scholarly journals Parasite-host dynamics throughout antimalarial drug development stages complicate the translation of parasite clearance

2021 ◽  
Author(s):  
Lydia Burgert ◽  
Sophie Zaloumis ◽  
Saber Dini ◽  
Louise Marquart ◽  
Pengxing Cao ◽  
...  
Keyword(s):  
Drug Development ◽  
Clearance Rate ◽  
Antimalarial Drug ◽  
Drug Efficacy ◽  
Parasite Clearance ◽  
Drug Clearance ◽  
Nmri Mouse ◽  
Clearance Rates ◽  
Sequential Approach ◽  
Stage Of Development

Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes pre-clinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage, informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose, and different maximum parasite clearance rates: in P. berghei-NMRI mouse infections we estimated a maximum parasite clearance rate of 0.2 [1/h]; in P. falciparum-SCID mouse infections 0.05 [1/h]; while in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 [1/h] and 0.18 [1/h] after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterising key parameters of drug action and dose response, and assist in decision-making regarding dosage for further drug development.

Clearance rate in relation to agglutinins for gelatin-stabilized colloid in the rat

1963 ◽  
Vol 204 (4) ◽  
pp. 655-659 ◽  
Author(s):  
I. MacKay Murray
Keyword(s):  
Iron Oxide ◽  
Clearance Rate ◽  
Reticuloendothelial System ◽  
Transient Increase ◽  
Clearance Rates ◽  
Time Intervals ◽  
Thorium Dioxide ◽  
Plasma Response ◽  
Circulating Levels

Intravascular clearance rates of gelatin-stabilized gold were compared with circulating titers of gelatin agglutinins in rats at increasing time intervals after blockading injections of gelatin-stabilized gold and S. marcescens endotoxin. The degree and duration of reticuloendothelial system (RES) blockade against the homologous colloid were directly related to the circulating levels of gelatin agglutinins. In contrast, plasma agglutinins were not decreased in endotoxin-induced blockade against the gelatin-stabilized colloid. In a further experiment, the plasma response to blockading injections of colloidal thorium dioxide, iron oxide, and zymosan was characterized by a transient increase in gelatin agglutinins suggesting the nonspecific release of opsonins from an extravascular source. The findings indicated that clearance rates of gelatin-stabilized colloids were dependent on the total available opsonin in the rat rather than the total circulating opsonin. It is suggested that RES blockade is effected by the prior nonspecific depletion of opsonins from an extravascular reserve which is the major component of the total available opsonin.

scholarly journals Improving the Role and Contribution of Pharmacokinetic Analyses in Antimalarial Drug Clinical Trials

2014 ◽  
Vol 58 (10) ◽  
pp. 5643-5649 ◽  
Author(s):  
Katherine Kay ◽  
Eva Maria Hodel ◽  
Ian M. Hastings
Keyword(s):  
Antimalarial Drug ◽  
Theoretical Data ◽  
Drug Efficacy ◽  
Cost Effective ◽  
Field Studies ◽  
World Health ◽  
Efficacy Trials ◽  
Drug Concentrations ◽  
Health Organization ◽  
Study Designs

ABSTRACTIt is now World Health Organization (WHO) policy that drug concentrations on day 7 be measured as part of routine assessment in antimalarial drug efficacy trials. The rationale is that this single pharmacological measure serves as a simple and practical predictor of treatment outcome for antimalarial drugs with long half-lives. Herein we review theoretical data and field studies and conclude that the day 7 drug concentration (d7c) actually appears to be a poor predictor of therapeutic outcome. This poor predictive capability combined with the fact that many routine antimalarial trials will have few or no failures means that there appears to be little justification for this WHO recommendation. Pharmacological studies have a huge potential to improve antimalarial dosing, and we propose study designs that use more-focused, sophisticated, and cost-effective ways of generating these data than the mass collection of single d7c concentrations.

scholarly journals Daily rhythms of both host and parasite affect antimalarial drug efficacy

