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1.
Pharm Res ; 36(11): 153, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482243

RESUMO

The purpose of this review is to discuss the challenges associated with the development of nanoparticle-based quality drug products in adhering to the principles of quality by design (QbD) and defining appropriate quality parameters towards successful product development. With the advent of nanotechnology into the pharmaceutical field, the novel field of nanomedicine was born. Due to their unique properties in terms of size, conformation and targeted delivery, nanomedicines are able to overcome many drawbacks of conventional medicine. As nano-sized formulations have made their way into more and more therapies, it has became clear that these very unique properties create hurdles for nanomedicines in successfully traversing the regulatory pathways and there is a need to develop nanomedicines in a more controlled and consistent fashion. The elements of a QbD methodology explained in this review enable the development of nano-based formulations in a way that maximizes the possibility of success. The identification of critical quality attributes (CQA) of the drug product and its intermediates are discussed in detail with a focus on nanomaterial-based formulations. In conclusion, QbD and the identification and specification of CQAs at its core are critical to the design, development and growth of nanomaterials in pharmaceuticals.


Assuntos
Desenvolvimento de Medicamentos/métodos , Nanocápsulas/química , Nanotecnologia/métodos , Animais , Preparações de Ação Retardada/química , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanomedicina , Resultado do Tratamento
2.
Expert Opin Ther Pat ; 29(9): 675-688, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31370713

RESUMO

Introduction: RAF kinase inhibitors block and regulate RAS/RAF/MEK/ERK signaling, which is a key to tumor treatment. At present, although RAF kinase inhibitors have good efficacy, there are few such drugs with low toxicity, and thus, it is urgent to find novel RAF kinase inhibitors associated with higher activity and fewer adverse reactions. This review highlights the anti-tumor effects of several published RAF kinase inhibitors and might be helpful in providing new ideas for the development of novel drug candidates in the future. Areas covered: This article covers the pertinent literature published on RAF kinase inhibitors from 2010 to 2018, as well as the potential use of these compounds as therapeutics for cancer. Expert opinion: To date, many RAF kinase inhibitors with different structures have been studied, many of which have prominent inhibitory activities toward RAF kinase. Further, the specificity of these drugs offers hope for the targeted therapy of tumors. Although RAF kinase inhibition has achieved promising results for the treatment of many cancers, overcoming limitations associated with drug resistance and safety comprises a new direction for the optimization and improvement of RAF kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Quinases raf/antagonistas & inibidores , Animais , Desenvolvimento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Patentes como Assunto , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases raf/metabolismo
3.
Expert Opin Ther Pat ; 29(9): 663-674, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31403347

RESUMO

Introduction: RORγt is critical for the differentiation of Th17 cells and the production of IL-17. Inhibition of RORγt is considered as a promising strategy to treat Th17-mediated autoimmune diseases. Quite a number of RORγt inhibitors have been progressed into clinical trials, besides much biological interests in this attractive target. Areas covered: This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019. Expert opinion: The development of RORγt inhibitors has gone through a boom period in the past three years. However, with a little bit frustration, some of the frontrunner clinical compounds were either discontinued or suspended for further development possibly due to some safety concerns or lack of efficacy in humans. There is a need to probe deeply into these concerns in the on-going pre-clinical and clinical studies. Given the effectiveness of a few recently FDA-approved anti-IL-17(R) antibodies on psoriasis, the discovery of RORγt inhibitors continues to be an exciting field for the development of novel treatment approaches.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Animais , Doenças Autoimunes/imunologia , Descoberta de Drogas , Humanos , Interleucina-17/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Patentes como Assunto , Células Th17/imunologia
4.
Expert Opin Drug Saf ; 18(8): 651-677, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31268355

RESUMO

INTRODUCTION: Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data. AREAS COVERED: Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for in vitro production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta and vessel-on-chip) and their importance for drug research and development are presented. EXPERT OPINION: OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions.


