scholarly journals In Vitro Antimalarial Activity of Azithromycin, Artesunate, and Quinine in Combination and Correlation with Clinical Outcome

2006 ◽  
Vol 51 (2) ◽  
pp. 651-656 ◽  
Author(s):  
Harald Noedl ◽  
Srivicha Krudsood ◽  
Wattana Leowattana ◽  
Noppadon Tangpukdee ◽  
Wipa Thanachartwet ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Geometric Mean ◽  
Parasite Clearance ◽  
Drug Susceptibility ◽  
Cross Sensitivity ◽  
Artemisinin Derivatives ◽  
Synergistic Interactions ◽  
Western Border ◽  
High Level

ABSTRACT Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI] = 0.77 to 1.08) and 0.78 (95% CI = 0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI = 2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R = 0.53; P = 0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R = 0.34; P = 0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.

scholarly journals Plasmodium falciparum-Based Bioassay for Measurement of Artemisinin Derivatives in Plasma or Serum

2004 ◽  
Vol 48 (3) ◽  
pp. 954-960 ◽  
Author(s):  
Paktiya Teja-Isavadharm ◽  
James O. Peggins ◽  
Thomas G. Brewer ◽  
Nicholas J. White ◽  
H. Kyle Webster ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
High Performance ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Response Curves ◽  
Artemisinin Derivatives ◽  
Treatment Regimens ◽  
Limit Of Quantitation

ABSTRACT Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for a Plasmodium falciparum clone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, ≤10.9%), with a lower limit of quantitation equivalent to 2.5 ng of DHA per ml. For plasma spiked with artesunate or artemether, there was good agreement of the results obtained by the bioassay and the concentrations measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The bioassay for measurement of the antimalarial activities of artemisinin derivatives in body fluids requires a smaller volume of plasma or serum and is more sensitive than the presently available HPLC methods, can provide pharmacodynamic parameters for determination of activity against the parasite, and should enhance the design of more appropriate dosage regimens for artemisinin drugs.

scholarly journals Artemisinin Therapy for Malaria in Hemoglobinopathies: A Systematic Review

2018 ◽  
Vol 66 (5) ◽  
pp. 799-804 ◽  
Author(s):  
Sri Riyati Sugiarto ◽  
Brioni R Moore ◽  
Julie Makani ◽  
Timothy M E Davis
Keyword(s):  
Clinical Studies ◽  
Antimalarial Activity ◽  
Artemisinin Combination Therapy ◽  
Plasma Concentrations ◽  
Parasite Clearance ◽  
Convincing Evidence ◽  
Hemoglobin E ◽  
Artemisinin Derivatives

Abstract Artemisinin derivatives are widely used antimalarial drugs. There is some evidence from in vitro, animal and clinical studies that hemoglobinopathies may alter their disposition and antimalarial activity. This review assesses relevant data in α-thalassemia, sickle cell disease (SCD), β-thalassemia and hemoglobin E. There is no convincing evidence that the disposition of artemisinin drugs is affected by hemoglobinopathies. Although in vitro studies indicate that Plasmodium falciparum cultured in thalassemic erythrocytes is relatively resistant to the artemisinin derivatives, mean 50% inhibitory concentrations (IC50s) are much lower than in vivo plasma concentrations after recommended treatment doses. Since IC50s are not increased in P. falciparum cultures using SCD erythrocytes, delayed post-treatment parasite clearance in SCD may reflect hyposplenism. As there have been no clinical studies suggesting that hemoglobinopathies significantly attenuate the efficacy of artemisinin combination therapy (ACT) in uncomplicated malaria, recommended artemisinin doses as part of ACT remain appropriate in this patient group.

scholarly journals In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

2011 ◽  
Vol 56 (2) ◽  
pp. 703-707 ◽  
Author(s):  
Sergio Wittlin ◽  
Eric Ekland ◽  
J Carl Craft ◽  
Julie Lotharius ◽  
Ian Bathurst ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Parasite Clearance ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Asexual Blood Stage ◽  
Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

scholarly journals In VivoandIn VitroEfficacy of Chloroquine againstPlasmodium malariaeandP. ovalein Papua, Indonesia

2010 ◽  
Vol 55 (1) ◽  
pp. 197-202 ◽  
Author(s):  
H. Siswantoro ◽  
B. Russell ◽  
A. Ratcliff ◽  
B. Prasetyorini ◽  
F. Chalfein ◽  
...  
Keyword(s):  
Parasite Clearance ◽  
Plasmodium Malariae ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Chloroquine Resistance ◽  
Ring Stage ◽  
Trophozoite Stage ◽  
Nm Range

ABSTRACTReports of potential drug-resistant strains ofPlasmodium malariaein western Indonesia raise concerns that chloroquine resistance may be emerging inP. malariaeandP. ovale. In order to assess this,in vivoandin vitroefficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due toP. ovaleorP. malariaewere enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients withP. malariaeorP. ovaleparasitemia greater than 1,000 per microliter underwentin vitroantimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae,n= 46;P. ovale,n= 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) forP. malariaeand 150 (95% CI, 54 to 245) forP. ovale(P= 0.18). One patient infected withP. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4.In vitrodrug susceptibility assays were carried out successfully for 40 isolates (34 infected withP. malariaeand 6 withP. ovale). TheP. malariaeinfections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC50s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0];P= 0.01). The EC50for chloroquine inP. ovalewas also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy againstP. ovaleandP. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.

