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1.
Medicine (Baltimore) ; 100(29): e26737, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398051

RESUMO

ABSTRACT: Cutaneous metastasis (CM) occurs infrequently and usually presents during the later stages of cancer, and has a poor prognosis. Although there are insufficient current data, cancer treatment changes could have a positive impact on the outcome. This retrospective study aimed to review the pattern and prognosis of CM in patients with solid malignancy in a tertiary cancer center in Thailand.We reviewed the medical records of cancer patients diagnosed with CM between October 2009 and August 2015 at Chulabhorn Hospital, a tertiary cancer center in Thailand. Patients with primary skin cancer and hematological malignancies were excluded. We collected and analyzed data, including the time of cancer diagnosis and CM, type of cancer, clinical characteristics, and survival outcome.Of 11,418 patients, there were 33 (0.3%) were diagnosed with CM. Breast cancer was the most common primary cancer (12 cases, 36%). Skin nodules were commonly detected on the anterior chest wall. Also, 79% of CM patients had concomitant visceral metastasis. The median overall survival of those with CM was 9.21 months (95% confidence interval 4.75-83.38 months) regardless of presentation either at onset or disease recurrence (P = .083). However, the change of management was affected in 78% diagnosed with a later stage of CM. No statistical difference in survival was observed between breast cancer and non-breast cancer patients (8.79 vs 9.21 months, P = .613).Despite CM being a sign of poor prognosis, it may still be an indicator for changing cancer patients' treatment. Hence, early CM diagnosis and prompt novel therapy may positively affect outcomes for cancer patients.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Registros Médicos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Análise de Sobrevida , Centros de Atenção Terciária , Tailândia/epidemiologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-34089852

RESUMO

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

4.
J Viral Hepat ; 28(7): 1034-1041, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33880807

RESUMO

Chronic hepatitis B (CHB) infection-associated hepatocellular carcinoma (HCC) is a major health problem in Asian countries. Several HCC risk prediction models have been developed using either treated or untreated CHB patients. However, there is limited validation of these risk scores in a treated and untreated mixed CHB patient cohort. This study analysed and validated HCC risk scores among 2208 CHB patients who enrolled in the HCC surveillance programme in Thailand during July 2010. The baseline clinical and radiologic data of these CHB patients were applied to calculate various HCC risk scores. There were 20 patients (0.9%) with HCC development at the 5.9-year follow-up. The areas under the receiver operating characteristic curves (AUROCs) predicting HCC risk at 5 years were 0.80 (0.68-0.91), 0.73 (0.60-0.85), 0.79 (0.67-0.91), 0.70 (0.58-0.82), 0.72 (0.59-0.85), 0.76 (0.63-0.87) and 0.77 (0.64-0.89) for the GAG-HCC, CU-HCC, REACH-B, PAGE-B, mPAGE-B, CAMD and AASL scores, respectively. The overall HCC risk scores were accurate and comparable. However, the subgroup analysis revealed better HCC-risk-predictive performance in the treated patients, while performance was less helpful in those not fulfilling criteria for antiviral therapy. Clinicians should be aware of these data when using the HCC risk score in untreated CHB patients.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Fatores de Risco , Tailândia/epidemiologia
5.
Clin Cancer Res ; 27(13): 3649-3660, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33879458

RESUMO

PURPOSE: HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988). PATIENTS AND METHODS: A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 µg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1. RESULTS: IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses. CONCLUSIONS: IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 µg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.

