scholarly journals In SilicoSearch of Energy Metabolism Inhibitors for Alternative Leishmaniasis Treatments

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Lourival A. Silva ◽  
Marina C. Vinaud ◽  
Ana Maria Castro ◽  
Pedro Vítor L. Cravo ◽  
José Clecildo B. Bezerra
Keyword(s):  
Developing Countries ◽  
Energy Metabolism ◽  
Complex Disease ◽  
Current Treatment ◽  
New Drugs ◽  
Socioeconomic Impact ◽  
Search Criterion ◽  
Metabolism Enzymes ◽  
Target Database ◽  
Specific Inhibitors

Leishmaniasis is a complex disease that affects mammals and is caused by approximately 20 distinct protozoa from the genusLeishmania. Leishmaniasis is an endemic disease that exerts a large socioeconomic impact on poor and developing countries. The current treatment for leishmaniasis is complex, expensive, and poorly efficacious. Thus, there is an urgent need to develop more selective, less expensive new drugs. The energy metabolism pathways ofLeishmaniainclude several interesting targets for specific inhibitors. In the present study, we sought to establish which energy metabolism enzymes inLeishmaniacould be targets for inhibitors that have already been approved for the treatment of other diseases. We were able to identify 94 genes and 93Leishmaniaenergy metabolism targets. Using each gene’s designation as a search criterion in the TriTrypDB database, we located the predicted peptide sequences, which in turn were used to interrogate the DrugBank, Therapeutic Target Database (TTD), and PubChem databases. We identified 44 putative targets of which 11 are predicted to be amenable to inhibition by drugs which have already been approved for use in humans for 11 of these targets. We propose that these drugs should be experimentally tested and potentially used in the treatment of leishmaniasis.

scholarly journals In silico Repositioning of Approved Drugs Against Schistosoma mansoni Energy Metabolism Targets

2018 ◽  
Author(s):  
Nicole Melo Calixto ◽  
Daniela Braz dos Santos ◽  
José Clecildo Barreto Bezerra ◽  
Lourival de Almeida Silva
Keyword(s):  
Energy Metabolism ◽  
Schistosoma Mansoni ◽  
In Silico ◽  
New Drugs ◽  
Effective Alternative ◽  
Metabolism Enzymes ◽  
Low Efficiency ◽  
Approved Drugs ◽  
Expensive Process ◽  
Analyze Data

AbstractSchistosomiasis is a neglected parasitosis caused by Schistosoma spp. Praziquantel is used for the chemoprophylaxis and treatment of this disease. Although this monotherapy is effective, the risk of resistance and its low efficiency against immature worms compromises its effectiveness. Therefore, it is necessary to develop new schistosomicide drugs. However, the development of new drugs is a long and expensive process. The repositioning of approved drugs has been proposed as a quick, cheap, and effective alternative to solve this problem. This study employs chemogenomic analysis with use of bioinformatics tools to search, identify, and analyze data on approved drugs with the potential to inhibit Schistosoma mansoni energy metabolism enzymes. The TDR Targets Database, Gene DB, Protein, DrugBank, Therapeutic Targets Database (TTD), Promiscuous, and PubMed databases were used. Fifty-nine target proteins were identified, of which 18 had one or more approved drugs. The results identified 20 potential drugs for schistosomiasis treatment, all approved for use in humans.

scholarly journals MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2108
Author(s):  
Manuela Tosi ◽  
Orietta Spinelli ◽  
Matteo Leoncin ◽  
Roberta Cavagna ◽  
Chiara Pavoni ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Current Treatment ◽  
New Drugs ◽  
Term Survival ◽  
Therapeutic Decisions ◽  
Key Factor ◽  
Combined Strategy

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

scholarly journals Research in Medicine: Essentials for Developing Countries

2014 ◽  
Vol 1 (1) ◽  
pp. 1-2
Author(s):  
Yusuf Yakupogullari ◽  
Adam KOSE
Keyword(s):  
Developing Countries ◽  
Research Ethics ◽  
Human Resource ◽  
Well Being ◽  
Current Treatment ◽  
The Other ◽  
Data Recording ◽  
Human Resource Research ◽  
The Earth ◽  
Resource Research