2021 ◽  
Author(s):  
Alíz T Y Owolabi ◽  
Sarah E Reece ◽  
Petra Schneider
Keyword(s):  
Drug Treatment ◽  
Developmental Stage ◽  
Antimalarial Drug ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Time Of Day ◽  
Parasite Development ◽  
Daily Rhythms ◽  
Parasite Plasmodium

Abstract Background and objectives Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test if the daily rhythms of hosts, parasites, and their interactions, affect sensitivity to the key antimalarial, artemisinin. Methodology Asexual malaria parasites develop rhythmically in the host’s blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity. Results We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned. Conclusions and implications Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach. Lay Summary We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites’ developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

scholarly journals Plasmodium falciparum: new molecular targets with potential for antimalarial drug development

2009 ◽  
Vol 7 (9) ◽  
pp. 1087-1098 ◽  
Author(s):  
Donald L Gardiner ◽  
Tina S Skinner-Adams ◽  
Christopher L Brown ◽  
Katherine T Andrews ◽  
Colin M Stack ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Molecular Targets ◽  
New Molecular Targets

scholarly journals Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1647
Author(s):  
Keishi Kisoh ◽  
Go Sugahara ◽  
Yuko Ogawa ◽  
Suzue Furukawa ◽  
Yuji Ishida ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Efficacy ◽  
Developed Countries ◽  
Liver Disorder ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Chimeric Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Nash Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

scholarly journals Bivalve Feeding on the Brown Tide Aureoumbra lagunensis in a Shallow Coastal Environment

2021 ◽  
Vol 8 ◽  
Author(s):  
Eve Galimany ◽  
Jessica Lunt ◽  
Christopher J. Freeman ◽  
I. Segura-García ◽  
M. Mossop ◽  
...  
Keyword(s):  
Clearance Rate ◽  
Indian River Lagoon ◽  
Brown Tide ◽  
Bivalve Species ◽  
Clearance Rates ◽  
Interspecific Differences ◽  
Brown Tides ◽  
Indian River ◽  
Aureoumbra Lagunensis ◽  
Fish And Shellfish

Brown tides formed by Aureoumbra lagunensis decrease light penetration in the water column and are often followed by hypoxic events that result in the loss of fish and shellfish. To understand the ability of bivalve filter feeders to control and prevent A. lagunensis blooms, we exposed eastern oysters (Crassostrea virginica), hooked mussels (Ischadium recurvum), and hard clams (Mercenaria mercenaria) to a naturally co-occurring brown tide in the Indian River Lagoon (IRL), Florida, United States. Bivalves were exposed in the laboratory to multiple concentrations (104 to 106 cells mL–1) of isotopically labeled (13C and 15N) A. lagunensis cells. The standard clearance rate (herein clearance rate) of each bivalve species was calculated using flow cytometry to quantify A. lagunensis cell removal. The highest clearance rates were at 104 cells mL–1, but values varied across bivalve species (2.16 ± 0.30, 3.03 ± 0.58, and 0.41 ± 0.12 L h–1 for C. virginica, I. recurvum, and M. mercenaria, respectively). Although clearance rates decreased with increasing bloom concentrations, bivalves were still consuming algal cells at all concentrations and were retaining and assimilating more cells at the highest concentrations, as revealed by δ13C and δ15N values. We highlight interspecific differences among bivalve species in the removal of A. lagunensis, supporting the importance of healthy and diverse filter feeding communities in estuaries, especially as threats of brown tides and other HABs are increasing in the Anthropocene.

scholarly journals Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance

2019 ◽  
Author(s):  
Peter Spanogiannopoulos ◽  
Patrick H. Bradley ◽  
Jonathan Melamed ◽  
Ysabella Noelle Amora Malig ◽  
Kathy N. Lam ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Drug Disposition ◽  
Transcriptional Profiling ◽  
Drug Efficacy ◽  
Drug Clearance ◽  
Gut Bacteria ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Bacterial Strains