Assuntos
Desenvolvimento de Medicamentos/métodos , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Alternativas aos Testes com Animais , Animais , Humanos , Pesquisa Farmacêutica/métodos , Células-Tronco/citologia
5.
Expert Opin Investig Drugs ; 28(8): 687-694, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31269823

RESUMO

Introduction: Acute otitis media (AOM) is a common disease, particularly in infants and young children. Almost all children experience at least one episode of AOM in the first 3 years of age, and approximately 50% experience recurrent episodes in the same period of time. Areas covered: Some new potentially effective preventive or therapeutic approaches to AOM have been identified and are not discussed even in the most updated guidelines. The main aim of this narrative review is to detail what has been recently suggested. Expert opinion: Several new measures have been suggested to reduce systemic antibiotic abuse in AOM therapy and prophylaxis. For therapy, the administration of preparations containing antibiotics, bacteriophages or peptides can allow trans-tympanic passage of effective anti-otopathogen measures and the use of vaccines or immunoglobulins can disrupt biofilm. For AOM prophylaxis, new vaccines and the use of probiotics by nasal spray are in development. However, further advances in the selection of children for whom antimicrobial therapy and/or prophylaxis measures are truly needed could be derived from studies that analyse the association between genetic characteristics of the host and development of AOM with specific characteristics of aetiology or tendency to recur.


Assuntos
Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/uso terapêutico , Otite Média/tratamento farmacológico , Doença Aguda , Animais , Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Pré-Escolar , Humanos , Lactente , Otite Média/microbiologia , Seleção de Pacientes , Recidiva
6.
Expert Opin Investig Drugs ; 28(8): 675-686, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31327293

RESUMO

Introduction: Early phase clinical trials are the first clinical research step to bringing new cancer therapeutics to patients. At this stage, a new drug's safety, dosing, and scheduling profiles are established as the main endpoints. However, excellent responses due to biomarker-guided and immune checkpoint trials in early phase have resulted in direct approvals of new anti-cancer drugs. Despite doubling of the success rate of new drug approvals, many barriers exist to expeditiously bring active new drugs to the clinic. Areas covered: This review covers roles of members of the early phase program and the challenges they face in enrolling advanced cancer patients to trials. Practical solutions are provided from the perspective of the investigators, regulatory, investigational pharmacy, research nurses, clinical research coordinators, budgets, contracts, and data management. Expert opinion: We are witnessing a burgeoning era in drug development with rapid approval of efficacious drugs. This is achieved by a strong collaboration between investigators, academic institutions, pharmaceutical sponsors, scientists, Food and Drug Administration (FDA), and community practices. Herein, we discuss some of the challenges faced by early phase clinical trials programs and discuss methods of improvement.


Assuntos
Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Comportamento Cooperativo , Aprovação de Drogas , Desenvolvimento de Medicamentos/métodos , Humanos , Seleção de Pacientes , Estados Unidos , United States Food and Drug Administration
7.
Expert Opin Investig Drugs ; 28(8): 709-718, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31352835

RESUMO

Introduction: Pharmacologic interventions in Autism Spectrum Disorder (ASD) have historically focused on symptom-based approaches. However, a treatment for the core social deficits has remained unidentified. While a definitive theory for the cause of ASD is not yet known, recent advances in our understanding of ASD pathophysiology have opened the door for research on new pharmaceutical methods to target core symptomology. Areas covered: Herein, we review the novel pharmacologic therapies undergoing early-stage clinical trials for the treatment of the social symptoms associated with ASD. Specifically, these strategies center on altering neurologic excitatory and inhibitory imbalance, neuropeptide abnormalities, immunologic dysfunction, and biochemical deficiencies in ASD. Expert opinion: Utilizing the growing field of knowledge regarding the pathological mechanisms and altered neurobiology of individuals with ASD has led to the development of many innovative pharmaceutical interventions. Clinical trials for neurobiologic and immunologic targets show promise in impacting the social behavior and processing deficits in ASD but need evaluation in larger clinical trials and continued biomarker development to more effectively and consistently assess pharmacologic effects. Additionally, evaluating patient-specific drug responsivity and integrating behavioral intervention in conjunction with pharmacologic treatment is crucial to developing a successful approach to ASD treatment.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/uso terapêutico , Transtorno do Espectro Autista/fisiopatologia , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto/métodos , Drogas em Investigação/farmacologia , Humanos , Comportamento Social
8.
Expert Opin Ther Pat ; 29(8): 643-651, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31291131

