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1.
Lancet Glob Health ; 12(7): e1174-e1183, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38876763

RESUMO

We developed a comprehensive database of medicines that are used or are being investigated for pre-eclampsia or eclampsia, preterm birth or labour, postpartum haemorrhage, intrauterine growth restriction, and fetal distress and that were in active development between 2000 and 2021. A total of 444 candidates were identified: approximately half of candidates were in active development, two-thirds had been repurposed after initially being used for another condition, and just under half were in preclinical studies. Only 64 candidates were in active late-stage (phase 3) development as of Oct 25, 2021, and given the slow pace of biomedical development, it could take years before any of these products eventually make it to market. A lack of innovation for maternal health medicines persists, and the market continues to fail pregnant individuals. There is a need for collective action from all relevant stakeholders to accelerate investment in the development of new or improved medicines for pregnancy-related conditions.


Assuntos
Saúde Materna , Humanos , Feminino , Gravidez , Complicações na Gravidez/tratamento farmacológico , Desenvolvimento de Medicamentos , Pré-Eclâmpsia/tratamento farmacológico
2.
AAPS J ; 26(4): 71, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886275

RESUMO

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.


Assuntos
Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Humanos , Desenvolvimento de Medicamentos/métodos , Aprovação de Drogas , Interações Medicamentosas , Farmacologia Clínica/métodos , Farmacocinética , Ensaios Clínicos como Assunto/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Interações Alimento-Droga , Preparações Farmacêuticas/administração & dosagem
3.
Int J Mol Sci ; 25(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38891871

RESUMO

Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.


Assuntos
Antipsicóticos , Piperazinas , Receptores de Dopamina D3 , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/farmacologia , Piperazinas/uso terapêutico , Piperazinas/farmacologia , Receptores de Dopamina D3/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Animais , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Desenvolvimento de Medicamentos
4.
Int J Mol Sci ; 25(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38891882

RESUMO

According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin's possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.


Assuntos
Inibidores da Angiogênese , Glioblastoma , Metformina , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Neovascularização Patológica/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo
5.
Int J Mol Sci ; 25(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892264

RESUMO

Epilepsy is one of the most prevalent and serious brain disorders and affects over 70 million people globally. Antiseizure medications (ASMs) relieve symptoms and prevent the occurrence of future seizures in epileptic patients but have a limited effect on epileptogenesis. Addressing the multifaceted nature of epileptogenesis and its association with the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation requires a comprehensive understanding of the underlying mechanisms of these medications for the development of targeted therapeutic strategies beyond conventional antiseizure treatments. Several types of NLRP3 inhibitors have been developed and their effect has been validated both in in vitro and in vivo models of epileptogenesis. In this review, we discuss the advances in understanding the regulatory mechanisms of NLRP3 activation as well as progress made, and challenges faced in the development of NLRP3 inhibitors for the treatment of epilepsy.


Assuntos
Anticonvulsivantes , Descoberta de Drogas , Epilepsia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Humanos , Animais , Descoberta de Drogas/métodos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Desenvolvimento de Medicamentos
6.
Chem Biol Drug Des ; 103(6): e14568, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38898381

RESUMO

The utilization of large language models (LLMs) has become a significant advancement in the domains of medicine and clinical informatics, providing a revolutionary potential for scientific breakthroughs and customized therapies. LLM models are trained on large datasets and exhibit the capacity to comprehend and analyze intricate biological data, encompassing genomic sequences, protein structures, and clinical health records. With the utilization of their comprehension of the language of biology, they possess the ability to reveal concealed patterns and insights that may evade human researchers. LLMs have been shown to positively impact various aspects of molecular biology, including the following: genomic analysis, drug development, precision medicine, biomarker development, experimental design, collaborative research, and accessibility to specialized expertise. However, it is imperative to acknowledge and tackle the obstacles and ethical implications involved. The careful consideration of data bias and generalization, data privacy and security, explainability and interpretability, and ethical concerns around responsible application is vital. The successful resolution of these obstacles will enable us to fully utilize the capabilities of LLMs, leading to substantial progress in the fields of molecular biology and pharmaceutical research. This progression also has the ability to bolster influential impacts for both the individual and the broader community.


