RESUMEN
The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin-angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline's ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Hipertensión , Preeclampsia , Efectos Tardíos de la Exposición Prenatal , Insuficiencia Renal Crónica , Embarazo , Humanos , Femenino , Ratas , Animales , Masculino , Citrulina/farmacología , Citrulina/uso terapéutico , Ratas Sprague-Dawley , Hipertensión/etiología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/complicaciones , Adenina/efectos adversos , Efectos Tardíos de la Exposición Prenatal/inducido químicamenteRESUMEN
A hyperuricemic rat model induced by adenine and ethambutol was established to investigate the anti-hyperuricemia activity and its mechanism of the flavonoid extract from saffron floral bio-residues. Sixty-seven SD rats were randomly divided into control group, model group, positive control group, and flavonoid extract groups(with 3 doses), respectively, and each group contained 11 or 12 rats. The hyperuricemic model was established by continuous oral administration of adenine(100 mg·kg~(-1)) and ethambutol(250 mg·kg~(-1)) for 7 days. At the same time, the positive control group was given allopurinol(20 mg·kg~(-1) per day) and the flavonoid extract groups were given the flavonoid extract at doses of 340, 170 and 85 mg·kg~(-1) per day, respectively. On day 8, rat serum, liver, kidney, and intestinal tissues were collected, and the levels of uric acid in serum and tissue, the xanthine oxidase activities and antioxi-dant activities in serum and liver were evaluated, and the kidney histopathology was explored. In addition, an untargeted serum metabolomics study was performed. According to the results, the flavonoid extract effectively reduced the uric acid levels in serum, kidney and ileum and inhibited the xanthine oxidase activities and elevated the antioxidant activities of serum and liver in hyperuricemic rat. At the same time, it reduced the levels of inflammation factors in kidney and protected renal function. Moreover, 68 differential metabolites of hyperuricemic rats were screened and most of which were lipids and amino acids. The flavonoid extract significantly retrieved the levels of differential metabolites in hyperuricemic rats, such as SM(d18:1/20:0), PC[18:0/18:2(92,12Z)], palmitic acid and citrulline, possibly through the following three pathways, i.e., arginine biosynthesis, glycine, serine and threonine metabolism, and histidine metabolism. To sum up, the flavonoid extract of saffron floral bio-residues lowered the uric acid level, increased the antioxidant activity, and alleviated inflammatory symptoms of hyperuricemic rats, which may be related to its inhibition of xanthine oxidase activity and regulation of serum lipids and amino acids metabolism.
Asunto(s)
Crocus , Hiperuricemia , Ratas , Animales , Flavonoides/farmacología , Ácido Úrico , Xantina Oxidasa , Etambutol/efectos adversos , Ratas Sprague-Dawley , Hiperuricemia/tratamiento farmacológico , Riñón , Antioxidantes/farmacología , Extractos Vegetales/efectos adversos , Aminoácidos , Adenina/efectos adversos , LípidosRESUMEN
A hyperuricemic rat model induced by adenine and ethambutol was established to investigate the anti-hyperuricemia activity and its mechanism of the flavonoid extract from saffron floral bio-residues. Sixty-seven SD rats were randomly divided into control group, model group, positive control group, and flavonoid extract groups(with 3 doses), respectively, and each group contained 11 or 12 rats. The hyperuricemic model was established by continuous oral administration of adenine(100 mg·kg~(-1)) and ethambutol(250 mg·kg~(-1)) for 7 days. At the same time, the positive control group was given allopurinol(20 mg·kg~(-1) per day) and the flavonoid extract groups were given the flavonoid extract at doses of 340, 170 and 85 mg·kg~(-1) per day, respectively. On day 8, rat serum, liver, kidney, and intestinal tissues were collected, and the levels of uric acid in serum and tissue, the xanthine oxidase activities and antioxi-dant activities in serum and liver were evaluated, and the kidney histopathology was explored. In addition, an untargeted serum metabolomics study was performed. According to the results, the flavonoid extract effectively reduced the uric acid levels in serum, kidney and ileum and inhibited the xanthine oxidase activities and elevated the antioxidant activities of serum and liver in hyperuricemic rat. At the same time, it reduced the levels of inflammation factors in kidney and protected renal function. Moreover, 68 differential metabolites of hyperuricemic rats were screened and most of which were lipids and amino acids. The flavonoid extract significantly retrieved the levels of differential metabolites in hyperuricemic rats, such as SM(d18:1/20:0), PC[18:0/18:2(92,12Z)], palmitic acid and citrulline, possibly through the following three pathways, i.e., arginine biosynthesis, glycine, serine and threonine metabolism, and histidine metabolism. To sum up, the flavonoid extract of saffron floral bio-residues lowered the uric acid level, increased the antioxidant activity, and alleviated inflammatory symptoms of hyperuricemic rats, which may be related to its inhibition of xanthine oxidase activity and regulation of serum lipids and amino acids metabolism.
