RESUMEN

BACKGROUND: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. METHODS: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. RESULTS: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. CONCLUSIONS: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

Asunto(s)

Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Dolor Ocular/tratamiento farmacológico , Uveítis/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Cannabidiol/farmacología , Modelos Animales de Enfermedad , Dronabinol/farmacología , Evaluación Preclínica de Medicamentos , Leucocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Roedores

RESUMEN

OBJECTIVES: Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). METHODS: OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. RESULTS: Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. CONCLUSIONS: Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84-92.

RESUMEN

OBJECTIVES: To determine effect of gentle loads applied to the knee on mRNA expression of nerve growth factor, particularly, the active beta subunit (NGFß) in cartilage and chondrocyte. METHODS: Cyclic compressive loads in vivo and fluid flow in vitro were used to determine the mRNA levels. Alteration of Rac1 GTPase as well as effect of salubrinal, a specific inhibitor of eIF2α phosphatase was assessed using fluorescence resonance energy transfer (FRET)-based Rac1 biosensor. RESULTS: Knee loading at 1 N reduced mRNA levels of NGFß and its low affinity receptor, p75 in cartilage and subchondral bone. In cartilage, knee loading at 1 N reduced the phosphorylation level of p38 MAPK (p38-p) and activity of Rac1 GTPase. Consistent with in vivo results, fluid flow at 5 and 10 dyn/cm(2) reduced mRNA levels of NGFß and p75 in C28/I2 human chondrocytes. SB203580, which decreases p38-p, reduced the mRNA levels of NGFß and p75. Silencing Rac1 by siRNA decreased the levels of p38-p and NGFß mRNA but not p75. Furthermore, administration of salubrinal reduced FRET-based activity of Rac1 as well as the mRNA levels of NGFß and p75. CONCLUSIONS: These results provide evidence that mechanical stimulation and salubrinal may attenuate pain perception-linked NGFß signaling through Rac1-mediated p38 MAPK.

Asunto(s)

Cartílago/metabolismo , Condrocitos/metabolismo , Factor de Crecimiento Nervioso/biosíntesis , Transducción de Señal/fisiología , Soporte de Peso/fisiología , Proteína de Unión al GTP rac1/metabolismo , Animales , Western Blotting , Células Cultivadas , Femenino , Transferencia Resonante de Energía de Fluorescencia , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Estrés Mecánico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

OBJECTIVE: Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NFκB) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal. METHODS: Using C28/I2 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor α (TNFα) and interleukin 1ß (IL1ß). RNA interference with siRNA specific to NFκB p65 (RelA) was employed to examine a potential involvement of NFκB signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity. RESULTS: The result showed that tunicamycin activated p38 mitogen-activated protein kinase (MAPK), while inflammatory cytokines activated p38 MAPK and NFκB. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NFκB reduced inflammatory cytokine-driven upregulation of MMP13 activity. CONCLUSIONS: The results demonstrate that salubrinal downregulates expression and activity MMP13 through p38 and NFκB signaling, suggesting its potential usage to treat degenerative diseases such as osteoarthritis.

Asunto(s)

Condrocitos/efectos de los fármacos , Cinamatos/farmacología , Metaloproteinasa 13 de la Matriz/biosíntesis , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Tiourea/análogos & derivados , Muerte Celular/efectos de los fármacos , Células Cultivadas , Condrocitos/enzimología , Cinamatos/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Factor 2 Eucariótico de Iniciación/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/farmacología , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasas de la Matriz/biosíntesis , Metaloproteinasas de la Matriz/genética , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , Tiourea/administración & dosificación , Tiourea/farmacología , Factor de Transcripción ReIA/genética , Factor de Transcripción ReIA/fisiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/farmacología , Tunicamicina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

