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2.
Clin Drug Investig ; 39(9): 835-846, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31228017

RESUMO

BACKGROUND AND OBJECTIVE: Oral nucleoside/nucleotide analogues (NAs) have been advocated for chronic hepatitis B (CHB) treatment with good efficacy. However, less attention has been put on their adverse events. Therefore, a Bayesian network meta-analysis (NMA) was performed to evaluate the relative safety of five NAs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate) in CHB treatment among adults. METHODS: Eligible randomized clinical trials (RCTs) and prospective cohort studies were systematically and thoroughly searched until May 1, 2019. Poisson-prior-based Bayesian NMA was performed to synthesize both direct and indirect evidence with reporting hazard ratios (HRs) and 95% credible intervals (CrIs) for serious adverse events (SAEs) and hepatic/renal impairments. RESULTS: Thirty-three RCTs and 11 prospective cohort studies were identified. As to SAEs, no statistically significant difference was found of any comparison among five NAs. In terms of hepatotoxicity, lamivudine was safer than telbivudine (HR 0.45; 95% CrI 0.21, 0.85), and entecavir increased the risk by 102% (entecavir vs lamivudine: HR 2.02; 95% CrI 1.19, 3.27). CONCLUSIONS: The findings from this large NMA could influence clinical practice, and the methodological framework of this study could provide evidence-based support to analyze sparse safety data in the field.


Assuntos
Antivirais/efeitos adversos , Teorema de Bayes , Hepatite B Crônica/tratamento farmacológico , Meta-Análise em Rede , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/uso terapêutico , Antivirais/uso terapêutico , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/uso terapêutico , Humanos , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Estudos Prospectivos , Telbivudina/efeitos adversos , Telbivudina/uso terapêutico , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico
3.
Drug Des Devel Ther ; 13: 1127-1133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118563

RESUMO

Adefovir dipivoxil (ADV) is one of the most important nucleostide analogues currently in use for the treatment of chronic hepatitis B virus (HBV) infection. Low-dose ADV-induced nephrotoxicity in most cases was reported to be reversible after the discontinuation of ADV or by decreasing the dose of ADV. In our study, we have 5 documented cases of low-dose ADV-induced hypophosphatemia osteomalacia with or without Fanconi syndrome which were diagnosed in our hospital between 2010 and 2017. Three patients were observed to have a full recovery after the discontinuation of ADV. Two patients had persistently elevated urine ß2-microglobulin levels and out of these two patients, one patient had persistent hypophosphatemia after the cessation of ADV. These cases illustrated that the use of low-dose ADV increased the risk of nephrotoxicity, and in some patients, low-dose ADV-induced nephrotoxicity was not completely reversible. Patients of East Asian origin, especially those with a low body mass index, were prone to a relatively higher risk of developing low-dose ADV-induced nephrotoxicity; therefore, it was worth paying attention to the side effects caused by low-dose ADV.


Assuntos
Adenina/análogos & derivados , Hepatite B Crônica/complicações , Hipofosfatemia/induzido quimicamente , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Osteomalacia/induzido quimicamente , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Idoso , Relação Dose-Resposta a Droga , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/complicações , Feminino , Hepatite B Crônica/tratamento farmacológico , Humanos , Hipofosfatemia/complicações , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Osteomalacia/complicações
4.
Virol J ; 16(1): 61, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064399

RESUMO

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections. METHODS: We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response. RESULTS: Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05). CONCLUSIONS: In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients.


Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Curva ROC , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Soroconversão , Adulto Jovem
5.
Nihon Shokakibyo Gakkai Zasshi ; 116(4): 353-359, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30971673