Asunto(s)
Ratas , Animales , Flavonoides/farmacología , Ácido Úrico , Crocus , Xantina Oxidasa , Etambutol/efectos adversos , Ratas Sprague-Dawley , Hiperuricemia/tratamiento farmacológico , Riñón , Antioxidantes/farmacología , Extractos Vegetales/efectos adversos , Aminoácidos , Adenina/efectos adversos , LípidosRESUMEN
BACKGROUND: Extensive evidence suggests that gut microbiota may interact with the kidneys and play central roles in the pathogenesis of disease. However, the association of gut microbiota-kidneys in diarrhea remains unclear. METHODS: A diarrhea mouse model was constructed by combining adenine with Folium sennae. We analyzed the characteristics of the gut content microbiota and short chain fatty acids (SCFAs); and explored the potential link between gut content microbiota, SCFAs, intestinal inflammatory response and kidney function. RESULTS: Characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens were enriched in the gut contents of mice. The productions of SCFAs were remarkably inhibited. Model mice presented an increased trend of creatinine (Cr), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), a decreased trend of blood urea nitrogen (BUN) and secretory immunoglobulin A (SIgA). The pathological analysis proved obvious damage to the kidney structure. Lactobacillus intestinalis and Bacteroides acidifaciens exisited in the correlations with acetic acid, intestinal inflammatory response and kidney function. CONCLUSIONS: Adenine combined with Folium sennae-induced diarrhea, altered the structure and function of the gut content microbiota in mice, causing the enrichment of the characteristic bacteria Lactobacillus intestinalis and Bacteroides acidifaciens. The interactions between Lactobacillus intestinalis, Bacteroides acidifaciens and acetic acid, intestinal inflammation, and kidney function might be involved in the process of gut-kidney impairment in adenine, combined with Folium sennae-induced diarrhea.
Asunto(s)
Bacteroides , Colitis , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Enfermedades Renales , Lactobacillus , Factor de Necrosis Tumoral alfa , Animales , Ratones , Ácido Acético/efectos adversos , Adenina/efectos adversos , Creatinina , Diarrea/inducido químicamente , Ácidos Grasos Volátiles/metabolismo , Inmunoglobulina A Secretora , Inflamación , Interleucina-6 , Riñón , Extracto de Senna , Modelos Animales de Enfermedad , Bacteroides/fisiología , Lactobacillus/fisiología , Colitis/microbiología , Enfermedades Renales/microbiologíaRESUMEN
Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-ß, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.
