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1.
Expert Opin Investig Drugs ; 28(8): 733-740, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347405

RESUMO

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue. Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life. Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.


Assuntos
Caquexia/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Neoplasias/complicações , Apetite/efeitos dos fármacos , Caquexia/etiologia , Caquexia/fisiopatologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Apoio Nutricional/métodos , Qualidade de Vida , Projetos de Pesquisa
4.
World J Gastroenterol ; 25(15): 1783-1796, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057294

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.


Assuntos
Reposicionamento de Medicamentos , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos
5.
BMC Cancer ; 19(1): 361, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30991990

RESUMO

BACKGROUND: Phase I trials aim to identify the recommended dose for further development. Health-related quality of life (HRQoL) could be a complement to the usual National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale to detect adverse events and define the doses. The objective of this study is to review the phase I in oncology which used HRQoL as endpoint. METHODS: A search in PubMed database identified phase I trials in oncology with HRQoL as endpoint, published between January 2012 to May 2016. Hematological and pediatric phase I were excluded. RESULTS: A total of 1333 phase I were identified and 15 trials were identified with HRQoL as endpoint (1.1%). The European Organisation for Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was the most frequently used instrument: 5 studies (33.3%). The targeted dimensions of HRQoL and the minimal clinically important difference were prespecified in 1 study (6.7%) and 2 studies (13.3%), respectively. Twelve studies (80%) described the statistical approach to analyze HRQoL data. Eight studies used the mean change from baseline (60%) to analyse longitudinal HRQoL data, two the mean score at certain times (13.3%), one the linear mixed model for repeated measures (6.7%), one the time to HRQoL score deterioration (6.7%), one percentage of patient-reported symptoms (6.7%). None of the studies used HRQoL to determine the recommended doses. CONCLUSION: Few phase I studies used HRQoL as endpoint and among studies with HRQoL as endpoint, the methodology of HRQoL measurement and statistical analysis was heterogeneous. HRQoL. endpoint not used for assessing the recommended phase II doses.


Assuntos
Neoplasias/epidemiologia , Qualidade de Vida , Ensaios Clínicos Fase I como Assunto , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/terapia , Avaliação de Resultados (Cuidados de Saúde) , Inquéritos e Questionários , Resultado do Tratamento
6.
Phys Med ; 60: 111-119, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31000070

RESUMO

PURPOSE: Synchrotron Microbeam Radiation Therapy (MRT) is a pre-clinical modality characterised by spatial dose fractionation on a microscopic scale. Treatment planning studies using clinical datasets have not yet been conducted. Our aim was to investigate MRT dose-distributions in scenarios refractory to conventional treatment and to identify optimal settings for a future Phase I trial. METHODS: MRT plans were generated for seven scenarios where re-irradiation was performed clinically. A hybrid algorithm, combining Monte Carlo and convolution-based methods, was used for dose-calculation. The valley dose to organs at risk had to respect the single fraction tolerance doses achieved in the corresponding re-irradiation plans. The resultant peak dose and the peak-to-valley dose ratio (PVDR) at the tumour target volume were assessed. RESULTS: Peak doses greater than 80 Gy in a single fraction, and PVDRs greater than 10, could be achieved for plans with small (<35 cm3) or shallow volumes, particularly recurrent glioblastoma, head and neck tumours, and select loco-regionally recurrent breast cancer sites. Treatment volume was a more important factor than treatment depth in determining the PVDR. The mean PVDR correlated strongly with the size of the target volume (rs = -0.70, p = 0.01). The PVDRs achieved in these clinical scenarios are considerably lower than those reported in previous pre-clinical studies. CONCLUSION: Our findings suggest that head and neck sites will be optimal scenarios for MRT.


Assuntos
Fracionamento da Dose de Radiação , Planejamento da Radioterapia Assistida por Computador/métodos , Adulto , Idoso , Algoritmos , Ensaios Clínicos Fase I como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Neoplasias/radioterapia , Órgãos em Risco , Síncrotrons
7.
Nat Med ; 25(5): 738-743, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011204

RESUMO

Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.


