Antimalarial Interaction Research Articles

Evaluation of chloroquine and hydroxychloroquine as ACE-2 Inhibitors By In Silico Approaches: Cardiac Arrhythmia Cause?

• CQ and HCQ could modulate the ACE- 2 and cause cardiotoxic effect. • Molecular docking identified that ionic interactions are the main driving forces of the CQ and HCQ in catalytic domain of the ACE-2. • In molecular dynamics was observed that the stability of the ionic interactions were present in the R-conformers of the CQ and HCQ. • This work may be helpful to better understand the cardiotoxic effects attributed to aminoquinoline drugs. Chloroquine and hydroxychloroquine impair in vitro the terminal glycosylation of angiotensin-converting enzyme 2 (ACE-2), which is known to be cardioprotective. As these aminoquinoline antimalarials are associated with cardiovascular effects, details of their molecular basis on human ACE-2 inhibition still need moving forward with scientific information. Here, molecular docking and dynamics were applied to promote molecular understanding of the antimalarial isomers interactions with human ACE-2. We identified by docking that ionic interactions are the main driving forces. In molecular dynamics, it was observed that the stability of these interactions were present only in R-conformers. These findings may be helpful to better understand the cardiotoxic effects attributed to drugs with the potential to modulate human ACE-2.

Chemotherapeutic Interaction of Vernonia amygdalina (Delile) Leaf Extract with Artesunate and Amodiaquine in Murine Malaria Model

Aim of the Study: Conventional antimalarial drugs are used concurrently with herbal remedies in malarial endemic developing countries. Vernonia amygdalina is one of such popular herbs used in the treatment of malaria. This study aimed at investigating the antimalarial chemotherapeutic interaction of Vernonia amygdalina (VA) when combined with Amodiaquine (AQ) and/or Artesunate (AS) in a murine Plasmodium berghei malaria model.
 Methodology: Various doses of aqueous VA leaf extract (100-500 mg/kg/day), AQ (2-10 mg/kg/day) and AS (0.8-4 mg/kg/day) were administered orally to P berghei.-infected Swiss albino mice to determine their sub-therapeutic doses. These doses were subsequently used to investigate the chemotherapeutic interactions of VA with AQ and/or AS in both early and established malaria infection test models. The survival of animals with established infections that received different drug/herb treatments were determined using their mean survival time (days) and Kaplan-Meier survival curves (percentage). Using GraphPad Instat (version 3.10) and PrismR (version 5.01) the data obtained were subjected to One-way ANOVA, followed by Student-Newman-Keuls test. P < .05 was considered statistically significant.
 Results: The sub-therapeutic doses of VA, AQ and AS were found to be 100 mg/kg, 2 mg/kg and 2.4 mg/kg, respectively. The chemosuppressive effect of AQ or AS was significantly increased (p< 0.05) when administered in combination with the VA extract. Similarly, combination of VA extract with AQ or AS resulted in significant (P < .05) parasite clearance when compared to the effects of the herb or the conventional drugs administered separately. The mean survival period of animals with established infection was also significantly enhanced by the VA alone or with AQ (or AS) compared to placebo.

Drug interactions with antimalarial medications in older travelers: a clinical guide.

