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1.
Expert Opin Investig Drugs ; 29(2): 125-133, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899984

RESUMO

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is strongly associated with obesity and insulin resistance. NAFLD refers to a spectrum of disorders ranging from asymptomatic hepatic steatosis (nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), which increases the risk of developing more severe forms of liver disease such as progressive fibrosis, cirrhosis, and liver cancer. Currently, there are no food and drug administration (FDA) approved drugs to treat NASH. Pegbelfermin (BMS-986036) is a PEGylated fibroblast growth factor 21 (FGF21) analogue that is under investigation for the treatment of NASH.Areas covered: We reviewed the (pre)clinical pegbelfermin studies and compared these with other studies that assessed FGF21 and FGF21 analogues in the treatment of NASH.Expert opinion: With no FDA approved treatments available for NASH, there is an urgent need for novel therapies. Pegbelfermin is a systemic treatment with pleiotropic effects on various tissues. Short-term adverse effects are limited, but more research is required to study potential long-term safety issues. In a phase 2a trial, pegbelfermin has shown promising improvements in several NASH related outcomes. However, clinical trials demonstrating long-term benefits on hard outcomes such as liver histology, cirrhosis development, or survival are required for further validation.


Assuntos
Fatores de Crescimento de Fibroblastos/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Animais , Progressão da Doença , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/complicações , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia
2.
Expert Opin Investig Drugs ; 29(2): 135-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31519114

RESUMO

Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Isobutiratos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Acetil-CoA Carboxilase/antagonistas & inibidores , Animais , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Humanos , Isobutiratos/efeitos adversos , Isobutiratos/farmacologia , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxazóis/efeitos adversos , Oxazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Triglicerídeos/sangue
3.
Expert Opin Investig Drugs ; 29(1): 33-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31869253

RESUMO

Introduction: Despite current guideline-based, secondary prevention strategies in patients with the acute coronary syndrome, the residual ischemic risk is still at an unacceptable rate, and there is a concomitant high bleeding event rate. These observations mandate investigations of novel treatment strategies to meet the unmet need to improve outcomes in patients with ACS.Areas covered: In this review, the author(s) focus on new agents with ongoing or recently completed phase II trials for the treatment of ACS. We searched MEDLINE and clinicaltrials.org for Phase II trials in ACS patients, and important original investigations are reviewed.Expert opinion: Some of the novel drugs evaluated in the Phase II trials hold promise for future therapies such as AZD5718, anakinra, tocilizumab, CSL112, MEDI 6102, inclisiran, PZ128, selatogrel, and RVX-208. Their efficacy and safety should be evaluated in large scale Phase III trials. The higher cost of the drug will be a major limitation for wide-spread use of novel agents in general practice in future.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/prevenção & controle , Animais , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/efeitos adversos , Humanos , Guias de Prática Clínica como Assunto , Prevenção Secundária/métodos
4.
J Oncol Pharm Pract ; 26(1): 29-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30832556

RESUMO

OBJECTIVES: This study aimed to investigate the effectiveness of pharmacist intervention in reducing and preventing prescribing errors of investigational drugs for cancer patients. MATERIALS AND METHODS: A retrospective study was conducted during two periods: a baseline period from December 2015 to June 2016 and an intervention period from July 2016 to February 2017. The investigational drug service (IDS) pharmacists performed active interventions during the intervention period. RESULTS: Among 12,387 investigational drug orders, 395 (6.1%) prescribing errors were detected in 6477 orders at the baseline period, and 278 errors (4.7%) were detected in 5,910 orders at the intervention period. To identify factors that affect prescribing errors, three models were constructed for the multivariate analysis. Among factors affecting prescribing errors, sponsor initiated trial (SIT) was the strongest factor (AOR: 4.16, 95% CI: 3.31-5.23). Pharmacist intervention reduced prescribing errors by at least 25% in all constructed models after adjusting for confounding variables. Prescribing errors were 1.3 times higher when dealing with intravenous medications than when dealing with oral medications. There were 60% fewer prescribing errors in the blinded study than in the open study. SIT and multi-center/multi-nation studies had 4.2 and 2.4 times more frequent prescribing errors than in investigator-initiated trials (IIT) and single-center/single-nation studies, respectively. Fewer errors occurred in phase 2 and trials covering both phase 1 and phase 2 (phase 1/2) than in phase 3 trials. CONCLUSIONS: The IDS pharmacist intervention in cancer clinical trials was associated with significant reductions in prescribing errors and may lead to increased medication safety.


