scholarly journals A theoretical examination of the relative importance of evolution management and drug development for managing resistance

2014 ◽  
Vol 281 (1797) ◽  
pp. 20141861 ◽  
Author(s):  
Nathan S. McClure ◽  
Troy Day
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Public Health Problem ◽  
The Other ◽  
New Drugs ◽  
Relative Importance ◽  
Simple Mathematical Model ◽  
Significant Component ◽  
Evolution Of Resistance ◽  
Effective Drugs

Drug resistance is a serious public health problem that threatens to thwart our ability to treat many infectious diseases. Repeatedly, the introduction of new drugs has been followed by the evolution of resistance. In principle, there are two complementary ways to address this problem: (i) enhancing drug development and (ii) slowing the evolution of drug resistance through evolutionary management. Although these two strategies are not mutually exclusive, it is nevertheless worthwhile considering whether one might be inherently more effective than the other. We present a simple mathematical model that explores how interventions aimed at these two approaches affect the availability of effective drugs. Our results identify an interesting feature of evolution management that, all else equal, tends to make it more effective than enhancing drug development. Thus, although enhancing drug development will necessarily be a central part of addressing the problem of resistance, our results lend support to the idea that evolution management is probably a very significant component of the solution as well.

scholarly journals Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 154 ◽  
Author(s):  
Jakub Treml ◽  
Markéta Gazdová ◽  
Karel Šmejkal ◽  
Miroslava Šudomová ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Natural Products ◽  
Drug Development ◽  
Large Scale ◽  
Biologically Active ◽  
New Drugs ◽  
In Vivo Studies ◽  
Limited Attention ◽  
Hsv Infections

Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

scholarly journals Novel Antiviral Strategies in the Treatment of COVID-19: A Review

2020 ◽  
Vol 8 (9) ◽  
pp. 1259 ◽  
Author(s):  
Shiu-Jau Chen ◽  
Shao-Cheng Wang ◽  
Yuan-Chuan Chen
Keyword(s):  
Public Health ◽  
Public Health Problem ◽  
New Drugs ◽  
Global Public Health ◽  
Compassionate Use ◽  
Safety And Efficacy ◽  
The People ◽  
The World ◽  
Effective Drugs ◽  
Global Public Health Problem

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2), is still a global public health problem for humans. It has caused more than 10,000,000 infections and more than 500,000 deaths in the world so far. Many scientists have tried their best to discover safe and effective drugs for the treatment of this disease; however, there are still no approved standard therapeutics or effective antiviral drugs on the market. Many new drugs are being developed, and several traditional drugs that were originally indicated or proposed for other diseases are likely to be effective in treating COVID-19, but their safety and efficacy are controversial, under study, or in clinical trial phases. Fortunately, some novel antiviral strategies, such as convalescent plasma, clustered regularly interspaced short palindromic repeats (CRISPR), and mesenchymal stem cell (MSC) therapy, potentially offer an additional or alternative option or compassionate use for the people suffering from COVID-19, especially for critically ill patients, although their safety and efficacy are also under study. In this review, we explore the applications, possible mechanisms, and efficacy in successful cases using convalescent plasma, CRISPR, and MSC therapy for COVID-19 treatment, respectively. Furthermore, the perspectives and limitations of these novel antiviral strategies are evaluated.

Recent Advances in the Synthesis and Development of Nitroaromatics as Anti-Infective Drugs

2020 ◽  
Vol 26 (36) ◽  
pp. 4658-4674 ◽  
Author(s):  
Christina Kannigadu ◽  
David. D. N'Da
Keyword(s):  
Infectious Disease ◽  
Drug Resistance ◽  
Chest Pain ◽  
Muscle Pain ◽  
New Drugs ◽  
Lymph Glands ◽  
Recent Advances ◽  
Personality Changes ◽  
Clinical Drugs ◽  
Antiparasitic Agents

