scholarly journals Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

2011 ◽  
Vol 56 (1) ◽  
pp. 163-173 ◽  
Author(s):  
Jin Guo ◽  
Armand W. Guiguemde ◽  
Annael Bentura-Marciano ◽  
Julie Clark ◽  
Richard K. Haynes ◽  
...  
Keyword(s):  
Safety Margin ◽  
Drug Combinations ◽  
Parasite Development ◽  
Content Type ◽  
Drug Concentrations ◽  
One Step ◽  
High Concentrations ◽  
Malaria Model

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.

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

scholarly journals Transcriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against Tuberculosis

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Shuyi Ma ◽  
Suraj Jaipalli ◽  
Jonah Larkins-Ford ◽  
Jenny Lohmiller ◽  
Bree B. Aldridge ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Computational Model ◽  
Drug Combinations ◽  
Broth Culture ◽  
Multiple Drug ◽  
Content Type ◽  
Drug Synergy ◽  
Drug Regimens

ABSTRACT The rapid spread of multidrug-resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen Mycobacterium tuberculosis (MTB), coupled with the large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico more than 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c upregulation reduces the antagonism of the bedaquiline-streptomycin combination. A retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (P value = 1 × 10−4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens. IMPORTANCE Multidrug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.

scholarly journals Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives

2013 ◽  
Vol 58 (2) ◽  
pp. 820-827 ◽  
Author(s):  
Natalie G. Sanders ◽  
David J. Meyers ◽  
David J. Sullivan
Keyword(s):  
Plasmodium Berghei ◽  
Herg Channel ◽  
Preclinical Studies ◽  
Related Gene ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Channel Inhibition ◽  
Malaria Model

ABSTRACTQuinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM againstPlasmodium falciparumquinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerantP. falciparumstrains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50of 313 nM. In the lethal mouse malaria modelPlasmodium bergheiANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quininein vitroandin vivoforPlasmodiuminhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.

scholarly journals Importance of Confirming Data on theIn VivoEfficacy of Novel Antibacterial Drug Regimens against Various Strains of Mycobacterium tuberculosis

2011 ◽  
Vol 56 (2) ◽  
pp. 731-738 ◽  
Author(s):  
Mary A. De Groote ◽  
Veronica Gruppo ◽  
Lisa K. Woolhiser ◽  
Ian M. Orme ◽  
Janet C. Gilliland ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Studies ◽  
Strain Difference ◽  
Drug Combinations ◽  
Antibacterial Drug ◽  
Preclinical Testing ◽  
Content Type ◽  
Drug Regimens

ABSTRACTIn preclinical testing of antituberculosis drugs, laboratory-adapted strains ofMycobacterium tuberculosisare usually used both forin vitroandin vivostudies. However, it is unknown whether the heterogeneity ofM. tuberculosisstocks used by various laboratories can result in different outcomes in tests of antituberculosis drug regimens in animal infection models. In head-to-head studies, we investigated whether bactericidal efficacy results in BALB/c mice infected by inhalation with the laboratory-adapted strains H37Rv and Erdman differ from each other and from those obtained with clinical tuberculosis strains. Treatment of mice consisted of dual and triple drug combinations of isoniazid (H), rifampin (R), and pyrazinamide (Z). The results showed that not all strains gave the samein vivoefficacy results for the drug combinations tested. Moreover, the ranking of HRZ and RZ efficacy results was not the same for the two H37Rv strains evaluated. The magnitude of this strain difference also varied between experiments, emphasizing the risk of drawing firm conclusions for human trials based on single animal studies. The results also confirmed that the antagonism seen within the standard HRZ regimen by some investigators appears to be anM. tuberculosisstrain-specific phenomenon. In conclusion, the specific identity ofM. tuberculosisstrain used was found to be an important variable that can change the apparent outcome ofin vivoefficacy studies in mice. We highly recommend confirmation of efficacy results in late preclinical testing against a differentM. tuberculosisstrain than the one used in the initial mouse efficacy study, thereby increasing confidence to advance potent drug regimens to clinical trials.

