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BACKGROUND: Macroscopic vascular invasion (MVI) significantly impacts survival in patients with hepatocellular carcinoma (HCC), warranting systemic therapy over locoregional therapy. Despite novel approaches, HCC with MVI has a poor prognosis compared to early-to intermediate-stage HCC. This study aimed to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for HCC characterized by MVI. METHODS: This retrospective cohort study evaluated HCC patients with MVI treated using C-ion RT with a dose of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions between 1995 and 2020 at our institution in Japan. We analyzed the prognostic factors and rates of local recurrence, survival, and adverse events. The local recurrence rate was determined using the cumulative incidence function, with death as a competing event. Survival rates were determined using the Kaplan-Meier method. The log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis were used to compare subgroups. RESULTS: In total, 76 patients with a median age of 71 years (range, 45-86 years) were evaluated. Among them, 68 had Child-Pugh grade A while eight had grade B disease. In 17 patients, the vascular tumor thrombus reached the inferior vena cava or main trunk of the portal vein. Over a median follow-up period of 27.9 months (range, 1.5-180.4 months), the 2-year overall survival, progression-free survival, and local recurrence rates were 70.0% (95% confidence interval [CI]: 57.7-79.4%), 32.7% (95% CI: 22.0-43.8%), and 8.9% (95% CI: 1.7-23.5%), respectively. A naïve tumor and a single lesion were significant prognostic factors for overall survival in the univariate analysis. Albumin-bilirubin grade 1 and a single lesion were independent prognostic factors in the multivariate analysis. Overall, four patients (5%) experienced grade 3 late adverse events, with no observed grade 4 or 5 acute or late adverse events. CONCLUSIONS: C-ion RT for HCC with MVI showed favorable local control and survival benefits with minimal toxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Invasividade Neoplásica , Processos Neoplásicos , Recidiva Local de Neoplasia/patologia , Carbono , PrognósticoRESUMO
Carbon-ion radiotherapy (CIRT) is one of the most effective radiotherapeutic modalities. This study aimed to select robust-beam configurations (BC) by water equivalent thickness (WET) analysis in passive CIRT for pancreatic cancer. The study analyzed 110 computed tomography (CT) images and 600 dose distributions of eight patients with pancreatic cancer. The robustness in the beam range was evaluated using both planning and daily CT images, and two robust BCs for the rotating gantry and fixed port were selected. The planned, daily, and accumulated doses were calculated and compared after bone matching (BM) and tumor matching (TM). The dose-volume parameters for the target and organs at risk (OARs) were evaluated. Posterior oblique beams (120-240°) in the supine position and anteroposterior beams (0° and 180°) in the prone position were the most robust to WET changes. The mean CTV V95% reductions with TM were -3.8% and -5.2% with the BC for gantry and the BC for fixed ports, respectively. Despite ensuring robustness, the dose to the OARs increased slightly with WET-based BCs but remained below the dose constraint. The robustness of dose distribution can be improved by BCs that are robust to ΔWET. Robust BC with TM improves the accuracy of passive CIRT for pancreatic cancer.
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BACKGROUND: Three-dimensional image-guided brachytherapy is the standard of care in cervical cancer radiotherapy. In addition, the usefulness of the so-called "hybrid brachytherapy (HBT)" has been reported, which involves the addition of needle applicators to conventional intracavitary brachytherapy for interstitial irradiation. AIM: To evaluate the clinical outcomes of CT-based HBT consisting of transvaginal insertion of needle applicators (CT-based transvaginal HBT) and only intravenous sedation without general or saddle block anesthesia. METHODS AND RESULTS: This is a retrospective chart review of patients who received definitive radiotherapy, including CT-based transvaginal HBT, between February 2012 and July 2019. The inclusion criteria were as follows: (i) histologically diagnosed disease, (ii) untreated cervical cancer, (iii) International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA disease in the 2008 FIGO staging system, and (iv) patients who underwent CT-based transvaginal HBT at least once in a series of intracavitary brachytherapy. Overall, 54 patients fulfilled the eligibility criteria in the present study. The median follow-up period was 32 (IQR, 19-44) months. No patient complained of symptoms such as persistent bleeding or abdominal pain after the treatment. The 3-year local control (LC), disease-free survival, and overall survival rates for all 54 patients were 86.6%, 60.3%, and 90.7% (95% CI [81.3%-100.0%]), respectively. The 3-year LC rate was 87.7% in patients with FIGO III-IVA and 90.4% in tumor size >6.0 cm. The incidence rate of late adverse events, grade ≥3, in the rectum and bladder was 0% and 1.8%, respectively. In the dose-volume histogram analyses, transvaginal HBT increased the dose of HR-CTVD90 by ~7.5% without significantly increasing the dose of organs at risk. CONCLUSION: Considering the favorable clinical outcomes, CT-based transvaginal HBT may be a good option for treating cervical cancer.