Asunto(s)
Adenina/efectos adversos , Medicamentos Herbarios Chinos/administración & dosificación , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/patología , Túbulos Renales/patología , Administración Oral , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Medicamentos Herbarios Chinos/farmacología , Fibrosis , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Inflamación , Fallo Renal Crónico/inducido químicamente , Fallo Renal Crónico/prevención & control , Túbulos Renales/metabolismo , Ratones Endogámicos BALB C , Factor de Crecimiento Transformador beta/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Rehmanniae Radix Preparata (RR) and Corni Fructus (CF), well-known traditional Chinese medicines (TCMs), were generally used together in the clinical practices to treat chronic kidney disease (CKD) with synergistic effects for thousands of years, but their combination mechanism remains largely unknown so far. Recent evidences have implicated intestinal flora as potential targets for the therapy of CKD. In this study, the CKD rat model was induced by adenine. The levels of proteinuria, serum creatine (SCr), blood urea nitrogen (BUN) and creatinine clearance (Ccr) were used to assess the cooperation effect of RR and CF. Furthermore, high-throughput 16S ribosomal RNA (rRNA) gene sequencing combined with fecal metabonomics based on UPLC-Q-TOF-MS/MS were applied to explore the variations of intestinal flora and their metabolic profiles. 16S rRNA gene sequencing data indicated that CKD rats treated with RR, CF and RC showed the differences in the composition of gut microbiota. The abundance of beneficial bacteria including Ruminococcaceae UCG-014, Ruminococcus 1, Prevotellaceae_NK3B31_group, Lachnospiraceae NK4A136 group and Lachnospiraceae UCG-001 were elevated in various degrees, while the opportunistic pathogen such as Desulfovibrio was markedly decreased after the treatment. Moreover, fecal metabolite profiles revealed 15 different metabolites associated with CKD. These metabolites were mainly involved in the related metabolic pathways such as amino acid metabolism, bile acids metabolism and glycerophospholipid metabolism. The results implied that gut flora and their metabolites might play a vital role in the progress of CKD, which provided a potential target for the development of novel drugs for the therapy of CKD.
Asunto(s)
Cornus , Heces/microbiología , Microbioma Gastrointestinal , Rehmannia , Insuficiencia Renal Crónica , Adenina/efectos adversos , Animales , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Metaboloma/efectos de los fármacos , Sustancias Protectoras/farmacología , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/metabolismo , Espectrometría de Masas en TándemRESUMEN
Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.
Asunto(s)
Microbioma Gastrointestinal/fisiología , Metilaminas/efectos adversos , Metilaminas/metabolismo , Insuficiencia Renal Crónica/etiología , Adenina/administración & dosificación , Adenina/efectos adversos , Albuminuria/etiología , Animales , Cardiomegalia/etiología , Cardiomegalia/prevención & control , Colina/administración & dosificación , Colina/efectos adversos , Colina/análogos & derivados , Colina/farmacología , Modelos Animales de Enfermedad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Fibrosis , Riñón/patología , Metilaminas/administración & dosificación , Ratones , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/prevención & controlRESUMEN
Ibrutinib-based combination therapy with high-dose methotrexate (HD-MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real-world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD-MTX was given at 3.5 g/m2 every 2-week for eight doses. Ibrutinib was held upon HD-MTX infusion until clearance and was administered daily post-induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD-MTX combination regimen in treating newly diagnosed PCNSL patients in a real-world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.
Asunto(s)
Adenina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Uso Fuera de lo Indicado , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Nervioso Central/enzimología , Neoplasias del Sistema Nervioso Central/mortalidad , Progresión de la Enfermedad , Femenino , Humanos , Linfoma/enzimología , Linfoma/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Piperidinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de TiempoRESUMEN
Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.