scholarly journals Inhibition of Plasmodium Liver Infection by Ivermectin

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
António M. Mendes ◽  
Inês S. Albuquerque ◽  
Marta Machado ◽  
Joana Pissarra ◽  
Patrícia Meireles ◽  
...  
Keyword(s):  
Control Strategies ◽  
Parasite Development ◽  
Mammalian Host ◽  
Mosquito Vector ◽  
Content Type ◽  
Vector Borne Diseases ◽  
Host Infection ◽  
Liver Infection

ABSTRACT Avermectins are powerful endectocides with an established potential to reduce the incidence of vector-borne diseases. Here, we show that several avermectins inhibit the hepatic stage of Plasmodium infection in vitro. Notably, ivermectin potently inhibits liver infection in vivo by impairing parasite development inside hepatocytes. This impairment has a clear impact on the ensuing blood stage parasitemia, reducing disease severity and enhancing host survival. Ivermectin has been proposed as a tool to control malaria transmission because of its effects on the mosquito vector. Our study extends the effect of ivermectin to the early stages of mammalian host infection and supports the inclusion of this multipurpose drug in malaria control strategies.

scholarly journals Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer

Angiogenesis ◽  
2015 ◽  
Vol 18 (3) ◽  
pp. 233-244 ◽  
Author(s):  
Andrea Weiss ◽  
Xianting Ding ◽  
Judy R. van Beijnum ◽  
Ieong Wong ◽  
Tse J. Wong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Drug Combination ◽  
Search Algorithm ◽  
Drug Combinations ◽  
System Control ◽  
Single Drug ◽  
Drug Concentrations

Abstract Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

scholarly journals Vitamin C Potentiates the Killing of Mycobacterium tuberculosis by the First-Line Tuberculosis Drugs Isoniazid and Rifampin in Mice

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Catherine Vilchèze ◽  
John Kim ◽  
William R. Jacobs
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Vitamin C ◽  
Mouse Serum ◽  
First Line ◽  
Content Type ◽  
Tb Treatment ◽  
High Concentrations

ABSTRACT The treatment of drug-susceptible tuberculosis (TB) is long and cumbersome. Mismanagement of TB treatment can lead to the emergence of drug resistance in patients, so shortening the treatment duration could significantly improve TB chemotherapy and prevent the development of drug resistance. We previously discovered that high concentrations of vitamin C sterilize cultures of drug-susceptible and drug-resistant Mycobacterium tuberculosis . Here, we tested subinhibitory concentration of vitamin C in combination with TB drugs against M. tuberculosis in vitro and in a mouse model of M. tuberculosis infection. In vivo , we showed that the vitamin C level in mouse serum can be increased by intraperitoneal injection of vitamin C to reach vitamin C levels close to the concentrations required for activity in vitro . Although vitamin C had no activity by itself in M. tuberculosis -infected mice, the combination of vitamin C with the first-line TB drugs isoniazid and rifampin reduced the bacterial burden in the lungs of M. tuberculosis -infected mice faster than isoniazid and rifampin combined in two independent experiments. These experiments suggest that the addition of vitamin C to first-line TB drugs could shorten TB treatment. Vitamin C, an inexpensive and nontoxic compound, could easily be added to the TB pharmacopeia to substantially improve chemotherapy outcome, which would have a significant impact on the worldwide TB community.

scholarly journals Synergistic Effect of Antituberculosis Drugs and AzolesIn Vitroagainst Histoplasma capsulatum var. capsulatum

2011 ◽  
Vol 55 (9) ◽  
pp. 4482-4484 ◽  
Author(s):  
Rossana de Aguiar Cordeiro ◽  
Francisca Jakelyne de Farias Marques ◽  
Raimunda Sâmia Nogueira Brilhante ◽  
Kylvia Rocha de Castro e Silva ◽  
Charles Ielpo Mourão ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Histoplasma Capsulatum ◽  
Drug Combinations ◽  
Antituberculosis Drug ◽  
Growth Forms ◽  
Antituberculosis Drugs ◽  
Content Type ◽  
Synergistic Interactions

ABSTRACTThis study evaluatedin vitrointeractions of antituberculosis drugs and triazoles againstHistoplasma capsulatum. Nine drug combinations, each including an antituberculosis drug (isoniazid, pyrazinamide, or ethambutol) plus a triazole (itraconazole, fluconazole, or voriconazole), were tested against both growth forms ofH. capsulatum. Stronger synergistic interactions were seen in isoniazid or pyrazinamide plus triazoles for the mold form and ethambutol plus voriconazole for the yeast-like form. Further studies should evaluate these combinationsin vivo.