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Anestesia , Braquiterapia , Neoplasias do Colo do Útero , Feminino , Gravidez , Humanos , Braquiterapia/efeitos adversos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/radioterapia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND PURPOSE: In carbon-ion radiotherapy for pancreatic cancer, altered dose distributions due to changes in the gastrointestinal gas volume and anatomy during irradiation are an unresolved therapeutic issue. We developed and investigated an adaptive strategy involving beam angle selection to improve dose distributions in pancreatic cancer. MATERIALS AND METHODS: In the adaptive strategy, multiple beams were prepared with angles similar to those of the conventional strategy, and the beam that best reproduces the dose distribution of the treatment plan was used. The dose distributions of the adaptive strategy were compared with those of the conventional strategy for five patients. Patients underwent computed tomography (CT) before every irradiation. The adaptive strategy was evaluated using the same irradiation schedule as that of the conventional method and an adjusted method based on anatomical changes per fraction. Dose distributions on the pre-treatment CT and accumulated dose distributions on the treatment planning CT were evaluated using the volume receiving ≥95% of the prescription dose (V95) from the clinical target volume (CTV) between strategies. RESULTS: There were significant differences in the CTV V95 values for the pre-treatment CT between all strategies. The median (range) CTV V95 for the conventional strategy was 92.7% (87.1-96.1%), for the proposed adaptive strategy without adjusted schedules was 96.9% (95.1-97.8%), and for the proposed strategy with adjusted schedules was 97.8% (96.5-99.2%). CONCLUSIONS: The adaptive strategy can improve target coverage for the pre-treatment CT and accumulated dose distributions for the treatment planning CT without increasing the dose to critical organs.
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BACKGROUND: Daily anatomical deviations may distort the dose distribution in carbon ion radiotherapy (CIRT), which may cause treatment failure. Therefore, this study aimed to perform re-planning to maintain the dose coverage in patients with pancreatic cancer with passive scattering CIRT. METHODS: Eight patients with pancreatic cancer and 95 daily computed tomography (CT) sets were examined. Two types of adaptive plans based on new range compensators (RCs) (AP-1) and initial RCs (AP-2) were generated. In AP-2, each beam was optimized by manually adjusting the range shifter thickness and spread-out Bragg peak size to make dose reduction by < 3% of the original plan. Doses of the original plan with bone matching (BM) and tumor matching (TM) were examined for comparison. We calculated the accumulated dose using the contour and intensity-based deformable image registration algorithm. The dosimetric differences in respect to the original plan were compared between methods. RESULTS: Using TM and BM, mean ± standard deviations of daily CTV V95 (%) difference from the original plan was - 5.1 ± 6.2 and - 8.8 ± 8.8, respectively, but 1.2 ± 3.4 in AP-1 and - 0.5 ± 2.1 in AP-2 (P < 0.001). AP-1 and AP-2 enabled to maintain a satisfactory accumulated dose in all patients. The dose difference was 1.2 ± 2.8, - 2,1 ± 1.7, - 7.1 ± 5.2, and - 16.5 ± 15.0 for AP-1, AP-2, TM, and BM, respectively. However, AP-2 caused a dose increase in the duodenum, especially in the left-right beam. CONCLUSIONS: The possible dose deterioration should be considered when performing the BM, even TM. Re-planning based on single beam optimization in passive scattering CIRT seems an effective and safe method of ensuring the treatment robustness in pancreatic cancer. Further study is necessary to spare healthy tissues, especially the duodenum.