Increasingly older adults are traveling to international destinations with malaria as a present risk. Surveillance systems indicate that older adults are more likely to suffer severe complications from malaria. The role of health care providers in selecting an appropriate medication for chemoprophylaxis or treatment of malaria in adults becomes more difficult as older adults undergo physiologic changes that alter the pharmacokinetic and pharmacodynamic nature of medications potentially causing increased drug interactions, adverse events and altered drug action. A comprehensive literature search from 1970 to present, with a focus on the past 10years, was conducted on drug interactions, pharmacokinetic and pharmacodynamic effects on antimalarials in adults. It was determined that due to pharmacodynamic and pharmacokinetic changes in older adults, especially renal and cardiovascular, special attention should be given to this population of travelers in order to minimize the likelihood of adverse events or altered drug efficacy. Antimalarial drug-disease interactions in older adults can occur more often due to QT prolongation, exacerbation of hypoglycemia, decreased renal elimination and decreased hepatic metabolism. Older antimalarials have well-documented drug-drug interactions. Tafenoquine, a new antimalarial, requires glucose-6-phosphate dehydrogenase screening like primaquine and monitoring of new potential drug interaction with MATE1 and OCT2 substrates. While drug-drug interactions in older travelers may occur more often as a result of polypharmacy, data did not indicate adverse reactions or decreased drug efficacy is greater compared with younger adults. Overall, with the exception of recently approved tafenoquine, much is known about antimalarial drug and disease interactions, but new drugs are always being approved, requiring travel health providers to understand the pharmacokinetics and pharmacodynamics of antimalarial drugs to predict the impact on safety and efficacy in travelers. This guide provides travel health providers with valuable insights on potential outcomes associated with drug interactions in adults and recommended monitoring or drug regimen modification.

Interaction of alphamangostin and curcumin with dihydroartemisinin as antimalaria in vitro

To overcome malarial resistance tendency against the ACT (artemisinin-based combination therapy), several galenic preparations of Garciniamangostana L-rind and alphamangostin as the major xanthone in this rind have been studied, and they had antimalarial activity and showed its synergistic effect with artemisinin in vitro. Curcumin as anactive component of turmeric is also potentially to have antimalarial activity. This study aimed to evaluate the activity as antimalarial of curcumin and dihydroartemisinin, an active metabolite of all artemisinin derivates, and also to study the mechanism of action of aphamangostin, curcumin, and dihydroartemisinin as antimalaria.The interaction between them each other as the antimalarial in vitro was also investigated. The antimalarial activity was studied in in vitro 3D7 Plasmodium falciparum cultivation incubated with these compounds to look for the IC50 and ΣFIC50 of them. The mechanism of action of these compounds was observed electron microscopically. The result of this promising study showed that these compounds were active antimalaria agents which inhibited hemozoin formation and there is synergistic antimalarial activity interaction between alphamangostin and dihydroartemisinin.

In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine

BackgroundDiscovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues.MethodsThe resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7.ResultsCryptolepis sanguinolenta (IC50 = 49.65 nM) and its major alkaloid, cryptolepine (IC50 = 1965 nM), showed high inhibitory activity against the late stage gametocytes of P. falciparum (NF54). In the interaction assays in asexual stage, cryptolepine showed an additive effect with both lumefantrine and chloroquine with mean ΣFIC50s of 1.017 ± 0.06 and 1.465 ± 0.17, respectively. Cryptolepine combination with amodiaquine at therapeutically relevant concentration ratios showed a synergistic effect (mean ΣFIC50 = 0.287 ± 0.10) whereas an antagonistic activity (mean ΣFIC50 = 4.182 ± 0.99) was seen with mefloquine.ConclusionsThe findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose combinations.

Proguanil and cycloguanil are organic cation transporter and multidrug and toxin extrusion substrates