Assuntos
Drogas em Investigação/efeitos adversos , Erros de Medicação/prevenção & controle , Neoplasias/tratamento farmacológico , Farmacêuticos , Serviço de Farmácia Hospitalar/métodos , Papel Profissional , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Farmacêuticos/tendências , Serviço de Farmácia Hospitalar/tendências , República da Coreia/epidemiologia , Estudos Retrospectivos
5.
Expert Opin Investig Drugs ; 28(12): 1095-1100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31783714

RESUMO

Introduction: Checkpoint kinase 1 (CHK1) inhibitors have been in development for two decades. The initial CHK1 inhibitor staurosporine analog, UCN01, entered clinical trials whilst it was still considered to act via PKC inhibition; only later were trials performed in a more focused fashion to determine whether CHK1 inhibition could dysregulate cell cycle checkpoints. Many of the subsequently synthesized more specific CHK1 inhibitors have failed because of poor PK/PD or cumulative normal tissue toxicities in patients. CHK1 inhibitor monotherapy often demonstrates limited efficacy and in general, must be combined with other agents. The combination of CHK1 inhibitors with modern signaling regulators may be a better therapeutic strategy.Areas covered: This review discusses the history of, and translational use of CHK1 inhibitors; the latest generation of CHK1 inhibitors to enter clinic development are also examined.Expert opinion: Some CHK1 inhibitors can be administered safely, but that when they are combined with traditional cytotoxic DNA damaging agents, the normal tissue toxicities outweigh the very modest gains in therapeutic efficacy. Researchers need to think outside of the box and consider how CHK1 inhibitors can be combined with other signal transduction modulators such as MEK1/2 and PARP1 inhibitors to kill tumor cells.


Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/metabolismo , Desenvolvimento de Medicamentos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos
6.
Expert Opin Investig Drugs ; 28(11): 941-949, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31590579

RESUMO

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the burden of disease is increasing globally. Until recently, systemic therapies for HCC were limited and prognosis for advanced disease generally poor.Area covered: This article describes some recent phase I and II clinical trials for the treatment of HCC. We performed a search on Pubmed with keywords hepatocellular carcinoma, phase I clinical trial, phase II clinical trial, and immunotherapy. We also searched https://clinicaltrials.gov and identified relevant trials listed as active. Studies in progress or recently reported were conducted using novel therapies based on targets identified through molecular profiling of tumors or based on insights into immune system dysregulation in HCC. We also identified studies using drugs targeting recently discovered biomarkers such as endoglin or aldo-keto reductase 1c3. The major outcomes were safety and efficacy as measured by response rate, progression-free survival or overall survival.Expert opinion: HCC is a heterogeneous disease resulting from aberrations in intracellular signaling and immune system dysregulation. Thus, a multisystem approach will be required to deliver personalized therapy. Combination therapies are likely to be future options; it is also possible that modulation of the microbiome might form part of future treatment paradigms.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Imunoterapia , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Sobrevida
7.
Expert Opin Investig Drugs ; 28(10): 835-849, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31510809

RESUMO

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited. Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS. Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.


Assuntos
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida , Fatores de Tempo
8.
Nat Rev Clin Oncol ; 16(12): 773-778, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31477881

RESUMO

For many years, oncology phase I trials have been referred to as 'toxicity trials' and have been believed to have low clinical utility other than that of establishing the adverse event profile of novel therapeutic agents. The traditional distinction of clinical trials into three phases has been challenged in the past few years by the introduction of targeted therapies and immunotherapies into the routine management of patients with cancer. This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly reported from phase I trials. In this Perspectives, we highlight key elements of phase I trials and discuss how each one of them contributes to a new paradigm whereby preliminary measurements of the clinical benefit from a novel treatment can be obtained in current phase I trials, which can therefore be considered to have a therapeutic intent.


Assuntos
Ensaios Clínicos Fase I como Assunto , Neoplasias/terapia , Comportamento de Escolha , Ensaios Clínicos Fase I como Assunto/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Drogas em Investigação/efeitos adversos , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia/tendências , Oncologia/métodos , Oncologia/tendências , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Terapias em Estudo/métodos , Terapias em Estudo/tendências
9.
Expert Opin Investig Drugs ; 28(9): 799-809, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398295

RESUMO

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis. Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody. Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/efeitos adversos , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Estadiamento de Neoplasias , Síndrome de Sézary/tratamento farmacológico , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Taxa de Sobrevida
10.
Cancer Immunol Immunother ; 68(7): 1211-1222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069460