6.
Eur J Pharmacol ; 897: 173960, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33617828

RESUMO

Cholangiocarcinoma (CCA) is a malignant biliary tract epithelium tumor. The programmed death-1 (PD-1)/programmed receptor-ligand 1 (PD-L1) signaling pathway has been implicated as an immune escape mechanism in several cancers. The present study aimed to assess the expression of PD-L1 on human CCA cell lines and its potential role in suppressing CD8+ T- cell function. A panel of intrahepatic CCA cell lines was evaluated for immune regulatory checkpoint ligands and inflammation markers. Effects of pro-inflammatory cytokine, interferon gamma (IFN-γ), on the expression of immune regulatory checkpoint ligands and inflammation markers were determined. The PD-L1 function was measured by co-culturing CCA cells with lymphocytes. Most of the selected Thai CCA cell lines, including HuCCA-1, RMCCA-1, KKU-100, and KKU-213, expressed higher PD-L1 than normal cholangiocyte MMNK-1 and ANK-1 cells. Both PD-L1 and cyclooxygenase-2 (COX-2) expressions were highest in HuCCA-1 cells. A 48 h treatment with IFN-γ increased the expression of PD-L1 and COX-2 in CCA cells. The expression of CTLA-4 ligands, including H7-1 and H7-2, did not change after IFN-γ treatment. Rofecoxib, a specific COX-2 inhibitor, mitigated IFN-γ-induced PD-L1 expression. After 48 h co-incubation, CD8+ T-cell apoptosis was increased as compared to the control group. Pretreatment of CCA cells with IFN-γ further increased CD8+ T-cell apoptosis. Pembrolizumab, an anti-PD-1 antibody, mitigated CCA cell escape phenomenon. The inhibition of T-cell-mediated immune response via the PD-L1/PD-1 axis are evidenced in intrahepatic CCA. Immunotherapy with checkpoint inhibitor offers a potentially therapeutic strategy for CCA patients; however, further in vivo and clinical studies are required.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Criança , Colangiocarcinoma/imunologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral
7.
Hepatol Int ; 15(1): 71-81, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33394321

RESUMO

BACKGROUND: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. METHODS: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. RESULTS: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. CONCLUSION: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.

8.
Arch Dis Child Fetal Neonatal Ed ; 106(1): 31-38, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32561566

RESUMO

OBJECTIVE: We aimed to systematically review and analyse the outcomes of non-endotracheal suctioning (non-ETS) versus ETS in non-vigorous meconium-stained neonates. DESIGN: We conducted a systematic review of non-ETS and ETS in non-vigorous infants born through meconium-stained amniotic fluid (MSAF). We searched PubMed/Medline, Scopus, Clinical Trials.gov, Cumulative Index to Nursing and Allied Health, and Cochrane Library databases from inception to November 2019, using keywords and related terms. Only non-vigorous infants born through MSAF included in randomised controlled trials, were included. We calculated overall relative risks (RRs) and mean differences with 95% CIs using a random-effects model, to determine the impact of ETS in non-vigorous infants born through MSAF. MAIN OUTCOME MEASURES: The primary outcome was the incidence of meconium aspiration syndrome (MAS). Secondary outcomes were respiratory outcome measures (pneumothorax, persistent pulmonary hypertension of the newborn, secondary pneumonia, need for respiratory support, duration of mechanical ventilation), initial resuscitation and others including shock, perinatal asphyxia, convulsions, neonatal mortality, blood culture-positive sepsis and duration of hospital stay. RESULTS: A total of 2085 articles were identified in the initial database search. Four studies, including 581 non-vigorous meconium-stained infants, fulfilled the inclusion criteria, comprising 292 infants in the non-ETS group and 289 in the ETS group. No statistically significant difference was found for MAS (RR 0.98; 95% CI 0.71 to 1.35). CONCLUSIONS: Initiating ETS soon after birth in non-vigorous meconium-stained infants may not alter their neonatal outcomes.


Assuntos
Líquido Amniótico/química , Intubação Intratraqueal/métodos , Doenças Respiratórias/prevenção & controle , Feminino , Humanos , Recém-Nascido , Mecônio , Síndrome de Aspiração de Mecônio/prevenção & controle , Complicações do Trabalho de Parto/epidemiologia , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
9.
Clin Transl Gastroenterol ; 11(9): e00196, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33094953

RESUMO

INTRODUCTION: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics. METHODS: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed. RESULTS: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state. DISCUSSION: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).