Asunto(s)
Hipertensión/metabolismo , Óxido Nítrico/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Insuficiencia Renal Crónica/metabolismo , Adenina/efectos adversos , Adenina/metabolismo , Animales , Modelos Animales de Enfermedad , Disbiosis/genética , Disbiosis/microbiología , Femenino , Desarrollo Fetal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Hipertensión/etiología , Hipertensión/microbiología , Hipertensión/patología , Herencia Materna/genética , Óxido Nítrico/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/microbiología , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/patología , Sistema Renina-Angiotensina/genéticaRESUMEN
BACKGROUND: Our case of a patient with untreated lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia with extramedullary pleural effusion is the first documented case of pleural fluid MYD88 L265P mutation status in a community hospital setting. Our patient was intolerant to 420 mg ibrutinib, but still achieved a lasting complete remission, as defined by National Comprehensive Cancer Network guidelines, with a dose reduction to 240 mg of ibrutinib. CASE PRESENTATION: A 72-year-old Caucasian (white) man diagnosed with monoclonal immunoglobin M kappa lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia monitored without treatment for 2 years, presented with dyspnea and a left pleural effusion. At presentation, computed tomography scans of his chest, abdomen, and pelvis showed layering left pleural effusion and para-aortic lymphadenopathy. Pleural fluid cytology demonstrated B-cell lymphoma of the lymphoplasmacytic subtype, with monoclonal kappa B-cell population on flow and a positive MYD88 L265P mutation. The pleural effusion recurred post-thoracentesis and he achieved a lasting complete remission as defined by National Comprehensive Cancer Network guideline with 240 mg ibrutinib. CONCLUSIONS: Our discussion details a comprehensive literature review of extramedullary pulmonary involvement in Waldenstrom's macroglobulinemia. Establishing a malignant etiology for pleural effusion in Waldenstrom's macroglobulinemia can be challenging, as standard techniques may be insensitive. Allele-specific polymerase chain reaction for detecting MYD88 L265P mutations is more sensitive for confirming lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia in pleural fluid. Extramedullary pulmonary involvement usually presents post-diagnosis of Waldenstrom's macroglobulinemia and responds well to Waldenstrom's macroglobulinemia-directed treatment regimens. Allele-specific polymerase chain reaction is a sensitive assay for detecting MYD88 L265P mutations in pleural fluid to support the diagnosis of malignant pleural effusion in the setting of Waldenstrom's macroglobulinemia and helps guide the treatment decision to use ibrutinib. Although intolerant of ibrutinib 420 mg, our patient achieved complete and sustained remission of pleural effusion with a dose of 240 mg with progression free survival of over 30 months.
Asunto(s)
Adenina/análogos & derivados , Factor 88 de Diferenciación Mieloide/genética , Piperidinas/administración & dosificación , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/administración & dosificación , Adenina/efectos adversos , Anciano , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Mutación , Piperidinas/efectos adversos , Derrame Pleural Maligno/diagnóstico por imagen , Derrame Pleural Maligno/patología , Inducción de Remisión , Tomografía Computarizada por Rayos X , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/patologíaRESUMEN
Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.
Asunto(s)
Fosfatos de Inositol/química , Fosfatos de Inositol/farmacología , Calcificación Vascular/tratamiento farmacológico , 6-Fitasa/metabolismo , Adenina/efectos adversos , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Dispersión Dinámica de Luz , Glicol de Etileno/química , Humanos , Inyecciones Subcutáneas , Fosfatos de Inositol/farmacocinética , Masculino , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Ratas Sprague-Dawley , Uremia/tratamiento farmacológico , Uremia/fisiopatología , Calcificación Vascular/inducido químicamente , Difracción de Rayos XRESUMEN
Introduction: In the last few years, the expansion of therapy with pathway inhibitors has revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). As a matter of fact, ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, became a milestone in the treatment of both naïve or relapsed/refractory CLL patients. Most patients treated with such an agent achieve durable clinical response; however, a deeper response is rarely reached and continuous treatment is required. Since ibrutinib-resistant CLL clones can develop in about 20% of patients and toxicities, leading to drug discontinuation, occur in about 30% of patients treated with ibrutinib, several new BTK inhibitors have been developed in order to lower off-target effects and overcome ibrutinib resistance.Areas covered: In this review, we summarize the main English publications exploring efficacy and side effects of first and next-generation BTK inhibitors. Results of clinical trials evaluating these novel agents are presented and critically discussed.Expert opinion: Efforts in the development of highly specific second-generation BTK inhibitors and combination strategies provide challenging options to overcome limitations of therapy with ibrutinib. It is also crucial to identify additional risk factors and to understand disease biology underlying clonal evolution of CLL in the context of novel agents.