RESUMO

Introduction: LAG-3 is checkpoint inhibitor in cancer that coordinates the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of LAG-3 and consequently improving the immune response in the various types of cancer. Areas covered: The patent literature reveals novel therapies, which provide information on cancer therapies. The authors used the patent databases of the six main patent offices of the world: United States Patent and Trademark Office, European Patent Office, World Intellectual Property Organization, Japan Patent Office, State Intellectual Property Office of China and Korean Intellectual Property Office, to generate a detailed landscape of patents and patent applications of active companies related to LAG-3 inhibitors. Specific patents have been grouped into innovative patents and adopting patents. Expert opinion: There is a continuing development of LAG-3 inhibitors, and these inhibitors are being used in combination with other cancer treatment schemes, for example, antibodies against PD-1, PD-L1, and CTLA-4. Immutep and IO Therapeutics were the leaders in generating innovator patents, followed by Gustave Roussy Institute, and Applied Research Systems ARS. Dana-Farber Cancer Institute was the leader in the generation of adopter patents, followed by Novartis .


Assuntos
Antígenos CD/efeitos dos fármacos , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Anticorpos/administração & dosagem , Antígenos CD/imunologia , Antígenos CD/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desenvolvimento de Medicamentos/métodos , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Patentes como Assunto
9.
Expert Opin Ther Pat ; 29(8): 605-621, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31298602

RESUMO

Introduction: Retinoid X receptor (RXR) agonists have a limited role in cancer therapy with bexarotene and alitretinoin as approved drugs but their use is limited by adverse effects. Several evidence from in vitro, in vivo, and small clinical studies points to various further potential applications of RXR ligands in neurodegenerative and inflammatory diseases. Areas covered: The authors review known RXR ligand classes with their key structure-activity relationships and recent reports on pharmacological effects of RXR modulation. Based on these aspects, the authors evaluate recent patents claiming novel RXR ligands or their use. Expert opinion: While the use of RXR modulators has been claimed in several novel and promising indications, little progress has been made in the development of innovative rexinoids with improved (subtype-)selectivity. Next-generation RXR modulators that selectively target the RXR subtypes for individual indications may be required to exhaustively exploit the therapeutic potential of RXRs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores X Retinoide/efeitos dos fármacos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Desenvolvimento de Medicamentos/métodos , Humanos , Ligantes , Neoplasias/patologia , Patentes como Assunto , Receptores X Retinoide/metabolismo , Relação Estrutura-Atividade
10.
Expert Opin Ther Pat ; 29(8): 623-641, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353978

RESUMO

Introduction: About 20 patents have been published from 2013 to 2018 for developing advanced cancer therapeutics by targeting tubulin polymerization. Currently, there are several tubulin inhibitors that are in the drug development pipeline for various cancers alone or in combination including antibody-conjugated drugs (ACDs). Areas covered: Important patents focusing on the development of tubulin inhibitors published from 2013 to 2018 are covered. This review mainly focuses on the tubulin inhibitors that are being synthesized and studied in cancer research along with their structures and their phases of development in preclinical and clinical research. Expert opinion: Regulation of microtubules is important for cell division, cell motility, intracellular transport, and cell shape maintenance. Modulating its activity proved to be very effective in various diseases including different types of cancers. Microtubules are composed of two units, namely, alpha and beta-tubulin, and modifications at these ends affect both its functions and dynamics. A number of compounds that have been designed and synthesized bearing various heterocyclic scaffolds have been proven to modulate its activity and have emerged as potent tubulin inhibitors. This encourages more to study microtubules in order to find a variety of novel, potent compounds as anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/química , Desenho de Drogas , Desenvolvimento de Medicamentos/métodos , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Neoplasias/patologia , Patentes como Assunto , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
11.
Expert Rev Clin Pharmacol ; 12(9): 893-900, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295413

RESUMO

Introduction: Despite considerable advances in our understanding of how sepsis develops and multiple clinical trials of potential therapies, no new pharmacologic agent has been consistently shown to improve survival. Areas covered: We reviewed relevant publications identified through PubMed and from the authors' knowledge of this field. We discuss the main reasons why clinical trials on new therapeutic interventions have failed in the past, including heterogeneity of study populations and choice of outcome measures. We discuss how changes in study design and in patient selection could help improve identification of effective agents in the future. Expert opinion: The search for new sepsis therapies must continue but lessons must be learned from previous clinical trials so that the same mistakes are not repeated. Rather than grouping all patients with sepsis together, we should study only those most likely to benefit from the intervention. Better characterization of patients will be facilitated using modern 'omics technology and analysis of the increasingly large quantities of clinical data available, enabling more personalized patient selection for trial inclusion. New clinical trial design and inclusion of other endpoints in addition to mortality will also aid our search for the elusive positive clinical trial and effective interventions for sepsis.


