RESUMEN
We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Proliferación Celular , Neoplasias Pulmonares , Ratones Desnudos , Receptores de Vasopresinas , Carcinoma Pulmonar de Células Pequeñas , Tolvaptán , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Tolvaptán/farmacología , Tolvaptán/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Humanos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Receptores de Vasopresinas/metabolismo , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kgã»minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.
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Lesión Renal Aguda , Antagonistas de los Receptores de Hormonas Antidiuréticas , Dopamina , Quimioterapia Combinada , Insuficiencia Cardíaca , Tolvaptán , Humanos , Tolvaptán/administración & dosificación , Tolvaptán/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Masculino , Femenino , Dopamina/administración & dosificación , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Anciano , Persona de Mediana Edad , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Péptido Natriurético Encefálico/sangre , Resultado del Tratamiento , Benzazepinas/administración & dosificación , Fragmentos de Péptidos/sangreRESUMEN
Vasopressin or arginine-vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted-though less well-known-role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic-pituitary-adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress-related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders.
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Arginina Vasopresina , Biomarcadores , Trastornos del Humor , Humanos , Arginina Vasopresina/sangre , Arginina Vasopresina/metabolismo , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/fisiopatología , Biomarcadores/sangre , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatologíaAsunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Concentración Osmolar , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Masculino , Femenino , Adulto , Resultado del Tratamiento , Biomarcadores/sangre , Persona de Mediana EdadRESUMEN
We have previously shown that kidney collecting ducts make vasopressin. However, the physiological role of collecting duct-derived vasopressin is uncertain. We hypothesized that collecting duct-derived vasopressin is required for the appropriate concentration of urine. We developed a vasopressin conditional knockout (KO) mouse model wherein Cre recombinase expression induces deletion of arginine vasopressin (Avp) exon 1 in the distal nephron. We then used age-matched 8- to 12-wk-old Avp fl/fl;Ksp-Cre(-) [wild type (WT)] and Avp fl/fl;Ksp-Cre(+) mice for all experiments. We collected urine, serum, and kidney lysates at baseline. We then challenged both WT and knockout (KO) mice with 24-h water restriction, water loading, and administration of the vasopressin type 2 receptor agonist desmopressin (1 µg/kg ip) followed by the vasopressin type 2 receptor antagonist OPC-31260 (10 mg/kg ip). We performed immunofluorescence and immunoblot analysis at baseline and confirmed vasopressin KO in the collecting duct. We found that urinary osmolality (UOsm), plasma Na+, K+, Cl-, blood urea nitrogen, and copeptin were similar in WT vs. KO mice at baseline. Immunoblots of the vasopressin-regulated proteins Na+-K+-2Cl- cotransporter, NaCl cotransporter, and water channel aquaporin-2 showed no difference in expression or phosphorylation at baseline. Following 24-h water restriction, WT and KO mice had no differences in UOsm, plasma Na+, K+, Cl-, blood urea nitrogen, or copeptin. In addition, there were no differences in the rate of urinary concentration or dilution as in WT and KO mice UOsm was nearly identical after desmopressin and OPC-31260 administration. We conclude that collecting duct-derived vasopressin is not essential to appropriately concentrate or dilute urine.NEW & NOTEWORTHY Hypothalamic vasopressin is required for appropriate urinary concentration. However, whether collecting duct-derived vasopressin is involved remains unknown. We developed a novel transgenic mouse model to induce tissue-specific deletion of vasopressin and showed that collecting duct-derived vasopressin is not required to concentrate or dilute urine.