Asunto(s)
Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Estudios Multicéntricos como Asunto , Piperidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
AIM: Renal toxicity of adefovir disoproxil (ADV) and tenofovir disoproxil fumarate (TDF) is a significant concern in chronic hepatitis B (CHB) patients. Early observational clinical data suggested that telbivudine (LdT) might have renoprotective effects. METHODS: In this prospective study, consecutive CHB patients on combined lamivudine (LAM) + ADV/TDF were switched to LdT + ADV/TDF at recruitment and were followed up for 24 months. Estimated glomerular filtration rate (eGFR) was calculated with the modification of diet in renal disease equation. The effects of LdT on cell viability and expression of kidney injury or apoptotic biomarkers were investigated in cultured renal tubular epithelial cell line HK-2. RESULTS: Thirty-one patients (median age 55 years, 90.3% male) were recruited (54.8% TDF: 45.2% ADV). Serum HBV DNA was undetectable at all time points. Median eGFR was 70.2 (IQR 62.6-77.9) and 81.5 (IQR 63.6-99.1) mL/min/1.73 m2 at baseline and 24 months, respectively (p < 0.001). Downstaging of chronic kidney disease was observed in eight (25.8%) patients and was more common in ADV-treated compared to TDF-treated patients (7/8 vs. 1/17, p = 0.011; OR 16, 95% CI 1.643-155.766, p = 0.017). In vitro data showed that adding LdT to ADV or TDF was associated with improved cell viability and lower expression of injury and apoptotic biomarkers compared with ADV or TDF alone. Treatment was prematurely discontinued in four(12.9%) patients due to myalgia. CONCLUSIONS: Clinical and in vitro data suggest that LdT has renoprotective effects in patients on long-term ADV/TDF treatment. LdT may be considered as an adjuvant therapy in this special group of patients with renal impairment (NCT03778567).
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Tasa de Filtración Glomerular , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/efectos adversos , Insuficiencia Renal Crónica/metabolismo , Telbivudina/uso terapéutico , Tenofovir/efectos adversos , Factor de Transcripción Activador 4/efectos de los fármacos , Factor de Transcripción Activador 4/genética , Adenina/efectos adversos , Adenina/farmacología , Antivirales/farmacología , Apoptosis/efectos de los fármacos , Caspasa 12/efectos de los fármacos , Caspasa 12/genética , Línea Celular , Supervivencia Celular/efectos de los fármacos , Chaperón BiP del Retículo Endoplásmico , Células Epiteliales , Femenino , Proteínas de Choque Térmico/efectos de los fármacos , Proteínas de Choque Térmico/genética , Receptor Celular 1 del Virus de la Hepatitis A/efectos de los fármacos , Receptor Celular 1 del Virus de la Hepatitis A/genética , Hepatitis B Crónica/complicaciones , Humanos , Técnicas In Vitro , Interleucina-18/genética , Túbulos Renales , Lamivudine/farmacología , Lipocalina 2/efectos de los fármacos , Lipocalina 2/genética , Masculino , Persona de Mediana Edad , Organofosfonatos/farmacología , Estudios Prospectivos , Sustancias Protectoras , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/complicaciones , Índice de Severidad de la Enfermedad , Tenofovir/farmacologíaRESUMEN
PBI-4050 (3-pentylbenzenacetic acid sodium salt), a novel first-in-class orally active compound that has completed clinical Phases Ib and II in subjects with chronic kidney disease (CKD) and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the G protein receptor 40 (GPR40) receptor. Here we evaluate the effects of PBI-4050 in both WT and Gpr40-/- mice on adenine-induced tubulointerstitial injury, anemia and activation of the unfolded protein response (UPR) pathway. Adenine-induced CKD was achieved in 8-week-old C57BL/6 mice fed a diet supplemented with 0.25% adenine. After 1 week, PBI-4050 or vehicle was administered daily by oral-gavage for 3 weeks. Gpr40-/- mice were also subjected to adenine-feeding, with or without PBI-4050 treatment. PBI-4050 improved renal function and urine concentrating ability. Anemia was present in adenine-fed mice, while PBI-4050 blunted these effects