RESUMO
ABSTRACT Background. Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. Objective. To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. Material and methods. This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. Results. No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. Conclusion. Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.
Assuntos
Humanos , Antivirais/uso terapêutico , Fosfatos/sangue , Osso e Ossos/efeitos dos fármacos , Cálcio/sangue , Lamivudina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/sangue , Tenofovir/uso terapêutico , Guanina/análogos & derivados , Antivirais/efeitos adversos , Fatores de Tempo , Deficiência de Vitamina D/induzido quimicamente , Osso e Ossos/metabolismo , Osso e Ossos/diagnóstico por imagem , Biomarcadores/sangue , Absorciometria de Fóton , Densidade Óssea/efeitos dos fármacos , Estudos Transversais , Fatores de Risco , Resultado do Tratamento , Remodelação Óssea/efeitos dos fármacos , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/sangue , Fraturas Ósseas/induzido quimicamente , Tenofovir/efeitos adversos , Guanina/efeitos adversos , Guanina/uso terapêuticoRESUMO
BACKGROUND: Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. OBJECTIVE: To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. MATERIAL AND METHODS: This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. RESULTS: No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (<-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. CONCLUSION: Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.
Assuntos
Antivirais/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Cálcio/sangue , Fatores de Crescimento de Fibroblastos/sangue , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Fosfatos/sangue , Tenofovir/uso terapêutico , Absorciometria de Fóton , Adulto , Idoso , Antivirais/efeitos adversos , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Estudos Transversais , Feminino , Fator de Crescimento de Fibroblastos 23 , Fraturas Ósseas/induzido quimicamente , Guanina/efeitos adversos , Guanina/uso terapêutico , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tenofovir/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Deficiência de Vitamina D/induzido quimicamenteRESUMO
It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30mN NaOH), inosine or guanine (up to 600nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors.
Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacologia , Guanina/administração & dosagem , Guanina/farmacologia , Injeções Espinhais , Inosina/administração & dosagem , Inosina/farmacologia , Analgésicos/efeitos adversos , Animais , Guanina/efeitos adversos , Inosina/efeitos adversos , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/fisiopatologia , Purinas/líquido cefalorraquidiano , Receptores Purinérgicos P1/metabolismoRESUMO
BACKGROUND: The effectiveness of nucleoside analogue (NA) treatment in patients with chronic hepatitis B (CHB) -associated liver failure is still controversial. Severe lactic acidosis has been reported during entecavir (ETV) treatment in patients with impaired liver function. AIM: To investigate the rescuing efficacy and safety of ETV in patients with CHB-associated liver failure. MATERIAL AND METHODS: A literature search was carried out to collect articles dated up to December, 2013 on ETV therapy for patients with CHB-associated liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was used as the primary efficacy measure. The safety of ETV was assessed. RESULTS: Six randomized controlled trials were selected. The overall analysis revealed ETV significantly improved survival at 4 weeks (RR = 1.35; 95% CI [1.16, 1.57]; p < 0.0001), 8 weeks (RR = 1.33; 95% CI [1.07, 1.64]; p = 0.009), 12 weeks (RR = 1.68; 95% CI [1.24, 2.28]; p = 0.0008). Pooled data also showed beneficial effects of antiviral therapy compared with control for HBV DNA negative change (RR = 5.35; 95% CI [2.06, 13.88]; p = 0.0006), TBIL and PTA improvement (TBIL: MD = -69.36; 95% CI [-134.37, -4.36]; p = 0.04. PTA: MD = 16.26; 95% CI [8.59, 23.94]; p < 0.0001). No adverse effect was identified in the examined studies. CONCLUSION: Our results showed that antiviral therapy with ETV improved the short-term survival of patients with CHB-associated liver failure. In addition, ETV was well tolerated during the treatment period. Further studies are still needed to strengthen these results.