RESUMO

Human tumor cells express antigens that serve as targets for the host cellular immune system. This phase 1 dose-escalating study was conducted to assess safety and tolerability of G305, a recombinant NY-ESO-1 protein vaccine mixed with glucopyranosyl lipid A (GLA), a synthetic TLR4 agonist adjuvant, in a stable emulsion (SE). Twelve patients with solid tumors expressing NY-ESO-1 were treated using a 3 + 3 design. The NY-ESO-1 dose was fixed at 250 µg, while GLA-SE was increased from 2 to 10 µg. Safety, immunogenicity, and clinical responses were assessed prior to, during, and at the end of therapy. G305 was safe and immunogenic at all doses. All related AEs were Grade 1 or 2, with injection site soreness as the most commonly reported event (100%). Overall, 75% of patients developed antibody response to NY-ESO-1, including six patients with increased antibody titer ( ≥ 4-fold rise) and three patients with seroconversion from negative (titer < 100) to positive (titer ≥ 100). CD4 T-cell responses were observed in 44.4% of patients; 33.3% were new responses and 1 was boosted ( ≥ 2-fold rise). Following treatment, 8 of 12 patients had stable disease for 3 months or more; at the end of 1 year, three patients had stable disease and nine patients were alive. G305 is a potent immunotherapeutic agent that can stimulate NY-ESO-1-specific antibody and T-cell responses. The vaccine was safe at all doses of GLA-SE (2-10 µg) and showed potential clinical benefit in this population of patients.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Glucosídeos/administração & dosagem , Lipídeo A/administração & dosagem , Proteínas de Membrana/administração & dosagem , Neoplasias/terapia , Adjuvantes Imunológicos/efeitos adversos , Adulto , Idoso , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Glucosídeos/imunologia , Humanos , Imunogenicidade da Vacina , Injeções Intramusculares , Lipídeo A/efeitos adversos , Lipídeo A/imunologia , Masculino , Proteínas de Membrana/efeitos adversos , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto Jovem
12.
Expert Opin Investig Drugs ; 28(5): 411-420, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30916583

RESUMO

INTRODUCTION: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1+ patients or is attributed to inhibition of the fusion protein alone, or a combined effect on several kinases, and whether dasatinib-containing combination treatment should be preferred in these patients instead of other emerging strategies, e.g. monoclonal antibodies.


Assuntos
Dasatinibe/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dasatinibe/efeitos adversos , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Indução de Remissão
13.
Expert Opin Emerg Drugs ; 24(1): 55-61, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30845846

RESUMO

INTRODUCTION: Thromboembolic diseases are leading cause of mortality accounting for an estimated 1 in 4 deaths all over the world. Anticoagulation remains the mainstay of prevention and treatment of venous thromboembolic disorders. Conventional anticoagulants have been efficiently used over the last decades, but their clinical use encounters safety and convenience issues. To overcome these limitations, research have focused on development of new targets for anticoagulation leading to a relatively new class of drugs, non-vitamin K antagonist oral anticoagulants, specifically targeting activated factor X and thrombin. However, the search for more potent anticoagulant agents with reduced bleeding risk is still continuing. Areas covered: In this review, we provide an overview on emerging investigational anticoagulant drugs targeting factor XI in the coagulation cascade. We review data about the role of intrinsic pathway in thrombosis and haemostasis and the rationale of different pharmacodynamic approaches targeting factor XI. Expert opinion: Recent evidence suggests that the contact pathway plays a significant role in thrombosis by thrombus stabilization and growth without perturbing haemostasis. Factor XI might be a promising drug target to develop highly effective antithrombotic therapy with safety bleeding profile. Most of these investigational agents are in early development phases, only few have reached early phase clinical trials.


Assuntos
Anticoagulantes/farmacologia , Fator XI/antagonistas & inibidores , Tromboembolia/prevenção & controle , Animais , Anticoagulantes/efeitos adversos , Desenho de Drogas , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Hemorragia/induzido quimicamente , Humanos , Terapia de Alvo Molecular , Trombose/prevenção & controle
14.
Expert Opin Investig Drugs ; 28(4): 351-363, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30753792

RESUMO

INTRODUCTION: Despite advances in treatment, head and neck squamous cell carcinoma (HNSCC) survival rates remain stagnant. Current treatment is associated with significant toxicities and includes chemotherapy, radiation, surgery, and few targeted treatments. Targeted treatments, epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, and immune checkpoint inhibitors, pembrolizumab and nivolumab, show improved toxicity profiles and modestly improved survival in select patients. An urgent need remains to identify novel targeted treatments for single-agent or combined therapy use. AREAS COVERED: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy. EXPERT OPINION: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia
15.
Expert Opin Investig Drugs ; 28(3): 261-266, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30678501