BackgroundMalaria, HIV/AIDS, and tuberculosis endemic areas show considerable geographical overlap, leading to incidence of co-infections. This requires treatment with multiple drugs, potentially causing adverse drug–drug interactions (DDIs). As anti-malarials are generally positively charged at physiological pH, they are likely to interact with human organic cation transporters 1 and 2 (OCT1 and OCT2). These transporters are involved in the uptake of drugs into hepatocytes and proximal tubule cells for subsequent metabolic conversion or elimination. This efflux of cationic drugs from hepatocytes and proximal tubule cells into bile and urine can be mediated by multidrug and toxin extrusion 1 and 2-K (MATE1 and MATE2-K) transporters, respectively.MethodsHere, the interaction of anti-malarials with these transporters was studied in order to predict potential DDIs. Using baculovirus-transduced HEK293 cells transiently expressing human OCT1, OCT2, MATE1 and MATE2K uptake and inhibition was studied by a range of anti-malarials.ResultsAmodiaquine, proguanil, pyrimethamine and quinine were the most potent inhibitors of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP) transport, a known substrate of OCT1/2, resulting in half maximal inhibitory concentrations (IC50) of 11, 13, 1.6, and 3.4 µM, respectively. Only quinine had a drug–drug index higher than the cut-off value of 0.1 for OCT2, therefore, in vivo pharmacokinetic studies focusing on DDIs involving this compound and other OCT2-interacting drugs are warranted. Furthermore, proguanil appeared to be a substrate of OCT1 and OCT2 with affinities of 8.1 and 9.0 µM, respectively. Additionally, MATE1 and MATE2-K were identified as putative transport proteins for proguanil. Finally, its metabolite cycloguanil was also identified as an OCT1, OCT2, MATE1 and MATE2-K substrate.ConclusionAnti-malarials can reduce OCT1 and OCT2 transport activity in vitro. Furthermore, proguanil and cycloguanil were found to be substrates of OCT1, OCT2, MATE1 and MATE2-K, highlighting the importance of these transporters in distribution and excretion. As these compounds shares substrate overlap with metformin DDIs can be anticipated during concurrent treatment.

Structural insight into binding mode of inhibitor with SAHH of Plasmodium and human: interaction of curcumin with anti-malarial drug targets.

S-adenosyl-L-homocysteine hydrolase of Plasmodium falciparum (PfSAHH) is a potential drug target against malaria, and selective inhibition of PfSAHH is the excellent strategy to prevent the growth of parasite inside the host. Therefore, a comparative analysis of human S-adenosyl-L-homocysteine hydrolase (HsSAHH) and PfSAHH has been performed to explore the structural differences. Structural superimposition of PfSAHH and HsSAHH has generated the RMSD of 0.749Å over 394 alpha carbon pairs. Residues of PfSAHH from position Tyr152 to Lys193 aligned with insertion/deletion region in HsSAHH, and these extra residues results in an extent of variation in cavity region of PfSAHH. Nicotinamide adenine dinucleotide (NAD) was observed to form hydrogen bonding with Thr201, Thr202, Thr203, Asn235, Val268, Glu287, Asn322, Ile343, Asn391, Lys473, and Tyr477 and also forms hydrophobic interactions with Val268, Ile288, and Thr320 of PfSAHH. In comparison to HsSAHH, Asn322, Lys473, and Tyr477 residues of PfSAHH are unique in interaction with NAD. 2-Fluoroaristeromycin and other analogues of aristeromycin have shown the good binding affinity for both enzymes. Structural differences between PfSAHH and HsSAHH might be employed to design the potential inhibitor of PfSAHH. To find the target enzyme responsible for an anti-malarial effect, molecular docking and interaction analysis of curcumin were performed with 34 drug targets of P. falciparum. Curcumin shows high affinity for binding with HGPRT of PfHGPRT, and an anti-malarial effect of curcumin might be due to binding with PfHGPRT.

Synergistic anti-malarial action of cryptolepine and artemisinins.

