RESUMO
Therapeutic drug development is a long, expensive, and complex process that usually takes 12-15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.
Assuntos
Caenorhabditis elegans/fisiologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Avaliação Pré-Clínica de Medicamentos/economia , Ensaios de Triagem em Larga Escala/economia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Modelos Animais , Especificidade da EspécieRESUMO
The current outbreak of Covid-19 infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major threat to human healthcare. The virus has already infected more than 44 M people and the number of deaths reported has reached more than 1.1 M which may be attributed to lack of medicine. The traditional drug discovery approach involves many years of rigorous research and development and demands for a huge investment which cannot be adopted for the ongoing pandemic infection. Rather we need a swift and cost-effective approach to inhibit and control the viral infection. With the help of computational screening approaches and by choosing appropriate chemical space, it is possible to identify lead drug-like compounds for Covid-19. In this study, we have used the Drugbank database to screen compounds against the most important viral targets namely 3C-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the spike (S) protein. These targets play a major role in the replication/transcription and host cell recognition, therefore, are vital for the viral reproduction and spread of infection. As the structure based computational screening approaches are more reliable, we used the crystal structures for 3C-like main protease and spike protein. For the remaining targets, we used the structures based on homology modeling. Further, we employed two scoring methods based on binding free energies implemented in AutoDock Vina and molecular mechanics-generalized Born surface area approach. Based on these results, we propose drug cocktails active against the three viral targets namely 3CLpro, PLpro and RdRp. Interestingly, one of the identified compounds in this study i.e. Baloxavir marboxil has been under clinical trial for the treatment of Covid-19 infection. In addition, we have identified a few compounds such as Phthalocyanine, Tadalafil, Lonafarnib, Nilotinib, Dihydroergotamine, R-428 which can bind to all three targets simultaneously and can serve as multi-targeting drugs. Our study also included calculation of binding energies for various compounds currently under drug trials. Among these compounds, it is found that Remdesivir binds to targets, 3CLpro and RdRp with high binding affinity. Moreover, Baricitinib and Umifenovir were found to have superior target-specific binding while Darunavir is found to be a potential multi-targeting drug. As far as we know this is the first study where the compounds from the Drugbank database are screened against four vital targets of SARS-CoV-2 and illustrates that the computational screening using a double scoring approach can yield potential drug-like compounds against Covid-19 infection.
Assuntos
Infecções por Coronavirus/tratamento farmacológico , Bases de Dados de Produtos Farmacêuticos , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular , Pneumonia Viral/tratamento farmacológico , COVID-19 , Proteases 3C de Coronavírus , Análise Custo-Benefício , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Avaliação Pré-Clínica de Medicamentos/economia , Humanos , Simulação de Acoplamento Molecular , Pandemias , Conformação Proteica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Opioid-related death and overdose have now reached epidemic proportions. In response to this public health crisis, the National Institutes of Health (NIH) launched the Helping to End Addiction Long-term InitiativeSM, or NIH HEAL InitiativeSM, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis. Herein, we describe two NIH HEAL Initiative programs to accelerate development of non-opioid, non-addictive pain treatments: The Preclinical Screening Platform for Pain (PSPP) and Early Phase Pain Investigation Clinical Network (EPPIC-Net). These resources are provided at no cost to investigators, whether in academia or industry and whether within the USA or internationally. Both programs consider small molecules, biologics, devices, and natural products for acute and chronic pain, including repurposed and combination drugs. Importantly, confidentiality and intellectual property are protected. The PSPP provides a rigorous platform to identify and profile non-opioid, non-addictive therapeutics for pain. Accepted assets are evaluated in in vitro functional assays to rule out opioid receptor activity and to assess abuse liability. In vivo pharmacokinetic studies measure plasma and brain exposure to guide the dose range and pretreatment times for the side effect profile, efficacy, and abuse liability. Studies are conducted in accordance with published rigor criteria. EPPIC-Net provides academic and industry investigators with expert infrastructure for phase II testing of pain therapeutics across populations and the lifespan. For assets accepted after a rigorous, objective scientific review process, EPPIC-Net provides clinical trial design, management, implementation, and analysis.
