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1.
Medicina (Kaunas) ; 59(1)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36676801

RESUMO

Background and objectives: EG-Mirotin (active ingredient EGT022) targets nonproliferative diabetic retinopathy (NPDR), the early stage of retinopathy. EG-Mirotin reverses capillary damage before NPDR progresses to an irreversible stage. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. End of study was approximately 8 ± 1 weeks (57 ± 7 days) after the first drug administration. Results: EG-Mirotin injections were well tolerated, with no dose-limiting adverse events, serious adverse events, or deaths. Four treatment-emergent adverse events (TEAEs) unrelated to the investigational drug were observed in 2 out of 10 participants (20%) who had received the investigational drug. The overall average percent change in ischemic index at each evaluation point compared with baseline was statistically significant (Greenhouse-Geisser F = 9.456, p = 0.004 for the main effect of time), and a larger change was observed when the baseline ischemic index value was high (Greenhouse-Geisser F = 10.946, p = 0.002 for time × group interaction). Conclusions: The EG-Mirotin regimen established in this study was shown to be feasible and safe and was associated with a trend toward potential improvement in diabetes-induced ischemia and retinal capillary leakage.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Preparações Farmacêuticas , Drogas em Investigação/uso terapêutico , Angiofluoresceinografia , Peptídeos/uso terapêutico
2.
Comput Biol Med ; 153: 106494, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36587568

RESUMO

One of the major challenges in drug development is having acceptable levels of efficacy and safety throughout all the phases of clinical trials followed by the successful launch in the market. While there are many factors such as molecular properties, toxicity parameters, mechanism of action at the target site, etc. that regulates the therapeutic action of a compound, a holistic approach directed towards data-driven studies will invariably strengthen the predictive toxicological sciences. Our quest for the current study is to find out various reasons as to why an investigational candidate would fail in the clinical trials after multiple iterations of refinement and optimization. We have compiled a dataset that comprises of approved and withdrawn drugs as well as toxic compounds and essentially have used time-split based approach to generate the training and validation set. Five highly robust and scalable machine learning binary classifiers were used to develop the predictive models that were trained with features like molecular descriptors and fingerprints and then validated rigorously to achieve acceptable performance in terms of a set of performance metrics. The mean AUC scores for all the five classifiers with the hold-out test set were obtained in the range of 0.66-0.71. The models were further used to predict the probability score for the clinical candidate dataset. The top compounds predicted to be toxic were analyzed to estimate different dimensions of toxicity. Apparently, through this study, we propose that with the appropriate use of feature extraction and machine learning methods, one can estimate the likelihood of success or failure of investigational drugs candidates thereby opening an avenue for future trends in computational toxicological studies. The models developed in the study can be accessed at https://github.com/gnsastry/predicting_clinical_trials.git.


Assuntos
Drogas em Investigação , Aprendizado de Máquina , Drogas em Investigação/uso terapêutico
3.
Nature ; 612(7941): S54-S55, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36536215
4.
JAMA Health Forum ; 3(12): e224627, 2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36525254

RESUMO

This Viewpoint assesses patient access to compassionate use treatments for medical care and advocates a framework for helping to facilitate such access.


Assuntos
Ensaios de Uso Compassivo , Drogas em Investigação , Humanos , Empatia
5.
JAMA Netw Open ; 5(11): e2239766, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318206