Bone remodelling in adult skeleton is a process of maintaining bone mass through combined activities of bone forming osteoblasts and bone resorbing osteoclasts. Focusing on a molecular pathway mediated by osteoprotegerin, the authors derived a mathematical formulation for molecular interactions and cellular behaviours. The authors also treated this remodelling process as a homeostatic regulator in a framework of linear quadratic problems. A primary question was: does a solution of a matrix Riccati equation provide a guideline for therapeutic interventions for prevention of bone loss? In order to elucidate the systems dynamics, the authors analysed the perturbed set of equations around a stable equilibrium state together with the original equations. The results demonstrate that a homeostatic regulator with the selected control variables effectively reduces bone degradation activities and restore a physiological remodelling process. To partially validate efficacy of the described intervention strategy, biological experiments were conducted with an osteoblast cell line using one of the control variables, salubrinal (chemical agent). The authors observed that administration of salubrinal activated mRNA levels of transcription factors and an osteogenic marker gene as well as enhancement of mineralisation. Taken together, the current study supports a potential usage of control theories in active regulation of bone remodelling homeostasis.

Asunto(s)

Remodelación Ósea/fisiología , Huesos/fisiología , Calcificación Fisiológica/fisiología , Retroalimentación Fisiológica/fisiología , Homeostasis/fisiología , Modelos Biológicos , Osteoblastos/fisiología , Células 3T3 , Animales , Huesos/citología , Simulación por Computador , Ratones , Osteoblastos/citología , Biología de Sistemas/métodos

RESUMEN

BACKGROUND AND AIMS: Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not been fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. METHODS: 62 patients with naive HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm(2) in males, >90 cm(2) in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients' background, tumour-related factors and liver function-related factors. RESULTS: The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm(2), p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. CONCLUSIONS: Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.

Asunto(s)

Carcinoma Hepatocelular/terapia , Ablación por Catéter , Grasa Intraabdominal , Neoplasias Hepáticas/terapia , Recurrencia Local de Neoplasia/etiología , Anciano , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Métodos Epidemiológicos , Hígado Graso/complicaciones , Hígado Graso/mortalidad , Hígado Graso/virología , Femenino , Hepacivirus , Hepatitis B/complicaciones , Hepatitis B/mortalidad , Virus de la Hepatitis B , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/mortalidad , Humanos , Grasa Intraabdominal/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/mortalidad , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND: The bioavailability of gamma-tocopherol and metabolites of vitamin E after gamma-tocopherol administration is not well understood. We investigated the effect of gamma-tocopherol administration on the levels and metabolism of alpha- and gamma-tocopherol in healthy volunteers. METHODS: We measured two metabolites of vitamin E (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC)) in plasma and urine by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) during administration of gamma-tocopherol. Two groups of volunteers were enrolled. The gamma-tocopherol group received two gamma-tocopherol capsules (each containing 186.4 mg of gamma-tocopherol and 5 mg of alpha-tocopherol) for 28 days, while the control group received d-alpha-tocopherol at 5 mg/day, which was the same dose as that given to the gamma-tocopherol group. Blood and urine samples were obtained on days 0, 14, 28, 35, 42, and 56 after the initiation of gamma-tocopherol administration. RESULTS: The plasma gamma-tocopherol concentration increased markedly during administration of gamma-tocopherol and the plasma gamma-CEHC concentration increased along with that of gamma-tocopherol. The plasma alpha-tocopherol concentration decreased significantly during gamma-tocopherol administration. The plasma concentration of alpha-CEHC decreased significantly and urinary excretion of alpha-CEHC tended to increase in the gamma-tocopherol group. Urinary sodium secretion was significantly increased at 1 week after the cessation of gamma-tocopherol administration, but there was no significant difference of urine volume between the two groups. CONCLUSION: Metabolism of alpha-tocopherol is accelerated and the plasma alpha-tocopherol concentration is decreased during gamma-tocopherol administration.