RESUMO

A woman in her 60s visited our hospital due to elevation of ALP (1357U/L). The patient had been treated with lamivudine (LAM) in 2005, LAM+adefovir (ADV) in 2009, and ADV+entecavir in 2015 for chronic hepatitis B (CH-B). The ALP isozyme was predominantly bone type. Urinary ß-2 microglobulin (MG) and α-1MG increased to 49635µg/L and 64.1mg/L, respectively. Though no fractures were found during bone scintigraphy, the patient was diagnosed with Fanconi syndrome. However, 3 months after switching from ADV to tenofovir alafenamide (TAF), ALP decreased to 856U/L, and urinary ß-2MG and α-1MG decreased to 624µg/L and 6.0mg/L, respectively. Fanconi syndrome should be considered when an increase in ALP is observed in patients treated with ADV, and urinary ß-2MG and α-1MG assays are useful for establishing a diagnosis. Switching from ADV to TAF was an effective therapeutic option.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Síndrome de Fanconi/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Fosfatase Alcalina/metabolismo , Biomarcadores/metabolismo , DNA Viral , Farmacorresistência Viral , Quimioterapia Combinada , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/metabolismo , Feminino , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do Tratamento
6.
Yakugaku Zasshi ; 139(4): 641-645, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30930400

RESUMO

We herein present the case of a 66-year-old Japanese man with Fanconi's syndrome. He had been receiving adefovir dipivoxil (ADV) for the treatment of entecavir (ETV)-resistant chronic hepatitis B (CHB) for four years in his 8-year treatment of hepatocellular carcinoma (HCC), but was referred to our hospital after increased levels of bone pain in his ribs, knees, and ankles. Renal dysfunction, hypophosphatemia, and increased levels of bone alkaline phosphatase were found by a hematology test after admission for treatment of HCC. Radiography and 99m Tc-labeled hydroxymethylene diphosphonate (HMDP) scintigraphy revealed multiple insufficiency fractures in the ribs, knees, ankles, and heels. After switching from ADV to tenofovir disoproxil fumarate (TDF) and treatment with calcitriol and sodium dihydrogenphosphate, the patient's serum phosphate levels slightly increased and renal dysfunction did not improve, but after six months his clinical symptoms disappeared. To detect and prevent adverse effects from ADV, physicians and pharmacists should carefully monitor renal function and serum phosphate levels in patients with hepatitis B virus (HBV) treated for a long time with ADV.


Assuntos
Adenina/análogos & derivados , Síndrome de Fanconi/induzido quimicamente , Fraturas Ósseas/induzido quimicamente , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/efeitos adversos , Organofosfonatos/uso terapêutico , Osteomalacia/induzido quimicamente , Adenina/efeitos adversos , Adenina/uso terapêutico , Idoso , Carcinoma Hepatocelular/complicações , Hepatite B Crônica/complicações , Humanos , Hipofosfatemia/induzido quimicamente , Neoplasias Hepáticas/complicações , Masculino , Fatores de Tempo
7.
Acta Gastroenterol Belg ; 82(1): 31-34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30888751

RESUMO

AIMS: To compare the efficacy of treatment with lamivudine (LAM) plus adefovir (ADV) or entecavir (ETV) monotherapy in LAM treatment failure patients with HBeAg negative chronic hepatitis B (CHB) patients during 48 weeks of therapy. PATIENTS AND METHODS: Thirty patients with HBeAg negative CHB were enrolled in the study. The serum levels of HBV DNA, HBsAg/HBsAb, and ALT were assessed by enzyme-linked immunosorbent assay at 0, 12, 24, 36, and 48 weeks. RESULTS: The rate of undetectable HBV DNA in the LAM+ADV group was 100%, which was higher than the ETV group at 48 weeks (73.33%, χ2 = 4.615, P = 0.032). Multivariate analysis using the Cox proportional hazards model showed that therapy with LAM+ADV or baseline levels of HBV DNA <107 copies/ml were independent predictive factors for undetectable HBV DNA rates in all patients (RR: 2.488, P = 0.042; RR: 0.201, P = 0.035). CONCLUSIONS: During the 48 weeks of treatment in patients with HBeAg negative CHB, LAM plus ADV suppressed HBV replication more effectively than ETV monotherapy. In addition, no virologic breakthrough was detected in the LAM add-on ADV group. Additionally, therapy with LAM+ADV or baseline levels of HBV DNA <107copies/ml were independent predictive factors for undetectable HBV DNA rates in patients.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , DNA Viral/efeitos dos fármacos , Farmacorresistência Viral/efeitos dos fármacos , Guanina/análogos & derivados , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , DNA Viral/sangue , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Guanina/efeitos adversos , Guanina/uso terapêutico , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Humanos , Lamivudina/efeitos adversos , Organofosfonatos/efeitos adversos , Modelos de Riscos Proporcionais , Falha de Tratamento , Resultado do Tratamento
8.
J Coll Physicians Surg Pak ; 29(4): 317-323, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30925952