RESUMO

Importance: The expanded access (EA) pathway permits patients to be treated with investigational medical products outside clinical trials. Because cancer care is a common indication for which EA is sought and these efforts require physician management, understanding oncologists' perspectives can help illuminate factors influencing patient access. Objective: To learn how oncologists practicing at academic medical centers (AMCs) perceive EA and their role in offering it. Design, Setting, and Participants: This qualitative study used data from semistructured interviews conducted from February 2020 to September 2021 with a purposive sample of oncologists recruited from large, urban AMCs in the northeast United States. Oncologists who had submitted at least 1 single-patient EA request to the institutional review boards at the University of Pennsylvania, Children's Hospital of Philadelphia, NYU Langone Health, and Dana-Farber Cancer Institute from January 1, 2014, through January 31, 2020, were eligible to participate. Data were analyzed from July 2021 to March 2022. Main Outcomes and Measures: Interviews focused on oncologist practice demographics, experience with EA, factors relevant to decisions to pursue EA and comfort with those decisions, perspectives on oncologists' role in EA, perspectives on the FDA's role, and the Right to Try pathway to access investigational drugs. Results: Eligible oncologists were interviewed until thematic saturation was reached, resulting in 25 interviews; most participants were women (15 participants [60%]), reported primarily treating adult patients (15 participants [60%]), had more than 10 years of clinical experience (16 participants [64%]), and had submitted at least 2 single-patient EA requests to their institutional review boards during the relevant period (14 participants [56%]). Oncologists viewed EA as an important tool for securing what they determined to be the best treatment option for their patients based on their own expert assessment of available data. Interviewees reported that they would rather access interventions as commercially available products or through clinical trials; however, if the preferred option was not available through these means, they viewed pursuit of EA as part of their obligation to patients, while often recognizing the potential for inequities in the broader patient population beyond their institutions. Participating oncologists felt confident pursuing investigational drugs for treatment use, despite the absence of FDA marketing approval, and did not necessarily view EA as a last resort. Conclusions and Relevance: These findings indicate that oncologists practicing in large academic settings sought to treat patients with the interventions they deemed most likely to be beneficial, regardless of approval status. As such, they viewed EA as an unexceptional means to obtain promising products, although it remains unclear whether their confidence in evaluating investigational treatments was justified. Future research should examine whether oncologists outside large AMCs share this confidence, as differences may influence patient access to the EA treatment pathway.


Assuntos
Drogas em Investigação , Oncologistas , Adulto , Criança , Humanos , Feminino , Masculino , Ensaios de Uso Compassivo , Organizações , Projetos de Pesquisa
6.
Dis Markers ; 2022: 8809956, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225197

RESUMO

Lung adenocarcinoma (LUAD) is the most common subtype of nonsmall cell lung cancer. Cytochrome c (Cyt c), which is produced from mitochondria, interacts with a protein called Apaf-1 to form the heptameric apoptosome. This heptameric apoptosome then activates the caspase cascade, which ultimately results in the execution of apoptosis. The purpose of our research was to discover a new prognostic model that is based on cytochrome c-related genes (CCRGs) for LUAD patients. Through LASSO regression analysis conducted on the LUAD datasets included in the TCGA datasets, a CCRGs signature was created. The diagnostic accuracy of the multigene signature was verified by an independent source using the GSE31210 and GSE72094 datasets. The GO and KEGG enrichment analysis were performed. In this study, there were 159 differentially expressed CCRGs in the TCGA dataset, while there were 68 differentially expressed CCRGs in the GSE31210 dataset. Additionally, there were 57 genes that overlapped across the two datasets. Using LASSO and Cox regression analysis, a signature consisting of 12 differentially expressed CCRGs was developed from the total of 57 such genes. On the basis of their risk ratings, patients were categorized into high-risk and low-risk categories, with low-risk patients having lower risk scores and a greater likelihood of surviving the disease. Univariate and multivariate analyses both concluded that this signature is an independent risk factor for LUAD. ROC curves demonstrated that this risk signature is capable of accurately predicting the 1-year, 2-year, 3-year, and 5-year survival rates of patients who have LUAD. The infiltration of antigen-presenting cells was higher in the low-risk group, such as aDCs, DCs, pDCs, and iDCs. The expression of multiple immune checkpoints was significantly higher in the low-risk group, such as BTLA, CD28, and CD86. Finally, we showed that the signature can be used to predict the drug sensitivity of already available or under investigational drugs. Overall, patient classification and individualized therapy options may benefit from this study's development of a powerful gene signature with high value for prognostic prediction in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Apoptossomas , Antígenos CD28 , Caspases , Citocromos c , Drogas em Investigação , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
7.
Nat Commun ; 13(1): 5879, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202818

RESUMO

Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1 infection. While weak interactions of short phenylalanine-glycine (FG) containing peptides with isolated capsid hexamers have been characterized, how these cellular factors functionally engage with biologically relevant mature HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices. Structural studies revealed that multivalent CPSF6 assembly is mediated by LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a subset of hydrophobic capsid pockets positioned along adjoining hexamers. In infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for functional virus-host interactions. The investigational drug lenacapavir accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1 inside the nucleus without displacing the tightly bound cellular cofactor from virus cores. These results establish previously undescribed mechanisms of virus-host interactions and antiviral action.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Príons , Proteínas do Capsídeo/metabolismo , Drogas em Investigação , Glicina/metabolismo , HIV-1/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fenilalanina/metabolismo , Príons/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
8.
J Hematol Oncol ; 15(1): 139, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36199142