Asunto(s)

Antioxidantes/farmacocinética , Vitamina E/metabolismo , alfa-Tocoferol/metabolismo , gamma-Tocoferol/farmacocinética , Adulto , Disponibilidad Biológica , Cromanos , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Propionatos , Sodio/orina , Vitamina E/sangre , Vitamina E/orina , alfa-Tocoferol/sangre , alfa-Tocoferol/orina

RESUMEN

METHOD: alpha-Tocopherol and gamma-tocopherol are metabolized into 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), respectively. We analyzed alpha- and gamma-CEHC concentrations in human serum and urine by high-performance liquid chromatography during administration of alpha-tocopherol. Fourteen healthy adult male volunteers received 1,200 IU per day of RRR-alpha-tocopherol for 28 days. Blood and urine samples were obtained on days 0, 14, 28, and 56. RESULTS: During alpha-tocopherol administration, the plasma gamma-tocopherol concentration decreased significantly, but there was marked elevation of the alpha-tocopherol concentration. Increased concentration of alpha-CEHC and gamma-CEHC in both serum and urine indicated the acceleration of vitamin E metabolism. CONCLUSION: High-dose administration of alpha-tocopherol caused an increase of gamma-tocopherol metabolism, which might have caused a decrease of the plasma gamma-tocopherol concentration.

Asunto(s)

Antioxidantes/administración & dosificación , Antioxidantes/análisis , Vitamina E/análisis , alfa-Tocoferol/administración & dosificación , Adulto , Antioxidantes/metabolismo , Área Bajo la Curva , Cromanos/sangre , Cromanos/orina , Cromatografía Líquida de Alta Presión/métodos , Humanos , Masculino , Propionatos/sangre , Propionatos/orina , Vitamina E/metabolismo , alfa-Tocoferol/análisis , alfa-Tocoferol/farmacocinética

RESUMEN

In this study, we investigated a change in the excretory content of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC), a gamma-tocopherol (gamma-Toc) metabolite, in rat urine and bile by using a new high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. In this determination, CEHC [alpha- and gamma-CEHC, where alpha-CEHC = 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman] in the biological specimens were treated with 3 N methanolic HCl to hydrolyze conjugates and to promote esterification. The methylated samples were extracted by n-hexane/water (1:2). The analyses of the methyl esters of alpha-CEHC and gamma-CEHC were performed by an HPLC-ECD using an ODS-3 column at 35 degrees C. The mobile phase was acetonitrile/water (45:55, vol/vol) containing 50 mM sodium perchlorate. After rat urine and bile samples, respectively, were methylated as described above, methylated biliary metabolites were identified by liquid chromatography-mass spectrometry as methyl esters of gamma-CEHC. Furthermore, we examined the differences in the excretion of gamma-CEHC between rat urine and bile after an oral administration of gamma-Toc or alpha- + gamma-Toc by the above HPLC method. In the gamma-Toc group, each vitamin E-deficient rat was given 0.5 mL of a stripped corn oil preparation containing 10 mg of gamma-Toc. In the alpha- + gamma-Toc group, the rat was given 10 mg of alpha-Toc and 10 mg of gamma-Toc. The content of gamma-CEHC in rat urine from the alpha- + gamma-Toc group was increased more in comparison to the gamma-Toc group at 18-36 h after oral administration. Moreover, the content of gamma-CEHC in rat bile in the alpha- + gamma-Toc group was increased more in comparison to the gamma-Toc group at 6-18 h after oral administration. Therefore, we have suggested that gamma-CEHC was shifted mainly to urinary excretion after gamma-CEHC had been excreted into the bile. Furthermore, we assume that alpha-Toc may affect the metabolism of gamma-Toc to gamma-CEHC in the body.

