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2.
N Engl J Med ; 381(9): 803-815, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31339677

RESUMO

BACKGROUND: Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries. METHODS: We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, -10 percentage points). We report the primary (48-week) efficacy and safety data. RESULTS: A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens. CONCLUSIONS: Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262.).


Assuntos
Adenina/análogos & derivados , Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Fosforosos/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adolescente , Adulto , Antirretrovirais/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Inibidores de Integrase de HIV/administração & dosagem , HIV-1/genética , HIV-1/isolamento & purificação , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Ácidos Fosforosos/efeitos adversos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pró-Fármacos/administração & dosagem , RNA Viral/sangue , Uracila/administração & dosagem , Uracila/análogos & derivados , Carga Viral , Adulto Jovem
3.
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
4.
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
5.
Pharmacol Res Perspect ; 7(3): e00475, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31049204

RESUMO

Chronic kidney disease (CKD) is characterized by progressive reduction in kidney function over time. CKD affects greater than 10% of the population and its incidence is on the rise due to the growing prevalence of its risk factors. Previous studies demonstrated CKD alters nonrenal clearance of drugs in addition to reducing renal clearance. We assessed the function and expression of hepatic CYP2B enzymes using a rat model of CKD. CKD was induced in Wistar rats by supplementing their chow with adenine and confirmed through the detection of elevated uremic toxins in plasma. Liver enzymes AST and ALT were unchanged by the adenine diet. Bupropion was used as a probe substrate for hepatic CYP2B function using rat liver microsomes. The resulting metabolite, hydroxy-bupropion, and bupropion were quantified by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. Level of mRNA and protein were determined by RT-PCR and Western blot, respectively. The results of our study demonstrate that CYP2B1 is downregulated in a rat model of CKD. CYP2B1 mRNA level was significantly decreased (88%, P < 0.001) in CKD relative to control. Similarly, maximal enzymatic velocity (V max) for CYP2B was decreased by 46% in CKD relative to control (P < 0.0001). Previous studies involving patients with CKD demonstrated altered bupropion pharmacokinetics compared to control. Hence, our results suggest that these alterations may be mediated by attenuated CYP2B hepatic metabolism. This finding may partially explain the alterations in pharmacokinetics and nonrenal drug clearance frequently observed in patients with CKD.


Assuntos
Bupropiona/farmacocinética , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Regulação para Baixo , Insuficiência Renal Crônica/induzido quimicamente , Adenina/efeitos adversos , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
6.
Korean J Intern Med ; 34(4): 802-810, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30959583

RESUMO

BACKGROUND/AIMS: The optimal management of chronic hepatitis B (CHB) patients with partial virologic response (PVR) to tenofovir disoproxil fumarate (TDF) remains unclear. We aimed to evaluate the long-term efficacy of prolonged TDF therapy in treatment-naïve CHB patients with PVR to TDF therapy in real practice. METHODS: We retrospectively investigated the efficacy of prolonged TDF therapy in treatment-naïve CHB patients with PVR to TDF. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA over 2 log10 IU/mL from baseline, with detectable HBV DNA by real-time polymerase chain reaction at week 48. RESULTS: We included 232 patients who underwent TDF therapy for over 48 weeks. Forty-two patients (18.1%) showed PVR. In multivariate analysis, hepatitis B e antigen (HBeAg) positivity, and high levels of serum HBV DNA at baseline and week 12 were independent predictive factors for PVR during TDF therapy. Out of 42 patients with PVR, 39 (92.9%) achieved virologic response (VR) during continuous TDF treatment; the cumulative VR rates at 24, 36, and 48 months were 79.8%, 88.2%, and 95.6%, respectively. With an additional 12 months of therapy, VR was achieved in 28/31 (90.3%) patients with HBV DNA < 100 IU/mL, compared to 5/11 (45.5%) patients with HBV DNA ≥ 100 IU/mL, at week 48. CONCLUSION: The vast majority of patients achieved VR through prolonged TDF therapy, thus TDF treatment can be maintained in nucleos(t)ide-naïve patients with PVR at week 48, especially in those with low viremia.