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Desamino Arginina Vasopresina , Túbulos Renales Colectores , Ratones Noqueados , Animales , Túbulos Renales Colectores/metabolismo , Túbulos Renales Colectores/efectos de los fármacos , Desamino Arginina Vasopresina/farmacología , Capacidad de Concentración Renal/efectos de los fármacos , Arginina Vasopresina/metabolismo , Masculino , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Ratones , Acuaporina 2/metabolismo , Acuaporina 2/genética , Fármacos Antidiuréticos/farmacología , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismo , Ratones Endogámicos C57BL , Privación de Agua , Concentración Osmolar , Sodio/orina , Sodio/metabolismo , Vasopresinas/metabolismo , BenzazepinasRESUMEN
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequent in lung cancer patients. Here, we report a case with persistent hyponatremia, which suggested malignant SIADH and facilitated an early diagnosis of small cell lung cancer (SCLC). A combined radio-chemotherapy led to a partial remission and resolution of SIADH. An early relapse was indicated by reoccurring severe hyponatremia and increased copeptin levels, which were used as surrogate markers for the antidiuretic hormone (ADH). As palliative immunochemotherapy, together with fluid restriction and solute substitution, were unable to control hyponatremia, treatment with the ADH V2-receptor antagonist tolvaptan was initiated. Over time, the dose of tolvaptan needed to be increased, paralleled by a well-documented exponential increase of copeptin levels. In summary and conclusion, this is a rare case of a secondary failure to tolvaptan with unique documentary evidence of increasing copeptin levels. This observation supports the hypothesis that exceedingly high ADH levels may lead to competitive displacement of tolvaptan from the V2 receptor.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Síndrome de Secreción Inadecuada de ADH , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Síndrome de Secreción Inadecuada de ADH/tratamiento farmacológico , Síndrome de Secreción Inadecuada de ADH/complicaciones , Carcinoma Pulmonar de Células Pequeñas/complicaciones , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Masculino , Hiponatremia/tratamiento farmacológico , Hiponatremia/etiología , Anciano , Insuficiencia del Tratamiento , Persona de Mediana EdadRESUMEN
INTRODUCTION: Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD). AREA COVERED: JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs. EXPERT OPINION: When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.
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Homeostasis , Aparato Yuxtaglomerular , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tolvaptán , Humanos , Homeostasis/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Animales , Aparato Yuxtaglomerular/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Tolvaptán/uso terapéutico , Tolvaptán/farmacología , Progresión de la Enfermedad , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/metabolismo , Riñón Poliquístico Autosómico Dominante/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Sodio/metabolismo , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacologíaRESUMEN
Vasopressin (AVP) regulates various social behaviors, often in sex-specific ways, including social play behavior, a rewarding behavior displayed primarily by juveniles. Here, we examined whether and how AVP acting in the brain's reward system regulates social play behavior in juvenile rats. Specifically, we focused on AVP signaling in the ventral pallidum (VP), a brain region that is a part of the reward system. First, we examined the organization of the VP-AVP system in juvenile rats and found sex differences, with higher density of both AVP-immunoreactive fibers and AVP V1a receptor (V1aR) binding in males compared to females while females show a greater number of V1aR-expressing cells compared to males. We further found that, in both sexes, V1aR-expressing cells co-express a GABA marker to a much greater extent (approx. 10 times) than a marker for glutamate. Next, we examined the functional involvement of V1aR-expressing VP cells in social play behavior. We found that exposure to social play enhanced the proportion of activated V1aR-expressing VP cells in males only. Finally, we showed that infusion of a specific V1aR antagonist into the VP increased social play behaviors in juvenile male rats while decreasing these behaviors in juvenile female rats. Overall, these findings reveal structural and functional sex differences in the AVP-V1aR system in the VP that are associated with the sex-specific regulation of social play behavior.