Asunto(s)

Bilis/efectos de los fármacos , Bilis/metabolismo , Cromanos/metabolismo , Cromanos/orina , Propionatos/metabolismo , Propionatos/orina , alfa-Tocoferol/metabolismo , alfa-Tocoferol/farmacología , Animales , Calibración , Cromatografía Líquida de Alta Presión , Humanos , Hidrólisis , Masculino , Espectrometría de Masas , Metilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Deficiencia de Vitamina E , alfa-Tocoferol/administración & dosificación

RESUMEN

The structures of an RNA component of ribonuclease P (RNase P RNA) were examined for Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio natriegens, Vibrio campbellii, Vibrio proteolyticus, Vibrio pelagius and Vibrio harveyi to clearly determine their genetic differences. The RNase P RNAs ranged from 382 to 454 nucleotides (nt) in size, and were remarkably different from each other in the structure of two helices, P3 and P12. The P3 helices were comprised of tandem repeats of a palindromic sequence (24 nt), resulting in the longitudinal repetition of a stem structure. The number of repetitions ranged from four in V. harveyi, to one in both V. alginolyticus and V. proteolyticus. The genes for the RNase P RNAs of all species were located between two open reading frames, the amino acid sequences of which were similar to the hypothetical proteins located at 70.92 and 1.94 min in the Escherichia coli chromosome.

Asunto(s)

Endorribonucleasas/química , Proteínas de Escherichia coli , Filogenia , ARN Bacteriano/química , ARN Catalítico/química , Vibrio/clasificación , Vibrio/genética , Secuencia de Bases , Modelos Moleculares , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Sistemas de Lectura Abierta , Reacción en Cadena de la Polimerasa/métodos , Ribonucleasa P , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Vibrio/enzimología , Vibrio cholerae/clasificación , Vibrio cholerae/genética , Vibrio parahaemolyticus/clasificación , Vibrio parahaemolyticus/genética

RESUMEN

Percutaneous ethanol injection therapy (PEIT) has been widely practiced in the treatment of liver tumors, especially of hepatocellular carcinoma (HCC). Histopathologic examinations, findings in imaging modalities and serum tumor marker levels have shown a remarkable anticancer effect of this procedure. In addition, PEIT has achieved considerably high long-term survival rates. For small HCC, PEIT has been generally accepted as an alternative to surgery. Here we will describe PEIT from the viewpoints of patient selection, technique, various evaluation procedures of efficacy, long-term results, side effects and complications, and relationship with other therapies.

Asunto(s)

Carcinoma Hepatocelular/terapia , Etanol/administración & dosificación , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/mortalidad , Embolización Terapéutica , Etanol/uso terapéutico , Humanos , Inyecciones , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/mortalidad , Recurrencia Local de Neoplasia , Tasa de Supervivencia , Ultrasonografía Intervencional

RESUMEN

A method for the enantiomeric determination of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman (LLU-alpha, gamma-CEHC) in rat plasma was developed using high-performance liquid chromatography (HPLC) with a fluorimetric derivatization with 4-N, N-dimethylaminosulfonyl-7-piperazino-2,1,3-benzoxadiazole (DBD-PZ) followed by O-acetylation with acetyl chloride. The proposed HPLC system used two non-chiral columns (phenyl and octadecylsilica) and a chiral column (a modified cellulose type), which were connected via two column-switching valves. A derivatized sample prepared from rat plasma was first separated on the phenyl column, and the fraction including LLU-alpha derivative was introduced to the octadecylsilica column to quantify the concentration of the mixture of S- and R-LLU-alpha. Finally, the LLU-alpha derivative was directly injected into the chiral column to obtain the ratio of the enantiomers. The proposed HPLC system was applied to the enantiomeric determination of LLU-alpha in plasma after intravenous administration of racemic LLU-alpha. S-LLU-alpha was eliminated faster than R-LLU-alpha, and its concentration in plasma decreased to one-third at 2 min after dosing.