Assuntos
Desenvolvimento de Medicamentos , Humanos , Biologia Molecular
7.
Sci Rep ; 14(1): 13328, 2024 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858562

RESUMO

The emphasis on sustainable sources of drug development seems imminent with phytochemicals emerging as promising candidates due to their minimal probability of adverse effects. This study focuses on utilizing simple cinnamic acid and nicotinic acid derivatives as starting materials, employing an efficient synthetic protocol to obtain methyl 5-((cinnamoyloxy)methyl)picolinate targeting CVD mediated by multiple enzymes such as MAPK, PCSK9, MPO, SIRT1 and TNF-α. Comprehensive characterization of synthesized molecule is achieved through 1H, 13C, FT-IR, and HRMS methods. Additionally, the crystal structure was established via SC-XRD. Comparative analysis with the DFT-optimized structure identifies key nucleophilic and electrophilic regions for determining interactions with bio-targets. Notably, Compound 5 adheres to all drug-likeness criteria, further validated through screening similar pharmacophoric drugs from databases. Targeting bio-relevant areas with a specific focus on CVD drug development. The molecular docking studies elucidate ligand-protein interactions for better binding connectivity. This investigation further underscores the importance of sustainable practices, simple chemical synthesis, and computational approaches, contributing to the pursuit of eco-friendly drug development with enhanced safety profiles (MTT assay).


Assuntos
Doenças Cardiovasculares , Simulação de Acoplamento Molecular , Ácidos Picolínicos , Ácidos Picolínicos/química , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/metabolismo , Desenvolvimento de Medicamentos
8.
Curr Opin Pharmacol ; 76: 102465, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38830321

RESUMO

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard to G protein-coupled receptors involved in analgesia, it could be advantageous to develop such drugs if the analgesic effect is mediated by a different cellular signalling pathway than the adverse effects associated with the drug. Whilst this has been explored over a number of years for the µ receptor, it remains unclear whether this approach offers significant benefit for the treatment of pain. Nevertheless, the development of biased ligands at other G protein-coupled receptors in the CNS does offer some promise for the development of novel analgesic drugs in the future. Here we summarise and discuss the recent evidence to support this.


Assuntos
Analgésicos , Desenvolvimento de Medicamentos , Transdução de Sinais , Humanos , Animais , Transdução de Sinais/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Ligantes
9.
Neurology ; 103(1): e209533, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38833654

RESUMO

BACKGROUND AND OBJECTIVES: Pivotal trials for neurologic drugs in clinical development are often initiated without a phase 2 trial ("bypass") or despite a negative phase 2 efficacy result ("override"). Such practices may degrade the risk/benefit ratio of phase 3 trials. The aim of this study is to estimate the proportion of phase 3 trials for 10 neurologic diseases started without a positive phase 2 trial, to identify factors associated with this practice, and to investigate any association with unfavorable phase 3 trial outcomes. METHODS: We searched ClinicalTrials.gov for phase 3 trials completed during 2011-2021, with at least 1 research site in the United States, Canada, the European Union, the United Kingdom, or Australia, and investigating drugs or biologics for treatment of 10 neurologic conditions. Our primary objective was to assess the prevalence of phase 2 bypass/override by searching for preceding phase 2 trials. We used Fisher exact tests to determine whether phase 3 trial characteristics and trial results were associated with phase 2 bypass/override. RESULTS: Of the 1,188 phase 3 trials captured in our search, 113 met eligibility for inclusion. Of these, 46% were not preceded by a phase 2 trial that was positive on an efficacy endpoint (31% bypassed and 15% overrode phase 2 trial). Phase 2 bypass/override was not associated with industry funding (77% vs 89%, 95% CI 0.75-7.55, p = 0.13) or testing already approved interventions (23% vs 15%, 95% CI 0.60-5.14, p = 0.33). Overall, phase 3 trials based on phase 2 bypassed/override were statistically significantly less likely to be positive on their primary outcome (31% vs 57%, respectively, 95% CI 1.21-6.92, p = 0.01). This effect disappeared when indications characterized by nearly universal positive or negative results were excluded. Trials that bypassed/overrode phase 2 trials were not statistically significantly more likely to be terminated early because of safety or futility (29% vs 15%, respectively, 95% CI 0.15-1.18, p = 0.11) and did not show increased risk of adverse events in experimental arms (RR = 1.46, 95% CI 1.19-1.79, vs RR = 1.36, 95% CI 1.10-1.69, respectively, p = 0.65). DISCUSSION: Almost half of the neurologic disease phase 3 trials were initiated without the support of a positive phase 2 trial. Although our analysis does not establish harm with bypass/override, its prevalence and the scientific rationale for phase 2 trial testing favor development of criteria defining when phase 2 bypass/override is justified.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Doenças do Sistema Nervoso , Humanos , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/epidemiologia , Desenvolvimento de Medicamentos/métodos , Prevalência
10.
Rinsho Ketsueki ; 65(5): 353-361, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38825514