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Prosencéfalo Basal , Receptores de Vasopresinas , Caracteres Sexuales , Conducta Social , Vasopresinas , Animales , Masculino , Femenino , Ratas , Receptores de Vasopresinas/metabolismo , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Vasopresinas/metabolismo , Juego e Implementos de Juego , Arginina Vasopresina/metabolismo , Conducta Animal/fisiología , Ratas Long-Evans , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacologíaRESUMEN
BACKGROUND: Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined. METHODS: Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4 days, comparing patients with AF (AF group) versus those with SR (SR group). RESULTS: There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9 years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm2, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7 mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2 kg [p < 0.01] and from 53.5 to 51.0 kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2 days of treatment with tolvaptan. CONCLUSIONS: Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Estenosis de la Válvula Aórtica , Fibrilación Atrial , Insuficiencia Cardíaca , Sistema de Registros , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Masculino , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/diagnóstico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Estudios Retrospectivos , Anciano , Enfermedad Aguda , Japón/epidemiología , Hemodinámica/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVES: Evidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. MATERIAL AND METHODS: A single-center observational study (2016-2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. RESULTS: A total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (-3.52ml/min/1.73m2 [-4.98%] vs -3.98ml/min/1.73m2 [-8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. CONCLUSIONS: This study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Tasa de Filtración Glomerular , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/complicaciones , Femenino , Masculino , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/efectos adversos , Persona de Mediana Edad , Adulto , Tasa de Filtración Glomerular/efectos de los fármacos , Resultado del Tratamiento , Creatinina/sangre , Albuminuria/etiología , Albuminuria/tratamiento farmacológicoRESUMEN
RATIONALE & OBJECTIVE: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR: Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME: Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH: Multinomial logistic regression and linear mixed models. RESULTS: In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS: Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY: We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.
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Progresión de la Enfermedad , Grasa Intraabdominal , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Humanos , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Tolvaptán/uso terapéutico , Tolvaptán/farmacología , Adulto , Grasa Intraabdominal/diagnóstico por imagen , Persona de Mediana Edad , Estudios de Cohortes , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Obesidad Abdominal , Índice de Masa Corporal , Imagen por Resonancia Magnética , AdiposidadRESUMEN
OBJECTIVE: Tolvaptan is a vasopressin V2 receptor antagonist that is commonly prescribed to alleviate edema associated with renal diseases. However, the clinical benefits of tolvaptan in chronic kidney disease (CKD) remain unclear. This study aimed to evaluate the effectiveness of tolvaptan in managing edema caused by CKD. MATERIALS AND METHODS: The efficacy and treatment regimen of tolvaptan were assessed in a cohort of 96 patients with renal edema and CKD. During the treatment, the patients' creatinine (CR), uric acid (UA), and estimated glomerular filtration rate (eGFR) were monitored as important indicators of kidney function. Coagulation-associated molecules including fibrinogen, D-dimer, and fibrin degradation products (FDPs) were measured. Electrolyte disorders and acute kidney injury were closely monitored. Tolvaptan was administered at a daily dose of 7.5 mg, and 30 mg of edoxaban was administered to manage deep vein thrombosis. RESULTS: During the course of tolvaptan therapy, the eGFR of the patients was not declined. Edema was eliminated in 82.18% of patients. Proteinuria was reduced in the patients (p < 0.05). There were no significant changes in serum sodium levels throughout treatment, and no significant difference was observed in blood volume between the end of treatment and baseline levels. Importantly, acute kidney injury did not occur, and renal edema and deep vein thrombosis were successfully treated. CONCLUSION: As long as a rational treatment regimen is followed, tolvaptan is a safe and effective diuretic for treating edema in CKD, even in the late stages of CKD without reducing residual renal function in the patients.