Assuntos
Dor Crônica/epidemiologia , Dor Crônica/terapia , Ensaios Clínicos Fase II como Assunto , Recursos em Saúde/tendências , National Institutes of Health (U.S.)/tendências , Animais , Dor Crônica/economia , Ensaios Clínicos Fase II como Assunto/economia , Ensaios Clínicos Fase II como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Recursos em Saúde/economia , Humanos , National Institutes of Health (U.S.)/economia , Medição da Dor/economia , Medição da Dor/métodos , Medição da Dor/tendências , Estados Unidos/epidemiologiaRESUMO
The number of people in the United States living with Alzheimer disease (AD) is growing, resulting in significant clinical and economic impact. Substantial research investment has led to drug development in stages of AD before symptomatic dementia, such as preclinical AD. Although there are no treatments approved for preclinical AD, there are currently 6 phase 3 clinical trials for preclinical AD treatments. In this article, we review these clinical trials and highlight considerations for future coverage decisions. In line with the definition of preclinical AD, enrollment in these trials focuses on cognitively unimpaired patients that are at high risk of AD because of family history and then genetic testing or brain imaging. Enrollment in most of these trials also allows for younger patients, including those aged under 65 years. Primary clinical trial endpoints focus on cognition often 4 or more years after treatment. Secondary endpoints include other measures of cognition and function, as well as biomarkers. Review of these trials brings to light a few potential considerations when covering these new medications in the future. First, novel and potentially costly approaches involving genetic testing and/or positron emission tomography imaging may be needed to identify appropriate patients and should be developed efficiently. Second, the long duration of these clinical trials suggest that there may be a need for alternative payment approaches in the United States that encourage early payers to pay for a medication for which the long-term benefits may not be realized until after the beneficiary is no longer with the health plan. Third, the value of AD treatments may differ across populations, creating a potential role for indication-based or population-based contracting. Finally, considering the potentially high budgetary impact and little real-world evidence for a new drug class, payers and manufacturers may want to consider outcomes-based payment approaches and coverage with evidence development to mitigate uncertainty about the value of the treatment demonstrated in well-defined populations in clinical trials versus more heterogeneous real-world settings. DISCLOSURES: This work was funded through a generous gift from the Global CEO Initiative on Alzheimer Disease. Hung reports grants from Agency for Healthcare Research and Quality and Pharmaceutical Research and Manufacturers of America outside the submitted work and past employment at CVS Health and BlueCross BlueShield Association. McClellan is an independent board member on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and Seer; co-chairs the Accountable Care Learning Collaborative and the Guiding Committee for the Health Care Payment Learning and Action Network; and receives fees for serving as an advisor for Cota and MITRE. Hamilton Lopez and Schneider have nothing to disclose. Part of this work was presented at the 2019 AMCP Nexus Meeting, October 29-November 1, 2019, in National Harbor, MD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto/métodos , Custos de Medicamentos , Desenvolvimento de Medicamentos/métodos , Doença de Alzheimer/economia , Doença de Alzheimer/epidemiologia , Ensaios Clínicos Fase III como Assunto/economia , Desenvolvimento de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Determinação de Ponto Final/economia , Determinação de Ponto Final/métodos , HumanosRESUMO
BACKGROUND: Graph edit distance is a methodology used to solve error-tolerant graph matching. This methodology estimates a distance between two graphs by determining the minimum number of modifications required to transform one graph into the other. These modifications, known as edit operations, have an edit cost associated that has to be determined depending on the problem. OBJECTIVE: This study focuses on the use of optimization techniques in order to learn the edit costs used when comparing graphs by means of the graph edit distance. METHODS: Graphs represent reduced structural representations of molecules using pharmacophore-type node descriptions to encode the relevant molecular properties. This reduction technique is known as extended reduced graphs. The screening and statistical tools available on the ligand-based virtual screening benchmarking platform and the RDKit were used. RESULTS: In the experiments, the graph edit distance using learned costs performed better or equally good than using predefined costs. This is exemplified with six publicly available datasets: DUD-E, MUV, GLL&GDD, CAPST, NRLiSt BDB, and ULS-UDS. CONCLUSION: This study shows that the graph edit distance along with learned edit costs is useful to identify bioactivity similarities in a structurally diverse group of molecules. Furthermore, the target-specific edit costs might provide useful structure-activity information for future drug-design efforts.
