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1.
Biomed Chromatogr ; 34(1): e4714, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31633806

RESUMO

Eucommia ulmoides Oliv. (E. ulmoides) is a valuable and nourishing medicinal herb in China that has been used in the treatment of hypertension. Given the fact that most traditional Chinese medicine is mainly used to treat disease, investigating the pharmacokinetics of traditional Chinese medicines in the pathological state is more useful than that in the normal state. However, the differences in the absorption kinetics of active ingredients of E. ulmoides extract between pathological and physiological conditions have not been reported. Therefore, in this study, the rat intestinal in situ circulatory perfusion model was used to investigate the differences in absorption kinetics of seven active ingredients of E. ulmoides extract in normal and spontaneously hypertensive rats, namely, genipinic acid, protocatechuic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, (+)-pinoresinol di-O-ß-D-glucopyranoside and (+)-pinoresinol 4'-O-ß-D-glucopyranoside. Our results indicate that the pathological state of spontaneous hypertension may change the absorption of active components of E. ulmoides extracts, and these findings may provide a reference for improving the rational use of E. ulmoides in the clinic.


Assuntos
Eucommiaceae , Absorção Intestinal , Extratos Vegetais , Animais , Anti-Hipertensivos/análise , Anti-Hipertensivos/farmacocinética , Líquidos Corporais/química , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/análise , Ácido Clorogênico/farmacocinética , Furanos/análise , Furanos/farmacocinética , Hidroxibenzoatos/análise , Hidroxibenzoatos/farmacocinética , Lignanas/análise , Lignanas/farmacocinética , Extratos Vegetais/análise , Extratos Vegetais/farmacocinética , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
2.
Biomed Chromatogr ; 34(1): e4717, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634986

RESUMO

A sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to analyze furanodienone in rat plasma. In the process of chromatographic separation, selected reaction monitoring transitions for furanodienone and patchouli alcohol (internal standard, IS) were m/z 231.1 → 83.2 and m/z 205.1 → 95.1, respectively. Great linearity of furanodienone in plasma samples was found in the corresponding concentration range (r > 0.995). Intra- and inter-day precisions (RSD, %) were <11.3% in plasma, and the accuracy (RE, %) was within ±10.7%. This method was used to the furanodienone study on rat pharmacokinetics after a single oral dose of 10 mg/kg of furanodiene. The results indicated that the maximum observed plasma concentration was 52.4 ± 19.1 ng/ml at 1.2 ± 0.7 h with an elimination half-life of 2.2 ± 0.7 h. The obtained data indicated that furanodienone could be moderately distributed and eliminated.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Furanos/sangue , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Furanos/química , Furanos/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Sesquiterpenos/farmacocinética
3.
Forensic Sci Int ; 304: 109915, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31416646

RESUMO

Fatal intoxications due to accidental or voluntary intake of synthetic opioids represent an actual emerging issue. We report a case where we have analyzed furanyl fentanyl and its metabolite 4-anilino-N-phenetyl-piperidine (4-ANPP) in blood, urine, gastric content, bile and cerebrospinal fluid. In this case, a 53-year-old man was found dead at home with a needle still inserted in a vein; a plastic bag containing a white powder (later identified as a furanyl fentanyl-based product) was discovered in the room. Biological samples were collected during autopsy and extracted/purified onto a SPE cartridge before instrumental analysis. Qualitative and quantitative analyses were performed by LC-MS/MS on peripheral and cardiac blood, urine, cerebrospinal fluid (CSF), bile and gastric content. Furanyl fentanyl was identified and quantified in all the biological fluids collected. Interestingly, gastric content revealed an unexpected high amount of furanyl fentanyl; yet, cardiac blood and femoral blood provided significantly different concentrations (11.8 and 2.7 ng/g respectively). The concentration of furanyl fentanyl in CSF was similar to that measured in femoral blood (2.6 ng/mL), thus confirming that CSF could be a good alternative biological fluid whenever a postmortem redistribution is suspected. Concentrations of 93.5, 50.4, 171.7, 41.9, 10.2 ng/mL(g) were measured for 4-ANPP in cardiac blood, femoral blood, urine, bile and cerebrospinal fluid, respectively. The outcomes from the presented case report suggest that the two substances have been not only injected intravenously, but probably also ingested by the man. Fentanyl derivative and its precursor seemed to undergo an extensive postmortem redistribution.