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Edema , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Masculino , Femenino , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Anciano , Tasa de Filtración Glomerular/efectos de los fármacos , Edema/tratamiento farmacológico , Edema/etiología , Resultado del Tratamiento , Adulto , Creatinina/sangre , Benzazepinas/uso terapéuticoAsunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Metformina , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Tolvaptán/uso terapéutico , Humanos , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Metformina/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Quimioterapia Combinada , Hipoglucemiantes/uso terapéutico , Masculino , Femenino , Resultado del Tratamiento , Persona de Mediana EdadAsunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Femenino , Humanos , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Ensayos de Uso Compasivo , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Tolvaptán/uso terapéutico , AncianoRESUMEN
AIMS: Renal dysfunction in patients with chronic heart failure predicts a poor prognosis. Tolvaptan has a diuretic effect in patients with chronic kidney disease and heart failure without adverse effects on renal function. We aimed to determine the effects of tolvaptan and predictors of worsening renal function in patients with heart failure. METHODS AND RESULTS: This post hoc analysis was a sub-analysis of a single-centre prospectively randomized trial on the early and short-term tolvaptan administration. We enrolled 201 participants with decompensated heart failure between January 2014 and March 2019 (early group, n = 104; age: 79.0 ± 12.8 years; late group, n = 97; age: 80.3 ± 10.8 years). Renal ultrasonography was performed before and after the administration of tolvaptan. Urine output and oral water intake significantly increased during tolvaptan administration. The difference between water intake and urine volume increased during tolvaptan administration. Changes in body weight, blood pressure, heart rate, and estimated glomerular filtration rate (eGFR) in both groups were comparable. The changes in peak-systolic velocity (PSV), acceleration time (AT) of the renal arteries, and resistance index were comparable. The changes in PSV and end-diastolic velocity (EDV) of the interlobar arteries increased following tolvaptan administration (Δmax PSV: 0.0 ± 14.8 cm/s before tolvaptan vs. 5.6 ± 15.7 cm/s after tolvaptan, P = 0.002; Δmean PSV: 0.4 ± 12.3 vs. 4.9 ± 12.7 cm/s, P = 0.002; Δmax EDV: -0.2 ± 3.5 vs. 1.4 ± 4.0 cm/s, P = 0.001; Δmean EDV: -0.0 ± 3.1 vs. 1.1 ± 3.4 cm/s, P = 0.003). The renal artery AT was negatively correlated with the eGFR (Δmax AT: beta = -0.2354, P = 0.044; Δmean AT: beta = -0.2477, P = 0.035). CONCLUSIONS: Tolvaptan increased the PSV and EDV of the interlobar artery, which may mean tolvaptan increased renal blood flow. The renal artery AT may be a surrogate for worsening renal function.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Tasa de Filtración Glomerular , Insuficiencia Cardíaca , Riñón , Tolvaptán , Ultrasonografía , Humanos , Tolvaptán/uso terapéutico , Tolvaptán/administración & dosificación , Masculino , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Anciano , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Tasa de Filtración Glomerular/fisiología , Riñón/fisiopatología , Estudios Prospectivos , Ultrasonografía/métodos , Anciano de 80 o más Años , Pronóstico , Estudios de Seguimiento , Progresión de la Enfermedad , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicacionesRESUMEN
The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.
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Riñón Poliquístico Autosómico Dominante , Humanos , Tolvaptán/uso terapéutico , Tolvaptán/metabolismo , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/metabolismo , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Riñón/metabolismo , Vasopresinas/metabolismo , Receptores de Vasopresinas/metabolismoAsunto(s)
Riñón Poliquístico Autosómico Dominante , Humanos , Tolvaptán/uso terapéutico , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Proyectos Piloto , Calidad de Vida , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Riñón , Tasa de Filtración GlomerularAsunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Tasa de Filtración Glomerular , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Humanos , Tolvaptán/uso terapéutico , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Masculino , Femenino , Adulto , Resultado del Tratamiento , Persona de Mediana EdadRESUMEN
Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.
Asunto(s)
Relación Dosis-Respuesta a Droga , Modelos Biológicos , Humanos , Niño , Preescolar , Adulto , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacocinética , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Adolescente , Masculino , Femenino , Benzazepinas/farmacocinética , Benzazepinas/administración & dosificación , Adulto Joven , Edema Encefálico/tratamiento farmacológico , Persona de Mediana Edad , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. METHODS: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. OUTCOMES: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. CONCLUSION: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.