RESUMO
ABSTRACT: Objective To discuss the related factors influencing the initiation time of forensic psychiatric assessment by analysis of the initiation time of forensic psychiatric assessment of criminal cases in Hunan Province. Methods Related data in assessment files of criminal cases accepted by 8 forensic psychiatric assessment institutions in Hunan Province from January 1, 2011 to December 31, 2016 were extracted. The Logistic regression analysis was used to explore the factors influencing the initiation time of forensic psychiatric assessment. After using property score matching ï¼PSMï¼ to control the influence of confounding factors, the efficiency of public security organs to initiate assessments of suspects with ï¼withoutï¼ mental disorders and with ï¼withoutï¼ responsibilities were compared. Results A total of 4 346 cases were included. The Logistic regression analysis suggested that the factors independently related to the initiation time of assessment includeï¼ cause of assessment, nationality of the assessed, history of diagnosis and treatment of mental illnesses, history of crimes, history of drug abuse, and status of alcohol consumption before the crime ï¼all P<0.05ï¼. The initiation time of assessment of suspects diagnosed with mental disorder was shorter than those with none ï¼P<0.05ï¼; the initiation time of assessment of suspects without criminal responsibility was shorter than those with responsibility ï¼P<0.05ï¼. After using PSM to control confounding factors, the differences above still existed. Conclusion The cause of assessment, nationality of the assessed, history of diagnosis and treatment of mental illnesses, history of crimes, history of drug abuse, and status of alcohol consumption before the crime are factors that influence the efficiency of public security organs to initiate forensic psychiatric assessments. Under the current assessment initiation mode, forensic psychiatric assessment of suspects who have mental disorders, especially those with no responsibility may be given priority to initiate.
Assuntos
Criminosos , Psiquiatria Legal , Transtornos Mentais/psicologia , Crime , Humanos , Escalas de Graduação PsiquiátricaRESUMO
Colorectal cancer is one of the most common malignant tumors worldwide. Surgical resection is the most important and decisive method in the treatment of rectal cancer. Total mesorectal excision (TME) has greatly reduced the local recurrence rate of middle and low rectal cancer. However, local recurrence and distant metastasis remain the leading cause of death in patients with rectal cancer. 5-fluorouracil (5-FU)-based neoadjuvant chemoradiotherapy has been widely accepted in locally advanced rectal cancer and was recommended by various clinical practice guidelines as the standard treatment option. Tumors often achieve satisfactory reduced stage after neoadjuvant radiotherapy, and some patients even achieve pathological complete regression, which brings much controversies to the choice of adjuvant chemotherapy. This article intends to introduce evidence-based evidences for adjuvant chemotherapy for rectal cancer, impact of current neoadjuvant models on choice of adjuvant chemotherapy strategies, controversies and considerations for adjuvant chemotherapy in the context of neoadjuvant radiotherapy.
Assuntos
Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Protectomia/métodos , Neoplasias Retais/terapia , Intervalo Livre de Doença , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Retais/patologiaRESUMO
OBJECTIVE: LncRNA downregulated in liver cancer stem cells (lnc-DILC) has been implicated as a tumor suppressor in colorectal cancer (CRC). However, the clinical significance of lnc-DILC in CRC patients has not been investigated. In this study, we aimed to explore the diagnostic and prognostic value of lnc-DILC in CRC patients. PATIENTS AND METHODS: The expression of lnc-DILC was measured in 174 paired CRC tissues and adjacent normal tissues using Real Time-Polymerase Chain Reaction (RT-PCR). The correlation of lnc-DILC expression with clinicopathological factors was statistically analyzed by the Chi-square test. Besides, overall survival analysis was carried out with the Kaplan-Meier curve with the log-rank test. Univariate and multivariate analyses were performed to explore the prognostic significance of lnc-DILC expression. RESULTS: We found that lnc-DILC expression was downregulated in CRC tissues compared to their adjacent normal tissues (p<0.01). ROC analyses showed that lnc-DILC levels were reliable in distinguishing patients with CRC from normal colorectal tissues. Then, down-regulation of lnc-DILC was positively associated with aggressive clinical characteristics, including depth of invasion (p=0.018) and advanced TNM stage (p=0.009). Moreover, the Kaplan-Meier analysis demonstrated that overexpression of lnc-DILC was associated with poorer overall survival (p=0.0205) and disease-free survival (p<0.001). Finally, multivariate analyses confirmed that expression of lnc-DILC was an independent prognostic factor in CRC. CONCLUSIONS: Our results firstly suggested that lnc-DILC could be a favorable indicator of prognosis in CRC.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Despite the improvements in the diagnosis and management during the past six decades, acute aortic dissection (AAD) remains a life-threatening condition associated with significant morbidity and mortality rates. Due to the relatively rare occurrence of AAD, several clinical registries have been established to gain insights into this lethal disease in a large number of patients, such as the International Registry of Acute Aortic Dissection (IRAD), the German Registry for Acute Aortic Dissection Type A (GERAADA), and the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database Aortic Section. This review aims to interpret and compare the latest results of the IRAD, STS and GERAADA database. It focuses on several controversial and key issues in the diagnosis and management of acute aortic dissection in hope of providing some insights and references for cardiovascular professionals engaged in the care of this deadly disease.
