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1.
J Pharm Biomed Anal ; : 113784, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33280996

RESUMO

Chinese herbal drugs are often combined with chemotherapy drugs for the treatment of cancers. However, the combination administrations often do not have scientifically sound bases established on full preclinical and clinical investigations. A commonly used anti-colon-cancer herb-drug pair, irinotecan (CPT-11) hydrochloride injection and Kang'ai (KA) injection was taken as an example to investigate the possible pharmacokinetic interactions between Chinese herbal drugs and chemotherapy injections to determine the potential adverse drug reactions (ADRs). Rats were randomly divided into three groups and received 20 mg/kg CPT-11 injection 15 min after administration of 4 mL/kg saline for the CPT-11 single administration group and 4 mL/kg KA injection for the separated co-administration group, respectively. In the pre-mixed co-administration group, rats received a mixture of 20 mg/kg CPT-11 injection and 4 mL/kg KA injection. Blood samples were collected at 10 pre-determined time points between 0 and 24 h. The tissue samples were collected at 5 and 8 min after the injections, respectively. A reliable LC-MS/MS method was established for the simultaneous determination of CPT-11 and its metabolites, SN-38, SN-38 G and APC in the rat plasma and tissue samples, after full confirmation of two injections chemical and stability compatibilities. Compared to the C0 (5129 ± 757 ng/mL) and AUC0-t (7858 ± 1307 ng h/mL) of CPT-11 in the CPT-11 single administration group, the C0 (4574 ± 371 ng/mL) and AUC0-t (8779 ± 601 ng h/mL) after the separated co-administration remained unchanged, but the pre-mixed co-administration resulted with a significant increased C0 (29,454 ± 12,080 ng/mL) and AUC0-t (15,539 ± 5165 ng h/mL) (p < 0.05). Since the exposures of CPT-11 in most tissues in the pre-mixed co-administration group were dramatically lower than the separated co-administration group, the increased CPT-11 plasma concentration may be produced by the delayed tissue distribution because of the encapsulation by the components contained in KA injection, such as polysaccharides. Similar differences were also found in its metabolite, SN-38 G. There are obvious herb-drug interactions between CPT-11 injection and KA injection after the pre-mixed co-administration. The resulting excessive CPT-11 in the plasma may lead to many serious ADRs. Therefore, the full evaluation of herb-drug interactions is necessary and inappropriate combinations should be avoided.

2.
Bioorg Med Chem ; 28(10): 115435, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32278711

RESUMO

Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC50 = 14.0 nM, NCI-H460) and 17p (IC50 = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.

3.
Bioorg Med Chem ; 28(1): 115186, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759826

RESUMO

The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50 = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC50 = 26.2 nM) and similar to Compound 6b (IC50 = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.

4.
Eur J Med Chem ; 174: 9-15, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31022552

RESUMO

Myricetin is a natural dietary flavonoid compound with multiple activities, such as anti-oxidant, anti-inflammatory, anti-carcinogenic and anti-proliferative effects. However, myricetin exhibited substantial limitations, such as poor water-solubility, and low stability in body when it was administrated by oral. To solve these problems, we designed and synthesized a series of derivatives based on the structure of myricetin. M10 was produced by adding a hydrophilic glycosylation group and then forming a sodium salt derivative, which exhibited excellent water-solubility (>100 mg/mL), and better stability in Wistar rat plasma and liver microsomes. In vivo study, M10 exhibited higher efficacy than myricetin and mesalazine in a dextran sulfate sodium (DSS) induced mice model with ulcerative colitis. In addition, M10 also exhibited high safety (LD50 > 5 g/kg) in mice. Based on these results, M10 could be developed as a potential therapeutic agent for treatment of ulcerative colitis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Flavonoides/uso terapêutico , Lactose/análogos & derivados , Lactose/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Colite Ulcerativa/induzido quimicamente , Colo/patologia , Sulfato de Dextrana , Estabilidade de Medicamentos , Feminino , Flavonoides/síntese química , Flavonoides/química , Flavonoides/farmacocinética , Glicosilação , Meia-Vida , Lactose/síntese química , Lactose/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Ratos Wistar , Solubilidade
5.
Bioorg Med Chem ; 27(9): 1836-1844, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30910474

RESUMO

MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.