11.
Gastroenterology ; 156(3): 635-646.e9, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30342034

RESUMO

BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection, but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations. METHODS: We searched PubMed, Embase, and the Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model. RESULTS: We analyzed 34 published studies (with 42,588 patients, 303,754 person-years of follow-up, and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24). There were no significant differences between the sexes. A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P < .01). Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 log10 IU/mL; 95% CI, 5.94-7.27) vs not having HBsAg seroclearance (7.71 log10 IU/mL; 95% CI, 7.41-8.02) (P < .01) and with a lower level of HBsAg at baseline (2.74 log10 IU/mL; 95% CI, 1.88-3.60) vs not having HBsAg seroclearance (3.90 log10 IU/mL, 95% CI, 3.73-4.06) (P < .01). HBsAg seroclearance was not associated with HBV genotype or treatment history. Heterogeneity was substantial across the studies (I2 = 97.49%). CONCLUSION: In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.


Assuntos
Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/imunologia , Adulto , Biomarcadores/sangue , DNA Viral/análise , Feminino , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Fatores de Risco , Estudos Soroepidemiológicos , Testes Sorológicos
12.
Biomed Rep ; 9(1): 42-52, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29930804

RESUMO

Cholangiocarcinoma (CCA) remains to be a major health problem in several Asian countries including Thailand. The molecular mechanism of CCA is poorly understood. Early diagnosis is difficult, and at present, no effective therapeutic drug is available. The present study aimed to identify the molecular mechanism of CCA by gene expression profile analysis and to search for current approved drugs which may interact with the upregulated genes in CCA. Gene Expression Omnibus (GEO) was used to analyze the gene expression profiles of CCA patients and normal subjects. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology enrichment analysis was also performed, with the KEGG pathway analysis indicating that pancreatic secretion, protein digestion and absorption, fat digestion and absorption, and glycerolipid metabolism may serve important roles in CCA oncogenesis. The drug signature database (DsigDB) was used to search for US Food and Drug Administration (FDA)-approved drugs potentially capable of reversing the effects of the upregulated gene expression in CCA. A total of 61 antineoplastic and 86 non-antineoplastic drugs were identified. Checkpoint kinase 1 was the most interacting with drug signatures. Many of the targeted protein inhibitors that were identified have been approved by the US-FDA as therapeutic agents for non-antineoplastic diseases, including cimetidine, valproic acid and lovastatin. The current study demonstrated an application for bioinformatics analysis in assessing the potential efficacy of currently approved drugs for novel use. The present results suggest novel indications regarding existing drugs useful for CCA treatment. However, further in vitro and in vivo studies are required to support the current predictions.

13.
Planta Med ; 83(9): 778-789, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28249303

RESUMO

Andrographis paniculata has been widely used in Scandinavian and Asian counties for the treatment of the common cold, fever, and noninfectious diarrhea. The present study was carried out to investigate the physiological effects of short-term multiple dose administration of a standardized A. paniculata capsule used for treatment of the common cold and uncomplicated upper respiratory tract infections, including blood pressure, electrocardiogram, blood chemistry, hematological profiles, urinalysis, and blood coagulation in healthy Thai subjects. Twenty healthy subjects (10 males and 10 females) received 12 capsules per day orally of 4.2 g of a standardized A. paniculata crude powder (4 capsules of 1.4 g of A. paniculata, 3 times per day, 8 h intervals) for 3 consecutive days. The results showed that all of the measured clinical parameters were found to be within normal ranges for a healthy person. However, modulation of some parameters was observed after the third day of treatment, for example, inductions of white blood cells and absolute neutrophil count in the blood, a reduction of plasma alkaline phosphatase, and an induction of urine pH. A rapid and transient reduction in blood pressure was observed at 30 min after capsule administration, resulting in a significant reduction of mean systolic blood pressure. There were no serious adverse events observed in the subjects during the treatment period. In conclusion, this study suggests that multiple oral dosing of A. paniculata at the normal therapeutic dose for the common cold and uncomplicated upper respiratory tract infections modulates various clinical parameters within normal ranges for a healthy person.