Assuntos
Adenina/análogos & derivados , Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Ácidos Fosforosos/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Antivirais/efeitos adversos , Esquema de Medicação , Feminino , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Fosforosos/efeitos adversos , Estudos Retrospectivos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Carga Viral
7.
Int J Mol Med ; 43(6): 2491-2498, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017265

RESUMO

Nucleos(t)ide analogues (NAs) are currently the most important anti­viral treatment option for patients with chronic hepatitis B (CHB). Adefovir dipivoxil (ADV), a diester pro­drug of adefovir, has been widely used for the clinical therapy of hepatitis B virus infection. It has been previously reported that adefovir induced chromosomal aberrations (CAs) in the in vitro human peripheral blood lymphocyte assay, while the genotoxic mechanism remains elusive. To evaluate the possible mechanisms, the genotoxic effects of ADV on the TK6 and DT40 cell lines, as well as DNA repair­deficient variants of DT40 cells, were assessed in the present study. A karyotype assay revealed ADV­induced CAs, particularly chromosomal breaks, in wild­type DT40 and TK6 cells. A γ­H2AX foci formation assay confirmed the presence of DNA damage following treatment with ADV. Furthermore, Brca1­/­ DT40 cells exhibited an increased sensitivity to ADV, while the knockdown of various other DNA damage­associated genes did not markedly affect the sensitivity. These comprehensive genetic studies identified the genotoxic capacity of ADV and suggested that Brca1 may be involved in the tolerance of ADV­induced DNA damage. These results may contribute to the development of novel drugs against CHB with higher therapeutic efficacy and less genotoxicity.


Assuntos
Adenina/análogos & derivados , Antivirais/efeitos adversos , Proteína BRCA1/metabolismo , Aberrações Cromossômicas/induzido quimicamente , Dano ao DNA/efeitos dos fármacos , Organofosfonatos/efeitos adversos , Adenina/efeitos adversos , Proteína BRCA1/genética , Linhagem Celular , Deleção de Genes , Hepatite B Crônica/tratamento farmacológico , Humanos
8.
Molecules ; 24(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30988271

RESUMO

Chronic renal failure (CRF) is a major public health problem worldwide. In this work, we investigated the effects of a purified Laminaria japonica polysaccharide (LJP61A) on renal function using an adenine-induced CRF mice model. Results exhibited that adenine treatment caused serious renal pathological damages and elevation of serum creatinine and blood urea nitrogen of mice. However, these changes could be significantly reversed by the administration of LJP61A in a dose-dependent manner. Additionally, LJP61A could dramatically reduce weight loss, improve the urine biochemical index, and regulate the electrolyte disturbance of CRF mice. These results suggest that the renal function of adenine-induced CRF mice can be improved by LJP61A, which might be developed into a potential therapeutic agent for CRF patients.


Assuntos
Adenina/efeitos adversos , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Laminaria/química , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Peso Corporal , Modelos Animais de Doenças , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/patologia , Masculino , Camundongos , Polissacarídeos/química , Substâncias Protetoras/química
9.
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
10.
J Med Case Rep ; 13(1): 99, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31003599

RESUMO

BACKGROUND: Adefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3. CASE PRESENTATION: A 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient's adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers. CONCLUSIONS: Although denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Denosumab/administração & dosagem , Síndrome de Fanconi/induzido quimicamente , Hipofosfatemia , Osteomalacia , Adenina/efeitos adversos , Adenina/análogos & derivados , Adulto , Antivirais/efeitos adversos , Síndrome de Fanconi/tratamento farmacológico , Hepatite B/tratamento farmacológico , Humanos , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Osteomalacia/induzido quimicamente , Osteomalacia/tratamento farmacológico , Tomografia Computadorizada de Emissão , Resultado do Tratamento
11.
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
12.
Neuropathology ; 39(2): 162-167, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30847961

RESUMO

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.


Assuntos
Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Miopatias Mitocondriais/induzido quimicamente , Miopatias Mitocondriais/patologia , Adenina/efeitos adversos , Adenina/análogos & derivados , Administração Oral , Idoso , DNA Mitocondrial , Feminino , Deleção de Genes , Hepatite B Crônica/complicações , Humanos , Lamivudina/efeitos adversos , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/genética , Músculo Esquelético/patologia , Organofosfonatos/efeitos adversos
13.
Cell Physiol Biochem ; 52(1): 27-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790503

RESUMO

BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1ß, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.


Assuntos
Adenina/efeitos adversos , Canagliflozina/farmacologia , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Adenina/farmacologia , Animais , Biomarcadores/urina , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/urina
14.
Int J Mol Sci ; 20(3)2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30708974

RESUMO

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.