Assuntos
DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Ensaios Clínicos Fase I como Assunto , Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Neoplasias/sangue , Neoplasias/genética , Neoplasias/terapia , Seleção de Pacientes , Análise de Sequência de DNA
8.
mSphere ; 4(2)2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894432

RESUMO

The repetitive interspersed family (RIFIN) and the subtelomeric variable open reading frame (STEVOR) family represent two of three major Plasmodium falciparum variant surface antigen families involved in malaria pathogenesis and immune evasion and are potential targets in the development of natural immunity. Protein and peptide microarrays populated with RIFINs and STEVORs associated with severe malaria vulnerability in Malian children were probed with adult and pediatric sera to identify epitopes that reflect malaria exposure. Adult sera recognized and reacted with greater intensity to all STEVOR proteins than pediatric sera did. Serorecognition of and seroreactivity to peptides within the semiconserved domain of STEVORs increased with age and seasonal malaria exposure, while serorecognition and seroreactivity increased for the semiconserved and second hypervariable domains of RIFINs only with age. Serologic responses to RIFIN and STEVOR peptides within the semiconserved domains may play a role in natural immunity to severe malaria.IMPORTANCE Malaria, an infectious disease caused by the parasite Plasmodium falciparum, causes nearly 435,000 deaths annually worldwide. RIFINs and STEVORs are two variant surface antigen families that are involved in malaria pathogenesis and immune evasion. Recent work has shown that a lack of humoral immunity to these proteins is associated with severe malaria vulnerability in Malian children. This is the first study to have compared serologic responses of children and adults to RIFINs and STEVORs in settings of malaria endemicity and to examine such serologic responses before and after a clinical malaria episode. Using microarrays, we determined that the semiconserved domains in these two parasite variant surface antigen families harbor peptides whose seroreactivity reflects malaria exposure. A similar approach has the potential to illuminate the role of variant surface antigens in the development of natural immunity to clinical malaria. Potential vaccines for severe malaria should include consideration of peptides within the semiconserved domains of RIFINs and STEVORs.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Sequências Repetitivas Dispersas/imunologia , Malária/imunologia , Adolescente , Adulto , Fatores Etários , Antígenos de Protozoários/genética , Criança , Pré-Escolar , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Doenças Endêmicas , Feminino , Humanos , Imunidade Inata , Lactente , Malária/sangue , Masculino , Mali/epidemiologia , Pessoa de Meia-Idade , Peptídeos/genética , Peptídeos/imunologia , Plasmodium falciparum , Análise Serial de Proteínas , Adulto Jovem
9.
Gynecol Oncol ; 153(2): 425-435, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30853360

RESUMO

OBJECTIVES: The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. METHODS: We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. RESULTS: ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. CONCLUSIONS: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias do Endométrio/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Idoso , Animais , Autofagia/efeitos dos fármacos , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Regulação para Cima/efeitos dos fármacos
11.
Future Oncol ; 15(12): 1313-1322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834780

RESUMO

Aim: This analysis compares safety data for Sandoz proposed biosimilar (LA-EP2006) and reference pegfilgrastim from a Phase I pharmacokinetic/pharmacodynamic study in healthy volunteers (HVs) and two Phase III confirmatory studies in patients with breast cancer (BC; total n = 808). Patients & methods: Baseline characteristics were summarized, and event rates of bone pain and headache calculated. Results: HVs in the Phase I pharmacokinetic/pharmacodynamic study were generally younger, with lower mean body mass index, versus BC patients in PROTECT-1/-2. Bone pain was the most frequent adverse event with similar incidences with reference versus proposed biosimilar in all studies. Conclusion: No differences in adverse events were found between Sandoz proposed biosimilar and reference pegfilgrastim, notwithstanding some differences between HVs and BC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Filgrastim/efeitos adversos , Polietilenoglicóis/efeitos adversos , Adulto , Medicamentos Biossimilares/administração & dosagem , Doenças Ósseas/induzido quimicamente , Doenças Ósseas/epidemiologia , Neoplasias da Mama/sangue , Neutropenia Febril Induzida por Quimioterapia/etiologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Estudos de Equivalência como Asunto , Feminino , Filgrastim/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dor/induzido quimicamente , Dor/epidemiologia , Polietilenoglicóis/administração & dosagem , Adulto Jovem
12.
Int J Immunopathol Pharmacol ; 33: 2058738419838383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900486

RESUMO

Neuropathic pain is characterized by abnormal hypersensitivity to stimuli (hyperalgesia) and nociceptive responses to non-noxious stimuli (allodynia). The conditions and the pathophysiological states that determine the onset of neuropathic pain are heterogeneous, such as metabolic disorders, neuropathy caused by viral infections, and autoimmune diseases affecting the central nervous system (CNS). Neuropathic pain in the general population is estimated to have a prevalence ranging between 3% and 17%. Most of the available treatments for neuropathic pain have moderate efficacy and present side effects that limit their use; therefore, other therapeutic approaches are needed for patients. In this article, the current standard of care treatment, the emerging pharmacological approaches from the completed phase III clinical trials, and the preclinical studies on novel promising therapeutic options will be reviewed.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/métodos , Analgésicos/farmacologia , Animais , Ensaios Clínicos Fase I como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Humanos , Neuralgia/diagnóstico , Neuralgia/epidemiologia , Medição da Dor/efeitos dos fármacos , Resultado do Tratamento
13.
Expert Opin Investig Drugs ; 28(5): 489-496, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30908082

RESUMO

BACKGROUND: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC). RESEARCH DESIGN AND METHODS: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared. RESULTS: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects. CONCLUSION: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.