: Infectious diseases commonly occur in tropical and sub-tropical countries. The pathogens of such diseases are able to multiply in human hosts, warranting their continual survival. Infections that are commonplace include malaria, chagas, trypanosomiasis, giardiasis, amoebiasis, toxoplasmosis and leishmaniasis. Malaria is known to cause symptoms, such as high fever, chills, nausea and vomiting, whereas chagas disease causes enlarged lymph glands, muscle pain, swelling and chest pain. People suffering from African trypanosomiasis may experience severe headaches, irritability, extreme fatigue and swollen lymph nodes. As an infectious disease progresses, the human host may also experience personality changes and neurologic problems. If left untreated, most of these diseases can lead to death. : Parasites, microbes and bacteria are increasingly adapting and generating strains that are resistant to current clinical drugs. Drug resistance creates an urgency for the development of new drugs to treat these infections. Nitro containing drugs, such as chloramphenicol, metronidazole, tinidazole and secnidazole had been banned for use as antiparasitic agents due to their toxicity. However, recent discoveries of nitrocontaining anti-tuberculosis drugs, i.e. delamanid and pretonamid, and the repurposing of flexinidazole for use in combination with eflornithine for the treatment of human trypanosomiasis, have ignited interest in nitroaromatic scaffolds as viable sources of potential anti-infective agents. : This review highlights the differences between old and new nitration methodologies. It furthermore offers insights into recent advances in the development of nitroaromatics as anti-infective drugs.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

4H-1,3-Benzothiazin-4-one a Promising Class Against MDR/XDR-TB

2019 ◽  
Vol 19 (8) ◽  
pp. 567-578 ◽  
Author(s):  
Marcus Vinicius Nora de Souza ◽  
Thais Cristina Mendonça Nogueira
Keyword(s):  
Treatment Time ◽  
Public Health Problem ◽  
New Drugs ◽  
Global Public Health ◽  
Synthesis Mechanism ◽  
Highly Active ◽  
Latent Disease ◽  
Resistant Strains ◽  
Chemical Class ◽  
Global Public Health Problem

Nowadays, tuberculosis (TB) is an important global public health problem, being responsible for millions of TB-related deaths worldwide. Due to the increased number of cases and resistance of Mycobacterium tuberculosis to all drugs used for the treatment of this disease, we desperately need new drugs and strategies that could reduce treatment time with fewer side effects, reduced cost and highly active drugs against resistant strains and latent disease. Considering that, 4H-1,3-benzothiazin-4-one is a promising class of antimycobacterial agents in special against TB-resistant strains being the aim of this review the discussion of different aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other drugs.

Synthesis and Antifungal Activity of Coumarins Derivatives Against Sporothrix spp.

2018 ◽  
Vol 18 (2) ◽  
pp. 164-171 ◽  
Author(s):  
Luana da S.M. Forezi ◽  
Luana Pereira Borba-Santos ◽  
Mariana F.C. Cardoso ◽  
Vitor F. Ferreira ◽  
Sonia Rozental ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Antifungal Agents ◽  
Sporothrix Schenckii ◽  
Public Health Problem ◽  
Domestic Animals ◽  
Coumarin Derivatives ◽  
Sporothrix Brasiliensis ◽  
Synthetic Routes ◽  
Effective Drugs

Sporotrichosis is a serious public health problem in Brazil that affects human patients and domestic animals, mainly cats. Thus, the search for new antifungal agents is required also due to the emergence and to the lack of effective drugs available in the therapeutic arsenal. The aim of this study was to evaluate the in vitro antifungal profile of two synthetic series of coumarin derivatives against Sporothrix schenckii and Sporothrix brasiliensis. The three-components synthetic routes used for the preparation of coumarin derivatives have proved to be quite efficient and compounds 16 and 17 have been prepared in good yields. The inhibitory activity of nineteen synthetic coumarins derivatives 16a-i and 17a-j were evaluated against Sporothrix spp. yeasts and the most potent compounds were 16b and 17i. However, according to concentrations able to inhibit (minimum inhibitory concentrations) and kill (minimum fungicidal concentrations) the cells, 17i was more effective than 16b against Sporothrix spp. Thus, 17i exhibited good antifungal activity against S. brasiliensis and S. schenckii, suggesting that it is an important scaffold for the development of novel antifungal agents.

pLoc_bal-mEuk: Predict Subcellular Localization of Eukaryotic Proteins by General PseAAC and Quasi-balancing Training Dataset

2019 ◽  
Vol 15 (5) ◽  
pp. 472-485 ◽  
Author(s):  
Kuo-Chen Chou ◽  
Xiang Cheng ◽  
Xuan Xiao
Keyword(s):  
Drug Development ◽  
Subcellular Localization ◽  
Basic Research ◽  
The Other ◽  
Training Dataset ◽  
Sequence Information ◽  
Eukaryotic Proteins ◽  
Validation Tests ◽  
User Friendly ◽  
Better Than