BackgroundCryptolepine (CPE) is the major indoloquinoline isolated from the popular West African anti-malarial plant, Cryptolepis sanguinolenta. CPE possesses various pharmacological activities with potent anti-malarial activity against both chloroquine (CQ)-resistant and -sensitive strains. The search for safe and novel anti-malarial agents and combinations to delay resistance development to Plasmodium falciparum directed this work aimed at evaluating the anti-malarial interaction and safety of CPE in combination with some artemisinin derivatives.MethodsThe in vitro SYBR Green I, fluorescent-based, drug sensitivity assay using a fixed ratio method was carried out on the CQ-sensitive plasmodial strain 3D7 to develop isobolograms from three CPE-based combinations with some artemisinin derivatives. CPE and artesunate (ART) combinations were also evaluated using the Rane’s test in ICR mice infected with Plasmodium berghei NK-65 strains in a fixed ratio combination (1:1) and fractions of their ED50s in order to determine the experimental ED50 (Zexp) of the co-administered compounds. Isobolograms were constructed to compare the Zexp to the Zadd.ResultsCPE exhibited promising synergistic interactions in vitro with ART, artemether and dihydroartemisinin. In vivo, CPE combination with ART again showed synergy as the Zexp was 1.02 ± 0.02, which was significantly less than the Zadd of 8.3 ± 0.31. The haematological, biochemical, organ/body weight ratio and histopathology indices in the rats treated with CPE at all doses (25, 50, 100 mg kg−1po) and in combination with ART (4 mg kg−1) showed no significant difference compared to the control group.ConclusionThe combination of CPE with the artemisinin derivatives were safe in the rodent model and showed a synergistic anti-malarial activity in vivo and in vitro. This study supports the basis for the selection of CPE as a prospective lead compound as the search for new anti-malarial combinations continues.

Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase

Interaction between antimalarial drugs is important in determining the outcome of chemotherapy using drug combinations. Inhibitors of dihydrofolate reductase (DHFR) such as pyrimethamine and of dihydropteroate synthase (DHPS) such as sulfa drugs are known to have synergistic interactions. However, studies of the synergism are complicated by the fact that the malaria parasite can also salvage exogenous folates, and the salvage may also be affected by the drugs. It is desirable to have a convenient system to study interaction of DHFR and DHPS inhibitors without such complications. Here, we describe the use of Escherichia coli transformed with malarial DHFR and DHPS, while its own corresponding genes have been inactivated by optimal concentration of trimethoprim and genetic knockout, respectively, to study the interaction of the inhibitors. Marked synergistic effects are observed for all combinations of pyrimethamine and sulfa inhibitors in the presence of trimethoprim. At 0.05μM trimethoprim, sum of fractional inhibitory concentrations, ΣFIC of pyrimethamine with sulfadoxine, pyrimethamine with sulfathiazole, pyrimethamine with sulfamethoxazole, and pyrimethamine with dapsone are in the range of 0.24–0.41. These results show synergism between inhibitors of the two enzymes even in the absence of folate transport and uptake. This bacterial surrogate system should be useful as a tool for assessing the interactions of drug combinations between the DHFR and DHPS inhibitors.

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

BackgroundEmergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT).MethodsFluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters’ four-day suppressive test.ResultsPromising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW).ConclusionsIn vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

The in vitro antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with mefloquine/artesunate.

Multidrug resistance Plasmodium falciparum is the major health problem in Thailand. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate the antimalarial interaction of 9-hydroxycalabaxanthone and α-mangostin with the standard antimalarial drugs mefloquine and artesunate in chloroquine sensitive (3D7) and chloroquine resistant (K1) P. falciparum clones in vitro. Median (range) IC50 (drug concentration which produces 50% parasite growth inhibition) values of the 9-hydroxycalabaxanthone, α-mangostin, artesunate and mefloquine for 3D7 vs K1 clones were 1.5 (0.9-2.1) vs 1.2 (1.1-1.6) μM, 17.9 (15.7.0-20.0) vs 9.7 (6.0-14.0) μM, 1.0 (0.4-3.0) vs 1.7 (1.0-2.5) nM, and 13.3 (11.1-13.3) vs 7.1 (6.7-12.2) nM, respectively. Analysis of isobologram and combination index (CI) of 9-hydroxycalabaxanthone with artesunate or mefloquine showed synergistic and indifference antimalarial interaction, respectively. α-mangostin-artesunate combination exhibited a slight antagonistic effect of antimalarial interaction, whereas α-mangostin and mefloquine combination showed indifference interaction in both clones. The combination of 9-hydroxycalabaxanthone with α-mangostin showed the synergistic antimalarial interaction in both clones.

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for Plasmodium falciparum.

Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

How experiences become data: the process of eliciting adverse event, medical history and concomitant medication reports in antimalarial and antiretroviral interaction trials

BackgroundAccurately characterizing a drug’s safety profile is essential. Trial harm and tolerability assessments rely, in part, on participants’ reports of medical histories, adverse events (AEs), and concomitant medications. Optimal methods for questioning participants are unclear, but different methods giving different results can undermine meta-analyses. This study compared methods for eliciting such data and explored reasons for dissimilar participant responses.MethodsParticipants from open-label antimalarial and antiretroviral interaction trials in two distinct sites (South Africa, n = 18 [all HIV positive]; Tanzania, n = 80 [86% HIV positive]) were asked about ill health and treatment use by sequential use of (1) general enquiries without reference to particular conditions, body systems or treatments, (2) checklists of potential health issues and treatments, (3) in-depth interviews. Participants’ experiences of illness and treatment and their reporting behaviour were explored qualitatively, as were trial clinicians’ experiences with obtaining participant reports. Outcomes were the number and nature of data by questioning method, themes from qualitative analyses and a theoretical interpretation of participants’ experiences.ResultsThere was an overall cumulative increase in the number of reports from general enquiry through checklists to in-depth interview; in South Africa, an additional 12 medical histories, 21 AEs and 27 medications; in Tanzania an additional 260 medical histories, 1 AE and 11 medications. Checklists and interviews facilitated recognition of health issues and treatments, and consideration of what to report. Information was sometimes not reported because participants forgot, it was considered irrelevant or insignificant, or they feared reporting. Some medicine names were not known and answers to questions were considered inferior to blood tests for detecting ill health. South African inpatient volunteers exhibited a “trial citizenship”, working to achieve researchers’ goals, while Tanzanian outpatients sometimes deferred responsibility for identifying items to report to trial clinicians.ConclusionsQuestioning methods and trial contexts influence the detection of adverse events, medical histories and concomitant medications. There should be further methodological work to investigate these influences and find appropriate questioning methods.

Antimalarial interaction of quinine and quinidine with clarithromycin

Quinine (QN) and quinidine (QND) have been commonly used as effective and affordable antimalarials for over many years. Quinine primarily is used for severe malaria treatment. However, plasmodia resistance to these drugs and poor patient compliance limits their administration to the patients. The declining sensitivity of the parasite to the drugs can thus be dealt with by combining with a suitable partner drug. In the present study QN/QND was assessed in combination with clarithromycin (CLTR), an antibiotic of the macrolide family. In vitro interactions of these drugs with CLTR against Plasmodium falciparum (P. falciparum) have shown a synergistic response with mean sum fractional inhibitory concentrations (ΣFICs) of ≤1 (0.85 ± 0.11 for QN + CLTR and 0.64 ± 0.09 for QND + CLTR) for all the tested combination ratios. Analysis of this combination of QN/QND with CLTR in mouse model against Plasmodium yoelii nigeriensis multi-drug resistant (P. yoelii nigeriensis MDR) showed that a dose of 200 mg/kg/day for 4 days of QN or QND produces 100% curative effect with 200 mg/kg/day for 7 days and 150 mg/kg/day for 7 days CLTR respectively, while the same dose of individual drugs could produce only up to a maximum 20% cure. It is postulated that CLTR, a CYP3A4 inhibitor, might have caused reduced CYP3A4 activity leading to increased plasma level of the QN/QND to produce enhanced antimalarial activity. Further, parasite apicoplast disruption by CLTR synergies the antimalarial action of QN and QND.