Assuntos
Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/terapia , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/terapia , Sistema de Registros , Doença Aguda , Procedimentos Cirúrgicos Cardíacos , HumanosRESUMO
We aimed to study the effect of fentanyl (Fen) preconditioning on cardiomyocyte apoptosis induced by ischemia-reperfusion (I/R) in rats. A total of 120 Sprague Dawley male rats (age: 3 months) were randomly divided into: sham operation group (S group), I/R group, normal saline I/R group (NS group), and fentanyl low, middle, and high dose groups (Fen1: 2 µg/kg; Fen2: 4 µg/kg; Fen3: 6 µg/kg). Heart rate (HR), mean arterial pressure (MAP), left ventricular developed pressure (LVDP), ±dp/dtmax, malondialdehyde (MDA), superoxide dismutase (SOD) activity, creatine phosphokinase-MB (CK-MB), and cardiac troponin-I (cTnI) were measured. Myocardial ischemic (MI) area, total apoptotic myocardial cells, and protein and mRNA expressions of B-cell lymphoma 2 (Bcl-2) and Bax were detected. HR and MAP were higher, while LVDP and ±dp/dtmax were close to the base value in the Fen groups compared to those in the I/R group. Decreased MDA concentration and CK-MB value and increased SOD activity were found in the Fen groups compared to the I/R group, while cTnI concentration was significantly lower in the Fen1 and Fen2 groups (all P<0.05). Myocardial damage was less in the Fen groups compared to the I/R group and the MI areas and apoptotic indexes were significantly lower in the Fen1 and Fen2 groups (all P<0.05). Furthermore, significantly increased protein and mRNA expressions of Bcl-2, and decreased protein and mRNA expressions of Bax were found in the Fen groups compared to the I/R group (all P<0.05). Fentanyl preconditioning may suppress cardiomyocyte apoptosis induced by I/R in rats by regulating Bcl-2 and Bax.