Assuntos
Ensaios Clínicos como Assunto/métodos , Projetos de Pesquisa , Sepse/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Humanos , Avaliação de Resultados (Cuidados de Saúde) , Seleção de Pacientes
12.
Expert Opin Drug Saf ; 18(9): 795-802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31305171

RESUMO

Introduction: Antibiotics have saved and are still saving countless human lives from the burden of infectious diseases. However, as with all other drugs, they can cause adverse events. Generally, these are uncommon, mild and spontaneously resolving. However, in some cases, they can cause relevant clinical problems. Compared with adults, children, particularly in the first years of life, have a higher risk of antibiotic-related adverse events for several reasons. Areas covered: In this paper, the conditions that can contribute to the elevated risk of antibiotic-related adverse events in children are discussed. Expert opinion: Antibiotic stewardship can be a solution to limit antibiotic abuse and misuse and consequently the incidence of antibiotic-related adverse events in children. Moreover, most of the antibiotic-associated adverse events can be avoided with more extensive pre-marketing medicine investigations, improved postmarket safety surveillance system, increased transparency throughout the clinical research enterprise, increased training of clinical pharmacologists and paediatric researchers, expanded pool of paediatric patients, and providing additional funding and incentives for paediatric drug development.


Assuntos
Antibacterianos/administração & dosagem , Gestão de Antimicrobianos/métodos , Desenvolvimento de Medicamentos/métodos , Fatores Etários , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Humanos , Lactente , Infecção/tratamento farmacológico , Vigilância de Produtos Comercializados , Fatores de Risco
14.
Expert Opin Drug Metab Toxicol ; 15(7): 595-612, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31174439

RESUMO

Introduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination.


Assuntos
Antiprotozoários/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Relação Dose-Resposta a Droga , Desenho de Drogas , Descoberta de Drogas/métodos , Resistência a Medicamentos , Humanos , Leishmaniose/parasitologia
15.
Expert Opin Ther Pat ; 29(7): 555-578, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31204543

RESUMO

INTRODUCTION: Human neutrophil elastase (HNE) is involved in a variety of serious chronic diseases, especially cardiopulmonary pathologies. For this reason, the regulation of HNE activity represents a promising therapeutic approach, which is evident by the development of a number of new and selective HNE inhibitors, both in the academic and pharmaceutical environments. AREAS COVERED: The present review analyzes and summarizes the patent literature regarding human neutrophil elastase inhibitors for the treatment of cardiopulmonary diseases over 2014-2018. EXPERT OPINION: HNE is an interesting and defined target to treat various inflammatory diseases, including a number of cardiopulmonary pathologies. The research in this field is quite active, and a number of HNE inhibitors are currently in various stages of clinical development. In addition, new opportunities for HNE inhibitor development stem from recent studies demonstrating the involvement of HNE in many other inflammatory pathologies, including rheumatoid arthritis, inflammatory bowel disease, skin diseases, and cancer. Furthermore, the development of dual HNE/proteinase 3 inhibitors is being pursued as an innovative approach for the treatment of neutrophilic inflammatory diseases. Thus, these new developments will likely stimulate new and increased interest in this important therapeutic target and for the development of novel and selective HNE inhibitors.


Assuntos
Desenvolvimento de Medicamentos/métodos , Elastase de Leucócito/efeitos dos fármacos , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Elastase de Leucócito/metabolismo , Pneumopatias/tratamento farmacológico , Pneumopatias/enzimologia , Pneumopatias/fisiopatologia , Patentes como Assunto
16.
Expert Opin Investig Drugs ; 28(7): 593-603, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31185180