Asunto(s)

Cromanos/sangre , Cromatografía Líquida de Alta Presión/métodos , Propionatos/sangre , Animales , Cromanos/farmacocinética , Propionatos/farmacocinética , Ratas , Ratas Sprague-Dawley , Espectrometría de Fluorescencia , Estereoisomerismo

Asunto(s)

Ablación por Catéter , Neoplasias Hepáticas/cirugía , Ablación por Catéter/métodos , Ensayos Clínicos como Asunto , Humanos , Resultado del Tratamiento

RESUMEN

Patients with hepatocellular carcinoma (HCC) frequently experience intrahepatic HCC recurrence even after complete ablation of primary lesions. Because the oncogenic process may be different for hepatitis B viral (B-viral) and hepatitis C viral (C-viral) HCC, the present study was conducted to elucidate the factors contributing to HCC recurrence with respect to the infected hepatitis virus. Two hundred thirty-six patients with a single HCC lesion who underwent complete ablation of the tumor by PEIT and/or PMCT or surgical resection at Tokyo University and its affiliated hospitals from 1993 to 1997 were enrolled. The patients were classified into 3 groups: the B-viral group, C-viral group, and NBNC group. After complete removal of tumors, the patients were followed for a mean period of 39 months. The factors contributing to HCC recurrence were analyzed by univariate and multivariate analysis using the Cox proportional hazard model. The rate of intrahepatic recurrence in enrolled patients at 1, 3, and 5 years was 19%, 50%, and 64%, respectively. The intrahepatic recurrence rate in C-viral and B-viral HCC was higher than that in the NBNC-related HCC. Fibrosis staging, pathological grading of HCC, and serum AFP levels were significantly linked to intrahepatic recurrence by univariate analysis, and fibrosis staging was strongest in the multivariate analysis for C-viral HCC (P = .004). In contrast, fibrosis staging did not affect the recurrence in B-viral (P = .51) and NBNC-related (P = .77) HCC. Risk factors for HCC recurrence differed according to the infected viral state.

Asunto(s)

Carcinoma Hepatocelular/virología , Hepatitis B/complicaciones , Hepatitis C/complicaciones , Hepatitis Viral Humana/complicaciones , Neoplasias Hepáticas/virología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Modelos de Riesgos Proporcionales , Factores de Riesgo , Análisis de Supervivencia

RESUMEN

We have performed percutaneous tumor ablation (PTA) including percutaneous ethanol injection therapy (PEIT) for 90% of the patients with hepatocellular carcinoma. Until December 1998, the 793 patients received PTA, 5 years survival rate reached 39.8%. Excluding the patients with Child C whose hepatic function were extremely low, 5 years survival rate reached to the level of 41.2%. Since 5 years survival rate in stage IV-A reached 24.4%, the patients of stage IV-A may be considered to have an indication for PTA. We have confirmed the effectiveness of the local treatment including radiotherapy for advanced hepatocellular carcinoma with portal vein invasion. We are attempting to perform PTA for the extra-hepatic lesions that had no indication of other treatment. However the indication of PTA is limited by the presence of diffuse nodules, exacerbation of the hepatic function, or tumor invasion to portal vein, bile duct, inferior vena cava.

Asunto(s)

Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Ablación por Catéter , Etanol/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Carcinoma Hepatocelular/mortalidad , Humanos , Inyecciones Intralesiones , Neoplasias Hepáticas/mortalidad , Tasa de Supervivencia

RESUMEN

OBJECTIVE: Haemobilia often results from iatrogenic injury caused by therapeutic procedures. The objective of this study was to evaluate the efficacy of early diagnosis of haemobilia based on ultrasonography in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection. PATIENTS AND METHODS: A combination retrospective and prospective study on the early detection of haemobilia caused by percutaneous ethanol injection was conducted on 365 patients in 1995-1996. The retrospective study reviewed the clinical, laboratory and imaging data of 172 patients who had undergone ethanol injection therapy in 1995. The results showed that ultrasonographic changes in the gallbladder, namely the rapid appearance of echogenic material in the gallbladder lumen, are a useful early sign of haemobilia. Based on the results of the retrospective study, a prospective study on the early detection of haemobilia was carried out in 1996. In the prospective study, percutaneous ethanol injection was halted as soon as haemobilia was detected. RESULTS: The incidence of haemobilia in the prospective group (3.6%) was not different from that in the retrospective group (4.7%). However, the mean duration between percutaneous ethanol injection and diagnosis of haemobilia was only 0.3 +/- 0.2 days in the prospective group, compared with 2.8 +/- 2.1 days in the retrospective group (P < 0.001), and the mean duration of jaundice in the prospective group (4.3 days) was significantly shorter than in the retrospective group (40.0 days) (P< 0.05). CONCLUSION: Early diagnosis of haemobilia based on ultrasonographic findings of the gallbladder lumen effectively reduces the severity of haemobilia-related complications due to immediate interruption of the interventional procedure.