RESUMO

For nearly 40 years, combination therapy with cytarabine and anthracycline has been the standard of care for acute myeloid leukemia (AML). The cytogenetics and molecular biology of AML are now understood, and the treatment of AML has undergone dramatic changes in Japan with the launch of drugs such as FLT3 inhibitors, Bcl2 inhibitors, and hypomethylating agents since 2018. However, AML remains very difficult to cure, with a high relapse rate. Here, we review novel agents that have not yet been approved in Japan (CPX-351, IDH inhibitors, menin inhibitors, and oral azacitidine) as potential treatments for AML, as well as therapeutic antibodies (BiTEs, DARTs, immune checkpoint inhibitors) currently under investigation in clinical trials or in development. These novel agents are being investigated not only as monotherapy but also as combination therapy with intensive chemotherapy or azacitidine/venetoclax. The new era of AML treatment is expected to support a variety of goals, including leukemic cell elimination, long-term remission, and improved quality of life.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Terapia de Alvo Molecular
11.
Bioorg Chem ; 149: 107466, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38843684

RESUMO

Targeted protein degradation (TPD) technologies have become promising therapeutic approaches through degrading disease-causing proteins via the protein degradation system. Autophagy is a fundamental biological process with a high relationship to protein degradation, which belongs to one of two main protein degradation pathways, the autophagy-lysosomal system. Recently, various autophagy-based TPD techniques ATTECs, AUTACs, and AUTOTACs, etc, have also been gradually developed, and they have achieved efficient degradation potency for the targeted protein, expanding the potential of degradation for large-size proteins or protein aggregates. Herein, we introduce the machinery of autophagy and its relation to protein degradation, and multiple methods for using autophagy to specifically degrade target proteins.


Assuntos
Autofagia , Desenvolvimento de Medicamentos , Proteólise , Autofagia/efeitos dos fármacos , Humanos , Proteólise/efeitos dos fármacos , Lisossomos/metabolismo , Animais , Proteínas/metabolismo , Proteínas/química , Proteínas/antagonistas & inibidores , Estrutura Molecular
12.
Eur J Med Chem ; 274: 116544, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38850855

RESUMO

Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0.78-1.56 µg/mL), poor hemolytic activity (HC50 > 200 µg/mL), and low cytotoxicity (CC50 > 100 µg/mL). Further biological evaluation results indicated that 43 exerted antibacterial effects by directly destroying bacterial cell membranes and displayed rapid bactericidal properties (within 0.5-1 h), leading to a very low probability of drug resistance. Moreover, in a murine model of corneal infection, 43 exhibited a strong in vivo antibacterial efficacy. These findings indicate that 43 is a promising candidate compound for the treatment of bacterial infections.