RESUMO

INTRODUCTION: Oxidative stress toxicity (OST) has been implicated in almost all pathological conditions. Despite the widespread use of natural antioxidants, no pharmaceutical antioxidants have yet been developed or prescribed in medical practise. Antioxidant drugs such as Deferiprone and N-acetylcysteine can target essential pathways of OST in many pathological conditions. The pharmacological parameters required by antioxidant drugs in relation to the OST target characteristics include the determination of the therapeutic index, ADMET and drug interactions. Antioxidant drug development efforts are currently targeting the treatment of severe diseases with no proven effective therapies. AREAS COVERED: This article addresses the damaging effects of OST, prospects for the development of pharmaceutical antioxidants and clinical studies using other drugs with antioxidant potential. EXPERT OPINION: Effective antioxidant therapeutic strategies should include the design of protocols for the inhibition of OST through iron chelation, administration of synthetic and natural antioxidants and enhancement of the antioxidant defences by increasing the production of endogenous antioxidants and activation of antioxidant mechanisms. Different therapeutic strategies apply in the use of antioxidant drugs for one or more targets, for prevention, treatment, or of post-treatment effects and for systematic, long-term or short-term applications. The design of new antioxidant drugs and effective protocols which can include Deferiprone and N-acetylcysteine combinations, could lead to the development of a new class of therapeutics for clinical use.


Assuntos
Antioxidantes/farmacologia , Depuradores de Radicais Livres/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Animais , Antioxidantes/administração & dosagem , Deferiprona/administração & dosagem , Deferiprona/farmacologia , Desenho de Drogas , Desenvolvimento de Medicamentos/métodos , Depuradores de Radicais Livres/administração & dosagem , Radicais Livres , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacologia , Terapia de Alvo Molecular
17.
Expert Opin Investig Drugs ; 28(7): 629-642, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31232099

RESUMO

INTRODUCTION: Actinic keratoses (AKs) are limited areas of irregular epidermal growth on a background of excessive solar exposure. The entire sun-damaged skin is considered a field of cancerization with multiple visible and subclinical lesions. AK management requires field-directed therapies to block lesion relapse and prevent squamous cell carcinoma (SCC). AREAS COVERED: In this review, we focused on phase II clinical trials for AKs, involving well-known agents and newer molecules such as proapoptotic drugs (VDA-1102, SR-T100, oleogel-S10, ICVT, eflornithine), immunomodulants (isotretinoin, tretinoin) and chemopreventive agents (nicotinamide, perillyl alcohol, liposomal T4N5). We used the website 'ClinicalTrials.Gov' as main reference. We selected and discussed completed and ongoing trials and analysed chemical structure and mechanism of action of the investigated molecules. EXPERT OPINION: AK therapy should be tailored on the patient's profile considering first of all the age and site of the AKs, which are relevant parameters for local immune response. The new molecules could be combined to obtain a synergic effect blocking the different steps of skin tumorigenesis. Phase II trials highlight a new therapeutic opportunity to block selectively cell proliferation regulators and work both on the field of cancerization and on the AKs currently present.


Assuntos
Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/farmacologia , Ceratose Actínica/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/administração & dosagem , Humanos , Ceratose Actínica/complicações , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle
18.
Expert Opin Drug Metab Toxicol ; 15(7): 541-552, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241371

RESUMO

Introduction: Pancreatic cancer (PC) remains a disease with a dismal prognosis. Despite accounting for only 3% of cancer diagnosis, 7% of all cancer deaths in the United States are from PC. This is explained by many being diagnosed with late-stage disease and the cancer's resistance to chemotherapy. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine, FOLFIRINOX (5-fluorouracil/leucovorin and oxaliplatin) and gemcitabine plus nab-paclitaxel. Areas covered: Clinical pharmacology of newer agents that are either approved or being investigated in the management of PC. Knowledge of their pharmacokinetics, pharmacodynamics, and pharmacogenetics can be used to predict outcomes for specific patient populations. Drugs discussed include nanoliposomal irinotecan, pegvorhyaluronidase alfa, poly (ADP-ribose) polymerase enzyme inhibitors, larotrectinib, and napabucasin. Expert opinion: PC is a heterogeneous disease and outcomes are likely to improve as better predictive models of an individual's response to different therapies are developed. This may be best accomplished through phase 0 studies and the use of tumor organoid models grown from initial biopsies or resected tissue. The genetic and physical makeup of the tumor as well as the functional characterization in patient-derived organoids (PDOs), can help guide which agents may be most efficacious or toxic.


Assuntos
Antineoplásicos/administração & dosagem , Desenvolvimento de Medicamentos/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Farmacogenética , Prognóstico
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