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Radioterapia com Íons Pesados/normas , Neoplasias Pancreáticas/radioterapia , Garantia da Qualidade dos Cuidados de Saúde/normas , Planejamento da Radioterapia Assistida por Computador/normas , Idoso , Idoso de 80 Anos ou mais , Feminino , Radioterapia com Íons Pesados/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Órgãos em Risco/efeitos da radiação , Prognóstico , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Taxa de Sobrevida , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: We aimed to assess the robustness of accumulated dose distributions for inter-fractional changes in passive carbon-ion radiotherapy for pancreatic cancer. METHODS: Ninety-five daily CT image sets acquired after the treatment of eight patients with pancreatic cancer were used in this prospective study. Dose distributions with treatment beam fields were recalculated for bone matching (BM) and tumor matching (TM) positions on all daily CT images, the accumulated doses being calculated using deformable image registration methods. The prescribed dose was 55.2 Gy (relative biological effectiveness [RBE]) in 12 fractions. Dose volume parameters of V95 (%) for CTV and GTV, and D2cc (Gy(RBE)) for the stomach and duodenum were evaluated. RESULTS: The medians (range) of CTV V95 (%) were 91.9 (86.1-100.0), 80.5 (56.1-90.6), and 86.4 (72.5-96.5) for the Plan, accumulated with BM and TM, respectively; GTV values (%) were 98.0 (85.7-100.0), 93.3 (65.7-99.9), and 96.2 (84.8-100.0), respectively. There were significant differences between all combinations apart from the Plan and TM for both targets. The values of stomach D2cc (Gy(RBE)) were 36.0 (16.9-43.4), 36.7 (17.9-45.0), and 35.2 (16.8-43.5), respectively; duodenum values (Gy(RBE)) were 25.2 (21.3-40.3), 30.1 (23.3-48.6), and 28.3 (20.4-50.6), respectively. There was a significant difference between the Plan and BM for duodenum only. CONCLUSIONS: TM is recommended over BM because it can achieve higher target dose coverage than BM. Nevertheless, it is not enough in some cases. Further technical improvements are necessary to improve the target dose coverage.
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Neoplasias Pancreáticas , Planejamento da Radioterapia Assistida por Computador , Carbono , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/radioterapia , Estudos Prospectivos , Dosagem RadioterapêuticaRESUMO
BACKGROUND/AIM: This study aimed to determine appropriate deformable image registration (DIR) algorithms for pancreatic cancer patients undergoing carbon ion radiotherapy (CIRT). PATIENTS AND METHODS: The performance of three types of DIR algorithms, including intensity-based DIR (iDIR), contour-based DIR (cDIR), and hybrid DIR (hDIR) were evaluated using seventy-one CT images from eight pancreatic cancer patients. Both the geometry of the CTV and subsequent dose warping discrepancies were evaluated using the dice similarity coefficient (DSC) and the difference in V95. RESULTS: cDIR and hDIR had superior performance than iDIR in both DSC and V95 (p<0.0001). iDIR caused accumulated dose to be underestimated by 5% in the median CTV V95 compared to the other methods. CONCLUSION: hDIR and cDIR can be utilized to assess the accumulated dose in CIRT for pancreatic cancer. iDIR can be considered when the obtained DSC is greater than 0.89.
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Radioterapia com Íons Pesados/métodos , Neoplasias Pancreáticas/radioterapia , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Idoso , Algoritmos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Neoplasias PancreáticasRESUMO
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm. Although surgical resection is the first-line treatment for primary MCCs, the characteristics of this disease (i.e., high prevalence in the elderly and in the head and neck region) generate a considerable number of inoperable cases. Radiation therapy shows potential as a definitive treatment alternative to surgery. In definitive radiation therapy for non-resected MCC, 60-66 Gy administered in 2 Gy per fraction and five fractions per week is recommended. However, such frequent visits to the hospital can be a great burden to elderly patients and family members. In this report, we present the case of an 89-year-old patient with MCC (cT2N0M0, stage IIA) of the left cheek. The patient was treated with radiation therapy using a mild hypofractionated schedule (57 Gy provided in 3 Gy per fraction and three fractions per week) targeting the gross tumor. The treatment led to complete tumor remission with well-tolerated acute toxicities at three months post-irradiation. This case indicates that a mild hypofractionated irradiation schedule may achieve tumor control in MCC patients who are inoperable and who cannot make frequent hospital visits.
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Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia. Surgical resection is the first-line therapeutic option, and radiation therapy is an alternative treatment for inoperable cases. Herein, we report a case of primary MCC (cT2N0M0, stage IIA) of the head and neck region. This case was misdiagnosed as a metastatic tumor and referred to the department of radiation oncology for palliative irradiation. Additional immunohistochemical analysis confirmed the diagnosis of MCC, and the tumor was treated with definitive radiation therapy (66 Gy in 33 fractions), leading to complete in-field control. This case indicates that even in patients with suspected metastatic tumors referred for palliative treatment, patient characteristics and pathology should be carefully examined to avoid missing potentially controllable primary tumors. In such cases, MCC, although rare, should be included in the differential diagnosis of head and neck lesions.
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Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.