Assuntos
Antibacterianos , Compostos Benzidrílicos , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Fenóis , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Fenóis/farmacologia , Fenóis/química , Fenóis/síntese química , Animais , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Relação Estrutura-Atividade , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/química , Compostos Benzidrílicos/síntese química , Estrutura Molecular , Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hemólise/efeitos dos fármacos , Desenvolvimento de Medicamentos
13.
Eur J Med Chem ; 274: 116559, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38850856

RESUMO

Tuberculosis remains the second deadliest infectious disease in humans and a public health threat due to the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. Therefore, it is urgent to identify new anti-tuberculosis treatments and novel therapeutic targets to prevent the emergence of resistance. In recent years, the study of anti-tuberculosis properties of nitroaromatic compounds has led to the identification of two novel biological targets, the deazaflavin (F420)-dependent nitroreductase Ddn and the decaprenylphosphoryl-ß-d-ribose 2'-epimerase DprE1. This review aims to show why Ddn and DprE1 are promising therapeutic targets and highlight nitroaromatic compounds interest in developing new anti-tuberculosis treatments active against MDR-TB and XDR-TB. Despite renewed interest in the development of new anti-tuberculosis nitroaromatic compounds, pharmaceutical companies often exclude nitro-containing molecules from their drug discovery programs because of their toxic and mutagenic potential. This exclusion results in missed opportunities to identify new nitroaromatic compounds and promising therapeutic targets.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Nitrorredutases , Antituberculosos/farmacologia , Antituberculosos/química , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrorredutases/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Nitrocompostos/química , Nitrocompostos/farmacologia , Estrutura Molecular , Testes de Sensibilidade Microbiana , Desenvolvimento de Medicamentos , Oxirredutases do Álcool
14.
Pharmacol Rev ; 76(4): 561-563, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38876495

RESUMO

Steatotic liver disease (SLD) is a highly prevalent chronic liver disease with significant challenges for global health. The pathophysiology of SLD involves an interplay among genetic, endocrine, and metabolic factors. Successful management of SLD entails accurate diagnosis and disease monitoring through noninvasive methods such as advanced imaging techniques and biomarkers. Many emerging pharmacotherapies for SLD are now in the pipeline, which target different pathways like collagen turnover, fibrogenesis, inflammation, and metabolism. The recent approval of resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has been a milestone in addressing the unmet medical need for an efficacious SLD treatment. Finally, the potential of personalized medicine approaches and interdisciplinary cooperation in improving patient outcomes and reducing disease burden should be strongly pursued. SIGNIFICANCE STATEMENT: The healthcare burden due to steatotic liver disease (SLD) is enormous. This perspective sheds light on the recent advances in understanding the pathophysiology and diagnosis of SLD as well as promising drug development approaches.


Assuntos
Fígado Gorduroso , Animais , Humanos , Desenvolvimento de Medicamentos , Fígado Gorduroso/terapia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Medicina de Precisão
15.
Cancer Cell ; 42(6): 923-929, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38861927

RESUMO

Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine.


Assuntos
Biomarcadores Tumorais , Desenvolvimento de Medicamentos , Inibidores de Poli(ADP-Ribose) Polimerases , Medicina de Precisão , Humanos , Desenvolvimento de Medicamentos/métodos , Medicina de Precisão/métodos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias/tratamento farmacológico
17.
Theranostics ; 14(8): 3300-3316, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855182

RESUMO

Patient-derived organoids (PDOs) have emerged as a promising platform for clinical and translational studies. A strong correlation exists between clinical outcomes and the use of PDOs to predict the efficacy of chemotherapy and/or radiotherapy. To standardize interpretation and enhance scientific communication in the field of cancer precision medicine, we revisit the concept of PDO-based drug sensitivity testing (DST). We present an expert consensus-driven approach for medication selection aimed at predicting patient responses. To further standardize PDO-based DST, we propose guidelines for clarification and characterization. Additionally, we identify several major challenges in clinical prediction when utilizing PDOs.