Exploring QSAR, Pharmacophore Mapping and Docking Studies and Virtual Library Generation for Cycloguanil Derivatives as PfDHFR-TS Inhibitors

Resistance of available antimalarial drugs against Plasmodium species is one of the major problems of malaria control in the developing world. In the present study, we have performed QSAR, pharmacophore mapping and molecular docking studies of cycloguanil derivatives as Plasmodium falciparum dihydrofolate reductase thymidylate synthase (PfDHFR-TS) inhibitors to explore essential features required for the antimalarial activity and important interaction patterns between the enzyme and ligands for the design of new potent PfDHFR-TS inhibitors. The QSAR studies have been carried out using topological parameters along with thermodynamic and structural descriptors. Acceptable values of internal and external validation parameters for the developed QSAR models confirm acceptability of the models. Pharmacophore mapping revealed that two hydrogen bond donor (HBD) features and a hydrophobic feature (HYD) are important parameters for PfDHFR-TS inhibitory activity. The docking studies suggest that the PfDHFR-TS inhibitors interact with Asp54, Ile14, Ile164, ser108, Ser111, Tyr170, Met55, Ala16, Thr185, Leu46, Cys15, Phe58, Ile112, Trp48, Tyr57 and Leu119 amino acid residues. The QSAR, pharmacophore and docking studies inferred that i) branching of the substituents at R1 and R2 positions should be less (small alkyl chain substituents are favored); ii) the electronegativity of the molecules should be high but within some limit; iii) the size and volume of the molecules should be high; iv) molecules should be flexible enough; v) R configuration at C6 position of the triazine ring favors the inhibitory binding affinity; vi) the substituents of the phenyl ring at 3, 4 and 5 position of the phenyl ring should be small hydrophobic groups. Based on these studies, we have designed a library of cycloguanil derivatives with good in silico predicted PfDHFR-TS inhibitory activity.

In vitro antimalarial interactions between mefloquine and cytochrome P450 inhibitors

The treatment and control of malaria is becoming increasingly difficult due to resistance of Plasmodium falciparum strains resistance to commonly used antimalarials. Combination therapy is currently the strategy for combating multi-drug resistant falciparum malaria, through exploiting phamacodynamic synergistic effect and delaying the emergence of drug resistance. The objective of the present study was to investigate antimalarial activity of inhibitors of cytochrome P450 (CYP) enzyme including their interactions with the antimalarial mefloquine against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) P. falciparum clones in vitro. Results showed IC 50 (drug concentration which produces 50% schizont maturation inhibition) values [mean (range)] of mefloquine against K1 and 3D7 clones to be 8.6 (8.0–9.3) and 12.1 (10.5–13.8) nM, respectively. The corresponding values for the IC 50 of quinidine were 32.2 (31.9–32.5) and 28.7 (28.4–29.0) nM, and for ketoconazole were 3.9 (3.7–4.1) and 4.8 (4.6–5.1) μM, respectively. Analysis of isobologram revealed a trend of decreasing of fraction IC 50 (FIC), which indicates synergistics of the either quinidine or ketoconazole with mefloquine for both chloroquine-resistant and chloroquine-sensitive clones.

Antimalarial pharmacodynamics of chalcone derivatives in combination with artemisinin against Plasmodium falciparum in vitro

Use of artemisinin based combination therapies (ACTs) is increasing in treatment of malaria. Their extensive and indiscriminate deployment will ultimately lead to selection of resistance. Thus, alternate ACTs are needed. We reported in vitro antimalarial potential of chalcone derivatives. A few potent chalcones were selected for their antimalarial interaction in combination with artemisinin in vitro. Combinations evaluated show synergistic or additive interactions. Chalcones act on broad range of asexual stages of the parasite. The synergistic combinations decrease hemozoin formation in parasitized erythrocytes. These combinations do not affect new permeation pathways induced in the host cells. This is the first report showing antiplasmodial interactions between artemisinin and synthetic chalcone azole derivatives. Thus, chalcones and artemisinin combinations open the possibility of novel ACTs.

