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 ROS as a novel indicator to predict anticancer drug efficacy

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Tarek Zaidieh ◽  
James R. Smith ◽  
Karen E. Ball ◽  
Qian An
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Ros Generation ◽  
Targeting Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

RNAi-mediated functional analysis of pathways influencing cancer cell drug resistance

2009 ◽  
Vol 11 ◽  
Author(s):  
Alvin J.X. Lee ◽  
Richard Kolesnick ◽  
Charles Swanton
Keyword(s):  
Drug Resistance ◽  
High Throughput Screening ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Successive Treatment ◽  
Acquired Drug Resistance ◽  
Treatment Regimens ◽  
Rnai Technology

Acquired drug resistance limits the efficacy of cytotoxics used in the management of haematological and solid tumours and is responsible for the declining clinical benefit following successive treatment regimens in metastatic cancers. Treatment failure has a major impact on quality of life and survival in advanced disease. Defining pathways of intrinsic and acquired drug resistance may provide new targets to prolong drug efficacy and time to disease progression. Predicting the intrinsic drug sensitivity of human tumours in advance of cytotoxic therapy is of paramount importance in order to limit unnecessary toxicity and optimise treatment outcome. RNA interference (RNAi) provides a powerful tool to annotate gene function and systematically define drug-resistance pathways. High-throughput screening RNAi technology has provided evidence for drug-specific resistance pathways as well as novel pathways implicated in multidrug sensitivity. The challenge is how to integrate these data with biological samples to define relevant drug-resistant pathways in vivo.

scholarly journals ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

2019 ◽  
Author(s):  
Tarek Zaidieh ◽  
James Smith ◽  
Karen Ball ◽  
Qian An
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Ros Generation ◽  
Targeting Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

PRACTICAL ASPECTS OF IN VIVO ANTIMALARIAL DRUG EFFICACY TESTING IN THE AMERICAS

2003 ◽  
Vol 68 (4) ◽  
pp. 391-397 ◽  
Author(s):  
TRENTON K. RUEBUSH ◽  
RODOLFO VILLAROEL ◽  
CÉSAR DÍAZ ◽  
JORGE ZEGARRA ◽  
JUAN CARLOS AVILA ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Drug Efficacy

scholarly journals Circadian clock neurons mediate time-of-day dependent responses to light

2018 ◽  
Author(s):  
Jeff R. Jones ◽  
Tatiana Simon ◽  
Lorenzo Lones ◽  
Erik D. Herzog
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Light Cycle ◽  
Hormone Release ◽  
Daily Rhythms ◽  
Light Responses ◽  
And Behavior

ABSTRACTCircadian (~24 h) rhythms influence nearly all aspects of physiology, including sleep/wake, metabolism, and hormone release. The suprachiasmatic nucleus (SCN) synchronizes these daily rhythms to the external light cycle, but the mechanisms by which this occurs is unclear. The neuropeptide vasoactive intestinal peptide (VIP) is the predominant contributor to synchrony within the SCN and is important for circadian light responses, but the role of VIP neurons themselves is unclear. Thus, we tested the hypothesis that rhythmic SCN VIP neurons mediate circadian light responses. Using in vivo fiber photometry recording of SCN VIP neurons we found daily rhythms in spontaneous calcium events that peaked during the subjective day and in light-evoked calcium events that exhibited the greatest response around subjective dusk. These rhythms were correlated with spontaneous and NMDA-evoked VIP release from SCN VIP neurons in vitro. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons are circadian and depolarize to light to modulate entrainment of daily rhythms in the SCN and behavior.

scholarly journals ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

2019 ◽  
Author(s):  
Tarek Zaidieh ◽  
James Smith ◽  
Karen Ball ◽  
Qian An
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Copy Number ◽  
Drug Sensitivity ◽  
Drug Efficacy ◽  
Ros Generation ◽  
Targeting Therapy ◽  
Mitochondrial Dna Copy Number ◽  
Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (MtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

scholarly journals Methodological Issues in the Assessment of Antimalarial Drug Treatment: Analysis of 13 Studies in Eight African Countries from 2001 to 2004

2006 ◽  
Vol 50 (11) ◽  
pp. 3734-3739 ◽  
Author(s):  
Jean-Paul Guthmann ◽  
Loretxu Pinoges ◽  
Francesco Checchi ◽  
Simon Cousens ◽  
Suna Balkan ◽  
...  
Keyword(s):  
Evaluable Patient ◽  
Test Performance ◽  
Antimalarial Drug ◽  
Drug Efficacy ◽  
Sub Saharan Africa ◽  
African Countries ◽  
Kaplan Meier ◽  
Sub Saharan ◽  
Pcr Genotyping

ABSTRACT The objectives of these analyses were to assess the feasibility of the latest WHO recommendations (28-day follow-up with PCR genotyping) for the assessment of antimalarial drug efficacy in vivo and to examine how different statistical approaches affect results. We used individual-patient data from 13 studies of uncomplicated pediatric falciparum malaria conducted in sub-Saharan Africa, using chloroquine (CQ), sulfadoxine/pyrimethamine (SP), or amodiaquine (AQ). We assessed the use effectiveness and test performance of PCR genotyping in distinguishing recurrent infections. In analyzing data, we compared (i) the risk of failure on target days (days 14 and 28) by using Kaplan-Meier and per-protocol evaluable patient analyses, (ii) PCR-corrected results allowing (method 1) or excluding (method 2) new infections, (iii) and day 14 versus day 28 results. Of the 2,576 patients treated, 2,287 (89%) were evaluable on day 28. Of the 695 recurrences occurring post-day 14, 650 could be processed and 584 were resolved (PCR use effectiveness, 84%; test performance, 90%). The risks of failure on day 28 with Kaplan-Meier and evaluable-patient analyses tended to be generally close (except in smaller studies) because the numbers of dropouts were minimal, but attrition rates on day 28 were higher with the latter method. Method 2 yielded higher risks of failure than method 1. Extending observation to 28 days produced higher estimated risks of failure for SP and AQ but not for CQ (high failure rates by day 14). Results support the implementation of the current WHO protocol and favor analyzing PCR-corrected outcomes by Kaplan-Meier analysis (which allows for dropouts) and retaining new infections (which minimizes losses).

scholarly journals Efficacy of sulfadoxine-pyrimethamine and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon basin of Peru

2004 ◽  
Vol 37 (3) ◽  
pp. 279-281 ◽  
Author(s):  
Alan J. Magill ◽  
Jorge Zegarra ◽  
Coralith Garcia ◽  
Wilmer Marquiño ◽  
Trenton K. Ruebush II
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Antimalarial Drug ◽  
Amazon Basin ◽  
Drug Efficacy ◽  
Plasmodium Falciparum Malaria ◽  
Uncomplicated Plasmodium Falciparum Malaria ◽  
Efficacy Studies

In vivo antimalarial drug efficacy studies of uncomplicated Plasmodium falciparum malaria at an isolated site in the Amazon basin of Peru bordering Brazil and Colombia showed >50% RII/RIII resistance to sulfadoxine-pyrimethamine but no evidence of resistance to mefloquine.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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