Assuntos
Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Glucocorticoides/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores de Glucocorticoides/agonistas , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Prednisolona/efeitos adversos , Prednisolona/farmacologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
14.
J Cancer Res Clin Oncol ; 145(6): 1635-1643, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30923943

RESUMO

PURPOSE: Radiation-induced cardiac toxicity (RICT) is an increasingly well-appreciated source of morbidity and mortality in patients receiving thoracic radiotherapy (RT). Currently available methods to predict RICT are suboptimal. We investigated circulating microRNAs (c-miRNAs) as potential biomarkers of RICT in patients undergoing definitive RT for non-small-cell lung cancer (NSCLC). METHODS: Data from 63 patients treated on institutional trials were analyzed. Prognostic models of grade 3 or greater (G3 +) RICT based on pre-treatment c-miRNA levels ('c-miRNA'), mean heart dose (MHD) and pre-existing cardiac disease (PCD) ('clinical'), and a combination of these ('c-miRNA + clinical') were developed. Elastic net Cox regression and full cross validation were used for variable selection, model building, and model evaluation. Concordance statistic (c-index) and integrated Brier score (IBS) were used to evaluate model performance. RESULTS: MHD, PCD, and serum levels of 14 c-miRNA species were identified as jointly prognostic for G3 + RICT. The 'c-miRNA and 'clinical' models yielded similar cross-validated c-indices (0.70 and 0.72, respectively) and IBSs (0.26 and 0.28, respectively). However, prognostication was not improved by combining c-miRNA and clinical factors (c-index 0.70, IBS 0.28). The 'c-miRNA' and 'clinical' models were able to significantly stratify patients into high- and low-risk groups of developing G3 + RICT. Chi-square testing demonstrated a marginally significantly higher prevalence of PCD in patients with high- compared to low-risk c-miRNA profile (p = 0.09), suggesting an association between some c-miRNAs and PCD. CONCLUSIONS: We identified a pre-treatment c-miRNA signature prognostic for G3 + RICT. With further development, pre- and mid-treatment c-miRNA profiling could contribute to patient-specific dose selection and treatment adaptation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cardiotoxicidade/sangue , Cardiotoxicidade/etiologia , MicroRNA Circulante/sangue , Neoplasias Pulmonares/radioterapia , Lesões por Radiação/sangue , Lesões por Radiação/etiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cardiotoxicidade/genética , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Lesões por Radiação/genética
15.
Cancer Commun (Lond) ; 39(1): 5, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786916

RESUMO

BACKGROUND: Glioblastoma (GBM) is a highly virulent tumor of the central nervous system, with a median survival < 15 months. Clearly, an improvement in treatment outcomes is needed. However, the emergence of these malignancies within the delicate brain parenchyma and their infiltrative growth pattern severely limit the use of aggressive local therapies. The particle therapy represents a new promising therapeutic approach to circumvent these prohibitive conditions with improved treatment efficacy. METHODS AND DESIGN: Patients with newly diagnosed malignant gliomas will have their tumor tissue samples submitted for the analysis of the status of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. In Phase I, the patients will undergo an induction carbon ion radiotherapy (CIRT) boost followed by 60 GyE of proton irradiation with concurrent temozolomide (TMZ) at 75 mg/m2. To determine the maximal dose of safe induction boost, the tolerance, and acute toxicity rates in a dose-escalation manner from 9 to 18 GyE in three fractions will be used. In Phase III, GBM-only patients will be randomized to receive either 60 GyE (2 GyE per fraction) of proton irradiation with concurrent TMZ (control arm) or a CIRT boost (dose determined in Phase I of this trial) followed by 60 GyE of proton irradiation with concurrent TMZ. The primary endpoints are overall survival (OS) and toxicity rates (acute and long-term). Secondary endpoints are progression-free survival (PFS), and tumor response (based upon assessment with C-methionine/fluoro-ethyl-tyrosine positron emission tomography [MET/FET PET] or magnetic resonance imaging [MRI] and detection of serologic immune markers). We hypothesize that the induction CIRT boost will result in a greater initial tumor-killing ability and prime the tumor microenvironment for enhanced immunologic tumor clearance, resulting in an expected 33% improvement in OS rates. DISCUSSION: The prognosis of GBM remains grim. The mechanism underpinning the poor prognosis of this malignancy is its chronic state of tumor hypoxia, which promotes both immunosuppression/immunologic evasion and radio-resistance. The unique physical and biological properties of CIRT are expected to overcome these microenvironmental limitations to confer an improved tumor-killing ability and anti-tumor immune response, which could result in an improvement in OS with minimal toxicity. Trial registration number This trial has been registered with the China Clinical Trials Registry, and was allocated the number ChiCTR-OID-17013702.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Radioterapia com Íons Pesados , Antineoplásicos Alquilantes/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Terapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Temozolomida/uso terapêutico
16.
Drug Des Devel Ther ; 13: 481-490, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774312