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Falência Hepática/virologia , Adulto , Antivirais/efeitos adversos , Distribuição de Qui-Quadrado , Feminino , Guanina/efeitos adversos , Guanina/uso terapêutico , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Humanos , Falência Hepática/diagnóstico , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Among the available nucleos(t)ide analogues adefovir dipivoxil (ADV) is relatively cheap and widely used in rural area in China. However, there are insufficient data on recommendation for patients with suboptimal response to ADV after 48 weeks of treatment in order to reduce the resistance rate in the long term. The aim of this study was to compare the efficacy and safety of LAM add-on combination therapy versus ETV monotherapy for patients with suboptimal response to ADV. MATERIAL AND METHODS: 136 patients with suboptimal response to ADV were randomly assigned to the add-on LAM with ADV combination therapy (68 patients) group and the ETV monotherapy (68 patients) group. Patients in the add-on group were prescribed 100 mg LAM and 10 mg ADV per day, while the monotherapy group received 0.5 mg ETV per day for 48 weeks. Tests for liver and kidney function, HBV serum markers, HBV DNA load, were performed every 3 months. RESULTS: The mean patient age in LAM add-on group and ETV monotherapy was 38.59 ± 7.65 and 37.56 ± 8.67 years respectively. The HBV DNA undetectable rate in the LAM add-on group and the ETV group were not significant difference at week 4, 12 and 24 (P > 0.05). However, the HBV undetectable rate in the ETV group was higher than that in the LAM add-on group at week 36 and 48 (P = 0.043 for week 36 and P = 0.038 for week 48). There was no significant difference both for HBeAg loss and HBeAg seroconversion between two groups (P > 0.05) at 48 weeks. Meanwhile, our study also demonstrated that the mean eGFR levels in LAM add-on group was decreased from 99.6 ± 8.71 at baseline to 86.4 ± 9.83 at the end of 48 weeks, which was significantly higher than that in the ETV monotherapy group (P < 0.05). 8.8% of patients in LAM add-on group experienced eGFR reduction by 20-30% from baseline at 48 weeks. No patients developed hyposphosphatemia in our study. CONCLUSION: Our study clearly showed that switch to ETV monotherapy was the more effective and more safe than that of LAM add-on combination therapy for patients with suboptimal response to ADV.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Substituição de Medicamentos , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Antivirais/efeitos adversos , Biomarcadores/sangue , China , Quimioterapia Combinada , Feminino , Guanina/efeitos adversos , Guanina/uso terapêutico , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
Results from phase III clinical trials clearly demonstrate the efficacy and safety of entecavir and tenofovir in the controlled environment of randomized clinical studies. There are several studies with both drugs performed in clinical practice (also called "real life studies"). Despite the pros and cons, studies performed in real life conditions represent everyday practice and add important information about long term treatment effectiveness and safety in this clinical setting. This review shows that patients treated with first line nucleos(t)ide analogs at referral centres, with good clinical follow-up and adherence to international guidelines, can achieve high treatment response rates with a very low rate of adverse events.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Antivirais/efeitos adversos , Guanina/efeitos adversos , Guanina/uso terapêutico , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/virologia , Humanos , Organofosfonatos/efeitos adversos , Tenofovir , Resultado do TratamentoRESUMO
Pemetrexed is a novel, multitargeted antifolate approved for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. Although pemetrexed is a safe drug, some adverse effects such as myelosupression and cutaneous reactions are observed. Pemetrexed-induced eyelid edema is a rare side effect of pemetrexed treatment, and until this moment few cases were reported in the medical literature. We reported a new case of pemetrexed-induced eyelid edema in a patient with adenocarcinoma of the lung with brain metastases.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Edema/induzido quimicamente , Doenças Palpebrais/induzido quimicamente , Glutamatos/efeitos adversos , Guanina/análogos & derivados , Adenocarcinoma/radioterapia , Adenocarcinoma/secundário , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carboplatina/uso terapêutico , Dexametasona/uso terapêutico , Diuréticos/uso terapêutico , Edema/tratamento farmacológico , Doenças Palpebrais/tratamento farmacológico , Feminino , Ácido Fólico/uso terapêutico , Furosemida/uso terapêutico , Glucocorticoides/uso terapêutico , Guanina/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Pemetrexede , Vitamina B 12/uso terapêuticoRESUMO