RESUMO

OBJECTIVE: To compare the reduction of hepatocellular carcinoma (HCC) risk between long-term treatment of entecavir and low genetic barrier antiviral agents in hepatitis B virus (HBV)-related cirrhotic patients. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Department of Infectious Diseases and Hepatology, the Second Hospital of Shandong University, Jinan, China, from October 2008 to October 2016. METHODOLOGY: HBV-related cirrhotic patients with antiviral treatment for at least 12 months were consecutively included. Propensity score matching analysis was performed to improve comparability of the data from both entecavir group and the control group. Log-rank test was used to compare influence of various nucleos(t)ide analogs (NAs) for incidence of HCC. Independent risk factors were estimated by multivariable Cox proportional hazards models. RESULTS: The total cohort included 207 HBV-related cirrhotic patients, of which 83 patients were treated with entecavir initially. The present study found no statistical difference for the incidence of HCC between entecavir group and the control group in the total cohort (p=0.525). However, the difference became statistically significant (p=0.014) after propensity score matching. Number needed to treat (NNT) were 8 patients, 6 patients and 3 patients at years 2, 3 and 4, respectively. Multivariable Cox regression in propensity score matching cohort revealed older age (HR: 1.066, p=0.041), NAs of low generic barrier (HR: 6.944, p=0.016), NAs resistance (HR: 3.648, p=0.041), and lower platelet counts (<80x10 9/L) (HR: 6.718, p=0.009) as independent risk factors for HCC incidence. CONCLUSION: Entecavir is more efficient in reducing the incident HCC risk for HBV-related cirrhotic patients in comparison to low genetic barrier NAs.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , China/epidemiologia , Feminino , Guanina/uso terapêutico , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Incidência , Lamivudina/uso terapêutico , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Telbivudina/uso terapêutico
9.
Medicine (Baltimore) ; 98(6): e14386, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732177

RESUMO

Numerous studies suggested that antiviral therapy could reduce the recurrence in hepatocellular carcinoma (HCC) patients after hepatectomy. The impact of nucleotide and nucleoside analogues on prognosis of chronic hepatitis B (CHB) related HCC remains to be explored. We aimed to investigate the role of the telbivudine and adefovir dipivoxil on the prognosis of CHB-related HCC patients after hepatectomy.One hundred eighty-eight CHB-related patients who received hepatectomy from February 2010 to February 2017 were divided into telbivudine (LdT) and adefovir dipivoxil (ADV) groups. The characteristics and survival information of both groups were retrospectively compared and analyzed.One hundred eleven and 77 patients received telbivudine and adefovir dipivoxil monotherapy, respectively. Alanine aminotransferase (ALT), total bilirubin level, status of hepatitis B e antigen (HBeAg), serum HBV-DNA level were compared between groups. OS and DFS in ADV-treatment group were significantly better than it in LdT-treatment group (P < .05). In the subgroups analysis, we found that ADV treatment was significantly associated with better DFS and OS among patients with cirrhosis, HBeAg-negative patients, or those with detectable HBV-DNA.CHB-related HCC patients receiving long-term ADV-treatment had a better OS and DFS than patients receiving LdT-treatment after hepatectomy.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Organofosfonatos/uso terapêutico , Telbivudina/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , DNA Viral , Feminino , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/complicações , Humanos , Testes de Função Hepática , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/cirurgia , Masculino , Recidiva Local de Neoplasia , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , Organofosfonatos/administração & dosagem , Prognóstico , Estudos Retrospectivos , Telbivudina/administração & dosagem
10.
Eur J Pharmacol ; 846: 79-85, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30639798