Assuntos
Adenina/efeitos adversos , Hipocampo/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Insuficiência Renal Crônica/terapia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular , Técnicas de Cocultura , Cresóis/efeitos adversos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Proteínas PrPC/genética , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Regulação para Cima
16.
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
17.
Clin Nephrol ; 91(3): 180-186, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30614440

RESUMO

AIMS: To investigate the clinicopathological features and outcomes of adefovir dipivoxil (ADV)-related renal impairment in Chinese patients. MATERIALS AND METHODS: Clinical, pathological, and follow-up data from 15 patients with ADV-related renal impairment were studied. Proximal renal tubular dysfunction (PRTD) was defined by the presence of at least two of the following four abnormalities: hypophosphatemia, hypouricemia, nondiabetic glucosuria, and proteinuria. RESULTS: All patients were treated for 3 - 15 (mean 6.7) years with daily ADV of 10 mg. Renal impairment manifested as PRTD (12, 80%), elevated serum creatinine (12, 80%), and hematuria (2, 13.3%). Mild to moderate tubulointerstitial injury primarily affecting the proximal tubules by light microscopy, and enlarged, dysmorphic mitochondria with loss and disorientation of cristae by electron microscope were identified in all of our cases. Four patients had pathological evidence of IgA nephropathy. The phosphorus, serum uric acid, and creatinine levels were normalized after ADV cessation in 66.7% (8/12) of affected patients, 27.3% (3/11) of affected patients, and 25% (3/12) of affected patients, respectively; proteinuria was eliminated in 7 of 13 affected patients (53.8%); and glucosuria and hematuria both disappeared in all affected patients. These abnormalities had hardly any recovery, and even aggravated with new-onset glucosuria, new-onset hematuria in 3 patients who replaced ADV with tenofovir. CONCLUSION: Nephrotoxicity developed in patients undergoing long-term ADV treatment and was partially reversible after drug cessation. Tubulointerstitial lesions and heteromorphic mitochondria were the predominant pathological changes. Patients with ADV-induced renal impairment should replace ADV with other antiviral agents other than tenofovir.
.


Assuntos
Adenina/análogos & derivados , Antivirais/efeitos adversos , Organofosfonatos/efeitos adversos , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/patologia , Adenina/efeitos adversos , Adulto , Creatinina/sangue , Feminino , Glicosúria/induzido quimicamente , Hematúria/induzido quimicamente , Hepatite B Crônica/tratamento farmacológico , Humanos , Hipofosfatemia/induzido quimicamente , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Fósforo/sangue , Proteinúria/induzido quimicamente , Insuficiência Renal/fisiopatologia , Ácido Úrico/sangue
19.
Infection ; 47(1): 115-119, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30145772

RESUMO

INTRODUCTION: Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF). MATERIAL AND METHODS: We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject. RESULTS: A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes. The suicide attempt seemed unrelated to the integrase strand transfer inhibitor, being evenly explained within the context of stressful personal conflicts. CONCLUSION: A suicidal attempt with an E/C/F/TAF overdose in an HIV-infected patient, resulted in a favourable outcome from a renal and neuropsychiatric standpoint.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Overdose de Drogas/diagnóstico , Infecções por HIV/tratamento farmacológico , Insuficiência Renal/fisiopatologia , Tentativa de Suicídio , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Cobicistat/administração & dosagem , Cobicistat/efeitos adversos , Combinação de Medicamentos , Overdose de Drogas/complicações , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Insuficiência Renal/induzido quimicamente
20.
Int J Hematol ; 109(1): 59-69, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30232784

RESUMO

Although the primary cause of anemia in chronic kidney disease (CKD) is lack of sufficient erythropoietin (EPO), other factors may be involved, including the deregulation of iron metabolism. To clarify the mechanism of deranged erythropoiesis in CKD, we evaluated bone marrow (BM) cells in adenine-induced CKD mice. They showed even higher EPO expression in the kidney. Hepatic hepcidin mRNA and plasma hepcidin and ferritin levels were increased. Flow cytometry revealed a decrease in the number of cells expressing transferrin receptor (TfR), or late erythroid progenitors in BM; these cells correspond to proerythroblasts, and basophilic and polychromatic erythroblasts. In CKD mice, levels of erythroferrone mRNA in BM and splenic cells were significantly decreased, and MafB protein levels in BM cells were significantly increased. These results suggest that, in BM, the decrease in TfR, which may be associated with increased MafB levels, and the decrease in erythroferrone increase hepatic hepcidin expression, which may perturb iron recycling and erythropoiesis.


Assuntos
Adenina/efeitos adversos , Medula Óssea/metabolismo , Ferro/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Citocinas/metabolismo , Eritropoese , Eritropoetina/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Rim/metabolismo , Fator de Transcrição MafB/metabolismo , Camundongos , Proteínas Musculares/metabolismo , Receptores da Transferrina/metabolismo , Insuficiência Renal Crônica/induzido quimicamente
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