Asunto(s)

Carcinoma Hepatocelular/tratamiento farmacológico , Etanol/efectos adversos , Vesícula Biliar/diagnóstico por imagen , Hemobilia/diagnóstico por imagen , Administración Cutánea , Anciano , Carcinoma Hepatocelular/complicaciones , Etanol/uso terapéutico , Femenino , Hemobilia/etiología , Humanos , Enfermedad Iatrogénica , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Factores de Tiempo , Ultrasonografía

RESUMEN

BACKGROUND: Although the importance of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the clinical treatment of hepatocellular carcinoma (HCC) has been studied extensively, the authors examined the clinical picture of HCC with regard to the state of these two tumor markers. METHODS: The authors categorized 237 HCC cases into 4 groups according to levels of AFP and DCP: high levels of AFP with low DCP levels, high DCP levels with low AFP levels, high levels of both tumor markers, and low levels of both tumor markers. Comparisons of survival rates were made among these groups using the Kaplan-Meier product limit method, and for other comparisons of clinical parameters the Fisher PSLD test was used. Prognostic significance was tested with the Cox proportional hazards model. RESULTS: The cutoff values were set at 100 ng/mL for AFP and 0.0625 AU/mL for DCP. Forty-eight patients (20.7%) had high levels of AFP and low levels of DCP, 22 (9.3%) had high DCP levels and low levels of AFP, 12 (4.6%) had high levels of both AFP and DCP, and 155 (65.4%) had low levels of both DCP and AFP. Patients with high levels of DCP but low levels of AFP were predominantly male and had large lesions but few nodules. Patients with high levels of both tumor markers had the most discouraging outcome observed in this study (death within 3 years). CONCLUSIONS: Patients with high levels of DCP and low levels of AFP exhibited the unique clinical characteristic of large HCC nodules that were few in number. In addition, it was observed that measurement of both AFP and DCP can predict the survival of patients.

Asunto(s)

Biomarcadores , Carcinoma Hepatocelular/sangre , Neoplasias Hepáticas/sangre , Precursores de Proteínas/análisis , Protrombina/análisis , alfa-Fetoproteínas/análisis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/mortalidad , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico

RESUMEN

Biliary and urinary metabolites were examined after intravenous administration of 14C-coenzyme Q10 (14C-CoQ) to guinea pigs. Cumulative recovery of administered radioactivity for up to 8 hours by bile drainage was 4.8%. The greater part of radioactivity was detected in conjugate form. After hydrolyzing with beta-glucuronidase, aglycone fragments were subjected to methylation and reductive acetylation. The main metabolite was demonstrated to be Q acid-1 1,4-hydroquinone diacetate methyl ester (M-1) on HPLC. Then, the main metabolite was assumed to be glucuronide of 2,3-dimethoxy-5-methyl-6-(3'-methyl-5'-carboxy-2'-pentenyl)-1, 4-benzohydroquinone [Q acid-I hydroquinone]. The cumulative urinary recovery of the administered radioactivity over 48 hours was 8.3%. The labeled samples were treated similarly to bile. The urinary metabolites of CoQ10 consisted of unconjugated and conjugated forms. Lyophilized urine was treated as a bile sample and analyzed. The two major metabolites were assigned to be M-1 and Q acid-II 1,4-hydroquinone diacetate methyl ester (M-2). Then, the two metabolites were assumed to be composed of Q acid-I and 2,3-dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (Q acid-II) in free and corresponding hydroquinone conjugate forms. To investigate the effect of exogenous labeled CoQ10 on unlabeled CoQ10 (endogenous) metabolites in urine, simultaneous quantitative determination was performed using deuterium labeled CoQ10 (CoQ10-d5). Urine collected over a 72-hour period after intravenous administration of CoQ10-d5 was processed similarly to that described above and two derivatized metabolites (M-1 and M-2) were quantified by gas chromatography-mass fragmentography with the multi-ion detection method. The analytical results showed that the addition of exogenous labeled CoQ10 did not influence the metabolism (or breakdown) of unlabeled (endogenous) CoQ10.