RESUMO

The booming of gene and cell therapy (GCT) worldwide in recent years has been observed, especially in the field of cancers. In order to provide the comprehensive GCT landscape in China with a focus on differential development pathways under the current dual-track regulation mode, we analyzed 953 clinical trials initiated by March 2021 including Investigational New Drugs (IND) registered trials and investigator-initiated trials (IITs). We classified GCT products into three categories and analyzed the clinical development by phases and regulation tracks, disease areas, indications, and targets. We found that CAR-T therapies from ex vivo category and stem and somatic cells from non-gene category are two most studied therapy types and GCT mostly focused on cancers. The number of IITs far exceeded IND-registered trials except for in vivo category. After 2017, when the cell therapy guideline issued, products of all categories boomed, especially the ex vivo categories. These data showed that current dual regulation tracks in China complemented each other and together facilitated the GCT development, especially after 2017. More consistent technical standards and risk-based regulation will help bring more GCT products to patients.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Drogas em Investigação , Terapia Genética , Humanos , Neoplasias/genética , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética
9.
Expert Opin Investig Drugs ; 31(10): 1101-1107, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36194037

RESUMO

INTRODUCTION: Generic fibrates are used off-label as add-in therapy for the management of primary biliary cholangitis (PBC) but with unproven long-term liver-related survival benefits. The recently developed fibrate, seladelpar, has shown promising results in clinical trials, but these outcomes have been previously marred by safety concerns. AREAS COVERED: We summarize existing treatment options in PBC and evaluate current trial data for seladelpar in relation to liver biochemistry, symptomology, and safety. EXPERT OPINION: Seladelpar leads to marked improvement in liver biochemistry and may improve symptoms. Safety concerns around liver toxicity appear to have been addressed. With likely increasing evidence compared to existing off-label fibrates, seladelpar has the potential as an attractive future second-line agent in PBC.


Assuntos
Acetatos , Drogas em Investigação , Cirrose Hepática Biliar , Humanos , Acetatos/efeitos adversos , Drogas em Investigação/efeitos adversos , Cirrose Hepática Biliar/tratamento farmacológico , Ensaios Clínicos como Assunto
10.
MMWR Morb Mortal Wkly Rep ; 71(37): 1190-1195, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36107794

RESUMO

Currently, no Food and Drug Administration (FDA)-approved treatments for human monkeypox are available. Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. CDC holds a nonresearch EA-IND protocol that facilitates access to and use of tecovirimat for treatment of monkeypox.§ The protocol includes patient treatment and adverse event reporting forms to monitor safety and ensure intended clinical use in accordance with FDA EA-IND requirements. The current multinational monkeypox outbreak, first detected in a country where Monkeypox virus infection is not endemic in May 2022, has predominantly affected gay, bisexual, and other men who have sex with men (MSM) (1,2). To describe characteristics of persons treated with tecovirimat for Monkeypox virus infection, demographic and clinical data abstracted from available tecovirimat EA-IND treatment forms were analyzed. As of August 20, 2022, intake and outcome forms were available for 549 and 369 patients, respectively; 97.7% of patients were men, with a median age of 36.5 years. Among patients with available data, 38.8% were reported to be non-Hispanic White (White) persons, 99.8% were prescribed oral tecovirimat, and 93.1% were not hospitalized. Approximately one half of patients with Monkeypox virus infection who received tecovirimat were living with HIV infection. The median interval from initiation of tecovirimat to subjective improvement was 3 days and did not differ by HIV infection status. Adverse events were reported in 3.5% of patients; all but one adverse event were nonserious. These data support the continued access to and treatment with tecovirimat for patients with or at risk for severe disease in the ongoing monkeypox outbreak.