(Extract) The well-being has been the highest topic for humanity throughout the adventure of mankind on the earth. Therefore, extensive efforts have been performed on the science of medicine, and glorious advances have been gained especially in the last two centuries. Research is essential for medicine to develop new therapeutic methods and to monitor the results of the current treatment given to the patient. These are possibly the simplest reasons for investigations in medicine. On the other hand, qualified human resource, research ethics, financial supports, regular data recording and analysis, and publication are important issues for improvement of the medical researches in the developing countries.

scholarly journals ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

2018 ◽  
Vol 24 (2) ◽  
pp. 96-120 ◽  
Author(s):  
Xavier Montalban ◽  
Ralf Gold ◽  
Alan J Thompson ◽  
Susana Otero-Romero ◽  
Maria Pia Amato ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pharmacological Treatment ◽  
Complex Disease ◽  
Treatment Decisions ◽  
Current Data ◽  
New Drugs ◽  
Nominal Group ◽  
Disease Modifying Drugs ◽  
Quality Of Evidence

Background: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions. Objectives: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS. Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion: The present guideline will enable homogeneity of treatment decisions across Europe.

Ponatinib, Lestaurtinib and mTOR/PI3K inhibitors are promising repurposing candidates against Entamoeba histolytica

2021 ◽  
Author(s):  
Monica M. Kangussu-Marcolino ◽  
Upinder Singh
Keyword(s):  
Entamoeba Histolytica ◽  
Current Treatment ◽  
Clinical Development ◽  
New Drugs ◽  
Phase Iii ◽  
Significant Advance ◽  
Pi3k Inhibitors ◽  
Treatment Regimens ◽  
Clinical Resistance ◽  
Tk Inhibitors

Dysentery caused by Entamoeba histolytica affects millions of people annually. Current treatment regimens are based on metronidazole to treat invasive parasites combined with paromomycin for luminal parasites. Issues with treatment include significant side effects, inability to easily treat breastfeeding and pregnant women, the use of two sequential agents, and concern that all therapy is based on nitroimidazole agents with no alternatives if clinical resistance emerges. Thus, the need for new drugs against amebiasis is urgent. To identify new therapeutic candidates, we screened the ReFRAME library (11,948 compounds assembled for Repurposing, Focused Rescue, and Accelerated Medchem) against E. histolytica trophozoites. We identified 159 hits in the primary screen at 10 μM and 46 compounds were confirmed in secondary assays. Overall, 26 were selected as priority molecules for further investigation including 6 FDA approved, 5 orphan designation, and 15 which are currently in clinical trials (3 phase III, 7 phase II and 5 phase I). We found that all 26 compounds are active against metronidazole resistant E. histolytica and 24 are able to block parasite recrudescence after drug removal. Additionally, 14 are able to inhibit encystation and 2 (lestaurtinib and LY-2874455) are active against mature cysts. Two classes of compounds are most interesting for further investigations: the Bcr-Abl TK inhibitors, with the ponatinib (EC 50 0.39) as most potent and mTOR or PI3K inhibitors with 8 compounds in clinical development, of which 4 have nanomolar potency. Overall, these are promising candidates and represent a significant advance for drug development against E. histolytica .

scholarly journals Targeting the Serine Pathway: A Promising Approach against Tuberculosis?

2019 ◽  
Vol 12 (2) ◽  
pp. 66 ◽  
Author(s):  
Marie Haufroid ◽  
Johan Wouters
Keyword(s):  
Treatment Options ◽  
Infectious Agent ◽  
Selective Inhibition ◽  
Current Treatment ◽  
New Drugs ◽  
Therapeutic Drug ◽  
Regulatory Domains ◽  
Starting Point ◽  
Drug Discovery Program ◽  
Serine Pathway

Tuberculosis is still the leading cause of death by a single infectious agent. Effective chemotherapy has been used and improved since the 1950s, but strains resistant to this therapy and most antibacterial drugs on the market are emerging. Only 10 new drugs are in clinical trials, and two of them have already demonstrated resistance. This paper gives an overview of current treatment options against tuberculosis and points out a promising approach of discovering new effective drugs. The serine production pathway is composed of three enzymes (SerA1, SerC and SerB2), which are considered essential for bacterial growth, and all of them are considered as a therapeutic drug target. Their crystal structure are described and essential regulatory domains pointed out. Sequence alignment with similar enzymes in other host would help to identify key residues to target in order to achieve selective inhibition. Currently, only inhibitors of SerB2 are described in the literature. However, inhibitors of human enzymes are discussed, and could be used as a good starting point for a drug discovery program. The aim of this paper is to give some guidance for the design of new hits for every enzyme in this pathway.