Assuntos
Analgésicos Opioides/análise , Analgésicos Opioides/farmacocinética , Fentanila/análogos & derivados , Furanos/análise , Furanos/farmacocinética , Mudanças Depois da Morte , Bile/química , Cromatografia Líquida , Fentanila/análise , Fentanila/farmacocinética , Toxicologia Forense/métodos , Conteúdo Gastrointestinal/química , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/complicações , Medicamentos Sintéticos/análise , Medicamentos Sintéticos/farmacocinética
4.
J Ethnopharmacol ; 243: 112098, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31325605

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The major terpene lactones of ginkgo biloba extract (GBE) include ginkgolide A, B, C and bilobalide are used for the protection of cardiovascular, cerebrovascular and neurodegenerative diseases. Terpene lactones are orally bioavailable and predominantly eliminated via the renal pathway. However, information on the transporters involved in the pharmacokinetics (PK) and renal excretion of terpene lactones is limited. AIM OF THE STUDY: The objective of this study is to assess the role of OAT1/3 which are important transporters in the human kidney in the PK and renal excretion ginkgolide A, B, C and bilobalide. MATERIALS AND METHODS: Uptake of ginkgolide A, B, C and bilobalide in Madin-Darby Canine Kidney (MDCK) and human embryonic kidney 293 (HEK293) cells overexpressing OAT1 or OAT3, respectively were studied. To verify the result from in vitro cell models, the studies on PK, kidney accumulation and urinary excretion of ginkgolide A, B, C and bilobalide were carried out in rats. RESULTS: The result showed that ginkgolide A, B, C and bilobalide are low-affinity substrates of OAT1/3. Following co-administration with probenecid, a typical inhibitor of OAT1/3, the rat plasma concentrations of ginkgolide A, B, C and bilobalide increased significantly. AUC showed a significant increase in the probenecid-treated rats compared to control rats (893.48 vs. 1123.85, 314.91 vs. 505.74, and 2724.97 vs. 3096.40 µg/L*h for ginkgolide A, B and bilobalide, respectively), while the clearance of these compounds significantly decreased. The accumulation of ginkgolide A, B and bilobalide in the kidney of the probenecid-treated rats was reduced by 1.8, 2.4, and 1.5-fold, respectively; further reducing the cumulative urinary recovery of these compounds. CONCLUSION: The findings indicated that ginkgolide A, B and bilobalide are excreted via OAT1/3-mediated transport in the kidney and OAT1/3 inhibitor significantly influence the PK ginkgolides and bilobalide.


Assuntos
Ciclopentanos/farmacocinética , Furanos/farmacocinética , Ginkgolídeos/farmacocinética , Rim/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Animais , Transporte Biológico , Ciclopentanos/sangue , Cães , Furanos/sangue , Ginkgolídeos/sangue , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Masculino , Proteína 1 Transportadora de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Ratos , Eliminação Renal , Distribuição Tecidual
5.
Br J Cancer ; 120(6): 579-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30783204

RESUMO

BACKGROUND: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. METHODS: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. RESULTS: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. CONCLUSIONS: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Capecitabina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Furanos/farmacocinética , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Cetonas/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Intervalo Livre de Progressão
6.
Bioorg Med Chem Lett ; 29(4): 577-580, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611618

RESUMO

The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC50 value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.