Assuntos
Dicetopiperazinas/química , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Deutério/química , Dicetopiperazinas/metabolismo , Dicetopiperazinas/farmacologia , Dicetopiperazinas/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Conformação Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Estrutura Terciária de Proteína , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico
6.
Xenobiotica ; 48(3): 279-284, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28906164

RESUMO

1. There are numerous investigations demonstrating that the cyclooxygenase-2 (COX-2) inhibitors might enhance the efficiency of anastrozole in breast cancer. Hence, this study was conducted to investigate the comparative pharmacokinetics of anastrozole after single administration and combination with celecoxib. 2. A simple protein precipitation procedure was adopted for the sample preparation with satisfactory extraction recovery for both anastrozole and the internal standard, and then anastrozole was separated and analysed on an ACQUITY BEH UPLC C18 column (50 × 2.0 mm, 1.7 µm, Waters) within 2 min. The calibration curves showed good linarites (r = 0.994). Intra- and inter-day precision were within 4.93 and 13.83%, respectively. The mean extraction recoveries across QC levels were within 91.4%, and the matrix effects were within 94.5%. 3. Results showed that the method was reliable to determine anastrozole in rat plasma. Compared with rats in single administration group, no significant difference was found in the combination group. It is workable to use celecoxib combined with anastrozole in clinical therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cromatografia Líquida/métodos , Nitrilos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Anastrozol , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Celecoxib/administração & dosagem , Celecoxib/farmacocinética , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Feminino , Limite de Detecção , Nitrilos/administração & dosagem , Nitrilos/sangue , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Triazóis/administração & dosagem , Triazóis/sangue
7.
Xenobiotica ; 48(8): 824-830, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28786731

RESUMO

1. (S)-MP3950 is the (S)-enantiomer of active metabolite of mosapride, which exhibits higher 5-HT4 receptor agonistic effect than mosapride. It shows promise to become a novel drug candidate for the treatment of gastrointestinal motility disorders (GMDs). However, the pharmacokinetic behavior of (S)-MP3950 in the pathological state of GMDs remains unclear. Herein, we investigated the comparative pharmacokinetics of (S)-MP3950 in normal and GMDs rats. 2. The comparative pharmacokinetics of (S)-MP3950 in normal and atropine-induced GMD rats were studied by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The validated UPLC-MS/MS method was successfully applied to investigate the pharmacokinetic profiles of (S)-MP3950 in normal and atropine-induced GMDs rats. Results showed that comparing to normal rats, Cmax reduced by 73.8%, AUC0-t decreased by 57.6% and AUC0-∞ declined by 56.8% in model rats. Additionally, the elimination half-life (t1/2) and Tmax were prolonged slightly. 3. The pharmacokinetic results demonstrated that the atropine-induced GMDs reduced the absorption of (S)-MP3950. The pharmacokinetics research in the pathological state might provide more useful information for further study of novel gastric motility candidates.


Assuntos
Atropina/efeitos adversos , Benzamidas/farmacocinética , Gastroenteropatias , Motilidade Gastrointestinal/efeitos dos fármacos , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Animais , Atropina/farmacologia , Benzamidas/farmacologia , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia
8.
Rapid Commun Mass Spectrom ; 32(3): 269-276, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29105858

RESUMO

RATIONALE: Pimavanserin, a selective serotonin 2A receptor inverse agonist, is a promising candidate for treating Parkinson's disease psychosis. Our previous study revealed that there might be the presence of extensive metabolites of pimavanserin in rats. However, the metabolic fate of pimavanserin in vivo remains unknown. Thus, it is essential to develop an efficient method to investigate the metabolic profile of pimavanserin in rats. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to date has the highest mass measurement accuracy and resolution of any mass spectrometry platform. METHODS: After a single intragastric administration of pimavanserin at a dose of 50 mg kg-1 , plasma, bile, urine and feces were collected from rats. A novel and efficient strategy was developed to analyze the metabolic profile of pimavanserin in vivo based on ultrahigh-performance liquid chromatography (UHPLC) coupled with FT-ICR-MS. RESULTS: A total of 23 metabolites were detected and tentatively identified through comparing their mass spectrometry profiles with those of pimavanserin. These metabolites were found in feces (22), bile (21), rat urine (16) and plasma (15). Results demonstrated that metabolic pathways of pimavanserin in rats included dehydrogenation, demethylation, deethylation, depropylation, debutylation, hydroxylation, dihydroxylation and trihydroxylation. CONCLUSIONS: A total of 22 phase I metabolites of pimavanserin were detected and tentatively identified. This report presents the first study of screening and identification of the metabolites of pimavanserin. The UHPLC/FT-ICR-MS method is a powerful tool for exploring and identifying metabolites in complex biological samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Piperidinas/farmacocinética , Ureia/análogos & derivados , Administração Oral , Animais , Bile/química , Fezes , Análise de Fourier , Masculino , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Ratos Sprague-Dawley , Distribuição Tecidual , Ureia/administração & dosagem , Ureia/metabolismo , Ureia/farmacocinética
9.
Mol Med Rep ; 17(1): 1041-1048, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115493