RESUMO

Organophosphonates are a group of chemical agents which have high bioactivity. In the present study, we aimed to investigate the anticancer activity of the synthesized ß-lactam derivatives of α-amino phosphonates on solid tumor and human leukemic cell lines. The results show that one of these compounds, Diethyl [(3-phenoxy-2-oxo-4-phenyl-azetidine-1-yl)-phenyl-methyl]-phosphonate, is a potent anticancer agent which especially shows anti-leukemic activity. Flow cytometry study showed that this chemical agent causes the G1 phase cell cycle arrest and consequently apoptosis in NB4 cell line as an acute promyelocytic leukemia model. In fact, this agent induces cell differentiation and apoptosis, at low and high concentrations, respectively. Its combination with All-Trans Retinoic Acid shows a higher percentage of cells in the terminal differentiation stage. This evidence suggested that diethyl phosphonate might be a proper candidate for chemo-differentiation therapy in acute promyelocytic leukemia and even in other types of acute myeloid leukemia.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Organofosfonatos/uso terapêutico , Tretinoína/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citometria de Fluxo/métodos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacologia
11.
Int J Med Sci ; 16(1): 17-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662324

RESUMO

Introduction: Most chronic hepatitis B (CHB) patients in China are primitively treated with a combination of lamivudine (LAM) and adefovir dipivoxil (ADV). Although antiviral resistance can be avoided with this combination therapy, using it can have harmful side effects related to ADV, specifically kidney and bone injury. This study was designed to compare viral suppression and kidney safety when switching LAM and ADV combination therapy de novo to entecavir (ETV) monotherapy in patients with CHB and compensated hepatic cirrhosis. Materials and methods: In total, 360 CHB and compensated liver cirrhosis patients who received treatment of LAM and ADV combination therapy for more than 1 year were included in this study. One hundred and eighty patients continued combination therapy to serve as a control group and the other 180 patients were switched to ETV monotherapy to serve as the experimental group. The total course of therapy was 3 years. Laboratory studies were done every 3 months to measure liver and kidney function. Studies included glomerular filtration rate (eGFR), HBV-DNA, urine ß2-microglobulin (ß2-M) and retinol binding protein (RBP). Results: In the experimental group, an HBV-DNA level below 20 IU/ml was found in 77.65%, 85.88%, and 94.77% in years 1, 2, and 3, respectively. In the control group, HBV-DNA levels were below 20 IU/ml in 69.66%, 75.42%, and 85.80% in years 1, 2, and 3, respectively. Low HBV-DNA levels in the experimental group were significantly less common than in the control group on the second and third year; P values were 0.009 and 0.006 for years 2 and 3, respectively. The cumulative genetic mutation rate was 3.49% in the experimental group and 8.88% in the control group (P=0.044). Decreases in eGFR more than 30% from baseline were found in 0%, 0.56%, and 1.74% of patients in the experimental group and 4.49%, 9.14% and 14.79% in patients in the control group in the first, second, and third year, respectively. Serum creatinine more than 50 µmol/L above baseline was found in 0%, 0% and 1.74% of patients in the experimental group and 1.12%, 4.00% and 5.32% of patients in the control group in years 1, 2, and 3, respectively. The urine ß2-M and RBP levels were abnormal more often in the experimental group than in the control group. Conclusion: Switching to ETV monotherapy can decrease HBV-DNA levels, reduce the genetic mutation rate, and prevent renal damage caused by LAM and ADV combination therapy in patients with CHB and compensated liver cirrhosis. Patients receiving LAM and ADV combination therapy de novo should be switched to ETV monotherapy immediately.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Rim/fisiopatologia , Lamivudina/efeitos adversos , Cirrose Hepática/tratamento farmacológico , Organofosfonatos/efeitos adversos , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , China , Creatinina/metabolismo , DNA Viral , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Guanina/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Humanos , Lamivudina/uso terapêutico , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Organofosfonatos/uso terapêutico , Proteínas de Ligação ao Retinol/metabolismo , Adulto Jovem
13.
Intern Med ; 58(6): 821-825, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30333420

RESUMO

A 68-year-old man with type 2 diabetes mellitus and chronic hepatitis B infection was referred to the nephrology department before planned surgery for hepatocellular carcinoma. He had been receiving low-dose adefovir dipivoxil (ADV) for 11 years. Laboratory findings revealed impaired re-absorption in the proximal renal tubules. He had been diagnosed with diabetic kidney disease and osteomalacia due to vitamin D deficiency; thus, ADV was not discontinued until he was referred to us. In this case, concomitant diabetes mellitus and vitamin D deficiency might have prevented the early diagnosis of ADV-induced Fanconi syndrome.