Assuntos
Gráficos por Computador/economia , Aprendizagem , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos/economia , LigantesRESUMO
This study aims to benchmark and analyze the process development and manufacturing costs across the biopharmaceutical drug development cycle and their contribution to overall research and development (R&D) costs. This was achieved with a biopharmaceutical drug development lifecycle cost model that captured the costs, durations, risks and interdependencies of the clinical, process development and manufacturing activities. The budgets needed for process development and manufacturing at each phase of development to ensure a market success each year were estimated. The impact of different clinical success rate profiles on the process development and manufacturing costs at each stage was investigated, with a particular focus on monoclonal antibodies. To ensure a market success each year with an overall clinical success rate (Phase I to approval) of ~12%, the model predicted that a biopharmaceutical company needs to allocate process development and manufacturing budgets in the order of ~$60 M for pre-clinical to Phase II material preparation and ~$70 M for Phase III to regulatory review material preparation. For lower overall clinical success rates of ~4%, which are more indicative of diseases such as Alzheimer's, these values increase to ~$190 M for early-phase and ~$140 Mfor late-phase material preparation; hence, the costs increase 2.5 fold. The costs for process development and manufacturing per market success were predicted to represent 13-17% of the R&D budget from pre-clinical trials to approval. The results of this quantitative structured cost study can be used to aid decision-making during portfolio management and budget planning procedures in biopharmaceutical development.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Benchmarking/métodos , Produtos Biológicos/uso terapêutico , Aprovação de Drogas/métodos , Desenvolvimento de Medicamentos/métodos , Indústria Farmacêutica/métodos , Benchmarking/economia , Ensaios Clínicos como Assunto/economia , Aprovação de Drogas/economia , Custos de Medicamentos/estatística & dados numéricos , Desenvolvimento de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/economia , Indústria Farmacêutica/economia , Humanos , Modelos Econômicos , Preparações Farmacêuticas/economia , Pesquisa/economia , Pesquisa/estatística & dados numéricos , Tecnologia Farmacêutica/economia , Tecnologia Farmacêutica/métodosRESUMO
Cell-based assays are an important part of the drug discovery process and clinical research. One of the main hurdles is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the cells and not interfering with the pharmacology of target being investigated. A plethora of assays that assess cell viability (or cell heath in general) are commercially available and can be classified under different categories according to their concepts and principle of reactions. The assays are valuable tools, however, suffer from a large number of limitations. Some of these limitations can be procedural or operational, but others can be critical as those related to a poor concept or the lack of proof of concept of an assay, e.g. those relying on differential permeability of dyes in-and-out of viable versus compromised cell membranes. While the assays can differentiate between dead and live cells, most, if not all, of them can just assess the relative performance of cells rather than providing a clear distinction between healthy and dying cells. The possible impact of relatively high molecular weight dyes, used in most of the assay, on cell viability has not been addressed. More innovative assays are needed, and until better alternatives are developed, setup of current cell-based studies and data interpretation should be made with the limitations in mind. Negative and positive control should be considered whenever feasible. Also, researchers should use more than one orthogonal method for better assessment of cell health.
