS or CQ are thus potential antimalarial drug combinations if their clinical efficacy and safety are ascertained.

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