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Radioterapia com Íons Pesados , Recidiva Local de Neoplasia/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Células A549 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Feminino , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Indazóis/farmacologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Projetos Piloto , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapiaRESUMO
Photon radiation therapy is a major curative treatment for cancer. However, the lack of robust predictive biomarkers for radiosensitivity precludes personalized radiation therapy. Clonogenic assays are the gold standard method for measuring the radiosensitivity of cancer cells. Although a large number of publications describe the use of clonogenic assays to measure cancer cell radiosensitivity, the robustness of results from different studies is unclear. To address this, we conducted a comprehensive detailed literature search of 256 common cancer cell lines and identified the eight cell lines most-frequently examined for photon sensitivity using clonogenic assays. Survival endpoints and experimental parameters from all 620 relevant experiments were compiled and analyzed. We found that the coefficients of variation for SF2 (surviving fraction after 2 Gy irradiation) and for D10 (dose that yields a surviving fraction of 10%) were below 30% for all cell lines, indicating that SF2 and D10 have acceptable inter-assay precision. These data support further analysis of published data on clonogenic assays using SF2 and D10 as survival endpoints, which facilitates robust identification of biological profiles representative of cancer cell sensitivity to photons.
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Biomarcadores , Sobrevivência Celular/efeitos da radiação , Tolerância a Radiação , Ensaio Tumoral de Célula-Tronco , Linhagem Celular Tumoral , Humanos , Fótons , Radioterapia , Células Tumorais CultivadasRESUMO
BACKGROUND AND PURPOSE: Integrated analysis of existing radiosensitivity data obtained by the gold-standard clonogenic assay has the potential to improve our understanding of cancer cell radioresistance. However, extraction of radiosensitivity data from the literature is highly labor-intensive. To aid in this task, using deep convolutional neural networks (CNNs) and other computer technologies, we developed an analysis pipeline that extracts radiosensitivity data derived from clonogenic assays from the literature. MATERIALS AND METHODS: Three classifiers (C1-3) were developed to identify publications containing radiosensitivity data derived from clonogenic assays. C1 uses Faster Regions CNN with Inception Resnet v2 (fRCNN-IRv2), VGG-16, and Optical Character Recognition (OCR) to identify publications that contain semi-logarithmic graphs showing radiosensitivity data derived from clonogenic assays. C2 uses fRCNN-IRv2 and OCR to identify publications that contain bar graphs showing radiosensitivity data derived from clonogenic assays. C3 is a program that identifies publications containing keywords related to radiosensitivity data derived from clonogenic assays. A program (iSF2) was developed using Mask RCNN and OCR to extract surviving fraction after 2-Gy irradiation (SF2) as assessed by clonogenic assays, presented in semi-logarithmic graphs. The efficacy of C1-3 and iSF2 was tested using seven datasets (1805 and 222 publications in total, respectively). RESULTS: C1-3 yielded sensitivity of 91.2%⯱â¯3.4% and specificity of 90.7%⯱â¯3.6%. iSF2 returned SF2 values that were within 2.9%⯱â¯2.6% of the SF2 values determined by radiation oncologists. CONCLUSION: Our analysis pipeline is potentially useful to acquire radiosensitivity data derived from clonogenic assays from the literature.
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Mineração de Dados , Aprendizado Profundo , Tolerância a Radiação , Sobrevivência Celular/efeitos da radiação , HumanosRESUMO
The electrochemical oxidation of 2-propanol over Pt and Pd electrodes was evaluated in alkaline media. Linear sweep voltammograms (LSVs), chronoamperograms (CAs), and simultaneous time-resolved attenuated total reflection infrared (ATR-IR) spectra of both electrodes were obtained in a 0.25 M KOH solution containing 1 M 2-propanol. The onset potential of 2-propanol oxidation for Pt was lower than that for Pd in LSVs while the degree of performance degradation observed for Pd was significantly smaller than that observed for Pt in CAs. The main product of 2-propanol oxidation was acetone over both electrodes and, over Pt only, acetone produced was catalytically oxidized to the enolate ion, which was accumulated on the Pt surface, leading to significant performance degradation. Carbon dioxide and carbonate species (CO3(2-), HCO3(-)) were not observed during 2-propanol oxidation over both electrodes, indicating that the complete oxidation of 2-propanol to CO2 will be a minor reaction.
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A high proton-conducting phase appears in the composites of zirconium- and titanium-oxide nanoparticles and polyphosphoric acid (HPO(3)). Metal oxide nanoparticles (ZrO(2) and TiO(2)) react with HPO(3) and form composite electrolytes containing pyrophosphates (ZrP(2)O(7) or TiP(2)O(7)) and shortened HPO(3) chains. The ZrO(2)-HPO(3) composite exhibits eleven times higher conductivity than sole HPO(3) at the maximum. A formed layer of shortened HPO(3) chains surrounding the pyrophosphates enhances the proton conductivities of the composite electrolytes and reduces the activation energies for the proton conductivities from 50 to 30 kJ mol(-1).