Assuntos
Andrographis , Coagulação Sanguínea/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Preparações de Plantas/farmacologia , Administração Oral , Adulto , Análise Química do Sangue , Cápsulas , Feminino , Humanos , Masculino , Fitoterapia , Preparações de Plantas/administração & dosagem , Pulso Arterial , Tailândia
14.
Medicine (Baltimore) ; 96(13): e6554, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28353619

RESUMO

To evaluate quantitative hepatitis B surface antigen (qHBsAg) as a diagnostic marker for inactive carriers (ICs) and hepatitis B surface antigen (HBsAg) seroclearance in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. We retrospectively studied 300 HBeAg-negative CHB patients with initial serum hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) levels <2000 IU/mL. Serum HBV DNA and alanine aminotransferase (ALT) levels were monitored every 6 months for 24 months. ICs were identified as having persistent HBV DNA levels <2000 IU/mL and normal ALT levels, whereas active carriers (ACs) were identified as having HBV DNA levels ≥2000 IU/mL, with or without elevated ALT levels. The serum qHBsAg level was defined at baseline and evaluated as a diagnostic predictor using a receiver-operating characteristic curve. The study group comprised 134 men and 166 women with a median age of 41.5 years. At baseline, 200 ICs displayed lower levels of qHBsAg (1492 IU/mL) compared with 100 ACs (2936 IU/mL) (P = 0.005). The qHBsAg level was independently associated with the IC state and HBsAg seroclearance. Baseline qHBsAg levels <1000 IU/mL and HBV DNA levels <2000 IU/mL, when detected simultaneously, allowed for identification of ICs with 41% sensitivity and 72% specificity. Fifteen patients (5%) displayed HBsAg seroclearance after 24 months. A qHBsAg cutoff value of <50 IU/mL provided 100% sensitivity and 92% specificity in predicting HBsAg seroclearance. The qHBsAg level at a single timepoint among HBeAg-negative CHB patients with low HBV DNA levels at baseline was not a predictive marker for ICs; however, it accurately predicted spontaneous HBsAg seroclearance at 24 months.


Assuntos
Portador Sadio/sangue , Portador Sadio/diagnóstico , Países em Desenvolvimento , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/sangue , Adulto , Portador Sadio/imunologia , Feminino , Hepatite B Crônica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
Hepatol Res ; 47(3): E161-E168, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27176630

RESUMO

AIM: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are considered among the most potent antiviral agents for the treatment of chronic hepatitis B infection. We aimed to compare treatment efficacy and safety of ETV and TDF in nucleoside-naïve chronic hepatitis B patients. METHODS: Inclusion criteria were compensated chronic hepatitis B patients who were either hepatitis B e antigen (HBeAg)-positive or HBeAg-negative. Exclusion criteria were co-infection with hepatitis C virus and/or HIV, concurrent malignancy, and decompensated cirrhosis. Virological, biochemical, and serological end-points at week 96 and 144 were compared. Of 400 patients, 200 patients received ETV and 200 received TDF. RESULTS: There were no significant differences between the two groups in baseline characteristics including age (41.6 ± 11.5 vs. 41.2 ± 11.6, mean baseline hepatitis B virus DNA (5.91 ± 1.79 vs. 5.94 ± 1.68 log10 IU/mL), mean baseline alanine aminotransferase (68.1 ± 64.1 vs. 76.8 ± 79.8 U/L), and cirrhosis (15.5% vs. 14.5%). At week 144 of treatment, 91 and 94% of the ETV and TDF groups, respectively, achieved undetectable hepatitis B virus DNA. In HBeAg-positive patients, HBeAg seroconversion could be achieved in 27.4% and 33.7% at week 144 for ETV and TDF groups, respectively. Quantitative hepatitis B surface antigen dropped significantly over 144 weeks of treatment period but only 1.0 to 1.5% experienced hepatitis B surface antigen loss. Safety profiles were consistent with previous reports of monotherapy. CONCLUSION: Both ETV and TDF showed potent antiviral activity against hepatitis B. Either ETV or TDF can be recommended as a treatment of choice for patients with chronic hepatitis B. Both drugs were safe and well tolerated.