RESUMO

INTRODUCTION: Severe, inadequately-controlled asthma remains a clinical challenge. For this reason, clinical trials and preclinical experimental studies on novel agents as an add-on therapies continue emerge. Phosphodiesterases (PDEs) are enzymes that regulate the function of immune cells by hydrolyzing cyclic guanosine monophosphate/cGMP and cyclic adenosine monophosphate/cAMP. PDEs are divided into subfamilies [PDE3, PDE4, PDE5 and PDE7] which are mainly found in the respiratory tract. Inhibitors of PDEs have already been approved for COPD and pulmonary hypertension. AREAS COVERED: The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed. EXPERT OPINION: Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/efeitos adversos , Asma/fisiopatologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Diester Fosfórico Hidrolases/efeitos dos fármacos , Diester Fosfórico Hidrolases/metabolismo
16.
Basic Clin Pharmacol Toxicol ; 125(1): 75-84, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30694594

RESUMO

We report a 28-day repeat dose immunotoxicity evaluation of investigational drug MIDD0301, a novel oral asthma drug candidate that targets gamma amino butyric acid type A receptors (GABAA R) in the lung. The study design employed oral administration of mice twice daily throughout the study period with 100 mg/kg MIDD0301 mixed in peanut butter. Compound dosing did not reveal signs of general toxicity as determined by animal weight, organ weight or haematology. Peanut butter plus test drug (in addition to ad libitum standard rodent chow) did not affect weight gain in the adult mice, in contrast to weight loss in 5 mg/kg prednisone-treated mice. Spleen and thymus weights were unchanged in MIDD0301-treated mice, but prednisone significantly reduced the weight of those organs over the 28-day dosing. Similarly, no differences in spleen or thymus histology were observed following MIDD0301 treatment, but prednisone treatment induced morphological changes in the spleen. The number of small intestine Peyer's patches was not affected by MIDD0301 treatment, an important factor for orally administered drugs. Circulating lymphocyte, monocyte and granulocyte numbers were unchanged in the MIDD0301-treated animals, whereas differential lymphocyte numbers were reduced in prednisone-treated animals. MIDD0301 treatment did not alter IgG antibody responses to dinitrophenyl following dinitrophenyl-keyhole limpet haemocyanin immunization, indicating that systemic humoral immune function was not affected. Taken together, these studies show that repeated daily administration of MIDD0301 is safe and not associated with adverse immunotoxicological effects in mice.


Assuntos
Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Azepinas/administração & dosagem , Drogas em Investigação/administração & dosagem , Agonistas de Receptores de GABA-A/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Imidazóis/administração & dosagem , Tolerância Imunológica/efeitos dos fármacos , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios/efeitos adversos , Asma/sangue , Asma/imunologia , Azepinas/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Feminino , Agonistas de Receptores de GABA-A/efeitos adversos , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Imidazóis/farmacologia , Contagem de Leucócitos , Masculino , Camundongos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Perda de Peso
17.
J Clin Endocrinol Metab ; 104(2): 423-432, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252061

RESUMO

Context: Dimethandrolone (DMA) has androgenic and progestational activity. Single oral doses of DMA undecanoate (DMAU) were well tolerated and reversibly suppressed serum LH and testosterone (T) in men. Objective: Assess safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of oral DMAU. Design: Double-blind, randomized, placebo-controlled study. Setting: Two academic medical centers. Participants: Healthy men (18 to 50 years). Interventions: One hundred men received DMAU [0, 100, 200, or 400 mg, formulated in castor oil/benzyl benzoate (C) or powder (P)] for 28 days. Subjects underwent 24-hour PK sampling on days 1 and 28 and twice weekly ambulatory visits throughout treatment. Main Outcome Measures: Primary outcomes were safety and tolerability parameters (vitals, laboratory data, mood, and sexual function scores) and adverse events. Secondary outcomes were drug PK profiles and PD effects (serum LH, FSH, and sex hormones). Results: Eighty-two subjects completed the study and were included in the analysis. There were no serious adverse events. No clinically significant changes developed in safety laboratory parameters. A significant dose effect was seen for weight, hematocrit, high-density lipoprotein cholesterol, corrected QT interval, and sexual desire. Serum 24-hour average concentrations of DMAU and DMA showed dose-related increases (P < 0.001). All six subjects in the P400 group and 12 of 13 subjects in the C400 group achieved marked suppression of LH and FSH (<1.0 IU/L) and serum T (<50 ng/dL). Conclusions: Daily oral administration of DMAU for 28 days in healthy men is well tolerated. Doses of ≥200 mg markedly suppress serum T, LH, and FSH. These results support further testing of DMAU as a male contraceptive.


