scholarly journals A Novel Strategy for P. falciparum Malaria based on Syk Kinase Inhibitors to Design Triple Artemisininbased Combination Therapies (TACTs) to Counteract Delayed Parasite Clearance (Drug Resistance) Following Standard ACT Treatment

2021 ◽  
Vol 4 (1) ◽  
Keyword(s):  
Drug Resistance ◽  
Falciparum Malaria ◽  
Kinase Inhibitors ◽  
Parasite Clearance ◽  
Combination Therapies ◽  
Syk Kinase ◽  
Novel Strategy

scholarly journals Artesunate-amodiaquine versus artesunatesulfadoxine- pyrimethamine for uncomplicated falciparum malaria in children

2014 ◽  
Vol 54 (1) ◽  
pp. 46
Author(s):  
Novie H. Rampengan ◽  
Jane Metusala ◽  
Ronald Chandra ◽  
Praevilia Salendu
Keyword(s):  
Hospital Stay ◽  
Falciparum Malaria ◽  
Treatment Efficacy ◽  
Medical Records ◽  
Length Of Hospital Stay ◽  
Parasite Clearance ◽  
Uncomplicated Falciparum Malaria ◽  
Clearance Time ◽  
Combination Therapies ◽  
Fever Clearance Time

Background Malaria is a major cause of morbidity and mortalityin children, especially in developing countries. Art emisinincombination therapy (ACT) has higher rates of parasite clearanceand inhibition of anti-malarial drugs resistance than non-ACT.Hence, we compared the efficacies of artesunate-amodiaquine(AS-AQ) versus artesunate-sulfadoxine pyrimethamine (AS-SP)combination therapies in children with uncomplicated falciparummalaria.Objective To compare the fever clearance time, parasite clearancetime, and length of hospital stay in uncomplicated falciparummalaria patients treated with AS-AQ and AS-SP.Methods We reviewed the medical records of children aged 1- 14years with uncomplicated falciparum malaria admitted to Prof.Dr. R. D. Kandou Hospital between January 2002 - June 2010.Treatment efficacy was evaluated by fever clearance time, parasiteclearan ce time, and length of hospital stay. The differencesof treatment efficacy between the two groups of therapy werean alyzed by independent T test.Results We identified 185 children with uncomplicatedfalciparum malaria, 104 cases were treated with AS-AQ whilethe other 81 received AS-SP. Parasite clearance time was shorterin AS-AQ group than in AS-SP group at 1.38 (SD 0.69) versus1.91 (SD 0.93) days, respectively (95%CI of differences 0.3 0 to0. 76, P<0.05) . The length of hospital stay was shorterin AS-AQgroup than in the AS-SP group, at 5.01 (SD 1.22) versus 6.04(SD 0.98) days, respectively (95%CI of differences 0. 71 to 1.35,P < 0.05). However, there was no statistically significant differencein fever clearance time between the groups.Conclusion AS-AQ combination therapy reduces parasiteclearance time and length of hospital stay compared to AS-SP46 • Paediatrlndones, Vol. 54, No. 1, January 2014combination therapy in children with uncomplicated falciparummalaria.

scholarly journals Therapeutic Efficacies of Artesunate-Sulfadoxine-Pyrimethamine and Chloroquine-Sulfadoxine-Pyrimethamine in Vivax Malaria Pilot Studies: Relationship to Plasmodium vivax dhfr Mutations

2002 ◽  
Vol 46 (12) ◽  
pp. 3947-3953 ◽  
Author(s):  
Emiliana Tjitra ◽  
Joanne Baker ◽  
Sri Suprianto ◽  
Qin Cheng ◽  
Nicholas M. Anstey
Keyword(s):  
Plasmodium Vivax ◽  
Falciparum Malaria ◽  
Vivax Malaria ◽  
Parasite Clearance ◽  
Multidrug Resistant ◽  
World Health ◽  
New Combination ◽  
Combination Therapies ◽  
Pilot Studies ◽  
Future Utility

ABSTRACT Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T→M mutation at residue 61 linked to an S→T (but not an S→N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.