In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives

RSC Advances ◽  
2015 ◽  
Vol 5 (59) ◽  
pp. 47959-47974 ◽  
Author(s):  
Rashmi Gaur ◽  
Harveer Singh Cheema ◽  
Yogesh Kumar ◽  
Suriya Pratap Singh ◽  
Dharmendra K. Yadav ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Modeling ◽  
Cerebral Malaria ◽  
Antimalarial Activity ◽  
Anopheles Mosquito ◽  
Fatal Disease ◽  
Artemisinin Derivatives ◽  
Modeling Studies ◽  
Molecular Modeling Studies

Cerebral malaria is a serious and sometimes fatal disease caused by aPlasmodium falciparumparasite that infects a female anopheles mosquito which feeds on humans.

scholarly journals Susceptibility of Clostridium difficile Isolates of Varying Antimicrobial Resistance Phenotypes to SMT19969 and 11 Comparators

2015 ◽  
Vol 60 (1) ◽  
pp. 689-692 ◽  
Author(s):  
Jane Freeman ◽  
Jonathan Vernon ◽  
Richard Vickers ◽  
Mark H. Wilcox
Keyword(s):  
Clostridium Difficile ◽  
Antimicrobial Resistance ◽  
Geometric Mean ◽  
Multiple Resistance ◽  
Content Type ◽  
High Level

ABSTRACTWe determined thein vitroactivity of SMT19969 and 11 comparators, including metronidazole, vancomycin, and fidaxomicin, against 107C. difficileisolates of different antimicrobial resistance phenotypes. Fidaxomicin and SMT19969 were the most active. The fidaxomicin and SMT19969 geometric mean MICs were highest in ribotypes known to show multiple resistance. Coresistance to linezolid and moxifloxacin was evident in ribotypes 001, 017, 027, and 356. The high-level ceftriaxone resistance in ribotypes 356 and 018 was location linked.

scholarly journals Relationship between Antimalarial Activity and Heme Alkylation for Spiro- and Dispiro-1,2,4-Trioxolane Antimalarials

2008 ◽  
Vol 52 (4) ◽  
pp. 1291-1296 ◽  
Author(s):  
Darren J. Creek ◽  
William N. Charman ◽  
Francis C. K. Chiu ◽  
Richard J. Prankerd ◽  
Yuxiang Dong ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Antimalarial Activity ◽  
Biologically Active ◽  
Radical Intermediate ◽  
Reaction Conditions ◽  
Artemisinin Derivatives ◽  
Major Reaction Product ◽  
Major Reaction ◽  
Insight Into

ABSTRACT The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R 2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.

scholarly journals ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

2012 ◽  
Vol 56 (10) ◽  
pp. 5258-5263 ◽  
Author(s):  
Jutta Marfurt ◽  
Ferryanto Chalfein ◽  
Pak Prayoga ◽  
Frans Wabiser ◽  
Grennady Wirjanata ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Ex Vivo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Intrinsic Activity ◽  
Drug Resistant ◽  
The Novel ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study

Parasitology ◽  
2016 ◽  
Vol 143 (11) ◽  
pp. 1421-1432 ◽  
Author(s):  
SWAROOP KUMAR PANDEY ◽  
SUBHASISH BISWAS ◽  
SARIKA GUNJAN ◽  
BHAVANA SINGH CHAUHAN ◽  
SUNIL KUMAR SINGH ◽  
...  
Keyword(s):  
Malaria Parasite ◽  
Lethal Dose ◽  
Parasite Clearance ◽  
Multidrug Resistant ◽  
Mice Model ◽  
Artemisinin Derivatives ◽  
Swiss Mice ◽  
Function Test

SUMMARYAiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.

scholarly journals Antimalarial Activity of Tigecycline, a Novel Glycylcycline Antibiotic

2009 ◽  
Vol 53 (9) ◽  
pp. 4040-4042 ◽  
Author(s):  
P. Starzengruber ◽  
K. Thriemer ◽  
R. Haque ◽  
W. A. Khan ◽  
H. P. Fuehrer ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Confidence Interval ◽  
Antimalarial Activity ◽  
Drug Susceptibility ◽  
Clinical Isolates ◽  
In Vitro Drug Susceptibility ◽  
Antibacterial Spectrum ◽  
Susceptibility Assay ◽  
Broad Antibacterial Spectrum

ABSTRACT Tigecycline is a novel glycylcycline antibiotic with a broad antibacterial spectrum. Tigecycline was tested with 66 clinical isolates of Plasmodium falciparum from Bangladesh using the histidine-rich protein 2 in vitro drug susceptibility assay. The 50% and 90% inhibitory concentrations of tigecycline were 699 (95% confidence interval, 496 to 986) and 5,905 nM (4,344 to 8,028). Tigecycline shows no activity correlation with traditional antimalarials and has substantial antimalarial activity on its own.

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