In Vitro Activity of Artemisinin in Combination with Clotrimazole or Heat-treated Amphotericin B against Plasmodium falciparum

Currently available artemisinin-based combination therapies (ACTs) for malaria are inadequate. There remains an enormous unmet need for alternate artemisinin-based combination therapies. One of the fastest methods to identify promising artemisinin-based combination therapies is to look for synergistic or additive antimalarial interaction between artemisinin and an alternate drug against P. falciparum in vitro. Amphotericin B and clotrimazole are known drugs for treatment of human fungal infections. We repurposed clotrimazole or heat-treated amphotericin B in fixed ratio combination with artemisinin for antimalarial properties. Isobologram results show synergistic/additive interaction in both of the cases at therapeutically safe concentrations. Artemisinin, clotrimazole, and their synergistic combinations also decrease hemozoin production in parasitized erythrocytes. New permeation pathways induced in infected cells remain unaffected by drug combinations as indicated by sorbitol lysis. It would be interesting to extend the studies' in vivo system.

Influence of the Plasmodium falciparum P-glycoprotein homologue 1 (pfmdr1 gene product) on the antimalarial action of cyclosporin

The immunosuppressant cyclosporin A and a number of other cyclosporins have potent and selective antimalarial activity. Their exact mechanism of antimalarial action is unknown but the structure-activity relationships for malarial parasite inhibition and immunosuppression differ markedly. The 3'-keto derivative of cyclosporin D (valspodar) is particularly potent against the human malarial parasite Plasmodium falciparum in culture but causes negligible immunosuppression. Multidrug resistance in mammalian cancer cells, the result of overproduction of the P-glycoprotein, can be reversed by certain cyclosporins, particularly valspodar. We therefore investigated the possibility that the antimalarial target of cyclosporin might be a P-glycoprotein homologue. P. falciparum P-glycoprotein homologue 1 (Pgh1; the pfmdr1 gene product) is located in the digestive vacuole (DV) membrane of the parasite. Its function is unknown but it modulates the susceptibility of parasites to quinolines and related antimalarial drugs, including quinine, mefloquine, halofantrine and chloroquine, and to artemisinin. Here we demonstrate that (i) sequence polymorphisms in pfmdr1 altered the susceptibility of parasites to cyclosporin A and (ii) pfmdr1-overexpressing strains were slightly less susceptible to the drug. Furthermore, we found synergistic antimalarial interactions between cyclosporin A and quinine, mefloquine or halofantrine and antagonism between cyclosporin A and chloroquine. However, we were unable to detect a direct interaction between cyclosporin and Pgh1. The amino acid sequence and copy number of Pgh1 may influence cyclosporin susceptibility as a result of a direct interaction between the drug and the protein, or via indirect effects on the physiology of the DV.

Phytochemical and pharmacological study of roots and leaves of Guiera senegalensis J.F. Gmel (Combretaceae)

The chemical composition of total alkaloids from leaves and roots of Guiera senegalensis was investigated. Three beta-carboline alkaloids were purified: in addition to harman and tetrahydroharman, known in roots and leaves, harmalan (dihydroharman) was isolated for the first time from roots of Guiera senegalensis. Guieranone A, a naphthyl butenone, was also purified from leaves and roots. The in vitro antiplasmodial activity and the cytotoxicity of extracts and pure compounds were evaluated. Each total alkaloid extract and beta-carboline alkaloids presented an interesting antiplasmodial activity associated with a low cytotoxicity. Harmalan was less active than harman and tetrahydroharman. Guieranone A showed a strong antiplasmodial activity associated with a high cytotoxicity toward human monocytes. Its cytotoxicity was performed against two cancer cell lines and normal skin fibroblasts in order to study its anticancer potential: guieranone A presented a strong cytotoxicity against each cell strains. Finally, we evaluated the potent synergistic antimalarial interaction between Guiera senegalensis and two plants commonly associated in traditional remedies: Mitragyna inermis and Pavetta crassipes. Three associations evaluated were additive. A synergistic effect was shown between total alkaloids extracted from leaves of Guiera senegalensis and those of Mitragyna inermis. This result justified the traditional use of the plants in combination to treat malaria.