Assuntos
Adenina/análogos & derivados , Antivirais/efeitos adversos , Nefropatias Diabéticas/diagnóstico , Síndrome de Fanconi/diagnóstico , Hipofosfatemia/diagnóstico , Organofosfonatos/efeitos adversos , Osteomalacia/diagnóstico , Deficiência de Vitamina D/diagnóstico , Adenina/efeitos adversos , Adenina/uso terapêutico , Idoso , Antivirais/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Erros de Diagnóstico , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/complicações , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Hipofosfatemia/etiologia , Masculino , Organofosfonatos/uso terapêutico , Osteomalacia/etiologia
14.
Eur J Med Chem ; 164: 47-58, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30590257

RESUMO

We have designed a new type of AZT and ddU phosphoramidate diesters containing various combinations of 2-, 3-, 4-aminopyridine and 2-, 3-, 4-hydroxypyridine moieties attached to the phosphorus center, as potential anti-HIV pronucleotides. Depending on the pKa values of the aminopyridines and the hydroxypyridines used, alternative synthetic strategies based on H-phosphonate chemistry were developed for their preparation. Synthetic aspects of these transformations and the biological activity of the synthesized compounds are discussed.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/química , Desenho de Drogas , Organofosfonatos/uso terapêutico , Ácidos Fosfóricos/farmacologia , Amidas/síntese química , Amidas/química , Aminopiridinas , Fármacos Anti-HIV/síntese química , Didesoxinucleosídeos , Organofosfonatos/química , Ácidos Fosfóricos/síntese química , Ácidos Fosfóricos/química , Piridinas , Zidovudina
15.
Medicine (Baltimore) ; 97(44): e13063, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30383683

RESUMO

RATIONALE: Post transplantation lymphoproliferative disorder (PTLD) is a rare but severe complication. Epstein-Barr virus (EBV) is considered an important pathogen for PTLD and EBV deoxyribonucleic acid (DNA) load is widely monitored to detect PTLD early. Hepatitis B virus (HBV) infection is rarely reported to be related with PTLD. We report a case of EBV negative (EBV), HBV positive (HBV) diffuse large B cell lymphoma in a patient 12 years after liver transplantation. PATIENT CONCERNS AND DIAGNOSIS: A 52-year-old man complained of worsening appetite, abdominal distension, and pruritus. Abdominal computed tomography (CT) detected a huge retroperitoneal mass and pathology of the fine needle biopsy established the diagnosis of diffuse large B cell lymphoma. Virology showed active hepatitis B viral duplication and EBV DNA was negative. INTERVENTION: Treatment modalities for this patient included: reduction and subsequent cessation of immunosuppression; antiviral therapy for HBV with entecavir and adefovir; conventional chemotherapy consisting of cyclophosphamide, epirubicin, vindesine, and prednisone, followed by radiotherapy. He achieved complete remission (CR) and was kept on entecavir treatment afterwards. OUTCOMES: He has been in remission for 2 years. LESSONS: HBV infection might have played some role in this very late onset EBV PTLD patient. Therefore, HBV serology and HBV load should be monitored during the follow-up of HBV surface antigen positive (HBsAg) transplant recipients and life-long antiviral therapy is required.


Assuntos
Antivirais/uso terapêutico , Quimiorradioterapia/métodos , Hepatite B/terapia , Transplante de Fígado/efeitos adversos , Linfoma Difuso de Grandes Células B/diagnóstico , Adenina/análogos & derivados , Adenina/uso terapêutico , Biópsia por Agulha Fina , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B/virologia , Vírus da Hepatite B/fisiologia , Humanos , Imunossupressores/uso terapêutico , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Replicação Viral
16.
Chemotherapy ; 63(4): 225-237, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30372692

RESUMO

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50-70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi-voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.