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In order to characterize the chromosomal alterations in ameloblastomas, a combination of comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) techniques was performed on 9 tumors. Chromosomal alterations including a gain at 1q and losses at 1pter, 10q, and 22q could be detected by CGH only in 1 tumor. Interphase FISH analysis, using centromeric probes for chromosomes 1, 10, and 22 as well as region-specific probes for 1p36 and 10q26, revealed the most frequent alterations to exist in the tumor with the abnormal CGH profile. These alterations included marked to slight increases of monosomic cells for chromosome 10 (91.5%), 10q26 (35.8%), 1p36 (24.4%), and chromosome 22 (18.8%), as well as significant elevations of trisomic cells for chromosome 1 (41.2%). Moreover, FISH analysis revealed a frequent loss of chromosome 22 in all tumors examined, except for one lesion, indicating that loss of the entire or a part of this chromosome is a common event in ameloblastomas, possibly being a predisposing factor to ameloblastoma tumorigenesis.
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Aberrações Cromossômicas , Adolescente , Adulto , Idoso , Ameloblastoma , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 22 , Feminino , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido NucleicoRESUMO
(1S,2R)-2-Acylamino-1-methyl-2-phenylethyl phosphate derivatives 2a, 2b, 3a, and 5a, which are conformationally restricted and metabolically stable analogues of (2R)-2-acylamino-2-phenylethyl phosphate derivatives 1a and 1b, are a new class of inhibitors of TNF-alpha production. More efficient alternative synthesis of a key intermediate, (1R,2S)-1-amino-1-(3-methoxyphenyl)propan-2-ol hydrochloride (9), was achieved using one-step, three-component coupling of 3-methoxyphenyl boronic acid (13), (5S)-2,2,5-trimethyl-1,3-dioxolan-4-ol (14), and amino diphenyl methane (15), [as reported in J. Am. Chem. Soc. 1998, 120, 11798]. Evaluation of the hypotensive activity of these compounds was done to assess one of their side effects. Among the compounds tested, the above-mentioned four compounds (2a, 2b, 3a, and 5a) were identified as inhibitors with both sufficient potency and an acceptable safety margin regarding their hypotensive activity. The pharmacodynamics of these compounds were also investigated. Single-dose pharmacokinetic data for compounds 2a, 2b, 3a, and 5a are displayed. These compounds were estimated to be mainly metabolized by the liver in the species tested based on their in vitro stability in tissue homogenates and plasma. A representative compound, 2a, showed good linearity of its plasma concentration after intravenous injection.
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Proteínas de Neoplasias/síntese química , Proteínas de Neoplasias/farmacologia , Amino Álcoois/química , Amino Álcoois/farmacologia , Animais , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Meia-Vida , Humanos , Hipotensão/induzido quimicamente , Técnicas In Vitro , Fígado/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Tipo II do Fator de Necrose Tumoral , Estereoisomerismo , Relação Estrutura-Atividade , Receptores Chamariz do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Discovery of new chemical leads of inhibitors for TNF-alpha production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-alpha expression in the liver and spleen of mice. Structure-activity relationships (SARs) are also discussed and full details including the chemistry are reported.
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Indanos/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Feminino , Indanos/administração & dosagem , Indanos/farmacologia , Concentração Inibidora 50 , Injeções Intravenosas , Lipopolissacarídeos/farmacologia , Fígado/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Baço/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossínteseRESUMO
2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of sphingomyelinase was found to show inhibitory activity of TNF-alpha production. Structural optimization was started with the chemical modification of 6. The discovery of another chemical leads 7, 8, 10 and 16 for the development of structurally new inhibitors of TNF-alpha production is reported.
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Indanos/síntese química , Ácidos Fosfínicos/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Indanos/farmacologia , Concentração Inibidora 50 , Injeções Intraperitoneais , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ácidos Fosfínicos/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.
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Indanos/síntese química , Indanos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estabilidade de Medicamentos , Indanos/química , Injeções Intravenosas , Lipopolissacarídeos/farmacologia , Dose Máxima Tolerável , Camundongos , Conformação Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Ratos , Choque Séptico/induzido quimicamente , Choque Séptico/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Taxa de Sobrevida , Distribuição Tecidual , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The discovery of 2-acylamino-2-phenylethyl disodium phosphates and as structurally novel inhibitors of TNF-alpha production is reported. Structure-activity relationships (SARs) are also discussed.