Assuntos
Bioensaio/métodos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Bioensaio/economia , Bioensaio/instrumentação , Descoberta de Drogas/economia , Descoberta de Drogas/instrumentação , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/instrumentação , Ensaios de Triagem em Larga Escala/economia , Ensaios de Triagem em Larga Escala/instrumentação , HumanosAssuntos
Aprovação de Drogas , Desenvolvimento de Medicamentos , Comércio , Aprovação de Drogas/economia , Aprovação de Drogas/métodos , Aprovação de Drogas/organização & administração , Custos de Medicamentos , Desenvolvimento de Medicamentos/economia , Desenvolvimento de Medicamentos/organização & administração , Desenvolvimento de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/economia , Indústria Farmacêutica/economia , Indústria Farmacêutica/organização & administração , Indústria Farmacêutica/normas , Acessibilidade aos Serviços de Saúde/economia , Acessibilidade aos Serviços de Saúde/organização & administração , HumanosRESUMO
Angiotensin converting enzyme (ACE), fusing with FLAG tag, was overexpressed in human embryonic kidney 293T cells. This recombinant FLAG-tagged ACE was immobilized on anti-FLAG antibody coated magnetic beads by affinity method in crude cell lysate for the first time. The enzyme-immobilized magnetic beads (ACE-MB), without further cleavage procedure, were used directly to establish a cost-effective and reliable method for screening ACE inhibitors by coupling with fluorescence detection. The enzymatic activity of the ACE-MB was validated based on its Michaelian kinetic behavior towards hippuryl-histidyl-leucine by UHPLC-MS/MS method firstly. Then, several conditions were optimized including amount of magnetic beads, incubation temperature and time in the procedure of ACE immobilization and amount of ACE-MB in the microplate operation. Moreover, this screening assay was validated with Z' factors between 0.71 and 0.81 using four known ACE inhibitors (captopril, lisinopril, fosinopril and fosinoprilat). The developed method was applied for the screening of ACE inhibitors from a small compound library of 45 natural products. As a result, epiberberine and fangchinoline with certain ACE inhibitory activities were screened out in the assay and validated. The results demonstrate the usefulness of this screening method using ACE immobilized on magnetic beads and the advantage of great efficiency with respect to both time and reagents for screening ACE inhibitors.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Avaliação Pré-Clínica de Medicamentos/métodos , Enzimas Imobilizadas/química , Peptidil Dipeptidase A/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzilisoquinolinas/análise , Benzilisoquinolinas/química , Benzilisoquinolinas/farmacologia , Berberina/análogos & derivados , Berberina/análise , Berberina/química , Berberina/farmacologia , Cromatografia de Afinidade/economia , Cromatografia de Afinidade/instrumentação , Cromatografia de Afinidade/métodos , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Análise Custo-Benefício , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/instrumentação , Ensaios Enzimáticos/instrumentação , Ensaios Enzimáticos/métodos , Enzimas Imobilizadas/isolamento & purificação , Células HEK293 , Humanos , Oligopeptídeos/química , Peptidil Dipeptidase A/isolamento & purificação , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Espectrometria de Massas em Tandem/economia , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodosRESUMO
A novel, simple, one-step and one-tube detection method was developed for ultrasensitive detection of polynucleotide kinase (PNK) activity on the basis of dual enzyme-synergistic signal amplification. This method was also demonstrated to work well for PNK inhibitor screening and endogenous PNK detection in cell lysates at a single-cell level.
Assuntos
Ensaios Enzimáticos/métodos , Polinucleotídeo 5'-Hidroxiquinase/análise , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios Enzimáticos/economia , Células HeLa , Humanos , Polinucleotídeo 5'-Hidroxiquinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Espectrometria de Fluorescência/métodos , TemperaturaAssuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Apolipoproteína E4/genética , Callithrix , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Macaca mulatta , Camundongos Transgênicos , Pessoa de Meia-Idade , Modelos Biológicos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Células-Tronco Neurais/transplante , Organoides/efeitos dos fármacos , Organoides/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Agregação Patológica de Proteínas , Reprodutibilidade dos Testes , Pesquisa Translacional Biomédica/economia , Pesquisa Translacional Biomédica/métodos , Vacinas , Proteínas tau/metabolismoRESUMO
Co-amorphous systems are an attractive alternative for amorphous solid polymer dispersions in the formulation of poorly soluble drugs. Several studies have revealed that co-amorphous formulations can enhance the dissolution properties of poorly-soluble drugs and stabilize them in the amorphous form. However, the interplay between the drug dissolution rate, drug supersaturation and different co-formers on membrane permeability of the drug for co-amorphous formulations remains unexplored. By using side-by-side chambers, separated by a PAMPA (parallel artificial membrane permeability assay) membrane, we were able to simultaneously test dissolution and passive membrane permeability of the co-amorphous combinations (1:1â¯molar ratio) of a poorly soluble drug glibenclamide (GBC) in combination with two amino acids, either serine (SER) or arginine (ARG). In addition, a known passive permeability enhancer sodium lauryl sulfate (SLS) was included in the co-amorphous mixtures at two concentration levels. The mixtures were also characterized with respect to their solid-state properties and physical stability. It was found that GBC mixtures with ARG and SLS had superior dissolution and physical stability properties which was attributable to the strong intermolecular interactions formed between GBC and ARG. These formulations also had optimal permeability properties due to their high concentration gradient promoting permeation and possible permeation enhancing effect of the co-formers ARG and SLS. Thus, simultaneous testing of dissolution and permeation through a PAMPA membrane may represent a simple and inexpensive tool for screening the most promising amorphous formulations in further studies.