RESUMO

Introduction: Comparative pharmacokinetic (PK) data analysis of drugs administered using developed child-appropriate and market authorized dosage formulation is sparse and is important in pediatric drug development. Objectives: To compare and evaluate any differences in PK of enalapril administered using two treatments of child-appropriate orodispersible minitablets (ODMTs) and market authorized reference tablet formulation (Renitec®) using PK compartment model and validated least square minimization method (LSMM) of parameter estimation. Methods: Full profile data sets were obtained from a phase I clinical trial, whereby three treatments of enalapril, ie, reference tablets with 240 mL water (treatment A), child-appropriate ODMTs with 240 mL (treatment B), and ODMTs dispersed in the mouth with 20 mL water (treatment C), were administered to 24 healthy adult volunteers. Virtual validation analysis was conducted using R program to select accurate and precise LSMM of parameter estimation. For the selection of PK model and estimation of parameters, enalapril data were fitted with one-and two-compartment models with first order of absorption and elimination, with and without incorporated lag time parameter (tlag). The log-transformed PK parameters were statistically compared by the two-sided paired t-test with the level of significance of P<0.05. Results: One-compartment model with first-order absorption and elimination and incorporated lag time adequately predicted concentrations of enalapril. Reciprocal of predicted concentration using iteratively reweighted LSMM was selected as the most appropriate method of parameter estimation. Comparison of PK parameters including rate constant of absorption and elimination, volume of distribution, and tlag between the three treatments showed significant difference (P=0.018) in tlag between treatments B and A only. Conclusion: Compared with reference formulation, enalapril administered from child-appropriate ODMTs administered with 240 mL water appeared 4 minutes earlier in serum. No other differences were observed in absorption, elimination, and relative bioavailability of drug between the three treatment arms.


Assuntos
Enalapril/farmacocinética , Modelos Biológicos , Administração Oral , Criança , Ensaios Clínicos Fase I como Assunto , Enalapril/administração & dosagem , Enalapril/metabolismo , Voluntários Saudáveis , Humanos , Análise dos Mínimos Quadrados , Comprimidos/administração & dosagem , Comprimidos/metabolismo , Comprimidos/farmacocinética
17.
Expert Opin Investig Drugs ; 28(3): 235-247, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30677323

RESUMO

INTRODUCTION: Menopausal symptoms have a substantial effect on the quality of life of many women; hence, investigations for the amelioration of menopausal symptoms continue to be necessary. The two main approaches to the amelioration of symptoms are hormone therapy (HT) and non-hormonal therapy. AREAS COVERED: This review provides a background for understanding the types of menopausal symptoms and their underlying physiology. The early clinical development of natural estrogen (estetrol, E4), neurokinin 3 receptor (NK3R) antagonists, and other non-hormonal therapies are covered. The status and outcome of these novel treatment modalities are also discussed. EXPERT OPINION: The recent observation in the Women's Health Initiative (WHI) trials that HT was not associated in the long-term with all-cause mortality, brings renewed interest in the development of new treatment modalities in postmenopausal women. Estetrol (E4), a native estrogen with selective action in tissues, is a potential next-generation HT with improved cardiovascular and breast safety. NK3R antagonists may become an interesting new modality for the amelioration of hot flushes in women with contraindications to estrogens.