Assuntos
Infecções por HIV , Varíola dos Macacos , Minorias Sexuais e de Gênero , Adulto , Animais , Antivirais/uso terapêutico , Drogas em Investigação/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Homossexualidade Masculina , Humanos , Masculino , Varíola dos Macacos/tratamento farmacológico , Varíola dos Macacos/epidemiologia , Vírus da Varíola dos Macacos , Estados Unidos
11.
Ann Clin Transl Neurol ; 9(10): 1551-1564, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36083004

RESUMO

OBJECTIVE: ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, TURSO), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. Therefore, our goal was to obtain an unbiased landscape of the molecular effects of AMX0035 in ALS patient-derived cells. METHODS: We investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls (n = 12/group) treated with PB, TUDCA, or PB-TUDCA combination (Combo). Data were evaluated with multiple approaches including differential gene expression and metabolite abundance, Gene Ontology and metabolic pathway analysis, weighted gene co-expression correlation analysis (WGCNA), and combined multiomics integrated analysis. RESULTS: Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. WGCNA showed significant correlations between ALS gene expression modules and clinical parameters that were abolished by Combo treatment. INTERPRETATION: This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared with the individual compounds and provides clues to drug targets and mechanisms of action, which may underlie the benefits of this investigational drug combination.


Assuntos
Esclerose Amiotrófica Lateral , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Drogas em Investigação , Fibroblastos/metabolismo , Humanos , RNA , Ácido Tauroquenodesoxicólico
12.
Expert Opin Investig Drugs ; 31(10): 1087-1100, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36175360

RESUMO

INTRODUCTION: Kidney transplant rejection remains an important clinical problem despite the development of effective immunosuppressive therapy. Two major types of rejection are recognized, T-cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), which have a different pathophysiology and are treated differently. Unfortunately, long-term outcomes of both TCMR and ABMR remain unsatisfactory despite current therapy. Hence, alternative therapeutic drugs are urgently needed. AREAS COVERED: This review covers novel and investigational drugs for the pharmacological treatment of kidney transplant rejection. Potential therapeutic strategies and future directions are discussed. EXPERT OPINION: The development of alternative pharmacologic treatment of rejection has focused mostly on ABMR, since this is the leading cause of kidney allograft loss and currently lacks an effective, evidence-based therapy. At present, there is insufficient high-quality evidence for any of the covered investigational drugs to support their use in ABMR. However, with the emergence of targeted therapies, the potential arises for individualized treatment strategies. In order to generate more high-quality evidence for such strategies and overcome the obstacles of classic randomized controlled trials, we advocate the implementation of adaptive trial designs and surrogate clinical endpoints. We believe such adaptive trial designs could help to understand the risks and benefits of promising drugs such as tocilizumab, clazakizumab, belimumab, and imlifidase.


Assuntos
Nefropatias , Transplante de Rim , Biomarcadores , Drogas em Investigação/efeitos adversos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Rim , Nefropatias/tratamento farmacológico , Transplante de Rim/efeitos adversos
13.
Drug Des Devel Ther ; 16: 2995-3013, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110398

RESUMO

Purpose: The development of effective treatments for coronavirus infectious disease 19 (COVID-19) caused by SARS-Coronavirus-2 was hindered by the little data available about this virus at the start of the pandemic. Drug repurposing provides a good strategy to explore approved drugs' possible SARS-CoV-2 antiviral activity. Moreover, drug synergism is essential in antiviral treatment due to improved efficacy and reduced toxicity. In this work, we studied the effect of approved and investigational drugs on one of SARS-CoV-2 essential proteins, the main protease (Mpro), in search of antiviral treatments and/or drug combinations. Methods: Different possible druggable sites of Mpro were identified and screened against an in-house library of more than 4000 chemical compounds. Molecular dynamics simulations were carried out to explore conformational changes induced by different ligands' binding. Subsequently, the inhibitory effect of the identified compounds and the suggested drug combinations on the Mpro were established using a 3CL protease (SARS-CoV-2) assay kit. Results: Three potential inhibitors in three different binding sites were identified; favipiravir, cefixime, and carvedilol. Molecular dynamics simulations predicted the synergistic effect of two drug combinations: favipiravir/cefixime, and favipiravir/carvedilol. The in vitro inhibitory effect of the predicted drug combinations was established on this enzyme. Conclusion: In this work, we could study one of the promising SARS-CoV-2 viral protein targets in searching for treatments for COVID-19. The inhibitory effect of several drugs on Mpro was established in silico and in vitro assays. Molecular dynamics simulations showed promising results in predicting the synergistic effect of drug combinations.