Assuntos
Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Glibureto/farmacocinética , Membranas Artificiais , Arginina/química , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Avaliação Pré-Clínica de Medicamentos/economia , Estabilidade de Medicamentos , Estudos de Viabilidade , Glibureto/química , Permeabilidade , Polímeros/química , Serina/química , Dodecilsulfato de Sódio/química , Solubilidade , Difração de Raios XRESUMO
Myotonic dystrophy type 1 (DM1) is an autosomal dominantly inherited degenerative disease with a slow progression. At the present, there is no commercially available treatment, but sustained effort is currently undertaken for the development of a promising lead compound. In the present paper we report the development of a fast, versatile, and cost-effective affinity capillary electrophoresis (ACE) method for the screening and identification of potential drug candidates targeting pathological ARN probes relevant for DM1. The affinity studies were conducted in physiologically relevant conditions using 50 mM HEPES buffer (pH 7.4) in a fused silica capillary dynamically coated with poly(ethylene oxide), by testing a library of potential ligands against (CUG)50 RNA as target probe with a total run time of 4-5 h/ligand. For the most promising ligands, their affinity parameters were assessed and some results formerly reported on the affinity of pentamidine (PTMD) and neomycin against CUG repeats were confirmed. To the best of the authors' knowledge, the estimated binding stoichiometry for some of the tested compounds (i.e., ~ 121:1 for PTMD against the tested RNA probe) is reported for the first time. Additionally, the potential of a novel pentamidine like compound, namely 1,2-ethane bis-1-amino-4-benzamidine (EBAB) with much lower in vivo toxicity than its parent compound has also been confirmed studying its effect on a live cell model by fluorescence microscopy. Further tests, such as the evaluation of the rescue in the mis-splicing of the involved genes, can be performed to corroborate the potential therapeutic value of EBAB in DM1 treatment. Graphical abstract á .
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Eletroforese Capilar/métodos , Distrofia Miotônica/tratamento farmacológico , Benzamidinas/química , Benzamidinas/farmacologia , Avaliação Pré-Clínica de Medicamentos/economia , Eletroforese Capilar/economia , Células HeLa , Humanos , Ligantes , Pentamidina/química , Pentamidina/farmacologia , Motivos de Ligação ao RNA/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Human protection policies require favorable risk-benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010-2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk-benefit evaluation during ethical review of phase I/II studies.
Assuntos
Doenças Transmissíveis/economia , Avaliação Pré-Clínica de Medicamentos/economia , Drogas em Investigação/economia , Gastroenteropatias/economia , Doenças do Sistema Imunitário/economia , Neoplasias/economia , Doenças Respiratórias/economia , Animais , Viés , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Doenças Transmissíveis/tratamento farmacológico , Drogas em Investigação/farmacologia , Europa (Continente) , Gastroenteropatias/tratamento farmacológico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Neoplasias/tratamento farmacológico , Folhetos , Guias de Prática Clínica como Assunto , Doenças Respiratórias/tratamento farmacológico , Medição de Risco/estatística & dados numéricosRESUMO
Eighty percent of drugs that enter human clinical testing are never approved for use. This means that for every five drugs that make it into the clinic, there are four that failed to show effectiveness for treating the disease or condition the drug was designed to treat.This high failure rate means there are many existing, partially developed therapeutic candidates with known pharmacology, formulation, and potential toxicity. Finding new uses for existing experimental drugs or biologics "repositioning" builds upon previous research and development efforts, so new candidate therapies can be advanced to clinical trials for a new use more quickly than starting from scratch.Federal funding initiatives in the U.S. and UK started to support pre-clinical /or early stage trials for repositioning existing experimental drugs or biologics (therapies). This chapter covers some of the process issues that have been solved and the remaining challenges that are still in need of solutions. The chapter is primarily written from a U.S. federal funding perspective. The general concepts could be applied more globally to benefit rare and neglected disease populations. The drug development and process bottlenecks are the same for both rare and common disease.