16.
J Ethnopharmacol ; 194: 513-521, 2016 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-27702690

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata is included in 'The National List of Essential Herbal Drugs A.D. 1999' of Thailand as an herbal drug for the treatment of common cold symptoms and non-infectious diarrhea. The therapeutic activities of A. paniculata are attributed to four major active diterpenoids: andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4). However, the pharmacokinetic studies in humans of this plant were performed after a single oral dose administration and reported the parameters related to be of only 1. AIM OF THE STUDY: This study aims to determine the pharmacokinetic parameters of four major active diterpenoids after multiple oral dose administration of A. paniculata capsules in healthy volunteers. The dissolution testing of these four diterpenoids was also performed. MATERIALS AND METHOD: The dissolution testing of four major active diterpenoids was conducted in pH 1.2, pH 4.5, and pH 6.8 for 10-100min. The pharmacokinetic study of these active diterpenoids was designed as an open-label, multiple oral dose administration of A. paniculata capsules in 20 healthy Thai volunteers at 1:1 ratio of female and male. Each volunteer was given four A. paniculata capsules each time which contained 1, 2, 3, and 4 in the quantities of 32.64, 5.40, 3.60, and 3.84mg, respectively, three times a day for three consecutive days. On the fourth day, after the first dose of the day was administered, blood samples were collected at the predefined time points. The validated LC-MS/MS method was used to simultaneously determine the concentrations of these diterpenoids in the human plasma samples. The pharmacokinetic parameters of each active diterpenoid were determined. RESULTS: All four major active diterpenoids have been completely dissolved in the simulated pH of gastrointestinal tract within 60min of dissolution. The dissolution profiles were found to be highest in pH 6.8 and lowest in pH 1.2, especially for 3. In the pharmacokinetic study, although 1 was administered at the highest dose among these four diterpenoids, 2 exhibited the highest maximum concentrations (Cmax) of 44.89ng/mL and area under the plasma concentration-time curve (AUC) of 128.17h×ng/mL. Compound 1 had the second highest Cmax and AUC as 32.41ng/mL and 55.23h×ng/mL, respectively. The relative systemic exposure, represented by the dose normalized AUC [(h×ng/mL)/(mg/kg)], of 2 was approximately 14 times higher than that of 1, while those of 3 and 4 were approximately 1.5 and 1.6 times higher, respectively. Cmax, AUC, apparent volume of distribution, and apparent clearance of 2 were found to be significant difference between female and male. However, when these parameters were calculated as dose normalized basis, no statistically significant difference was found. CONCLUSION: The four major active diterpenoids in the A. paniculata capsules were soluble in all studied dissolution media. The pharmacokinetic parameters of these active diterpenoids in the present study could be applied for dose optimization of A. paniculata product in order to obtain good therapeutic efficacy and reduce the possible side effects that may occur from different active diterpenoids in this medicinal plant.


Assuntos
Andrographis/química , Diterpenos/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Diterpenos/administração & dosagem , Diterpenos/química , Feminino , Voluntários Saudáveis , Humanos , Masculino , Solubilidade , Tailândia
17.
World J Gastroenterol ; 22(34): 7806-12, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27678364