Assuntos
Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/administração & dosagem , Menopausa , Administração Oral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/farmacologia , Terapia de Reposição de Estrogênios/métodos , Feminino , Fogachos/tratamento farmacológico , Fogachos/etiologia , Humanos , Qualidade de Vida
19.
Med Phys ; 46(3): 1455-1466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661250

RESUMO

PURPOSE: The purpose of this work was to generate uncompressed heterogeneous breast phantom models using size-dependent fibroglandular distributions derived from a large cohort of breast CT (bCT) datasets, and to compare differences in normalized glandular dose coefficients for bCT "DgNCT " when the realistic heterogeneous model is considered relative to the simple, homogeneous model used in the past. METHODS: A cohort of 274 segmented bCT datasets were used to quantify the fibroglandular tissue distribution within the breast parenchyma. Each dataset was interpolated to an isotropic voxel size of 0.25 mm and the breast center-of-mass was aligned for all coronal slices. Each aligned dataset was converted into two binarized volumes representing voxels containing only glandular tissue "G(x,y,z)" and voxels containing glandular or adipose tissue "AG(x,y,z)". The datasets were classified by volume in accordance with previously reported size-dependent, breast-shaped phantoms. Within the five groups - each containing on average 55 datasets, all G(x,y,z) and AG(x,y,z) volumes were summed separately representing the cumulative distribution of glandular tissue or breast parenchyma (glandular + adipose), respectively. G(x,y,z) was divided by AG(x,y,z) on a voxel-by-voxel basis resulting in a glandular fraction "GF(x,y,z)" distribution for each phantom size. The GF(x,y,z) distributions were used to construct heterogeneous mathematical phantoms for the small, median, and large breast sizes with a 1.5 mm skin thickness - based on previously reported measurements from bCT, and a 5 mm skin thickness for comparison with outdated assumptions of skin thickness. A subset of 15 bCT datasets from the cohort (five for each breast size) were used to construct voxelized patient models for validation of the heterogeneous phantom models. Monte Carlo techniques were used to estimate monoenergetic DgN(E)C T values for photon energies from 9 to 70 keV (in 1 keV intervals) using the mathematical phantoms composed of either heterogeneous or homogeneous breast parenchyma. Polyenergetic (pDgNCT ) coefficients were determined by weighting the DgN(E)C T values by x-ray spectra tuned to the beam characteristic of breast CT. Dose coefficients were compared between the two breast compositions for each volume class, breast density, and skin thickness. RESULTS: For photon energies ≲45 keV, the homogeneous model overestimates DgN(E) values relative to the realistic heterogeneous model sorted into five volume classes. The 5 mm skin thickness underestimates DgN(E) values relative to the realistic 1.5 mm thickness for lower energies and the differences diminish up to 70 keV. Averaged across all phantom sizes the homogeneous model overestimates pDgNCT by 5.7% and 23.3% for the 60 kV W/Cu and 49 kV W/Al spectra, respectively. The heterogeneous model was also found to be in agreement with the voxelized bCT patient models with pDgNCT differences less than 2.3% and 5.2% for the 60 kV W/Cu and 49 kV W/Al spectra, respectively, across all phantom sizes. CONCLUSION: Anatomically accurate heterogeneous phantom models were developed using bCT image-derived fibroglandular tissue distributions. These new models improve the accuracy of bCT dosimetry, and in conjunction with previous models for mammography, may help in providing a more universally accepted breast dosimetry model.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Mamografia/métodos , Imagens de Fantasmas , Exposição à Radiação/análise , Tomografia Computadorizada por Raios X/métodos , Absorção de Radiação , Estudos de Casos e Controles , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Simulação por Computador , Feminino , Humanos , Modelos Estatísticos , Método de Monte Carlo
20.
Trials ; 20(1): 27, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621764

RESUMO

BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100-01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD. METHODS/DESIGN: We have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n = 6 for PP100-01 and NAC; n = 2 for NAC alone). The doses of PP100-01 are 2, 5, and 10 µmol/kg. The primary outcome is the safety and tolerability of PP100-01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100-01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers. DISCUSSION: The aim of the study is to test the safety and tolerability of a SOD mimetic, PP100-01, in combination with a 12-h NAC regimen in patients presenting within 24 h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100-01 regimen and may provide evidence of PP100-01 efficacy in the treatment of paracetamol-induced liver injury. TRIAL REGISTRATION: EudraCT, 2017-000246-21; ClinicalTrials.gov, NCT03177395 . Registered on 6 June 2017.


Assuntos
Acetaminofen/envenenamento , Acetilcisteína/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácido Edético/análogos & derivados , Fosfato de Piridoxal/análogos & derivados , Acetilcisteína/administração & dosagem , Comitês de Monitoramento de Dados de Ensaios Clínicos , Ensaios Clínicos Fase I como Assunto , Interpretação Estatística de Dados , Overdose de Drogas , Quimioterapia Combinada , Ácido Edético/administração & dosagem , Ácido Edético/efeitos adversos , Feminino , Humanos , Masculino , Avaliação de Resultados (Cuidados de Saúde) , Fosfato de Piridoxal/administração & dosagem , Fosfato de Piridoxal/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
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