RESUMO

Vascular smooth muscle cells (VSMCs) exhibit a notably increased rate of migration, which is one of the most common pathological changes in atherosclerosis. Investigations into the role of micro (mi)RNAs in the regulation of VSMC migration are beginning to emerge and additional miRNAs involved in VSMC migration modulation require identification. In the current study, VSMCs were primarily cultured from rat thoracic aortas, transfected with miR­92a mimics and induced by hydrogen peroxide (H2O2) for 24 h. Total mRNA and protein were collected for quantitative polymerase chain reaction and western blot analysis. In addition, the sirtuin 1 (SIRT1) gene was detected by luciferase reporter assay and VSMC migration was detected by Transwell migration assay. The current results demonstrated that reduced expression of miR­92a and overexpression of SIRT1 at the mRNA level were observed in H2O2­induced VSMCs. Furthermore, luciferase reporter assay demonstrated that the activity of the SIRT1 3'­untranslated region was reduced by miR­92a mimics. The upregulation of MMP9 and the downregulation of TIMP3 in H2O2­induced VSMCs were observed to be reversed by miR­92a mimics in addition to SIRT1 siRNA. Finally, Transwell migration assay revealed that miR­92a overexpression and silencing SIRT1 mitigated VSMC migration following H2O2 treatment. The present study indicated that miR­92a prevented the migration of H2O2­induced VSMCs by repressing the expression of SIRT1, and also provided a novel therapy to protect against the phenotypic change of VSMCs in atherosclerosis.


Assuntos
Peróxido de Hidrogênio/metabolismo , Metaloproteinase 9 da Matriz/genética , MicroRNAs/genética , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Transdução de Sinais , Sirtuína 1/metabolismo , Inibidor Tecidual de Metaloproteinase-3/genética , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Peróxido de Hidrogênio/farmacologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética
10.
Biochem Biophys Res Commun ; 493(4): 1573-1580, 2017 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-28989026

RESUMO

Myocardial oxidative stress injury plays a crucial role in the pathogenesis of diabetic cardiomyopathy (DCM). Wnt/ß-catenin signaling has been reported to involve in various heart diseases. However, the underlying mechanism associated with ß-catenin in DCM remains elusive. This study intended to explore the effect of ß-catenin on oxidative damage of DCM by establishing streptozotocin (STZ)-induced diabetic mouse model and hydrogen peroxide (H2O2)-treated myocardial cell model. Cardiac oxidative stress in DCM was detected by measurements of lipid peroxidation and anti-oxidative enzyme activities as well as DHE staining. Nuclear ß-catenin activity and oxidative damage degree were measured by western blotting, qPCR, MTT assay and TUNEL staining. Cardiac function and morphology were evaluated by echocardiography and histopathology. Under diabetic oxidative stress or H2O2 stimulation, nuclear ß-catenin accumulation upregulated downstream c-Myc and further facilitated DNA damage and p53-mediated apoptosis as well as cell viability reduction, followed by phenotypic changes of cardiac dysfunction, interstitial fibrosis deposition and myocardial atrophy. Conversely, through directly inhibiting nuclear ß-catenin/c-Myc axis, not only did siRNA knockdown of ß-catenin or c-Myc attenuate cell injury in H2O2-stimulated cardiomyocytes, but also diabetic cardiac-specific ß-catenin-knockout mice displayed the same prevention of heart injury as insulin-treated diabetic mice. The present study demonstrated that activated nuclear ß-catenin/c-Myc axis was responsible for oxidative cardiac impairment of DCM. Therefore, repressing functional nuclear ß-catenin may provide a hopeful therapeutic strategy for DCM.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Núcleo Celular/metabolismo , Células Cultivadas , Dano ao DNA , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/patologia , Técnicas de Silenciamento de Genes , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Ratos , Transdução de Sinais , beta Catenina/deficiência , beta Catenina/genética
11.
Mol Divers ; 21(3): 577-583, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28488201

RESUMO

Deuterium-enriched and fluorine-substituted compounds have been widely applied in drug discovery due to their advantages in the studies of clinical pharmacokinetics and metabolic profiles. Herein we synthesized a library of deuterated and fluorine-substituted plinabulin derivatives, and all 15 D- or F-compounds were characterized by MS, [Formula: see text] NMR and [Formula: see text]. Their antitumor activities were evaluated against human Jurkat T lymphocyte cells.