RESUMO

AIM: To determine the role of screening and surveillance of hepatocellular carcinoma (HCC) in treatment-naïve chronic hepatitis B (CHB) patients. METHODS: We recruited 2293 CHB patients (both males and females; aged 20-65 years). All patients were screened and underwent surveillance using abdominal ultrasonography (AUS) and serum alpha-fetoprotein (AFP) assay every 6 mo. The diagnosis, staging and treatment of HCC followed the American Association for the Study of Liver Diseases practice guidelines and the Barcelona Clinic Liver Cancer guidelines. The exclusion criteria included: decompensated cirrhosis; a history of any cancer in the last 5 years; previous antiviral treatment for CHB; concurrent infection with hepatitis C virus or human immunodeficiency virus; a Karnofsky Performance Status score < 60%; or any medical condition preventing eligibility to complete the protocol. The prevalence and incidence rates of HCC were determined; survival rates were calculated at 3-year post HCC diagnosis. The sensitivity and specificity were calculated on a per-patient basis. RESULTS: Among 2293 treatment-naïve CHB patients, seven cases had HCC at initial screening, giving a prevalence rate of 305 per 100000 persons; 3.3% were diagnosed with liver cirrhosis, all of which were Child-Pugh class A. With a median follow-up time of 42 (range, 3-48) mo, 10 additional cases were diagnosed with HCC, resulting in an incidence rate of 143 per 100000 persons per year. This burden was as high as that reported in other studies from East Asian countries. All HCC patients were aged ≥ 40 years. Most were at an early stage (Stage 0, A or B); 14/17 cases were successfully treated with surgical resection or radiofrequency ablation, with a high 3-year survival rate of 90%. Hemangioma was the most common focal liver lesion in CHB patients detected by AUS; the main causes of AFP elevation at the initial screening were cirrhosis, increased alanine aminotransferase level and HCC. AUS detected 16/17 HCC cases whereas AFP levels ≥ 20 µg/L at diagnosis were observed in only 7/17 patients, most with a tumor size > 5 cm. For HCC screening and surveillance, AUS had a sensitivity and specificity of 94% and 82%, respectively, whereas the sensitivity and specificity of AFP at a cut-off value of ≥ 20 µg/L were 41% and 98%, respectively. Combined use of AUS and AFP assay did not improve effectiveness. CONCLUSION: Implementation of active screening and surveillance using AUS to detect early-stage HCC in naïve CHB patients aged ≥ 40 years in an endemic area is of benefit.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Adulto , Idoso , Antivirais/uso terapêutico , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Resultado do Tratamento , Ultrassonografia , Adulto Jovem , alfa-Fetoproteínas/análise
19.
Planta Med ; 82(1-2): 113-20, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26576030

RESUMO

Andrographis paniculata contains four major active diterpenoids, including andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4), which exhibit differences in types and/or degrees of their pharmacological activity. Previous pharmacokinetic studies in humans reported only the parameters of compound 1 and its analytical method in human plasma. The purpose of this study was to develop a simple, sensitive, and selective liquid chromatography tandem-mass spectrometry technique for the simultaneous determination of all four major active diterpenoids in the A. paniculata product in human plasma. These four diterpenoids in plasma samples were extracted by a simple protein precipitation method with methanol and separated on a Kinetex C18 column using a gradient system with a mobile phase of acetonitrile and water. The liquid chromatography tandem-mass spectrometry was performed in the negative mode, and the multiple reaction monitoring mode was used for the quantitation. The method showed a good linearity over a wide concentration range of 2.50-500 ng/mL for 1 and over the range of 1.00-500 ng/mL for the other diterpenoids with a correlation coefficient R(2) > 0.995. The lower limit of quantification of 1 was found to be 2.50 ng/mL, while those of the other diterpenoids were 1.00 ng/mL. The intraday and interday accuracy (relative error) ranged from 0.03 % to 10.03 %, and the intraday and interday precisions (relative standard deviation) were in the range of 2.05-9.67 %. The extraction recovery (86.54-111.56 %) with a relative standard deviation of 2.78-8.61 % and the matrix effect (85.15-112.36 %) were within the acceptance criteria. Moreover, these four major active diterpenoids were stable in plasma samples at the studied storage conditions with a relative error ≤-9.79 % and a relative standard deviation ≤ 9.26 %. Hence, this present method was successfully validated and used in the pilot study to determine the pharmacokinetic parameters of all four major active diterpenoids in human plasma after multiple oral doses of the A. paniculata product were administered to a healthy, Thai female volunteer.


Assuntos
Andrographis/química , Cromatografia Líquida/métodos , Diterpenos/sangue , Espectrometria de Massas/métodos , Humanos , Projetos Piloto
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