Assuntos
Apoptose/efeitos dos fármacos , Fentanila/uso terapêutico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Masculino , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Patients with severe burns often develop acute lung injury (ALI), systemic inflammatory response syndrome (SIRS) often complicates with ALI. Sivelestat sodium hydrate is an effective drug against ALI. However, the mechanisms of this beneficial effect are still poorly understood. In the current study, we evaluate the effects of sivelestat sodium hydrate on systemic and local inflammatory parameters (neutrophil elastase [NE], interleukin [IL]-8, matrix metalloproteinase [MMP] 2 and 9) in a rat model of severe burns and ALI. And to analyze the correlations between expression of NE and IL-8 and acute lung injury. MATERIALS AND METHODS: 48 Sprague-Dawley (SD) rats were divided into 3 groups: normal control group, severe burns injury group and severe burns treated with sivelestat sodium hydrate group (SSI). The lung water content and PaO2 were detected in each group. Pathological manifestations in each group were observed for pathology scoring in SD rats with acute lung injury. ELISA was used for detecting expression of NE and IL-8 in serum and BAL specimens of SD rats in each group. RT-PCR was used to detect mRNA expression of NE and IL-8 in lung tissues of each group. Western blotting was used for detecting protein expression of MMP-2 and MMP-9 in lung tissues of each group. SPSS 18.0 was used for statistical analysis. RESULTS: The PaO2 was significantly increased after sivelestat sodium hydrate intravenous injection. Pathological score and water content of lung tissue were significantly decreased in SSI group compared with severe burns injury group, slightly higher than that normal control group. NE and IL-8 levels significantly decreased in serum, BAL and lung tissue specimens after sivelestat sodium hydrate intravenous injection; Expression of MMP-2 and MMP-9 were significantly up-regulated in severe burns group and showed no significantly changed after sivelestat sodium hydrate intravenous injection. CONCLUSIONS: In a rat model of severe burns and ALI, administration of sivelestat sodium hydrate improved symptoms of ALI and significantly decreased inflammatory parameters NE and IL-8.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Queimaduras/tratamento farmacológico , Modelos Animais de Doenças , Glicina/análogos & derivados , Mediadores da Inflamação/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Gasometria , Queimaduras/metabolismo , Queimaduras/patologia , Glicina/farmacologia , Glicina/uso terapêutico , Mediadores da Inflamação/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/metabolismo , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologiaRESUMO
P34, a storage protein and major soybean allergen, has undergone a functional transition from a cysteine peptidase to a syringolide receptor. An exploration of the evolutionary mechanism of this functional transition is made. To identify homologous genes of P34, syntenic network was constructed using syntenic relationships from the Plant Genome Duplication Database. The collected homologous genes, along with SPE31, a highly homologous protein to P34 from the seeds of Pachyrhizus erosus, were used to construct a phylogenetic tree. The results show that multiple gene duplications, exon shuffling and following granulin domain loss and some critical point mutations are associated with the functional transition. Although some tests suggested the existence of positive selection, the possibility that random fixation under relaxation of purifying selection results in the functional transition is also supported. In addition, the genes Glyma08g12340 and Medtr8g086470 may belong to a new group within the papain family.
Assuntos
Alérgenos/genética , Antígenos de Plantas/genética , Genoma de Planta , Glycine max/genética , Sementes/genética , Proteínas de Soja/genética , Alérgenos/química , Alérgenos/imunologia , Sequência de Aminoácidos , Antígenos de Plantas/química , Antígenos de Plantas/imunologia , Éxons , Duplicação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/genética , Modelos Moleculares , Dados de Sequência Molecular , Pachyrhizus/genética , Papaína/química , Papaína/genética , Filogenia , Mutação Puntual , Progranulinas , Estrutura Terciária de Proteína , Sementes/classificação , Seleção Genética , Homologia de Sequência de Aminoácidos , Proteínas de Soja/química , Proteínas de Soja/imunologia , Glycine max/classificação , SinteniaRESUMO