scholarly journals Hepatic Cystathionine β-Synthase Activity is Increased by Greater Post-ruminal Supply of Methionine During the Periparturient Period in Dairy Cows

2019 ◽  
Author(s):  
Mario Vailati-Riboni ◽  
Fernanda Batistel ◽  
Rainie R C S Yambao ◽  
Claudia Parys ◽  
Yuan-Xiang Pan ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Dairy Cows ◽  
Carbon Metabolism ◽  
Production Efficiency ◽  
Fumarate Hydratase ◽  
Mrna Abundance ◽  
Periparturient Period ◽  
Inflammatory Status ◽  
Metabolism Enzymes ◽  
One Carbon Metabolism

Abstract Background Post-ruminal supply of Met during the periparturient period enhances production efficiency (feed conversion to milk) in dairy cows partly through alleviation of oxidant and inflammatory status. Whether alterations in hepatic one-carbon (major contributor of antioxidants) and/or energy-metabolism contribute to these beneficial effects is unknown. Objectives Investigate alterations in hepatic one-carbon and energy metabolism and associations with plasma amino acids (AA) and production efficiency in response to enhanced post-ruminal supply of Met. Methods Holstein cows (n = 30/group) were fed during the last 28 days of pregnancy a control diet (CON) or the control plus ethyl-cellulose rumen-protected methionine (MET; 0.9 g·kg−1 of dry matter intake). Plasma (n = 15/group) and liver tissue (n = 10/group) were collected throughout the periparturient period to evaluate AA profiles, activity of TCA cycle, and one-carbon metabolism via mRNA abundance, enzyme activity, and targeted metabolomics. Results Cows in MET had greater overall (27%, P = 0.027) plasma Met concentrations, but had similar total plasma AA concentrations. Although mRNA abundance of one-carbon metabolism enzymes did not differ, hepatic activity of cystathionine β-synthase (CBS) (51.2 vs. 44.4 mmol·h−1·mg−1 protein; P = 0.032) and concentration (19%, P = 0.048) of the cellular antioxidant glutathione were greater overall in MET. mRNA abundance of aconitase 2 and fumarate hydratase was greater overall (P = 0.049), and phosphoenolpyruvate carboxykinase 1 tended (P = 0.093) to be greater overall in cows fed MET. There was a tendency (P ≤ 0.093) for greater overall hepatic concentrations of malic acid, α-ketoglutaric acid, and isocitric acid in cows fed MET. Conclusions Greater activity of CBS in response to enhanced post-ruminal supply of Met likely contributes to alleviating oxidant status by increasing concentrations of glutathione. Hence, transsulfuration plays an important role in the observed improvements in production efficiency of dairy cows during the periparturient period.

scholarly journals Gene expression signature: a powerful approach for drug discovery in diabetes

2017 ◽  
Vol 232 (2) ◽  
pp. R131-R139 ◽  
Author(s):  
Smithamol Sithara ◽  
Tamsyn M Crowley ◽  
Ken Walder ◽  
Kathryn Aston-Mourney
Keyword(s):  
Gene Expression ◽  
Complex Disease ◽  
Gene Expression Signature ◽  
New Drugs ◽  
Disease Symptoms ◽  
Current State ◽  
Powerful Approach ◽  
Underlying Causes ◽  
Underlying Pathophysiology

Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of antidiabetic drugs; however, those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease, and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved. Therefore, the approach of designing new drugs aimed at a specific molecular target is not optimal and a more expansive, unbiased approach is required. In this review, we will look at the current state of diabetes treatments and how these target the disease symptoms but are unable to combat the underlying causes. We will also review how the technique of gene expression signatures (GESs) has been used successfully for other complex diseases and how this may be applied as a powerful tool for the discovery of new drugs for T2D.

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