Asunto(s)

Bilis/metabolismo , Ubiquinona/análogos & derivados , Animales , Bilis/química , Radioisótopos de Carbono , Cromatografía en Capa Delgada , Coenzimas , Glucuronatos/orina , Cobayas , Masculino , Técnica de Dilución de Radioisótopos , Ubiquinona/metabolismo , Ubiquinona/orina

RESUMEN

Hematopoiesis requires specific interactions with the microenvironments, and VLA-4 has been implicated in these interactions based on in vitro studies. To study the role of VLA-4 in hematopoiesis in vivo, we performed in utero treatment of mice with an anti-VLA-4 monoclonal antibody. Although all hematopoietic cells in fetal liver expressed VLA-4, the treatment specifically induced anemia. It had no effect on the development of nonerythroid lineage cells, including lymphoids and myeloids. In the treated liver almost no erythroblast was detected, whereas the erythroid progenitors, which give rise to erythroid colonies in vitro, were present. These results indicate that VLA-4 plays a critical role in erythropoiesis, while it is not critical in lymphopoiesis in vivo.

Asunto(s)

Células Precursoras Eritroides/efectos de los fármacos , Eritropoyesis/fisiología , Integrinas/fisiología , Receptores Mensajeros de Linfocitos/fisiología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Adhesión Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides/fisiología , Femenino , Fibronectinas/fisiología , Edad Gestacional , Hematopoyesis Extramedular/fisiología , Factores de Crecimiento de Célula Hematopoyética/farmacología , Sistema Hematopoyético/efectos de los fármacos , Sistema Hematopoyético/enzimología , Humanos , Integrina alfa4beta1 , Integrinas/antagonistas & inhibidores , Integrinas/inmunología , Hígado/efectos de los fármacos , Hígado/embriología , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Embarazo , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Receptores Mensajeros de Linfocitos/inmunología , Proteínas Recombinantes/farmacología , Timo/efectos de los fármacos , Timo/embriología

RESUMEN

We investigated the binding of PCB by dietary fiber in vivo and in vitro. Forty male rats consisting of four rats a group were housed and rats of each group were given a treatment diet containing rice-bran fiber, spinach fiber, burdock fiber, cabbage fiber, soybean fiber Japanese-radish fiber, carrot fiber, corn fiber and cellulose for five days. The remaining four rats were fed a non-fiber diet as controls. The animals were administered with 0.5 ml of the race-bran oil used by Yusho patients and kept on the same diets for five days. Fecal excretion of PCB in the group fed rice-bran fiber and spinach fiber was significantly (p < 0.01) stimulated 6.6 and 4.1 times, respectively, as compared with controls. Dietary fiber was suspended in distilled water, and methanolic solution of PCB was added to these suspensions. The mixtures were then incubated. After centrifugation, the unbound PCB in supernatant was analyzed by gas chromatograph. Rice-bran fiber and spinach fiber bount more PCB than any of the other dietary fiber. A significant correlation existed between the amounts of binding PCB in vitro and fecal PCB output in rats by eight types of dietary fiber (r = 0.986, p < 0.01).

Asunto(s)

Fibras de la Dieta , Bifenilos Policlorados/metabolismo , Adsorción , Animales , Heces/química , Masculino , Bifenilos Policlorados/análisis , Ratas , Ratas Wistar