Polymorphisms of the major histocompatibility complex (MHC) have been linked to many diseases, especially autoimmune disorders. Previous studies have shown that genetic variants in MHC class III are associated with breast cancer. To determine if there is an association between MHC class III and breast cancer risk in the Chinese Han population, we carried out a hospital-based case-control study in Guangdong and Jiangsu Provinces, including 216 histologically confirmed breast cancer patients and 216 healthy controls. Nine SNP markers distributed in the class III-coding region were detected using the Sequenom MassARRAY(®) iPLEX System. Deviation from Hardy-Weinberg equilibrium was observed for seven SNPs. There was no significant association between these seven SNP variants and breast cancer in these Chinese women (unconditional logistic regression analysis). However, chr6_31697494 at BAT2, one of the seven SNPs, was found to be significantly associated with both ER- and PR-positive breast cancer. In addition, both chr6_31911109 at C6orf48 and chr6_31975605 at ZBTB12, another two of the seven SNPs, show relevance with ER-positive breast cancer. In conclusion, this is the first evidence that genetic polymorphisms in the MHC class III region are significantly associated with ER-positive breast cancer in the Han Chinese population.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Receptores de Estrogênio/metabolismo , Fatores de Transcrição/genética , Povo Asiático , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante , Receptores de Progesterona/metabolismoRESUMO
We examined the underlying neural-endocrine mechanisms of asthma associated with respiratory syncytial virus infection. Thirty Sprague-Dawley rats were randomly divided into control group, respiratory syncytial virus (RSV) group, and anti-nerve growth factor (NGF) IgG group. An RSV infection model was established by nasal drip once a week. In the anti-NGF antibody intervention group, each rat was given an intraperitoneal injection of anti-NGF IgG 3 h before RSV infection. Optical microscopy and transmission electron microscopy were used to observe the structural changes in adrenal medulla cells. Changes in adrenaline and norepinephrine in serum were detected by ELISA. NGF expression was assayed by immunohistochemistry. Expression differences in synaptophysin mRNA were detected by RT-PCR. Transmission electron microscopy displayed widened adrenal medulla intercellular spaces, reduced chromaffin particle concentration, and increased mitochondria in the RSV infection group. At the same time, NGF expression was increased in the RSV infection group significantly. In addition, the adrenaline concentration was significantly decreased compared with the control and anti-NGF antibody groups. Synaptophysin mRNA expression was significantly increased in the RSV infection and anti-NGF antibody groups. However, compared with the RSV infection group, synaptophysin mRNA expression was significantly decreased in the anti-NGF antibody group. We conclude that RSV infection could induce adrenal medulla cell differentiation to nerve cells by over-expression of NGF, resulting in the decreased endocrine function found in asthma progression.
Assuntos
Asma/complicações , Asma/virologia , Sistema Endócrino/metabolismo , Sistema Nervoso/metabolismo , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/fisiologia , Medula Suprarrenal/patologia , Medula Suprarrenal/ultraestrutura , Animais , Asma/fisiopatologia , Hiper-Reatividade Brônquica/complicações , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/virologia , Modelos Animais de Doenças , Epinefrina/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Imuno-Histoquímica , Hibridização In Situ , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Fator de Crescimento Neural/metabolismo , Norepinefrina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMO
OBJECTIVE: Objectives of this investigation were not merely to perform a comparative study with original docetaxel, but to define anti-proliferative and apoptotic effects of novel hydrophilic docetaxel (CQMU-0519) analogue on A549 lung, SKVO3 ovary and MCF7 breast carcinoma cell lines. MATERIALS AND METHODS: The materials for the study consist of a completely new docetaxel analogue (CQMU-0519), synthesized by the Department of Pharmacology, Chongqing Medical University, China, which is completely soluble in water. 