scholarly journals Mimicking in-vivo exposures to drug combinations in-vitro: anti-tuberculosis drugs in lung lesions and the hollow fiber model of infection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Frank Kloprogge ◽  
Robert Hammond ◽  
Karin Kipper ◽  
Stephen H. Gillespie ◽  
Oscar Della Pasqua
Keyword(s):  
Steady State ◽  
Hollow Fiber ◽  
Lung Lesion ◽  
Drug Combinations ◽  
Target Tissue ◽  
Fiber Model ◽  
Pharmacokinetic Profiles ◽  
Drug Concentrations

Abstract Here, we evaluate protocol requirements to mimic therapeutically relevant drug concentrations at the site of infection (i.e. lung lesion) in an in-vitro hollow fibre model of infection using pulmonary tuberculosis as a paradigm. Steady-state pharmacokinetic profiles in plasma, lung tissue and lung lesion homogenate were simulated for isoniazid, rifampicin and pyrazinamide and moxifloxacin. An R-shiny User Interface was developed to support conversion of in-vivo pharmacokinetic CMAX, TMAX and T1/2 estimates into pump settings. A monotherapy protocol mimicking isoniazid in lung lesion homogenate (isoniazid CMAX = 1,200 ng/ml, TMAX = 2.2 hr and T1/2 = 4.7 hr), and two combination therapy protocols including drugs with similar (isoniazid and rifampicin (CMAX = 400 ng/ml)) and different half-lives (isoniazid and pyrazinamide (CMAX = 28,900 ng/ml and T1/2 = 8.0 hr)) were implemented in a hollow-fiber system. Drug levels in the perfusate were analysed using ultra-high-performance liquid chromatographic-tandem mass spectrometric detection. Steady state pharmacokinetic profiles measured in the hollow fiber model were similar to the predicted in-vivo steady-state lung lesion homogenate pharmacokinetic profiles. The presented approach offers the possibility to use pharmacological data to study the effect of target tissue exposure for drug combinations. Integration with pharmacokinetics modelling principles through a web interface will provide access to a wider community interested in the evaluation of efficacy of anti-tubercular drugs.

scholarly journals Eradication of Staphylococcus aureus Catheter-Related Biofilm Infections Using ML:8 and Citrox

2016 ◽  
Vol 60 (10) ◽  
pp. 5968-5975 ◽  
Author(s):  
S. Hogan ◽  
M. Zapotoczna ◽  
N. T. Stevens ◽  
H. Humphreys ◽  
J. P. O'Gara ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Content Type ◽  
Catheter Lock ◽  
High Concentrations ◽  
Systemic Antibiotics

ABSTRACTStaphylococci are a leading cause of catheter-related infections (CRIs) due to biofilm formation. CRIs are typically managed by either device removal or systemic antibiotics, often in combination with catheter lock solutions (CLSs). CLSs provide high concentrations of the antimicrobial agent at the site of infection. However, the most effective CLSs against staphylococcal biofilm-associated infections have yet to be determined. The purpose of this study was to evaluate the efficacy and suitability of two newly described antimicrobial agents, ML:8 and Citrox, as CLSs againstStaphylococcus aureusbiofilms. ML:8 (1% [vol/vol]) and Citrox (1% [vol/vol]), containing caprylic acid and flavonoids, respectively, were used to treatS. aureusbiofilms grownin vitrousing newly described static and flow biofilm assays. Both agents reduced biofilm viability >97% after 24 h of treatment. Using a rat model of CRI, ML:8 was shown to inactivate early-stageS. aureusbiofilmsin vivo, while Citrox inactivated established, maturein vivobiofilms. Cytotoxicity and hemolytic activity of ML:8 and Citrox were equivalent to those of other commercially available CLSs. Neither ML:8 nor Citrox induced a cytokine response in human whole blood, and exposure ofS. aureusto either agent for 90 days was not associated with any increase in resistance. Taken together, these data reveal the therapeutic potential of these agents for the treatment ofS. aureuscatheter-related biofilm infections.

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