Assuntos
Furanos/síntese química , Furanos/farmacologia , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Animais , Área Sob a Curva , Linhagem Celular , Furanos/química , Furanos/farmacocinética , Concentração Inibidora 50 , Relação Estrutura-Atividade
7.
Br J Cancer ; 120(4): 379-386, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30679780

RESUMO

BACKGROUND: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours. METHODS: Eligible patients with ECOG PS 0-1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. PRIMARY OBJECTIVES: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. RESULTS: Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. CONCLUSIONS: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.


Assuntos
Furanos/administração & dosagem , Cetonas/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Composição de Medicamentos , Feminino , Furanos/efeitos adversos , Furanos/farmacocinética , Humanos , Cetonas/efeitos adversos , Cetonas/farmacocinética , Lipossomos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo
8.
J Med Chem ; 62(3): 1484-1501, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624934

RESUMO

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.


Assuntos
Fármacos Anti-HIV/farmacologia , Furanos/farmacologia , HIV-1/enzimologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Sítios de Ligação , Linhagem Celular Tumoral , Furanos/síntese química , Furanos/farmacocinética , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Masculino , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos Wistar , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-Atividade
9.
Chemosphere ; 214: 418-423, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30268897

RESUMO

Bioaccessibilities of PCDD/PCDF congeners contributing to cancer risk were determined in twelve soil samples from the American Creosote Works Superfund site in Florida. Based upon sample locations, congener profiles (i.e., the same dominant congeners), and total (Toxic Equivalent; TEQ) concentrations, each of these samples has PCDD/PCDF contamination reasonably attributable to the site. Bioaccessibility was determined using a 2-phase in vitro extraction method that included both simulated gastric and intestinal conditions of the human GI tract. Measured congener-specific bioaccessibility values ranged from 34.3 to 62.1%. There was no apparent relationship between the extent of chlorination of PCDD/PCDF congeners and their bioaccessibility. TEQ-weighted bioaccessibility values varied among individual soil samples, which is not unexpected based upon the literature. This variability could not be explained by differences in soil pH, composition, or organic carbon content. The average TEQ-weighted bioaccessibility value of 59% for the twelve samples was accepted as representing site-specific bioavailability of PCDD/PCDFs. This value is higher than most dioxin/furan bioaccessibility values reported in the literature and at the upper end of the range of relative oral bioavailability (RBA) values reported for PCDD/PCDFs from in vivo bioavailability studies. This study used a finer fraction of soil particles (<150 microns versus the more typical <250 microns) to better represent soil that is incidentally ingested. This finer fraction would be expected to have a greater surface area available for extraction of PCDD/PCDFs per unit mass, which might account for the greater than expected bioaccessibility.


Assuntos
Furanos/farmacocinética , Trato Gastrointestinal/metabolismo , Dibenzodioxinas Policloradas/farmacocinética , Eliminação de Resíduos , Poluentes do Solo/farmacocinética , Disponibilidade Biológica , Humanos , Distribuição Tecidual
10.
Bioorg Chem ; 82: 290-305, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30396063

RESUMO

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 µM, and inhibited ERK2 with IC50s of 0.6 and 0.16 µM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a Ki of 0.09 µM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 µM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.


Assuntos
Antineoplásicos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Naftoquinonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Proteína Quinase 1 Ativada por Mitógeno/química , Estrutura Molecular , Mutação , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Piranos/síntese química , Piranos/química , Piranos/farmacocinética , Piranos/farmacologia , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacocinética , Relação Estrutura-Atividade
11.
Biochemistry ; 57(30): 4518-4525, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-29975048

RESUMO

Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Furanos/química , Furanos/farmacologia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Domínio Catalítico/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Furanos/farmacocinética , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Éteres Fenílicos/farmacocinética , Inibidores da Fosfodiesterase 4/farmacocinética , Rolipram/análogos & derivados , Rolipram/farmacocinética , Rolipram/farmacologia , Estereoisomerismo , Água/química
12.
Cancer Sci ; 109(9): 2822-2829, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29933506