Assuntos
Antineoplásicos , Consenso , Desenvolvimento de Medicamentos , Neoplasias , Organoides , Medicina de Precisão , Organoides/efeitos dos fármacos , Humanos , Medicina de Precisão/métodos , Neoplasias/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais/métodos
18.
Clin Pharmacol Ther ; 116(1): 42-51, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38698592

RESUMO

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.


Assuntos
Arritmias Cardíacas , Síndrome do QT Longo , Humanos , Medição de Risco/métodos , Síndrome do QT Longo/induzido quimicamente , Arritmias Cardíacas/induzido quimicamente , Desenvolvimento de Medicamentos/legislação & jurisprudência , Desenvolvimento de Medicamentos/métodos , Eletrocardiografia/efeitos dos fármacos , Ensaios Clínicos como Assunto/legislação & jurisprudência , Ensaios Clínicos como Assunto/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos
19.
Drugs ; 84(5): 503-525, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38777962

RESUMO

IgA nephropathy is a common glomerulonephritis consequent to the autoimmune response to aberrant glycosylated immunoglobulin (Ig) A antibodies. Although it has historically been considered a benign disease, it has since become clear that a substantial percentage of patients reach end-stage kidney failure over the years. Several therapeutic attempts have been proposed, with systemic steroids being the most prevalent, albeit burdened by possible serious adverse events. Thanks to the more in-depth knowledge of the pathogenesis of IgA nephropathy, new treatment targets have been identified and new drugs developed. In this narrative review, we summarise the molecules under clinical development for the treatment of IgA nephropathy. As a search strategy, we used PubMed, Google, ClinicalTrials.gov and abstracts from recent international congresses. TRF budesonide and sparsentan are the two molecules at a more advanced stage, just entering the market. Other promising agents are undergoing phase III clinical development. These include anti-APRIL and anti-BLyS/BAFF antibodies and some complement inhibitors. Other new possible strategies include spleen tyrosine kinase inhibitors, anti-CD40 ligands and anti-CD38 antibodies. In an era increasingly characterised by 'personalised medicine' and 'precision therapy' approaches and considering that the potential therapeutic armamentarium for IgA nephropathy will be very broad in the near future, the identification of biomarkers capable of helping the nephrologist to select the right drug for the right patient should be the focus of future studies.


Assuntos
Desenvolvimento de Medicamentos , Glomerulonefrite por IGA , Glomerulonefrite por IGA/tratamento farmacológico , Humanos
20.
Expert Opin Ther Targets ; 28(5): 345-356, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38714500

RESUMO

INTRODUCTION: Mayaro fever is an emerging viral disease that manifests as an acute febrile illness. The disease is self-limiting, however joint pain can persist for months leading to chronic arthralgia. There is no specific treatment available, which ultimately leads to socioeconomic losses in populations at risk as well as strains to the public health systems. AREAS COVERED: We reviewed the candidate treatments proposed for Mayaro virus (MAYV) infection and disease, including antiviral compounds targeting viral or host mechanisms, and pathways involved in disease development and pathogenicity. We assessed compound screening technologies and experimental infection models used in these studies and indicated the advantages and limitations of available technologies and intended therapeutic strategies. EXPERT OPINION: Although several compounds have been suggested as candidate treatments against MAYV infection, notably those with antiviral activity, most compounds were assessed only in vitro. Compounds rarely progress toin vivo or preclinical studies, and such difficulty may be associated with limited experimental models. MAYV biology is largely inferred from related alphaviruses and reflected by few studies focusing on target proteins or mechanisms of action for MAYV. Therapeutic strategies targeting pathogenic inflammatory responses have shown potential against MAYV-induced disease in vivo, which might reduce long-term sequelae.


Assuntos
Infecções por Alphavirus , Antivirais , Descoberta de Drogas , Animais , Antivirais/farmacologia , Humanos , Infecções por Alphavirus/tratamento farmacológico , Infecções por Alphavirus/virologia , Alphavirus , Artralgia/tratamento farmacológico , Desenvolvimento de Medicamentos , Terapia de Alvo Molecular , Modelos Animais de Doenças
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