This study aimed to evaluate the efficacy and safety of entecavir and/or tenofovir in compensated (CC) or decompensated (DC) hepatitis B cirrhotic patients in real-life clinical practice. Of the 48 patients, included between April 2007 and March 2010, 12 were DC. The mean age was 55 ± 12.2 years, 85.4% were Caucasians and 8 patients were HBeAg positive. Mean viral load was 5.2 ± 1.9 log(10) UI/mL. HBV-DNA undetectability at 3, 6, 12 and 24 months were 53.3%, 78.3%, 83.7% and 97.1%, respectively, similar in CC and DC. At 6 and 12 months, ≥ 80% of CC achieved ALT normalization, while only 42.9% and 71.4% in DC. After a median follow-up of 27.1 (0.7-45.3) months, 43 patients were Child Pugh Turcotte (CPT) class A (n = 39 at entry). In DC, progressive improvement in the MELD scores was observed: 12.73 (SD 4.5), 10.4 (SD 3.6) and 8.2 (SD 2.6), at baseline, 12 and 24 months, respectively. During follow-up, 7 patients died, 4 received liver transplantation and 5 developed hepatocellular carcinoma. In three out of four DC who died due to hepatic causes, these events occurred between the first 0.7 and 6.7 months, and all were CPT class C. Cumulative survival in CC vs. DC at 12 and 24 months were 94.4% vs. 66.7%, and 88.2% vs. 57.1%, respectively (log rank p = 0.03). No severe adverse events associated with entecavir or tenofovir were reported. In conclusion, in compensated and decompensated cirrhotic patients, entecavir and tenofovir were effective and well tolerated.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Cirrose Hepática/virologia , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Idoso , Antivirais/efeitos adversos , Biomarcadores/sangue , Carcinoma Hepatocelular/virologia , Distribuição de Qui-Quadrado , DNA Viral/sangue , Progressão da Doença , Quimioterapia Combinada , Feminino , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/virologia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Estudos Retrospectivos , Tenofovir , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Pemetrexed maintenance therapy significantly improved overall survival and progression-free survival compared with placebo, and had a good safety profile in a phase 3 placebo-controlled study in patients with advanced non-small-cell lung cancer (NSCLC). Results for quality of life, symptom palliation, and tolerability are presented here. METHODS: After four cycles of platinum-based induction therapy, 663 patients with stage IIIB or stage IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (in a 2:1 ratio) from March 15, 2005, to July 20, 2007, using the Pocock and Simon minimisation method to receive pemetrexed (500 mg/m(2) every 21 days; n=441) or placebo (n=222) plus best supportive care until disease progression. The primary efficacy data have been reported previously. Patients completed the Lung Cancer Symptom Scale (LCSS) at baseline, after each cycle, and post-discontinuation. Worsening of symptoms was defined as an increase of 15 mm or more from baseline on a 100 mm scale for each LCSS item. The primary outcome for these quality-of-life analyses was time to worsening of symptoms, analysed for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: Baseline characteristics, including LCSS scores, were well balanced between groups. Baseline LCSS scores were low, indicating low symptom burden for patients without disease progression after completion of first-line treatment. Longer time to worsening was recorded for pain (hazard ratio [HR] 0·76, 95% CI 0·59-0·99; p=0·041) and haemoptysis (HR 0·58, 95% CI 0·34-0·97; p=0·038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4·3 mm vs 0·2 mm; p=0·028). Rates of resource use were statistically higher for pemetrexed than for placebo: admissions to hospital for drug-related adverse events (19 [4%] vs none; p=0·001), transfusions (42 [10%] vs seven [3%]; p=0·003), and erythropoiesis-stimulating agents (26 [6%] vs four [2%]; p=0·017). INTERPRETATION: Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy. FUNDING: Eli Lilly.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Idoso , Análise de Variância , Antimetabólitos Antineoplásicos/efeitos adversos , Apetite/efeitos dos fármacos , Ásia , Brasil , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Intervalo Livre de Doença , Método Duplo-Cego , Europa (Continente) , Feminino , Glutamatos/efeitos adversos , Guanina/efeitos adversos , Guanina/uso terapêutico , Hemoptise/etiologia , Hemoptise/prevenção & controle , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/psicologia , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Dor/prevenção & controle , Pemetrexede , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
INTRODUCTION: Platinum resistant ovarian cancer is a current challenge in Oncology. Current approved therapies offer no more of a 20% of response. New therapeutic options are urgently needed. PATIENTS AND METHODS: Patients were treated with the combination of Pemetrexed 500 mg/m(2) d1 and Gemcitabine 1000 mg/m(2) d1,8 in a 21 days basis. RESULTS: 10 platinum-resistant ovarian cancer patients were treated under compassionate use. Mean previous chemotherapy lines were 3.3. Mean administered cycles were 4. Mean CA 125 decrease was on average of 47%, with one patient experiencing a 95% decrease in her CA 125 level. 1 patient had a complete clinical remission, and 2, had partial radiological responses. Mean Progression free survival was 16.5 weeks, and Overall Survival was 21.2 weeks. Treatment was well tolerated. CONCLUSIONS: Deemd to the observed activity, the combination of Pemetrexed and Gemcitabine deserves deeper investigation in platinum-resistant ovarian cancer patients.