Assuntos
Adenina/análogos & derivados , Apoptose/efeitos dos fármacos , Citarabina/farmacologia , Organofosfonatos/farmacologia , Adenina/química , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Citarabina/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Composição de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Organofosfonatos/química , Organofosfonatos/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Transplante Heterólogo , Células Tumorais Cultivadas
17.
Transpl Infect Dis ; 20(6): e12977, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30120866

RESUMO

Allogeneic hematopoietic cell transplant (HCT) recipients are at risk for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Routine prophylaxis with acyclovir is recommended during periods of immunosuppression. Brincidofovir (BCV, CMX001), a lipid conjugate of cidofovir, has shown in vitro activity against HSV/VZV, but has not been formally studied for HSV/VZV prophylaxis. We report our clinical experience of BCV for HSV/VZV prophylaxis in HCT recipients. This was a retrospective review of 30 hematopoietic cell transplant (HCT) recipients between 8/2010 and 8/2015 who received BCV doses not exceeding 200 mg/week for adults/adolescents and 4 mg/kg/week for pediatric (<12 years) patients, for ≥14 days BCV without concomitant acyclovir under clinical trials or single patient use. HSV/VZV cases during BCV treatment were confirmed by viral culture or PCR and clinical symptoms. Of 30 patients who met the inclusion criteria, 27 (90%) patients were adults and 22 (73%) patients received T-cell depleted HCT. The most common indications for BCV were cytomegalovirus in 12 patients (40%) and adenovirus in 11 patients (37%). One patient was treated for acyclovir-resistant HSV and one for disseminated VZV. There were two breakthrough cases of HSV infection during 2170 patient-days. There were no cases of breakthrough VZV infection. The overall rate of breakthrough HSV infection was 1.0 per 1000 patient-days, without any breakthrough VZV infections. Our study provides the only available-albeit limited-evidence on the potential efficacy of BCV for HSV/VZV prophylaxis in HCT patients. Additional studies are needed to further assess the efficacy and safety of BCV in the setting.


Assuntos
Antibioticoprofilaxia/métodos , Citosina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpes Simples/prevenção & controle , Organofosfonatos/uso terapêutico , Infecção pelo Vírus da Varicela-Zoster/prevenção & controle , Adulto , Idoso , Criança , Pré-Escolar , Citosina/farmacologia , Citosina/uso terapêutico , Feminino , Herpes Simples/epidemiologia , Herpes Simples/virologia , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/isolamento & purificação , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Organofosfonatos/farmacologia , Estudos Retrospectivos , Simplexvirus/efeitos dos fármacos , Simplexvirus/isolamento & purificação , Resultado do Tratamento , Infecção pelo Vírus da Varicela-Zoster/epidemiologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Adulto Jovem
18.
Antiviral Res ; 158: 213-225, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30121196

RESUMO

BACKGROUND: We aimed to identify HBc amino acid differences between subgroups of chronic hepatitis B (CHB) patients. METHODS: Deep sequencing of HBc was performed in samples of 89 CHB patients (42 HBeAg positive, 47 HBeAg negative). Amino acid types were compared using Sequence Harmony to identify subgroup specific sites between HBeAg-positive and -negative patients, and between patients with combined response and non-response to peginterferon/adefovir combination therapy. RESULTS: We identified 54 positions in HBc where the frequency of appearing amino acids was significantly different between HBeAg-positive and -negative patients. In HBeAg negative patients, 22 positions in HBc were identified which differed between patients with treatment response and those with non-response. The fraction non-consensus sequence on selected positions was significantly higher in HBeAg-negative patients, and was negatively correlated with HBV DNA and HBsAg levels. CONCLUSIONS: Sequence Harmony identified a number of amino acid changes associated with HBeAg-status and response to peginterferon/adefovir combination therapy.