RESUMO

Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h-1 , neutrophil elimination rate constant = 0.0295 h-1 , and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Furanos/efeitos adversos , Cetonas/efeitos adversos , Vigilância de Produtos Comercializados , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Feminino , Furanos/farmacocinética , Furanos/farmacologia , Humanos , Cetonas/farmacocinética , Cetonas/farmacologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Albumina Sérica/análise
13.
PLoS One ; 13(6): e0198219, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29856804

RESUMO

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Arctium , Carcinoma Adenoescamoso/sangue , Carcinoma Ductal Pancreático/sangue , Medicamentos de Ervas Chinesas/uso terapêutico , Furanos/uso terapêutico , Ácido Láctico/sangue , Lignanas/uso terapêutico , Neoplasias Pancreáticas/sangue , Extratos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos/farmacocinética , Arctium/química , Área Sob a Curva , Biomarcadores/sangue , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/farmacocinética , Furanos/farmacocinética , Gluconeogênese/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Lignanas/farmacocinética , Fígado/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico
14.
Lancet Oncol ; 19(6): 812-824, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29706375

RESUMO

BACKGROUND: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. METHODS: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. FINDINGS: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. INTERPRETATION: The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. FUNDING: Polyphor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Furanos/administração & dosagem , Cetonas/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Receptor ErbB-2/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Furanos/efeitos adversos , Furanos/farmacocinética , Humanos , Cetonas/efeitos adversos , Cetonas/farmacocinética , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/farmacocinética , Receptores CXCR4/antagonistas & inibidores , Espanha , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
15.
Pediatr Blood Cancer ; 65(8): e27066, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29719113

RESUMO

BACKGROUND: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. METHODS: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. RESULTS: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2 /dose, respectively. One subject at the 1.4 mg/m2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). CONCLUSIONS: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2 /dose on days 1 and 8 of a 21-day cycle.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Furanos/administração & dosagem , Furanos/efeitos adversos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Neoplasias/tratamento farmacológico , Adolescente , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Furanos/farmacocinética , Humanos , Cetonas/farmacocinética , Masculino , Dose Máxima Tolerável , Microtúbulos/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico
16.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1087-1088: 80-89, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29723699

RESUMO

The compounds of N-Methylanhydrotetrahydroberberrubine A, dictamnine and eudesmin were the primary bioactive components in the roots of Zanthoxylum armatum DC (Z. armatum). To clarify the pharmacokinetics and distribution of these three compounds, an ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was employed to determine the contents of these three compounds in rat plasma and seven tissues. The separation was achieved on a Kinetex XB-C18 100A column (2.1 × 50 mm, 2.6 µm, Phenomenex). The optimized mobile phase system was set with 0.1‰ formic acid aqueous solution (A) and acetonitrile (containing 0.1‰ formic acid) (B) with a programmed elution of 0.00 to 0.50 min, 2% B; 0.51-4.00 min, 30%-60% B; and 4.01-5.00 min, 2% B. All analytes were measured with optimized multiple reaction monitoring (MRM) in the positive ion ESI mode. Berberine hydrochloride was selected as the internal standard (IS). The MS/MS transitions of N-Methylanhydrotetrahydroberberrubine A, dictamnine, eudesmin and IS were 339.9135.1, 200.1 → 129.1, 387.4 → 369.0 and 337.1 → 321.1, respectively. The lower limits quantification (LLOQ) of the three analytes was 0.5-20 ng/ml. The linear ranges were 0.5-400 ng/ml for N-Methylanhydrotetrahydroberberrubine A and dictamnine and 20-4000 ng/ml for eudesmin. The present analysis showed that the two alkaloids were quickly absorbed, with Tmax in 0.167-0.292 h, and eudesmin was absorbed in 2.5 h. Moreover, all compounds were found at high concentrations in the gastrointestinal track. These results are helpful for further investigation of the clinical application of Z. armatum.