and led to significantly higher plasma erythropoietin (EPO) levels. Adenine-induced renal fibrosis, endoplasmic reticulum (ER) stress and apoptosis were significantly decreased by PBI-4050. In parallel, Gpr40-/- mice were more susceptible to adenine-induced fibrosis, renal function impairment, anemia and ER stress compared with WT mice. Importantly, PBI-4050 treatment in Gpr40-/- mice failed to reduce renal injury in this model. Taken together, PBI-4050 prevented adenine-induced renal injury while these beneficial effects were lost upon Gpr40 deletion. These data reinforce PBI-4050's use as a renoprotective therapy and identify GPR40 as a crucial mediator of its beneficial effects.
Asunto(s)
Acetatos/administración & dosificación , Adenina/efectos adversos , Enfermedades Renales/tratamiento farmacológico , Riñón/lesiones , Receptores Acoplados a Proteínas G/metabolismo , Animales , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Acoplados a Proteínas G/genéticaRESUMEN
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 (Vmax) 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.
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Bupropión/farmacocinética , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Regulación hacia Abajo , Insuficiencia Renal Crónica/inducido químicamente , Adenina/efectos adversos , Animales , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Modelos Animales de Enfermedad , Regulación Enzimológica de la Expresión Génica , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismoRESUMEN
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.
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Conservadores de la Densidad Ósea/administración & dosificación , Denosumab/administración & dosificación , Síndrome de Fanconi/inducido químicamente , Hipofosfatemia , Osteomalacia , Adenina/efectos adversos , Adenina/análogos & derivados , Adulto , Antivirales/efectos adversos , Síndrome de Fanconi/tratamiento farmacológico , Hepatitis B/tratamiento farmacológico , Humanos , Hipofosfatemia/inducido químicamente , Hipofosfatemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Osteomalacia/inducido químicamente , Osteomalacia/tratamiento farmacológico , Tomografía Computarizada de Emisión , Resultado del TratamientoRESUMEN
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.â©.
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Adenina/análogos & derivados , Antivirales/efectos adversos , Organofosfonatos/efectos adversos , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/patología , Adenina/efectos adversos , Adulto , Creatinina/sangre , Femenino , Glucosuria/inducido químicamente , Hematuria/inducido químicamente , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Hipofosfatemia/inducido químicamente , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/fisiopatología , Masculino , Persona de Mediana Edad , Mitocondrias/patología , Fósforo/sangre , Proteinuria/inducido químicamente , Insuficiencia Renal/fisiopatología , Ácido Úrico/sangreRESUMEN
BACKGROUND: Adefovir dipivoxil (ADV)-induced renal tubular dysfunction and hypophosphatemic osteomalacia (HO) have been given great consideration in the past few years. However, no standard guidance is available due to a lack of powerful evidence from appropriate long-term prospective case-control studies and variations in the definition of renal adverse events. The aim of this study is to clarify clinical features of ADV-related HO in Chinese chronic hepatitis B patients with long-term ADV treatment in Chinese and non-Chinese comparative case series. METHODS: Retrieval of case reports was based on Pubmed, CNKI, Wan Fang and VIP databases using the key words adefovir dipivoxil, hypophosphatemia, osteomalacia and Fanconi syndrome. We divided patients into Chinese (C group) and Foreign (F group) groups according to their nationality. Comparisons involving demographics, clinical manifestations, tests, treatment and prognosis were conducted between the two groups. RESULTS: Of the patients screened, 120 Chinese patients were identified in the C group, and 32 non-Chinese patients