50 nm of drug concentration was utilized on all three cell lines where cell population growth was assessed using cell culture kit-8 and flow cytometry analysis, whereas apoptotic pathways were unveiled by use of annexin-V FITC, apoptosis DNA ladder, caspases-3, 6, 8 and 9; in the meanwhile, regulation of Bcl-2 family members was analysed by western blotting. RESULT: The novel docetaxel analogue (CQMU-0519) suppressed cell proliferation in all three cell lines, inhibition of cell proliferation and cell cycle arrest being more evident in G(2) /M phase. Also, in both lung and ovarian cell lines, apoptotic levels were higher as measured by the various tests performed, and downregulation of Bcl-2 and Bcl-xL with increased expressions of Bad and Bax indicated the intrinsic pathway for apoptosis. Nevertheless, it was found that MCF7 cells, although also manifesting high levels of apoptosis, used the extrinsic pathway instead. Hence, it was shown that novel docetaxel analogue (CQMU-0519) may have some prospective use in future clinical trials. CONCLUSIONS: Novel hydrophilic docetaxel analogue (CQMU-0519) inhibited cell proliferation and enhanced the intrinsic apoptotic pathway in lung and ovarian carcinoma cells, whereas it used the extrinsic one in breast adenocarcinoma cells.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Neoplasias Ovarianas/patologia , Taxoides/química , Western Blotting , Caspases/metabolismo , Linhagem Celular Tumoral , Colorimetria , Docetaxel , Ativação Enzimática , Feminino , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Taxoides/farmacologiaRESUMO
OBJECTIVE: To evaluate relevant arterial, hepatic, and portal venous anatomy using multidetector computed tomography (CT) angiography in potential living liver donors at a single liver transplantation center in China. METHODS: One hundred two consecutive potential liver donors underwent CT angiography in the arterial, portal, and hepatic venous phases with a 16-row CT scanner. All source and reconstructed images were evaluated for hepatic vasculature anatomy by an experienced radiologist and a surgeon in consensus. The anatomic variants of arterial system, portal venous system, and hepatic veins were characterized according to the classification system of Michels, Akgul, and Nakamura respectively. In 42 donors of right hepatic lobectomy, CT findings were compared with the results of surgery. RESULTS: Of 102 candidates, 63 had type I, 8 type II, 12 type III, 3 type IV, 11 type V, 2 type VI, 2 type VIII, and 1 type IX hepatic arterial anatomy. According to the classification of the portal venous system created by Akgul, type A was seen in 81 subjects. Type B, type C, and type E were revealed in 15, 4, and 2 subjects, respectively. According to the classification of the right hepatic drainage pattern by Nakamura, type 1 drainage was seen in 71 subjects (69.6%), type 2 in 22 candidates (21.6%), and type 3 in 9 subjects (8.8%). Forty five right inferior hepatic veins were identified in 41 potential donors, and 68.9% of these veins were larger than 5 mm in diameter. CT angiography findings were confirmed in all donors who underwent operations. CONCLUSIONS: Multidetector CT angiography can successfully show the relevant hepatic vascular anatomy in potential liver donors.
Assuntos
Artéria Hepática/diagnóstico por imagem , Veias Hepáticas/diagnóstico por imagem , Transplante de Fígado/métodos , Doadores Vivos , Veia Porta/diagnóstico por imagem , Adolescente , Adulto , Feminino , Hepatectomia/métodos , Artéria Hepática/anatomia & histologia , Artéria Hepática/cirurgia , Veias Hepáticas/anatomia & histologia , Veias Hepáticas/cirurgia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Veia Porta/anatomia & histologia , Veia Porta/cirurgia , RadiografiaRESUMO
This paper reports the comparative antimalarial efficacy of intravenous artelinate and artesunate in rats. Prior to efficacy experiments, a Plasmodium berghei-Sprague-Dawley rat model of malaria was developed, in which the clearance effects of intravenous drugs could be readily compared. In efficacy experiments, groups of P. berghei-infected rats were given 3 daily intravenous treatments of artelinate or artesunate at molar equivalent dose rates (total of 0-191.2 micromoles/kg). Artelinate was superior to artesunate in terms of clearance (100% clearance dose of 95.6 micromoles/kg (40 mg/kg) versus 191.2 micromoles/ kg for AS (73.4 mg/kg)) and parasite clearance time (1.7 +/- 0.5 days for AL versus 2.7 +/- 0.5 days for AS at a dose rate of 191.2 micromoles/kg, P < 0.01). No frank clinical toxicity was observed, though both artesunate and artelinate induced dose-related vascular necrosis at the site of injection. The necrosis was less severe and reversible when the drugs were administered via femoral, rather than tail/foot veins. The data suggest that the P. berghei-7-week-old Sprague-Dawley rat model of malaria is reproducible and useful for assessing the efficacy of antimalarials and that artelinate is at least as potent, and safe, as artesunate, the leading clinical treatment for severe malaria.