Assuntos
Anticoncepcionais Masculinos/administração & dosagem , Drogas em Investigação/administração & dosagem , Nandrolona/análogos & derivados , Administração Oral , Adulto , Anticoncepcionais Masculinos/efeitos adversos , Anticoncepcionais Masculinos/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Hormônio Foliculoestimulante/sangue , Voluntários Saudáveis , Humanos , Hormônio Luteinizante/sangue , Masculino , Nandrolona/administração & dosagem , Nandrolona/efeitos adversos , Nandrolona/farmacocinética , Placebos/administração & dosagem , Placebos/efeitos adversos , Testosterona/sangue , Adulto Jovem
18.
Expert Opin Investig Drugs ; 28(3): 223-234, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30580647

RESUMO

BACKGROUND: Advances in our understanding of the complex pathophysiologic mechanisms responsible for high-risk atherosclerotic plaque rupture resulting in acute myocardial infarction (AMI) have led to the development of numerous antiplatelet and anticoagulant agents for treatment of AMI. AREAS COVERED: We review various antithrombotic drugs which were recently investigated for the treatment of AMI. A MEDLINE search for relevant articles on newer antiplatelet agents and anticoagulants drugs for the treatment of AMI was performed, and important original investigations were reviewed. We also briefly discuss agents that completed evaluation and were recently recommended by expert guidelines. EXPERT OPINION: The antiplatelet agents cangrelor and vorapaxar and the anticoagulant rivaroxaban, have shown promise for the reduction of ischemic events when administered during, and in the acute phase following AMI. However, these agents have not been compared with more potent P2Y12 inhibitors, prasugrel, and ticagrelor. Finding an optimum combination of these agents to achieve an appropriate risk (bleeding) - benefit (reduction in ischemic events) balance is challenging. Further evaluation of agents that show promise is important for enhancing our armamentarium of pharmacologic agents for the successful treatment of AMI.


Assuntos
Anticoagulantes/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Doença Aguda , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/fisiopatologia , Placa Aterosclerótica/complicações , Placa Aterosclerótica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacologia
19.
Eur J Clin Pharmacol ; 75(4): 483-496, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30569285

RESUMO

PURPOSE: Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency's first-in-human and early clinical trial guideline. The increasing complexity and size of modern trial designs (e.g. integrated trials) raise potential issues with risk management, which, if also too complex, presents challenges for both regulators and investigators to implement. Therefore, there is a clear need for a standard, template, or algorithm-based approach to risk management, in particular rules concerning adverse reactions. The purpose of this manuscript is to present template stopping (or adverse reaction, AR) rules that fulfil regulatory requirements and that can be adapted, taking into account trial design, nature of the investigational medicinal product, and anticipated effects. METHODS: The template AR rules that use a systematic, objective and consistent process were developed, taking into account severity (using an objective grading system), seriousness, frequency and reversibility of ARs. These rules control decisions relating to individual trial participants, dosing regimens and dose escalation and/or progression to successive trial parts. For ease of use, the template rules consist of a single, one-page table. RESULTS: The template AR rules have been successfully applied to many early phase adaptive integrated trials that received regulatory authorisation and were performed in the UK. This manuscript presents the template rule table and case studies of some trial-specific adaptations. CONCLUSIONS: This work demonstrates how a systematic, objective and consistent approach to risk management of large integrated trials can be simple yet robust, facilitating effective decision making and trial progression whilst safeguarding participant safety.


Assuntos
Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Drogas em Investigação/efeitos adversos , Gestão de Riscos/métodos , Gestão de Riscos/normas , Ensaios Clínicos Fase I como Assunto/métodos , Ensaios Clínicos Fase I como Assunto/normas , Estudos de Coortes , Tomada de Decisões , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Drogas em Investigação/administração & dosagem , Humanos
20.
Expert Opin Investig Drugs ; 28(2): 121-130, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30572736

RESUMO

INTRODUCTION: The incidence of renal cell carcinoma (RCC) has increased in recent years and, unfortunately, many patients initially present with metastatic disease. When surgery is not an option, treatment involves administration of targeted therapies. The vascular endothelial growth factor (VEGF) pathway has been identified as an important mediator for the development of RCC. Numerous agents target VEGF-mediated signaling, yet resistance and progressive disease still persists. Novel small molecule VEGF inhibitors with high affinity for the VEGF receptor (VEGFR) have been discovered and are currently under investigation for the management of RCC. AREAS COVERED: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed. EXPERT OPINION: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma de Células Renais/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
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