Probing the methotrexate–protein interactions by proteomics and thermostability assay for drug resistance study

2021 ◽  
Author(s):  
Wenbo Zhang ◽  
Xiaoying Li ◽  
Xiaolei Zhang ◽  
Yan Dong ◽  
Lianghai Hu
Keyword(s):  
Drug Resistance ◽  
Protein Interactions ◽  
Quantitative Proteomics ◽  
Drug Action ◽  
Novel Strategy

Quantitative proteomics combined with thermostability assay provide a novel strategy for the study of mechanisms on drug action and resistance.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

scholarly journals Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lydia Ntari ◽  
Christoforos Nikolaou ◽  
Ksanthi Kranidioti ◽  
Dimitra Papadopoulou ◽  
Eleni Christodoulou-Vafeiadou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Therapeutic Effect ◽  
Expression Analysis ◽  
Mode Of Action ◽  
Gene Expression Analysis ◽  
Kinase Inhibitors ◽  
High Dose ◽  
Dependent Manner ◽  
Combination Therapies ◽  
Number Of Patients

Abstract Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

scholarly journals Severe orthostatic hypotension in otherwise uncomplicated Plasmodium vivax infection

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chaisith Sivakorn ◽  
Polrat Wilairatana ◽  
Srivicha Krudsood ◽  
Marcus J. Schultz ◽  
Tachpon Techarang ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Orthostatic Hypotension ◽  
Plasmodium Vivax ◽  
Falciparum Malaria ◽  
Fluid Resuscitation ◽  
Orthostatic Intolerance ◽  
Parasite Clearance ◽  
Chain Reaction ◽  
Thai Woman ◽  
Polymerase Chain

AbstractImpaired autonomic control of postural homeostasis resulting in orthostatic hypotension has been described in falciparum malaria. However, severe orthostatic intolerance in Plasmodium vivax has been rarely reported. A case of non-immune previously healthy Thai woman presenting with P. vivax infection with well-documented orthostatic hypotension is described. In addition to oral chloroquine and intravenous artesunate, the patient was treated with fluid resuscitation and norepinephrine. During hospitalization, her haemodynamic profile revealed orthostatic hypotension persisting for another three days after microscopic and polymerase chain reaction confirmed parasite clearance. Potential causes are discussed.

Cisplatin Resistance Reversal of Lung Cancers by Tumor Acidity-Activable Vesicular Nanoreactors via Tumor Oxidative Stress Amplification

2021 ◽  
Author(s):  
Jean Felix Mukerabigwi ◽  
Yu Han ◽  
Nannan Lu ◽  
Wendong Ke ◽  
Yuheng Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Therapeutic Efficacy ◽  
Cisplatin Resistance ◽  
Clinical Applications ◽  
Lung Cancers ◽  
Resistance Reversal ◽  
Tumor Acidity ◽  
Stress Amplification ◽  
Novel Strategy

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against a variety of cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing...

Rational design and synthesis of novel Syk-kinase inhibitors

2012 ◽  
Vol 22 (2) ◽  
pp. 73-74 ◽  
Author(s):  
Alexey A. Zeifman ◽  
Ilya Yu. Titov ◽  
Igor V. Svitanko ◽  
Tatiana V. Rakitina ◽  
Aleksey V. Lipkin ◽  
...  
Keyword(s):  
Rational Design ◽  
Kinase Inhibitors ◽  
Design And Synthesis ◽  
Syk Kinase

scholarly journals Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

2018 ◽  
Vol 62 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Peter T. Harrison ◽  
Paul H. Huang
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Effective Means ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Responses

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

scholarly journals Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1170 ◽  
Author(s):  
Emily S. Mathews ◽  
Audrey R. Odom John
Keyword(s):  
Drug Resistance ◽  
Malaria Elimination ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Control Measures ◽  
Multi Drug Resistance ◽  
Development Projects ◽  
Combination Therapies ◽  
The Past ◽  
Antimalarial Compounds

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.

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