Assuntos
Artemisininas/administração & dosagem , Artemisininas/farmacologia , Malária/tratamento farmacológico , Malária/parasitologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacologia , Animais , Artemisininas/efeitos adversos , Artesunato , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intravenosas , Masculino , Parasitemia/tratamento farmacológico , Extratos Vegetais/efeitos adversos , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/efeitos adversos , Fatores de TempoRESUMO
The neurotoxicity of beta-arteether (AE) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. In this efficacy and toxicity study of AE, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of AE. Dihydroartemisinin (DQHS), a more toxic and active metabolite of AE, was also analyzed. When administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of AE with sesame oil (AESO) was used had a 7.5-fold higher area under the curve (AUC) (on last versus first day dosing), while AE with cremophore (AECM) had only a 1.8-fold higher AUC. Although the accumulation of AECM was greatly reduced, its total exposure level (46.29 microg x h/ml) was 2.7-fold higher than with AESO (16.92 microg x h/ml) due to a higher bioavailability of AECM (74.5%) compared with AESO (20.3%). Total exposure time (calculated at over the minimal detected neurotoxicity level of 41.32 ng/ml) of AECM was 103 hours during the whole treatment period (192 hours), which was more than one-third (37%) less than with AESO (162 hours). Similar pharmacokinetic results were also shown with the active metabolite, DQHS. Anorexia and gastrointestinal toxicity with AESO were significantly more severe than with AECM (P < 0.001). Histopathologic examination of the brain demonstrated neurotoxic changes; the AESO rat group was significantly more severe than the AECM rat group. The brain injury scores with AECM were mild to moderate (2.3-3.0), and with AESO they were moderate to severe (3.0-4.7) on day 7 and day 10, respectively. In addition, the results of a 50% cure dose (CD50) against Plasmodium berghei in mice were 34.1 mg/kg for AESO and 14.2 mg/kg for AECM, indicating a significant higher efficacy was found in the AECM animals. Toxicity and efficacy of DQHS were also dependent on its exposure time and level, which was the same as its parent drug (AE). In conclusion, following the seven-day treatment in rats, AE and DQHS exposure time and level varied based on the vehicle used. The extension of drug exposure time and the low peak level of AE and DQHS were more associated with severe neurotoxicity and lower antimalarial efficacy, whereas the high level and short exposure time of AE and DQHS resulted in higher efficacy and milder toxicity.
Assuntos
Anorexia/induzido quimicamente , Antimaláricos/toxicidade , Artemisininas , Malária/tratamento farmacológico , Neurotoxinas/toxicidade , Sesquiterpenos/toxicidade , Sesquiterpenos/uso terapêutico , Animais , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Área Sob a Curva , Artemeter , Disponibilidade Biológica , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neurotoxinas/farmacocinética , Plasmodium berghei/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/farmacocinética , Distribuição TecidualRESUMO
New fluorogenic probes for restriction endonucleases based on molecular beacons were developed. These hairpin probes were single-stranded oligonucleotides that had stem-and-loop structure and carried 5'- fluorophor moiety and 3'-quencher moiety. Their stem sequences were designed as recognition sites for restriction endonucleases and loop sequences were unrelated nucleotides. Upon cleavage by endonuclease, these probes became fluorescent and thus could trace the enzyme activity continuously. Two probes were designed for BglII and NcoI, respectively, and each was labeled with a fluorophor of different color. The results showed that the two probes could specifically assay for the corresponding enzymes either individually or simultaneously in a real-time mode. Considering the simplicity, quantification and high throughput, these probes could be extended to other applications such as drug screening, protein-nucleic acid interaction study and searching for small molecule DNA cleavage agents.
Assuntos
Proteínas de Bactérias , DNA/metabolismo , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , DNA/química , Corantes Fluorescentes , Cinética , Conformação de Ácido NucleicoRESUMO
Restriction fragment analysis and sequencing of a serotype-specific region were used to type 12 and 2 clinical isolates, respectively. Both molecular methods produced clear-cut results that completely correlated with that of the neutralization test.