Microbiome surveys indicate that pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure1, consistent with in vitro evidence that non-antibiotic (i.e. host-targeted) drugs inhibit gut bacterial growth2and are subject to extensive metabolism by the gut microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6and toxicity7,8; however, the degree to which bacterial sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs broadly inhibit the growth of diverse gut bacterial strains. Media supplementation, transcriptional profiling (RNA-seq), and bacterial genetics implicated pyrimidine metabolism as a key target in bacteria, as in mammalian cells. Drug resistant bacteria metabolized 5FU to its inactive metabolite dihydrofluorouracil (DHFU) mimicking the major host pathway for drug clearance. Functional orthologs of the bacterial operon responsible (preTA) are widespread across human gut bacteria from the Firmicutes and Proteobacteria phyla. The observed conservation of both the targets and pathways for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug disposition9, efficacy, and side effect profiles.

Using What We Already Have: Uncovering New Drug Repurposing Strategies in Existing Omics Data

2020 ◽  
Vol 60 (1) ◽  
pp. 333-352 ◽  
Author(s):  
Jill M. Pulley ◽  
Jillian P. Rhoads ◽  
Rebecca N. Jerome ◽  
Anup P. Challa ◽  
Kevin B. Erreger ◽  
...  
Keyword(s):  
Decision Making ◽  
Drug Development ◽  
Drug Safety ◽  
Human Disease ◽  
Drug Repurposing ◽  
Drug Efficacy ◽  
Omics Data ◽  
New Drug ◽  
Cost Efficient

The promise of drug repurposing is to accelerate the translation of knowledge to treatment of human disease, bypassing common challenges associated with drug development to be more time- and cost-efficient. Repurposing has an increased chance of success due to the previous validation of drug safety and allows for the incorporation of omics. Hypothesis-generating omics processes inform drug repurposing decision-making methods on drug efficacy and toxicity. This review summarizes drug repurposing strategies and methodologies in the context of the following omics fields: genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiomics, phenomics, pregomics, and personomics. While each omics field has specific strengths and limitations, incorporating omics into the drug repurposing landscape is integral to its success.

Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine--new data and review.

1988 ◽  
Vol 34 (5) ◽  
pp. 863-880 ◽  
Author(s):  
L Ereshefsky ◽  
T Tran-Johnson ◽  
C M Davis ◽  
A LeRoy
Keyword(s):  
Dietary Habits ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Drug Clearance ◽  
Metabolic Phenotype ◽  
Therapeutic Monitoring ◽  
Fixed Dose ◽  
Oral Clearance ◽  
Clearance Rates ◽  
Factors Affecting

Abstract The selection of a starting dose for an antidepressant, and subsequent clinical titration to an appropriate therapeutic dosage, should be based on pharmacokinetic and pharmacodynamic principles. In the past decade, therapeutic monitoring of antidepressant drugs and use of pharmacokinetic principles have been shown to be an improvement over the dose-response approach. Endogenous (e.g., genetic metabolic phenotype, hepatic blood flow, and protein binding) and exogenous factors (e.g., smoking, dietary habits, concurrent medications) are capable of influencing physiological and pharmacokinetic variables in patients, accounting for the marked interindividual differences in the clearance rates of cyclic antidepressants. Interpatient variability for steady-state concentrations in plasma (Cpss) greater than 20-fold are observed at a fixed dose of imipramine (r2 = 0.525, df = 346, t = 19.541, P less than 0.0001) or doxepin (r2 = 0.506, df = 128, t = 11.403, P less than 0.0001). Analysis of doxepin in plasma vs estimated in oral clearance for 61 patients demonstrates a significant decline in oral clearance as a function of Cpss. At doses approaching the upper range recommended for the treatment of depression, Cpss appear to approach, in at least a few individuals, the maximum metabolic capacity of the patient (Vmax), leading to greater-than-expected increases in concentrations for a given dosage increment. Significant alterations in oral clearance are observed when medications are administered concomitantly. A greater-than-threefold difference in mean oral doxepin clearance rates is observed between two groups of patients receiving additional medications that are either inducers or inhibitors (P less than 0.0001, df = 32, t = 6.687). Pharmacokinetic principles defining and explaining the determinants of oral clearance can provide the clinician with a greater insight into the reasons for therapeutic failure and toxicity.

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