Assuntos
Antineoplásicos/síntese química , Deutério/química , Dicetopiperazinas/síntese química , Flúor/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Humanos , Células Jurkat , Espectrometria de Massas , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética
12.
Bioorg Med Chem Lett ; 27(6): 1416-1419, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28228362

RESUMO

Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Deutério/química , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Área Sob a Curva , Linhagem Celular , Humanos , Camundongos , Modelos Moleculares , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Asian J Pharm Sci ; 12(2): 202-208, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32104331

RESUMO

The present study was designed to investigate the influence of the pretreatment of piperazine ferulate on pharmacokinetic parameters of methotrexate in methotrexate-induced renal injury rats. A simple and efficient high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) method was developed to determine methotrexate in rat plasma. Methotrexate and syringic acid (internal standard) were extracted from rat plasma samples by protein precipitation with acetonitrile. The analysis was performed on a CAPCELL PAK C18 column (150 mm × 4.6 mm, 5 µm) with acetonitrile and 5 mmol/l ammonium acetate aqueous (10:90, v/v). The linear range was 5.0 × 10-2 to 100.0 µg/ml for methotrexate. Other parameters were all within the acceptance criteria. The validated method was successfully applied the pharmacokinetic study of methotrexate between two methotrexate treated groups (with and without the pretreatment of piperazine ferulate). Compared with the methotrexate treated alone group, the pharmacokinetic parameters in the methotrexate with the pretreatment of piperazine ferulate group showed significantly lower MRT(0-t), MRT(0-∞) and T 1/2. Results suggested that methotrexate can be rapidly eliminated, cleared or metabolized in rat blood, which might be related to the pretreatment of piperazine ferulate. The method provided deeper insights into rational clinical use of methotrexate with the pretreatment of piperazine ferulate on cancer patients with renal dysfunction.

14.
J Pharm Anal ; 7(2): 118-122, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29404026

RESUMO

Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC-MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH (1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0) and temperature (0, 25, 37 and 45 °C). The linear range was 0.5-25 µg/mL, the intra- and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4-104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 kJ/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q-TOF-MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.

15.
J Pharm Anal ; 7(6): 406-410, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29404067

RESUMO

A simple, rapid and sensitive method based on an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for the determination of pimavanserin in rat plasma. The analyte was extracted by protein precipitation with methanol and separated on an ACQUITY BEH C18 column (100 × 2.1 mm, 1.7 µm; Waters, USA), with an isocratic elution of acetonitrile-water containing 10 mM ammonium acetate (70:30, v/v), at a flow rate of 0.2 mL/min for 2.5 min. The analyte and clarithromycin (the internal standard) were detected and quantified in positive ion mode using multiple reaction monitoring transitions at m/z 428.2 → 223.0 for pimavanserin and m/z 748.5 → 589.5 for clarithromycin. Relative coefficient (r) for the calibration curve was more than 0.9980. The intra-day and inter-day precisions (relative standard deviation, RSD%) were less than 13.3% and 10.5%, respectively, and the accuracy (relative error, RE%) was within ± 11.5%. The analytical method was successfully applied to a routine pharmacokinetic study of pimavanserin in rats after oral administration at the dose of 10 mg/kg.

16.
Arch Pharm (Weinheim) ; 343(8): 473-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20803624

RESUMO

A simple pathway for the preparation of D-cycloserine is presented. The intermediates and D-cycloserine were characterized by FT-IR, (1)H-NMR spectra and elemental analysis. D-Cycloserine can inhibit the growth of Mycobacterium tuberculosis and can be used as a second-line drug for the treatment of tuberculosis, especially for the use in developing countries.


Assuntos
Ciclosserina/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Países em Desenvolvimento , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectroscopia de Infravermelho com Transformada de Fourier
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