Assuntos
Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas do Core Viral/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Antivirais/uso terapêutico , DNA Viral , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Organofosfonatos/uso terapêutico , Polietilenoglicóis/uso terapêutico , Conformação Proteica , Proteínas Recombinantes/uso terapêutico , Alinhamento de Sequência , Análise de Sequência de Proteína , Homologia de Sequência , Proteínas do Core Viral/química
19.
Indian J Med Microbiol ; 36(2): 217-223, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30084414

RESUMO

Background: Combination of tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and efavirenz (EFV) is preferred in the treatment of HIV/hepatitis B virus (HBV) coinfection. We postulated that a HBV active nucleoside reverse transcriptase (RT) inhibitor/nucleotide RT inhibitor backbone of adefovir dipivoxil (ADV) +3TC would be as effective as TDF +3TC for the Indian population. Objective: ADV + 3TC could be an alternative option for these HIV/HBV coinfected individuals, preserving the dually active TDF + 3TC as second-line nucleoside backbone following failure of the first-line ART. Materials and Methods: This randomised control trial (CTRI/2012/03/002471) was carried out at the ART Centre of Calcutta School of Tropical Medicine, India. Seventy-eight (39 on each arm) treatment-naïve HIV/HBV coinfected patients were randomised to receive either the combination of lamivudine + tenofovir + EFV or lamivudine + adefovir + zidovudine + EFV and followed up for 120 weeks. Results: Median age of the study participants was 36 years (21-62), majority were male (61/78; 78.2%) and heterosexually (39/78; 50%) infected. Baseline characteristics were identical in both arms. There was no statistically significant difference in median aspartate aminotransferase (37 vs. 29.5 U/L), alanine aminotransferase (ALT) (36 vs. 34.5 U/L), ALT normalisation rate (80 vs. 70%), AST to platelet ratio index (0.45 vs. 0.33), CD4 count (508 vs. 427 cells/mm3), HBV DNA suppression (81.8 vs. 70%), hepatitis B e antigen loss (9 vs. 5%), hepatitis B surface antigen seroclearance rate (6.06 vs. 18.75%) and death (3 vs. 3) at 120 weeks between TDF (n = 33) and ADV (n = 32), respectively. Conclusions: Adefovir plus lamivudine is an effective alternative of tenofovir plus lamivudine in long-term HBV treatment outcome in HIV/HBV coinfected patients.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Adulto , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Molecules ; 23(8)2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30096835

RESUMO

The work reports the facile synthesis of novel α-aminophosphonate derivatives coupled with indole-2,3-dione moieties, namely the diethyl(substituted phenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates derivatives 4(a⁻n). One-pot three component Kabachnik-Fields reactions were used to synthesize these derivatives. The reaction was carried out at room temperature by stirring in presence of ceric ammonium nitrate (CAN) as a green catalyst. The structures of the synthesized compounds were established by spectral studies. The synthesized derivatives 4(a⁻n) were evaluated for their in vitro anticancer activity against six human cancer cell lines by the SRB assay method. The cancer cell lines used in this research work are SK-MEL-2 (melanoma), MCF-7 (breast cancer), IMR-32 (neuroblastoma) MG-63 (human osteosarcoma), HT-29 (human colon cancer) and Hep-G2 (human hepatoma). All the synthesized derivatives inhibited the cell proliferation. Importantly, all the target compounds showed no cytotoxicity towards normal tissue cells (GI50 > 250 µM). A docking study was performed to predict the mode of action. Docking results indicate that the compounds have good binding with the enzyme tyrosine kinase as well as with microtubules, which makes them dual inhibitors. The result of in-silico bioavailability studies suggests that the compounds from the present series have good oral drug-like properties and are non-toxic in nature. In vivo acute oral toxicity study results indicate that the compounds can be considered safe, and therefore could be developed in the future as good anticancer agents or as leads for the design and synthesis of novel anticancer agents.


Assuntos
Antineoplásicos/uso terapêutico , Química Verde/métodos , Modelos Moleculares , Organofosfonatos/uso terapêutico , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Comportamento Animal , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imagem Tridimensional , Camundongos , Simulação de Acoplamento Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Organofosfonatos/farmacocinética , Testes de Toxicidade Aguda
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