Assuntos
Berberina , Furanos , Lignanas , Quinolinas , Zanthoxylum/química , Animais , Berberina/análogos & derivados , Berberina/análise , Berberina/química , Berberina/farmacocinética , Cromatografia Líquida de Alta Pressão , Feminino , Furanos/análise , Furanos/química , Furanos/farmacocinética , Lignanas/análise , Lignanas/química , Lignanas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Quinolinas/análise , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Distribuição Tecidual
17.
Acta Pharmacol Sin ; 39(5): 787-801, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29698388

RESUMO

Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Furanos/farmacologia , Glucosídeos/farmacologia , Lignanas/farmacologia , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Arctium , Linhagem Celular Tumoral , Nefropatias Diabéticas/tratamento farmacológico , Furanos/administração & dosagem , Furanos/farmacocinética , Furanos/uso terapêutico , Glucosídeos/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Lignanas/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico
18.
Future Oncol ; 14(16): 1531-1545, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29411654

RESUMO

Eribulin is a structurally simplified, synthetic macrocyclic ketone analog of halichondrin B, which is a natural, polyether macrolide derived from marine sponges. Eribulin exerts its cytotoxicity by its unique microtubule dynamics inhibitory action. Eribulin was approved in 2010 by the US FDA as a third-line therapy for metastatic breast cancer patients previously treated with an anthracycline and a taxane. In 2016, it was approved for treatment of metastatic liposarcoma for patients who have progressed with anthracycline treatment. In this article, we review the pharmacokinetics, mechanism of action of eribulin with focus on preclinical and clinical data in sarcoma and also the role of miRNAs in soft tissue sarcomas.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Furanos/farmacocinética , Furanos/uso terapêutico , Cetonas/farmacocinética , Cetonas/uso terapêutico , Sarcoma/tratamento farmacológico , Animais , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/métodos , Sarcoma/mortalidade , Sarcoma/patologia
19.
Sci Rep ; 8(1): 3307, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29459629

RESUMO

Arctigenin (ARG) is a functional active component that has important physiological and pharmacological activities. The anti-tumour and anti-inflammatory activities of ARG show good potential for application and development, but this material has the defect of low water solubility. In this experiment, the valine derivative of ARG (ARG-V) was designed and synthesized to overcome this disadvantage. The ARG amino acid, EDCI and DMAP were raw materials in the addition reaction, with a molar ratio of 1:2:2:0.5. The yield of ARG-V was up to 80%. ARG-V has strong anti-tumour activity in vivo and in vitro. The inhibitory rate of ARG-V was 69.2%, with less damage to the immune organs and different degrees of increased serum cytotoxicity. Moreover, the pharmacokinetics of ARG following oral administration and ARG-V following oral administration in rats were also studied. The Cmax and AUC values of ARG-V showed significant differences compared to ARG. The relative bioavailabilities of three doses of ARG-V compared to ARG were 664.7%, 741.5% and 812.9%. These pharmacokinetic results may be useful for further studies of the bioactive mechanism of ARG and provide a theoretical basic for clinical use.


Assuntos
Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Lignanas/farmacologia , Neoplasias/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Ésteres/química , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Humanos , Lignanas/síntese química , Lignanas/química , Lignanas/farmacocinética , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Wistar , Solubilidade
20.
Drug Metab Dispos ; 46(2): 89-99, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29150544

RESUMO

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.


Assuntos
Furanos/sangue , Furanos/farmacocinética , Inativação Metabólica/fisiologia , Oxazóis/sangue , Oxazóis/farmacocinética , Agonistas do Receptor de Serotonina/sangue , Agonistas do Receptor de Serotonina/farmacocinética , Adulto , Ciclização/fisiologia , Remoção de Radical Alquila/fisiologia , Feminino , Hepatócitos/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
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