Assuntos
Infecções por Adenoviridae/diagnóstico , Adenovírus Humanos/isolamento & purificação , Adenovírus Humanos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Pré-Escolar , Conjuntivite/virologia , Primers do DNA , Diarreia/virologia , Fezes/virologia , Humanos , Lactente , Meningoencefalite/virologia , Dados de Sequência Molecular , Faringite/virologia , Pneumonia Viral/virologia , Mapeamento por Restrição/métodos , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Sorotipagem/métodosRESUMO
HL-60 cells were treated by isoverbascoside with different time and different concentrations in vitro. The differentiation of HL-60 cells was evaluated by light and electron microscopy to observe morphological changes, by chemiluminence to detect phagocytosis and by tumorigenesis in nude mice to determine malignancy. The cytotoxical effect of isoverbascoside on HL-60 cells was examined by trypan blue excluding staining and electron microscopy. The influence of isoverbascoside on cell cycle was measured by flow cytometry. Granular differentiation of HL-60 cells was induced by isoverbascoside at 20-25 mumol/L within 1-3 days as the results of morphological changes, enhancement of phagocytosis and decreasing of tumorigenesis. Strong cytotoxicity was evidenced in HL-60 cells treated by isoverbascoside at 30-35 mumol/L. HL-60 cells treated by isoverbascoside at 20 mumol/L were delayed at G1 phase at 12 hours and G2/M phase at 72 hours.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glucosídeos/farmacologia , Células HL-60/efeitos dos fármacos , Animais , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , FenóisRESUMO
Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals received dihydroartemisinin formulated in 50% DMAC/oil, or artesunic acid and artelinic acid in 0.9% saline vehicle, they died between days 1 and 2. This suggests that delayed onset toxicity and death in the ARTE rats may also be due to slow absorption and prolonged drug exposure. Therefore multiple i.m. administrations cause anorexia and drug accumulation, possibly affecting the toxicokinetics and efficacy of the drug.
Assuntos
Artemisininas , Sesquiterpenos/farmacocinética , Sesquiterpenos/toxicidade , Absorção , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/administração & dosagemRESUMO
The pharmacokinetics, metabolism, protein binding, red blood cell (RBC) binding, stability in vitro, and acute and anorectic toxicity of artelinic acid (ARTL) were investigated in various animal species and human blood samples. Absorption and distribution following 10 mg/kg intramuscular or oral administration in dogs and rats were very rapid with t1/2 0.12-0.54; there were also a high AUC (11,262 ng/h/mL) and Vss (9.5 L/kg), low CL (15 mL/min/kg) and long elimination time (t1/2 = 2.6 h), compared with rat data. Oral bioavailability of ARTL was 79.7% in dogs and 30.1% in rats. The conversion of ARTL to dihydroartemisinin (DART) in dogs (0.1-0.5% of total dose) after 3 routes of administration (intravenous, intramuscular and oral) was 10-fold lower than that in rats. In rats dosed with [14C]ARTL, unchanged ARTL accounted for less than 13% of the total radioactivity after all 3 administration routes, suggesting that ARTL was extensively biotransformed. The half-lives of total radioactivity (21-49 h) in urine were much longer than that of unchanged ARTL in plasma (1.4-3.7 h), indicating that some long-lasting metabolites of ARTL were formed in rats. The mass balance data showed that 77-83% of total radioactivity was recovered in urine and faeces. High binding capacity (79-95%) and low binding affinity (1.1-9.3 x 10-7 M) of ARTL were measured in rat, rabbit, dog, monkey and human plasma. The RBC/plasma ratios of [14C]ARTL were 0.35 and 0.44 for dog and human plasma, respectively. ARTL was much more stable than artesunic acid (ARTS) in rat and dog plasma, and both ARTL and ARTS were more stable in dog plasma than in rat plasma in vitro. The 50% lethal dose (LD50) of ARTL in rats was about 535 mg/kg. Multiple intramuscular dosing for 7 d of 50 mg/kg/d of ARTL caused mild anorectic toxicity compared to ARTS in rats. In contrast to 4 other artemisinin derivatives, ARTL seems to be a good antimalarial candidate as it has the highest plasma concentration, the highest binding capacities in RBC, the highest oral bioavailability, the longest elimination half-life, the lowest metabolism rate and the lowest toxicity at equivalent dose levels.
Assuntos
Antimaláricos/farmacocinética , Artemisininas , Sesquiterpenos/farmacocinética , Animais , Antimaláricos/administração & dosagem , Antimaláricos/toxicidade , Cães , Ingestão de Alimentos/efeitos dos fármacos , Haplorrinos , Humanos , Masculino , Coelhos , Ratos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/toxicidadeRESUMO
The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.