Assuntos
Ensaios Clínicos como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Uso Off-Label , Produção de Droga sem Interesse Comercial , Doenças Raras/tratamento farmacológico , Projetos de Pesquisa , Ensaios Clínicos como Assunto/economia , Custos de Medicamentos , Avaliação Pré-Clínica de Medicamentos/economia , Reposicionamento de Medicamentos/economia , Humanos , Uso Off-Label/economia , Produção de Droga sem Interesse Comercial/economia , Segurança do Paciente , Parcerias Público-Privadas , Doenças Raras/diagnóstico , Doenças Raras/economia , Doenças Raras/epidemiologia , Apoio à Pesquisa como Assunto , Medição de RiscoAssuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Testes de Toxicidade/métodos , Animais , Avaliação Pré-Clínica de Medicamentos/economia , Edição de Genes , Ensaios de Triagem em Larga Escala/economia , Humanos , Modelos Animais , Impressão Tridimensional , Testes de Toxicidade/economiaAssuntos
Analgésicos Opioides/provisão & distribuição , Terapia Biológica , Biotecnologia , Empreendedorismo , Escherichia coli/metabolismo , Impressão Tridimensional , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Engenharia Tecidual , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/economia , Analgésicos Opioides/metabolismo , Animais , Bioengenharia , Reatores Biológicos , California , Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/tendências , Empreendedorismo/economia , Empreendedorismo/organização & administração , Escherichia coli/genética , Humanos , Investimentos em Saúde , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/terapia , Microbiota/genética , Microbiota/fisiologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Impressão Tridimensional/economia , Impressão Tridimensional/instrumentação , Pele , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
In this symposium, we reported the identification and mechanistic analysis of a novel antibiotic named lysocin E. Lysocin E was identified by screening for therapeutic effectiveness in a silkworm Staphylococcus aureus infection model. The advantages of the silkworm infection model for screening and purification of antibiotics from the culture supernatant of soil bacteria are: 1) low cost; 2) no ethical issues; 3) convenient for evaluation of the therapeutic effectiveness of antibiotics; and 4) pharmacokinetics similar to those of mammals. Lysocin E has remarkable features compared with known antibiotics such as a novel mechanism of action and target. Here, we summarize our reports presented in this symposium.
Assuntos
Antibacterianos/uso terapêutico , Bombyx , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/ética , Peptídeos Cíclicos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/farmacocinética , Peptídeos Cíclicos/farmacocinéticaAssuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Segurança do Paciente/normas , Projetos de Pesquisa/normas , Animais , Ensaios Clínicos como Assunto/economia , Ensaios Clínicos como Assunto/ética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/economia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/economia , Ética em Pesquisa , França , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Modelos Animais , Medição de Risco/normas , Falha de Tratamento , Estados Unidos , United States Food and Drug Administration/organização & administraçãoRESUMO
In any drug discovery and development effort, a reduction in the time of the lead optimization cycle is critical to decrease the time to license and reduce costs. In addition, ethical guidelines call for the more ethical use of animals to minimize the number of animals used and decrease their suffering. Therefore, any effort to develop drugs to treat cutaneous leishmaniasis requires multiple tiers of in vivo testing that start with higher-throughput efficacy assessments and progress to lower-throughput models with the most clinical relevance. Here, we describe the validation of a high-throughput, first-tier, noninvasive model of lesion suppression that uses an in vivo optical imaging technology for the initial screening of compounds. A strong correlation between luciferase activity and the parasite load at up to 18 days postinfection was found. This correlation allows the direct assessment of the effects of drug treatment on parasite burden. We demonstrate that there is a strong correlation between drug efficacy measured on day 18 postinfection and the suppression of lesion size by day 60 postinfection, which allows us to reach an accurate conclusion on drug efficacy in only 18 days. Compounds demonstrating a significant reduction in the bioluminescence signal compared to that in control animals can be tested in lower-throughput, more definitive tests of lesion cure in BALB/c mice and Golden Syrian hamsters (GSH) using Old World and New World parasites.