were identified in the F group. The average age of the C group was younger than that of the F group (51.89 years ±10.96 years versus 56.47 years ±11.36 years, t = - 2.084, P = 0.039). No significant difference was found in gender (male to female, 3.29:1 versus 3:1, χ 2 = 0.039, P = 0.844). Although there was no significant difference in the duration of ADV therapy before ostalgia onset, the C group tended to develop adverse events earlier, by 2-3 years, while the F group developed adverse events at 4-5 years (Z = - 1.517, P = 0.129). Prognosis was good after adjustment of the ADV dose and supplemental administration of phosphate and calcitriol. Time to resolution of tubular dysfunction was commenced at the first month, and Chinese patients were more prone to recover in the first 3 months than non-Chinese patients (91.3% of patients in the C group versus 56.3% in the F group, Z = - 3.013, P = 0.003). CONCLUSIONS: Sufficient attention is required for middle-aged males before and during exposure to long-term ADV therapy, regardless of nationality. The clinical picture, laboratory and radiograph alterations are important clues for those patients and are usually characterized by polyarthralgia, renal tubular dysfunction and mineralization defects. Implementation of an early renal tubular injury index is recommended for patients with higher risk, which would prevent further renal injury.
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Adenina/análogos & derivados , Antivirales/efectos adversos , Hepatitis B Crónica/tratamiento farmacológico , Hipofosfatemia/inducido químicamente , Organofosfonatos/efectos adversos , Osteomalacia/inducido químicamente , Adenina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT.
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Enfermedades Óseas Metabólicas/patología , Enfermedades Óseas/patología , Huesos/patología , Dieta/efectos adversos , Hiperparatiroidismo Secundario/patología , Fallo Renal Crónico/patología , Adenina/efectos adversos , Animales , Densidad Ósea , Enfermedades Óseas/complicaciones , Enfermedades Óseas/etiología , Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/etiología , Modelos Animales de Enfermedad , Hiperparatiroidismo Secundario/complicaciones , Hiperparatiroidismo Secundario/etiología , Riñón/patología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/etiología , Masculino , Fósforo/efectos adversos , Ratas , Ratas Sprague-Dawley , Microtomografía por Rayos XRESUMEN
OBJECTIVE: To investigate the predictors of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) and to monitor for early detection. PATIENTS AND METHODS: Hospitalized patients who were diagnosed with ADV-related hypo-phosphatemic osteomalacia were recruited and retrospectively analyzed in our hospital from January 2012 to December 2016. A telephone interview was conducted at 1, 3, 6, 9, 12, and 24 months after cessation of ADV. RESULTS: In the 8 patients enrolled in the study, the hypophosphatemic osteomalacia symptoms developed at an average of 5.14 (4-7) years since ADV treatment (10 mg/d). The average alkaline phosphatase (ALP) level was 279.50 (137-548) U/L, which was significantly higher than the normal level (45-125 U/L). The serum phosphorus level was an average of 0.59 (0.43-0.69) mmol/L, which was lower than the normal range (2.06-2.60 mmol/L). Serum calcium levels of the enrolled patients remained within normal limits. Reduced estimated glomerular filtration rate (eGFR <29 mL/min/1.73 m2) was seen in 4 cases. The clinical manifestations were mainly progressive systemic bone and joint pain, frequent fractures, trouble in walking, height reduction (4-6 cm), and so on. After cessation of ADV, symptoms like bone pain resolved gradually. Serum phosphorus level restored to normal in 4.5 months after the withdrawal of ADV. However, in 4 patients, renal function failed to return to normal in 24 months. CONCLUSION: More attention should be paid to the duration of ADV treatment. The level of serum phosphorus and ALP, as well as renal function, should be monitored for early detection of potential adverse drug reactions.