<P>Background/Objective: Information of protein subcellular localization is crucially important for both basic research and drug development. With the explosive growth of protein sequences discovered in the post-genomic age, it is highly demanded to develop powerful bioinformatics tools for timely and effectively identifying their subcellular localization purely based on the sequence information alone. Recently, a predictor called “pLoc-mEuk” was developed for identifying the subcellular localization of eukaryotic proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems where many proteins, called “multiplex proteins”, may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mEuk was trained by an extremely skewed dataset where some subset was about 200 times the size of the other subsets. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. </P><P> Methods: To alleviate such bias, we have developed a new predictor called pLoc_bal-mEuk by quasi-balancing the training dataset. Cross-validation tests on exactly the same experimentconfirmed dataset have indicated that the proposed new predictor is remarkably superior to pLocmEuk, the existing state-of-the-art predictor in identifying the subcellular localization of eukaryotic proteins. It has not escaped our notice that the quasi-balancing treatment can also be used to deal with many other biological systems. </P><P> Results: To maximize the convenience for most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mEuk/. </P><P> Conclusion: It is anticipated that the pLoc_bal-Euk predictor holds very high potential to become a useful high throughput tool in identifying the subcellular localization of eukaryotic proteins, particularly for finding multi-target drugs that is currently a very hot trend trend in drug development.</P>

Exploration of Product Centric Factors in Telecom Industry

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Swati Ganeti ◽  
Rajat Agarwal ◽  
Murali Krishna Medudula ◽  
Mahim Sagar
Keyword(s):  
Service Quality ◽  
Service Provider ◽  
Service Providers ◽  
Network Connectivity ◽  
Factor Loading ◽  
The Other ◽  
Relative Importance ◽  
Network Connection ◽  
Telecom Service ◽  
Telecom Industry

Telecom industry is one of those industries which has changed dramatically during the past decade. With more and more players entering in this industry, competition is ever increasing. The war between these players is slowly shifting from the price to the augmentation. This paper aims at exploring such factors which influence a customers preference of one telecom service provider (TSP) over the other. It is a descriptive research where study has been conducted among the consumers of different telecom service providers (TSPs). By reviewing the existing literature in this domain, we explored different factors which affect the consumers decision to prefer one telecom service provider over the other. A consumer targeted questionnaire was designed where consumers were asked about the factors they consider (with their relative importance quantified using Likert scale), before buying a new network connection to know the relative importance of the various factors. Factor Analysis was performed to club various variables into distinct factors. Statistical techniques then helped in identifying the relative importance. From the Factor Loading matrix the following five factors were generated:- Overall service quality, Point of Purchase Differentiator, Promotion Measures, Tariff Plans and Size of the Network. Further study in the behavioural perceptions of consumer shows that the most important factor in influencing the customer buying behavior is Service Quality. The second most important factor is cost and various plans offered by the telecom service provider. Network connectivity was considered by almost all the respondents and consumers prefer the largest network player. The study also found that promotional measures dont influence the customers as expected.

Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples

2019 ◽  
Vol 39 (2) ◽  
pp. 141-150
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Robert Roth ◽  
Kenneth L. Hastings
Keyword(s):  
Drug Development ◽  
Annual Meeting ◽  
Clinical Studies ◽  
Early Termination ◽  
New Drugs ◽  
Clinical Safety ◽  
Case Examples ◽  
Palm Springs ◽  
Starting Dose ◽  
Good Concordance

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

scholarly journals A Pharmacological Analysis of the Activity and Failure of the Medical Treatment of High-Grade Osteosarcoma

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 141
Author(s):  
Alessandro Comandone ◽  
Antonella Boglione ◽  
Tiziana Comandone ◽  
Fausto Petrelli
Keyword(s):  
Bone Cells ◽  
Age Groups ◽  
The Elderly ◽  
New Drugs ◽  
High Grade ◽  
Secondary Resistance ◽  
Orthopedic Surgeons ◽  
Close Cooperation ◽  
High Grade Osteosarcoma ◽  
Effective Drugs

Osteosarcomas (OSs) are a group of neoplasms originating from bone cells, usually presenting in three specific age groups: children, young adults, and the elderly. High-grade OS is an extremely malignant tumor mainly due to evolution into metastatic disease, usually in the lungs. Survival of these patients has improved since the 1980s thanks to close cooperation between oncologists, oncological surgeons and orthopedic surgeons. Unfortunately, no progress has been made in the last 30 years and new, more effective drugs are needed. This article reviews the biological and pharmacological basis of the treatment of OS. Models of clinical pharmacology of the active drugs, toxic effects and reasons for primary and secondary resistance to old and new drugs are discussed.

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