Assuntos
Proteases 3C de Coronavírus , Amidas , Antivirais/química , Antivirais/farmacologia , Carvedilol , Cefixima , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Drogas em Investigação , Humanos , Ligantes , Simulação de Dinâmica Molecular , Pirazinas , SARS-CoV-2 , Proteínas Virais
14.
Sci Adv ; 8(38): eabq0866, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36129975

RESUMO

Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1-mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration-approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.


Assuntos
Rim Policístico Autossômico Recessivo , Descoberta de Drogas , Drogas em Investigação , Humanos , Dispositivos Lab-On-A-Chip , Organoides/metabolismo , Rim Policístico Autossômico Recessivo/genética , Rim Policístico Autossômico Recessivo/metabolismo , Rim Policístico Autossômico Recessivo/patologia
15.
Clin Transl Sci ; 15(11): 2567-2575, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36066467

RESUMO

Human radiolabeled mass balance studies are an important component of the clinical pharmacology programs supporting the development of new investigational drugs. These studies allow for understanding of the absorption, distribution, metabolism, and excretion of the parent drug and metabolite(s) in the human body. Understanding the drug's disposition as well as metabolite profiling and abundance via mass balance studies can help inform the overall drug development program. A survey of the US Food and Drug Administration (FDA)-approved new drug applications (NDAs) indicated that about 66% of the drugs had relied on findings from the mass balance studies to help understand the pharmacokinetic characteristics of the drug and to inform the overall drug development program. When such studies were not available in the original NDA, adequate justifications were routinely provided. Of the 104 mass balance studies included in this survey, most of the studies were conducted in healthy volunteers (90%) who were mostly men (>86%). The studies had at least six evaluable participants (66%) and were performed using the final route(s) of administration (98%). Eighty-five percent of the studies utilized a dose within the pharmacokinetic linearity range with 54% of the studies using a dose the same as the approved dose. Nearly all studies were performed as a single-dose (97%) study using a fit-for-purpose radiolabeled formulation. In this analysis, we summarized the current practices for conducting mass balance studies and highlighted the importance of conducting appropriately designed human radiolabeled mass balance studies and the challenges associated with inadequately designed or untimely studies.


Assuntos
Drogas em Investigação , Farmacologia Clínica , Masculino , Estados Unidos , Humanos , Feminino , United States Food and Drug Administration , Preparações Farmacêuticas/metabolismo , Coleta de Dados , Aprovação de Drogas
16.
Expert Opin Investig Drugs ; 31(10): 1109-1124, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36066506

RESUMO

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic condition in childhood. The management of JIA has been revolutionized thanks to the development of new powerful drugs and the possibility to conduct controlled clinical trials with support from legislative initiatives and availability of international collaborative networks. Trials are still needed in children because we now have new drugs related to specific JIA category. AREAS COVERED: The review is centered on the latest achievements in the field, focusing on new investigational drugs which are currently or have been recently tested for JIA treatment, encompassing agents in early phase of clinical development. EXPERT OPINION: Despite the tremendous improvement witnessed in the field of JIA treatment in the past 20 years, there are still many unmet needs to be prioritized. Studies on disease pathogenesis will hopefully help in the identification of new treatment targets for individual JIA categories, that could possibly favor a stricter disease control and contribute to solve the issue of refractory JIA. Novel strategies aimed at the prevention of the risk of long-term joint damage are also desirable, as well as the discovery of predictive biomarkers for treatment efficacy and safety in the individual patient.


Assuntos
Antirreumáticos , Artrite Juvenil , Antirreumáticos/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Criança , Drogas em Investigação/efeitos adversos , Humanos , Resultado do Tratamento
17.
Am J Health Syst Pharm ; 79(23): 2118-2127, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36056791

RESUMO

PURPOSE: The process of providing treatment with investigational drugs through expanded access is explained. Roles and informational resources for pharmacists are discussed. SUMMARY: Expanded access is a regulatory pathway for the treatment of serious or life-threatening diseases or conditions with investigational agents outside of clinical trials. In the setting of no available therapies or ineligibility for clinical trials, a patient and their treating physician may pursue therapies that are not approved by the Food and Drug Administration (FDA). The drug manufacturer, FDA, and institutional review boards are required stakeholders in the expanded access process. Other pathways for obtaining investigational agents outside of clinical trials, including federal Right to Try and emergency use authorization, exist but differ in their level of involvement of these key stakeholders. Pharmacists are equipped to be involved in therapy identification, risk vs benefit evaluations, therapy preparation and administration, supportive care, transitions of care, and regulatory compliance. Specific websites, publications, and organizations can aid in navigating expanded access. CONCLUSION: Combining elements of traditional clinical care and research, expanded access involves direct treatment with non-FDA-approved agents outside of a clinical trial. Healthcare providers should be aware of the possibility of providing investigational treatments after all approved options have been exhausted.


Assuntos
Ensaios de Uso Compassivo , Farmacêuticos , Estados Unidos , Humanos , Drogas em Investigação/uso terapêutico , United States Food and Drug Administration , Terapias em Estudo
18.
Microbiol Spectr ; 10(5): e0269322, 2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36094219

RESUMO

The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD50) analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used as comparators during the future evaluation of novel antimicrobials, and we confirmed that the model can effectively differentiate between successful and unsuccessful treatments, as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa strains, with the ability to provide rapid preclinical evaluation of novel antimicrobials and support data from clinical studies during the investigational drug development process. IMPORTANCE The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials. Successful outcomes in animal models not only justify progression of new drugs into human clinical trials but also can support FDA decisions if clinical trial sizes are small due to a small population of infections with specific drug-resistant strains. However, in both cases the preclinical animal model needs to be well characterized and provide robust and reproducible data. Toward this goal, we have refined an existing mouse model to better predict the efficacy of novel antibiotics. This improved model provides an important tool to better predict the clinical success of new antibiotics.


Assuntos
Amicacina , Pseudomonas aeruginosa , Camundongos , Humanos , Animais , Amicacina/farmacologia , Aztreonam/farmacologia , Testes de Sensibilidade Microbiana , Drogas em Investigação/farmacologia , Farmacorresistência Bacteriana Múltipla , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias
19.
Lancet ; 400(10351): 512-521, 2022 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-35964611

RESUMO

BACKGROUND: The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time. METHODS: We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model. FINDINGS: We analysed 465 protocols that enrolled 13 847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13 847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer. INTERPRETATION: During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours. FUNDING: National Cancer Institute.


Assuntos
Antineoplásicos , Desenvolvimento de Medicamentos , Ensaios Clínicos Fase I como Assunto , Drogas em Investigação , Feminino , Humanos , Masculino , National Cancer Institute (U.S.) , Neoplasias/tratamento farmacológico , Estados Unidos/epidemiologia
20.
Expert Opin Investig Drugs ; 31(9): 895-904, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35961945

RESUMO

INTRODUCTION: Thymic epithelial tumors (TETs) are rare tumors of thymic epithelial cells. Treatment options for advanced disease patients who failed standard platinum-based chemotherapy are limited. AREAS COVERED: Phase I and II trials published in the last five years testing new systemic treatments for advanced TET patients are discussed, as well as ongoing trials. A PubMed database literature review was conducted for articles published between January 2016 and December 2021, and ongoing clinical trials were retrieved from ClinicalTrials.gov database. EXPERT OPINION: The most promising classes of new drugs in TET patients are angiogenesis inhibitors and immune checkpoint antibodies (ICIs). Sunitinib and Lenvatinib showed response rates of 26% and 38%, respectively, and ICIs showed durable responses in 20-25% in thymic carcinoma (TCs). Both approaches are mainly active in TCs, therefore new treatment options for thymomas are an unmet medical need.Two major new therapeutic strategies are ICI combinations with other drugs and drugs that target pathways that are dysregulated in TETs.Future challenges include the development of preclinical models to help identify novel targets and test new treatment strategies, and randomized clinical trials to provide reliable evidence based on survival endpoints.


Assuntos
Neoplasias Epiteliais e Glandulares , Timoma , Neoplasias do Timo , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Sunitinibe/uso terapêutico , Timoma/patologia , Timoma/terapia , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologia
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